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As with all drugs the potential exists for interaction with other drugs by a variety of mechanisms CNS Active Drugs Ethanol Sonata 10 mg potentiated the CNS impairing effects of ethanol 0 75 g kg on balance testing and reaction time for 1 hour after ethanol administration and on the digit symbol substitution test DSST symbol copying test and the variability component of the divided attention test for 2 5 hours after ethanol administration The potentiation resulted from a CNS pharmacodynamic interaction zaleplon did not affect the pharmacokinetics of ethanol Imipramine Coadministration of single doses of Sonata 20 mg and imipramine 75 mg produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration The interaction was pharmacodynamic with no alteration of the pharmacokinetics of either drug Paroxetine Coadministration of a single dose of Sonata 20 mg and paroxetine 20 mg daily for 7 days did not produce any interaction on psychomotor performance Additionally paroxetine did not alter the pharmacokinetics of Sonata reflecting the absence of a role of CYP2D6 in zaleplon s metabolism Thioridazine Coadministration of single doses of Sonata 20 mg and thioridazine 50 mg produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration The interaction was pharmacodynamic with no alteration of the pharmacokinetics of either drug Venlafaxine Coadministration of a single dose of zaleplon 10 mg and multiple doses of venlafaxine ER extended release 150 mg did not result in any significant changes in the pharmacokinetics of either zaleplon or venlafaxine In addition there was no pharmacodynamic interaction as a result of coadministration of zaleplon and venlafaxine ER Promethazine Coadministration of a single dose of zaleplon and promethazine 10 and 25 mg respectively resulted in a 15 decrease in maximal plasma concentrations of zaleplon but no change in the area under the plasma concentration time curve However the pharmacodynamics of coadministration of zaleplon and promethazine have not been evaluated Caution should be exercised when these 2 agents are coadministered Drugs That Induce CYP3A4 Rifampin CYP3A4 is ordinarily a minor metabolizing enzyme of zaleplon Multiple dose administration of the potent CYP3A4 inducer rifampin 600 mg every 24 hours q24h for 14 days however reduced zaleplon Cmax and AUC by approximately 80 The coadministration of a potent CYP3A4 enzyme inducer although not posing a safety concern thus could lead to ineffectiveness of zaleplon An alternative non CYP3A4 substrate hypnotic agent may be considered in patients taking CYP3A4 inducers such as rifampin phenytoin carbamazepine and phenobarbital Drugs That Inhibit CYP3A4 CYP3A4 is a minor metabolic pathway for the elimination of zaleplon because the sum of desethylzaleplon formed via CYP3A4 in vitro and its metabolites 5 oxo desethylzaleplon and 5 oxo desethylzaleplon glucuronide account for only 9 of the urinary recovery of a zaleplon dose Coadministration of single oral doses of zaleplon with erythromycin 10 mg and 800 mg respectively a strong selective CYP3A4 inhibitor produced a 34 increase in zaleplons maximal plasma concentrations and a 20 increase in the area under the plasma concentration time curve The magnitude of interaction with multiple doses of erythromycin is unknown Other strong selective CYP3A4 inhibitors such as ketoconazole can also be expected to increase the exposure of zaleplon A routine dosage adjustment of zaleplon is not considered necessary Drugs That Inhibit Aldehyde Oxidase The aldehyde oxidase enzyme system is less well studied than the cytochrome P450 enzyme system Diphenhydramine Diphenhydramine is reported to be a weak inhibitor of aldehyde oxidase in rat liver but its inhibitory effects in human liver are not known There is no pharmacokinetic interaction between zaleplon and diphenhydramine following the administration of a single dose 10 mg and 50 mg respectively of each drug However because both of these compounds have CNS effects an additive pharmacodynamic effect is possible Drugs That Inhibit Both Aldehyde Oxidase and CYP3A4 Cimetidine Cimetidine inhibits both aldehyde oxidase in vitro and CYP3A4 in vitro and in vivo the primary and secondary enzymes respectively responsible for zaleplon metabolism Concomitant administration of Sonata 10 mg and cimetidine 800 mg produced an 85 increase in the mean Cmax and AUC of zaleplon An initial dose of 5 mg should be given to patients who are concomitantly being treated with cimetidine Drugs Highly Bound to Plasma Protein Zaleplon is not highly bound to plasma proteins fraction bound 60 15 therefore the disposition of zaleplon is not expected to be sensitive to alterations in protein binding In addition administration of Sonata to a patient taking another drug that is highly protein bound should not cause transient increase in free concentrations of the other drug Drugs with a Narrow Therapeutic Index Digoxin Sonata 10 mg did not affect the pharmacokinetic or pharmacodynamic profile of digoxin 0 375 mg q24h for 8 days Warfarin Multiple oral doses of Sonata 20 mg q24h for 13 days did not affect the pharmacokinetics of warfarin R or S enantiomers or the pharmacodynamics prothrombin time following a single 25 mg oral dose of warfarin Drugs That Alter Renal Excretion Ibuprofen Ibuprofen is known to affect renal function and consequently alter the renal excretion of other drugs There was no apparent pharmacokinetic interaction between zaleplon and ibuprofen following single dose administration 10 mg and 600 mg respectively of each drug This was expected because zaleplon is primarily metabolized and renal excretion of unchanged zaleplon accounts for less than 1 of the administered dose No drug nutritional supplement food or herb interactions have yet been reported No formal drug drug interaction studies with Plenaxis were performed Cytochrome P 450 is not known to be involved in the metabolism of Plenaxis Plenaxis is highly bound to plasma proteins 96 to 99 Laboratory Tests Response to Plenaxis should be monitored by measuring serum total testosterone concentrations just prior to administration on Day 29 and every 8 weeks thereafter Serum transaminase levels should be obtained before starting treatment with Plenaxis and periodically during treatment Periodic measurement of serum PSA levels may also be considered Formal drug interaction studies have not been conducted with ORENCIA Population pharmacokinetic analyses revealed that MTX NSAIDs corticosteroids and TNF blocking agents did not influence abatacept clearance The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA MTX NSAIDs corticosteroids TNF blocking agents azathioprine chloroquine gold hydroxychloroquine leflunomide sulfasalazine and anakinra Concurrent administration of a TNF antagonist with ORENCIA has been associated with an increased risk of serious infections and no significant additional efficacy over use of the TNF antagonists alone Concurrent therapy with ORENCIA and TNF antagonists is not recommended There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with anakinra and therefore such use is not recommended Formal drug interaction studies with Abciximab have not been conducted Abciximab has been administered to patients with ischemic heart disease treated concomitantly with a broad range of medications used in the treatment of angina myocardial infarction and hypertension These medications have included heparin warfarin beta adrenergic receptor blockers calcium channel antagonists angiotensin converting enzyme inhibitors intravenous and oral nitrates ticlopidine and aspirin Heparin other anticoagulants thrombolytics and anti platelet agents are associated with an increase in bleeding Patients with HACA titers may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies The concomitant intake of alcohol and Acamprosate does not affect the pharmacokinetics of either alcohol or acamprosate Pharmacokinetic studies indicate that administration of disulfiram or diazepam does not affect the pharmacokinetics of acamprosate Co administration of naltrexone with Acamprosate produced a 25 increase in AUC and a 33 increase in the Cmax of acamprosate No adjustment of dosage is recommended in such patients The pharmacokinetics of naltrexone and its major metabolite 6 beta naltrexol were unaffected following co administration with Acamprosate Other concomitant therapies In clinical trials the safety profile in subjects treated with Acamprosate concomitantly with anxiolytics hypnotics and sedatives including benzodiazepines or non opioid analgesics was similar to that of subjects taking placebo with these concomitant medications Patients taking Acamprosate concomitantly with antidepressants more commonly reported both weight gain and weight loss compared with patients taking either medication alone Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control These drugs include the thiazides and other diuretics corticosteroids phenothiazines thyroid products estrogens oral contraceptives phenytoin nicotinic acid sympathomimetics calcium channel blocking drugs and isoniazid When such drugs are administered to a patient receiving Acarbose the patient should be closely observed for loss of blood glucose control When such drugs are withdrawn from patients receiving Acarbose in combination with sulfonylureas or insulin patients should be observed closely for any evidence of hypoglycemia Intestinal adsorbents e g charcoal and digestive enzyme preparations containing carbohydrate splitting enzymes e g amylase pancreatin may reduce the effect of Acarbose and should not be taken concomitantly Acarbose has been shown to change the bioavailabillty digoxin when they are co administered which may require digoxin dose adjustment Studies in healthy volunteers have shown that Acarbose has no effect on either the pharmacokinetics or pharmacodynamics of digoxin nifedipine propranolol or ranitidine Acarbose did not interfere with the absorption or disposition of the sulfonylurea glyburide in diabetic patients Acarbose may affect digoxin bioavailabillty and may require dose adjustment of digoxin by 16 90 confidence interval 8 23 decrease mean C max digoxin by 26 90 confidence interval 16 34 and decrease mean trough concentrations of digoxin by 9 90 confidence limit 19 decrease to 2 increase The amount of metformin absorbed while taking Acarbose was bioequivalent to the amount absorbed when taking placebo as indicated by the plasma AUC values However the peak plasma level of metformin was reduced by approximately 20 when taking Acarbose due to a slight delay in the absorption of metformin There is little if any clinically significant interaction between Acarbose and metformin Catecholamine depleting drugs such as reserpine may have an additive effect when given with beta blocking agents Patients treated with acebutolol plus catecholamine depletors should therefore be observed closely for evidence of marked bradycardia or hypotension which may present as vertigo syncope presyncope or orthostatic changes in blood pressure without compensatory tachycardia Exaggerated hypertensive responses have been reported from the combined use of beta adrenergic antagonists and alpha adrenergic stimulants including those contained in proprietary cold remedies and vasoconstrictive nasal drops Patients receiving beta blockers should be warned of this potential hazard Blunting of the antihypertensive effect of beta adrenoceptor blocking agents by nonsteroidal anti inflammatory drugs has been reported No significant interactions with digoxin hydrochlorothiazide hydralazine sulfinpyrazone oral contraceptives tolbutamide or warfarin have been observed DIAMOX modifies phenytoin metabolism with increased serum levels of phenytoin This may increase or enhance the occurrence of osteomalacia in some patients receiving chronic phenytoin therapy Caution is advised in patients receiving chronic concomitant therapy By decreasing the gastrointestinal absorption of primidone DIAMOX may decrease serum concentrations of primidone and its metabolites with a consequent possible decrease in anticonvulsant effect Caution is advised when beginning discontinuing or changing the dose of DIAMOX in patients receiving primidone Because of possible additive effects with other carbonic anhydrase inhibitors concomitant use is not advisable Acetazolamide may increase the effects of other folic acid antagonists Acetazolamide may increase or decrease blood glucose levels Consideration should be taken in patients being treated with antidiabetic agents Acetazolamide decreases urinary excretion of amphetamine and may enhance the magnitude and duration of their effect Acetazolamide reduces urinary excretion of quinidine and may enhance its effect Acetazolamide may prevent the urinary antiseptic effect of methenamine Acetazolamide increases lithium excretion and the lithium may be decreased Acetazolamide and sodium bicarbonate used concurrently increases the risk of renal calculus formation Acetazolamide may elevate cyclosporine levels Concomitant use with iron supplements may result in the reduced absorption of iron Co administration of probenecid with acyclovir has been shown to increase the mean half life and the area under the concentration time curve Urinary excretion and renal clearance were correspondingly reduced The clinical effects of this combination have not been studied Ethanol Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol Glibenclamide In a study of 7 healthy male volunteers acitretin treatment potentiated the blood glucose lowering effect of glibenclamide a sulfonylurea similar to chlorpropamide in 3 of the 7 subjects Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance Careful supervision of diabetic patients under treatment with Soriatane is recommended Hormonal Contraceptives It has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives However it has been established that acitretin interferes with the contraceptive effect of microdosed progestin minipill preparations Microdosed minipill progestin preparations are not recommended for use with Soriatane It is not known whether other progestational contraceptives such as implants and injectables are adequate methods of contraception during acitretin therapy Methotrexate An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate Consequently the combination of methotrexate with acitretin is also contraindicated Phenytoin If acitretin is given concurrently with phenytoin the protein binding of phenytoin may be reduced Tetracyclines Since both acitretin and tetracyclines can cause increased intracranial pressure their combined use is contraindicated Vitamin A and oral retinoids Concomitant administration of vitamin A and or other oral retinoids with acitretin must be avoided because of the risk of hypervitaminosis A Other There appears to be no pharmacokinetic interaction between acitretin and cimetidine digoxin or glyburide Investigations into the effect of acitretin on the protein binding of anticoagulants of the coumarin type warfarin revealed no interaction Laboratory Tests If significant abnormal laboratory results are obtained either dosage reduction with careful monitoring or treatment discontinuation is recommended depending on clinical judgement Blood Sugar Some patients receiving retinoids have experienced problems with blood sugar control In addition new cases of diabetes have been diagnosed during retinoid therapy including diabetic ketoacidosis In diabetics blood sugar levels should be monitored very carefully Lipids In clinical studies the incidence of hypertriglyceridemia was 66 hypercholesterolemia was 33 and that of decreased HDL was 40 Pretreatment and follow up measurements should be obtained under fasting conditions It is recommended that these tests be performed weekly or every other week until the lipid response to Soriatane has stabilized Liver Function Tests Elevations of AST SGOT ALT SGPT or LDH were experienced by approximately 1 in 3 patients treated with Soriatane It is recommended that these tests be performed prior to initiation of Soriatane therapy at 1 to 2 week intervals until stable and thereafter at intervals as clinically indicated Methotrexate HUMIRA has been studied in rheumatoid arthritis patients taking concomitant MTX The data do not suggest the need for dose adjustment of either HUMIRA or MTX Anakinra Concurrent administration of anakinra an interleukin 1 antagonist and another TNF blocking agent has been associated with an increased risk of serious infections an increased risk of neutropenia and no additional benefit compared to these medicinal products alone The safety and efficacy of anakinra used in combination with HUMIRA has not been studied Therefore the combination of anakinra with other TNF blocking agents including HUMIRA may also result i n similar toxicities As DIFFERIN Gel has the potential to produce local irritation in some patients concomitant use of other potentially irritating topical products medicated or abrasive soaps and cleansers soaps and cosmetics that have a strong drying effect and products with high concentrations of alcohol astringents spices or lime should be approached with caution Particular caution should be exercised in using preparations containing sulfur resorcinol or salicylic acid in combination with DIFFERIN Gel If these preparations have been used it is advisable not to start therapy with DIFFERIN Gel until the effects of such preparations in the skin have subsided Before using this medication tell your doctor or pharmacist of all prescription and nonprescription products you may use especially of aminoglycosides e g gentamicin amikacin amphotericin B cyclosporine non steroidal anti inflammatory drugs e g ibuprofen tacrolimus vancomycin Do not start or stop any medicine without doctor or pharmacist approval Intravenous Adenocard adenosine has been effectively administered in the presence of other cardioactive drugs such as quinidine beta adrenergic blocking agents calcium channel blocking agents and angiotensin converting enzyme inhibitors without any change in the adverse reaction profile Digoxin and verapamil use may be rarely associated with ventricular fibrillation when combined with Adenocard Because of the potential for additive or synergistic depressant effects on the SA and AV nodes however Adenocard should be used with caution in the presence of these agents The use of Adenocard in patients receiving digitalis may be rarely associated with ventricular fibrillation The effects of adenosine are antagonized by methylxanthines such as caffeine and theophylline In the presence of these methylxanthines larger doses of adenosine may be required or adenosine may not be effective Adenosine effects are potentiated by dipyridamole Thus smaller doses of adenosine may be effective in the presence of dipyridamole Carbamazepine has been reported to increase the degree of heart block produced by other agents As the primary effect of adenosine is to decrease conduction through the A V node higher degrees of heart block may be produced in the presence of carbamazepine Co administration with antifungal agents such as ketoconazole or itraconazole is not recommended Nafazodone fluvoxamine cimetidine consider Xanax dose reduction Fluoxetine OCs sertraline diltiazem macrolide antibiotics exercise caution No drug interaction studies were performed No in vitro metabolism studies were performed Dexamethasone Steady state trough concentrations of albendazole sulfoxide were about 56 higher when 8 mg dexamethasone was coadministered with each dose of albendazole 15 mg kg day in eight neurocysticercosis patients Praziquantel In the fed state praziquantel 40 mg kg increased mean maximum plasma concentration and area under the curve of albendazole sulfoxide by about 50 in healthy subjects n 10 compared with a separate group of subjects n 6 given albendazole alone Mean T max and mean plasma elimination half life of albendazole sulfoxide were unchanged The pharmacokinetics of praziquantel were unchanged following coadministration with albendazole 400 mg Cimetidine Albendazole sulfoxide concentrations in bile and cystic fluid were increased about 2 fold in hydatid cyst patients treated with cimetidine 10 mg kg day n 7 compared with albendazole 20 mg kg day alone n 12 Albendazole sulfoxide plasma concentrations were unchanged 4 hours after dosing Theophylline The pharmacokinetics of theophylline aminophylline 5 8 mg kg infused over 20 minutes were unchanged following a single oral dose of albendazole 400 mg in 6 healthy subjects No information provided PROLEUKIN may affect central nervous function Therefore interactions could occur following concomitant administration of psychotropic drugs e g narcotics analgesics antiemetics sedatives tranquilizers Concurrent administration of drugs possessing nephrotoxic e g aminoglycosides indomethacin myelotoxic e g cytotoxic chemotherapy cardiotoxic e g doxorubicin or hepatotoxic e g methotrexate asparaginase effects with PROLEUKIN may increase toxicity in these organ systems The safety and efficacy of PROLEUKIN in combination with any antineoplastic agents have not been established In addition reduced kidney and liver function secondary to PROLEUKIN treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose PROLEUKIN and antineoplastic agents specifically dacarbazine cis platinum tamoxifen and interferon alfa These reactions consisted of erythema pruritus and hypotension and occurred within hours of administration of chemotherapy These events required medical intervention in some patients Myocardial injury including myocardial infarction myocarditis ventricular hypokinesia and severe rhabdomyolysis appear to be increased in patients receiving PROLEUKIN and interferon alfa concurrently Exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders has been observed following concurrent use of interferon alfa and PROLEUKIN including crescentic IgA glomerulonephritis oculo bulbar myasthenia gravis inflammatory arthritis thyroiditis bullous pemphigoid and Stevens Johnson syndrome Although glucocorticoids have been shown to reduce PROLEUKIN induced side effects including fever renal insufficiency hyperbilirubinemia confusion and dyspnea concomitant administration of these agents with PROLEUKIN may reduce the antitumor effectiveness of PROLEUKIN and thus should be avoided 12 Beta blockers and other antihypertensives may potentiate the hypotension seen with PROLEUKIN Delayed Adverse Reactions to Iodinated Contrast Media A review of the literature revealed that 12 6 range 11 28 of 501 patients treated with various interleukin 2 containing regimens who were subsequently administered radiographic iodinated contrast media experienced acute atypical adverse reactions The onset of symptoms usually occurred within hours most commonly 1 to 4 hours following the administration of contrast media These reactions include fever chills nausea vomiting pruritus rash diarrhea hypotension edema and oliguria Some clinicians have noted that these reactions resemble the immediate side effects caused by interleukin 2 administration however the cause of contrast reactions after interleukin 2 therapy is unknown Most events were reported to occur when contrast media was given within 4 weeks after the last dose of interleukin 2 These events were also reported to occur when contrast media was given several months after interleukin 2 treatment No formal interaction studies have been performed The duration of the period following treatment with AMEVIVE before one should consider starting other immunosuppressive therapy has not been evaluated Carcinogenesis Mutagenesis and Fertility In a chronic toxicity study cynomolgus monkeys were dosed weekly for 52 weeks with intravenous alefacept at 1 mg kg dose or 20 mg kg dose One animal in the high dose group developed a B cell lymphoma that was detected after 28 weeks of dosing Additional animals in both dose groups developed B cell hyperplasia of the spleen and lymph nodes All animals in the study were positive for an endemic primate gammaherpes virus also known as lymphocryptovirus LCV Latent LCV infection is generally asymptomatic but can lead to B cell lymphomas when animals are immune suppressed In a separate study baboons given 3 doses of alefacept at 1 mg kg every 8 weeks were found to have centroblast proliferation in B cell dependent areas in the germinal centers of the spleen following a 116 day washout period The role of AMEVIVE in the development of the lymphoid malignancy and the hyperplasia observed in non human primates and the relevance to humans is unknown Immunodeficiency associated lymphocyte disorders plasmacytic hyperplasia polymorphic proliferation and B cell lymphomas occur in patients who have congenital or acquired immunodeficiencies including those resulting from immunosuppressive therapy No carcinogenicity or fertility studies were conducted Mutagenicity studies were conducted in vitro and in vivo no evidence of mutagenicity was observed Pregnancy Category B Women of childbearing potential make up a considerable segment of the patient population affected by psoriasis Since the effect of AMEVIVE on pregnancy and fetal development including immune system development is not known health care providers are encouraged to enroll patients currently taking AMEVIVE who become pregnant into the Biogen Pregnancy Registry by calling 1 866 AMEVIVE 1 866 263 8483 Reproductive toxicology studies have been performed in cynomolgus monkeys at doses up to 5 mg kg week about 62 times the human dose based on body weight and have revealed no evidence of impaired fertility or harm to the fetus due to AMEVIVE No abortifacient or teratogenic effects were observed in cynomolgus monkeys following intravenous bolus injections of AMEVIVE administered weekly during the period of organogenesis to gestation AMEVIVE underwent trans placental passage and produced in utero exposure in the developing monkeys In utero serum levels of exposure in these monkeys were 23 of maternal serum levels No evidence of fetal toxicity including adverse effects on immune system development was observed in any of these animals Animal reproduction studies however are not always predictive of human response and there are no adequate and well controlled studies in pregnant women Because the risk to the development of the fetal immune system and postnatal immune function in humans is unknown AMEVIVE should be used during pregnancy only if clearly needed If pregnancy occurs while taking AMEVIVE continued use of the drug should be assessed Nursing Mothers It is not known whether AMEVIVE is excreted in human milk Because many drugs are excreted in human milk and because there exists the potential for serious adverse reactions in nursing infants from AMEVIVE a decision should be made whether to discontinue nursing while taking the drug or to discontinue the use of the drug taking into account the importance of the drug to the mother Geriatric Use Of the 1357 patients who received AMEVIVE in clinical trials a total of 100 patients were 65 years of age and 13 patients were 75 years of age No differences in safety or efficacy were observed between older and younger patients but there were not sufficient data to exclude important differences Because the incidence of infections and certain malignancies is higher in the elderly population in general caution should be used in treating the elderly Pediatric Use The safety and efficacy of AMEVIVE in pediatric patients have not been studied AMEVIVE is not indicated for pediatric patients Drug Laboratory Interactions No formal drug interaction studies have been performed with Campath An immune response to Campath may interfere with subsequent diagnostic serum tests that utilize antibodies Intravenous ranitidine was shown to double the bioavailability of oral alendronate The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H2 antagonists is unknown no other specific drug interaction studies were performed Products containing calcium and other multivalent cations likely will interfere with absorption of alendronate Both the magnitude and duration of central nervous system and cardiovascular effects may be enhanced when ALFENTA is administered in combination with other CNS depressants such as barbiturates tranquilizers opioids or inhalation general anesthetics Postoperative respiratory depression may be enhanced or prolonged by these agents In such cases of combined treatment the dose of one or both agents should be reduced Limited clinical experience indicates that requirements for volatile inhalation anesthetics are reduced by 30 to 50 for the first sixty 60 minutes following ALFENTA induction The concomitant use of erythromycin with ALFENTA can significantly inhibit ALFENTA clearance and may increase the risk of prolonged or delayed respiratory depression Cimetidine reduces the clearance of ALFENTA Therefore smaller ALFENTA doses will be required with prolonged administration and the duration of action of ALFENTA my be extended Perioperative administration of drugs affecting hepatic blood flow or enzyme function may reduce plasma clearance and prolong recovery Drug Drug Interactions The pharmacokinetic and pharmacodynamic interactions between UROXATRAL and other alpha blockers have not been determined However interactions may be expected and UROXATRAL should NOT be used in combination with other alpha blockers No drug interaction studies have been performed Effects of Other Drugs on Aliskiren Based on in vitro studies aliskiren is metabolized by CYP 3A4 Co administration of lovastatin atenolol warfarin furosemide digoxin celecoxib hydrochlorothiazide ramipril valsartan metformin and amlodipine did not result in clinically significant increases in aliskiren exposure Co administration of irbesartan reduced aliskiren Cmax up to 50 after multiple dosing Co administration of atorvastatin resulted in about a 50 increase in aliskiren Cmax and AUC after multiple dosing Ketoconazole Co administration of 200 mg twice daily ketoconazole with aliskiren resulted in an approximate 80 increase in plasma levels of aliskiren A 400 mg once daily dose was not studied but would be expected to increase aliskiren blood levels further Effects of Aliskiren on Other Drugs Aliskiren does not inhibit the CYP450 isoenzymes CYP1A2 2C8 2C9 2C19 2D6 2E1 and CYP 3A or induce CYP 3A4 Co administration of aliskiren did not significantly affect the pharmacokinetics of lovastatin digoxin valsartan amlodipine metformin celecoxib atenolol atorvastatin ramipril or hydrochlorothiazide Warfarin The effects of aliskiren on warfarin pharmacokinetics have not been evaluated in a well controlled clinical trial Furosemide When aliskiren was co administered with furosemide the AUC and Cmax of furosemide were reduced by about 30 and 50 respectively Patients who are applying Panretin gel should not concurrently use products that contain DEET N N diethyl m toluamide a common component of insect repellent products Animal toxicology studies showed increased DEET toxicity when DEET was included as proof of the formulation Although there was no clinical evidence in the vehicle controlled studies of drug interactions with systemic antiretroviral agents including protease inhibitors macrolide antibiotics and azole antifungals the effect of Panretin gel on the steady state concentrations of these drugs is not known No drug interaction data are available on concomitant administration of Panretin gel and systemic anti KS agents The following drug interactions were observed in some patients undergoing treatment with oral allopurinol Although the pattern of use for oral allopurinol includes longer term therapy particularly for gout and renal calculi the experience gained may be relevant Mercaptopurine Azathioprine Allopurinol inhibits the enzymatic oxidation of mercaptopurine and azathioprine to 6 thiouric acid This oxidation which is catalyzed by xanthine oxidase inactivates mercaptopurine In patients receiving mercaptopurine Purinethol or azathioprine Imuran the concomitant administration of 300 600 mg of allopurinol per day will require a reduction in dose to approximately one third to one fourth of the usual dose of mercaptopurine or azathioprine Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects Dicumarol It has been reported that allopurinol prolongs the half life of the anticoagulant dicumarol The clinical basis of this drug interaction has not been established but should be noted when allopurinol is given to patients already on dicumarol therapy Consequently prothrombin time should be reassessed periodically in patients receiving both drugs Uricosuric Agents Since the excretion of oxipurinol is similar to that of urate uricosuric agents which increase the excretion of urate are also likely to increase the excretion of oxipurinol and thus lower the degree of inhibition of xanthine oxidase The concomitant administration of uricosuric agents and allopurinol has been associated with a decrease in the excretion of oxypurines hypoxanthine and xanthine and an increase in urinary uric acid excretion compared with that observed with allopurinol alone Although clinical evidence to date has not demonstrated renal precipitation of oxypurines in patients either on allopurinol alone or in combination with uricosuric agents the possibility should be kept in mind Thiazide Diuretics The reports that the concomitant use of allopurinol and thiazide diuretics may contribute to the enhancement of allopurinol toxicity in some patients have been reviewed in an attempt to establish a cause and effect relationship and a mechanism of causation Review of these case reports indicates that the patients were mainly receiving thiazide diuretics for hypertension and that tests to rule out decreased renal function secondary to hypertensive nephropathy were not often performed In those patients in whom renal insufficiency was documented however the recommendation to lower the dose of allopurinol was not followed Although a causal mechanism and a cause and effect relationship have not been established current evidence suggests that renal function should be monitored in patients on thiazide diuretics and allopurinol even in the absence of renal failure and dosage levels should be even more conservatively adjusted in those patients on such combined therapy if diminished renal function is detected Ampicillin Amoxicillin An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to patients who are not receiving both drugs The cause of the reported association has not been established Cytotoxic Agents Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease except leukemia in the presence of allopurinol However in a well controlled study of patients with lymphoma on combination therapy allopurinol did not increase the marrow toxicity of patients treated with cyclophosphamide doxorubicin bleomycin procarbazine and or mechlorethamine Chlorpropamide Chlorpropamides plasma half life may be prolonged by allopurinol since allopurinol and chlorpropamide may compete for excretion in the renal tubule The risk of hypoglycemia secondary to this mechanism may be increased if allopurinol and chlorpropamide are given concomitantly in the presence of renal insufficiency Cyclosporin Reports indicate that cyclosporine levels may be increased during concomitant treatment with allopurinol sodium for injection Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are co administered Tolbutamides conversion to inactive metabolites has been shown to be catalyzed by xanthine oxidase from rat liver The clinical significance if any of these observations is unknown Ergot Containing Drugs These drugs have been reported to cause prolonged vasospastic reactions Because there is a theoretical basis that these effects may be additive use of ergotamine containing or ergot type medications like dihydroergotamine or methysergide and AXERT within 24 hours of each other should be avoided Monoamine Oxidase Inhibitors Coadministration of moclobemide resulted in a 27 decrease in almotriptan clearance and an increase in Cmax of approximately 6 No dose adjustment is necessary Other 5 HT1B 1D Agonists Concomitant use of other 5 HT1B 1D agonists within 24 hours of treatment with AXERT is contraindicated Propanolol The pharmacokinetics of almotriptan were not affected by coadministration of propranolol Selective Serotonin Reuptake Inhibitors SSRIs SSRIs e g fluoxetine fluvoxamine paroxetine sertraline have been rarely reported to cause weakness hyperreflexia and incoordination when coadministered with 5 HT1 agonists If concomitant treatment with AXERT and an SSRI is clinically warranted appropriate observation of the patient is advised Verapamil Coadministration of almotriptan and verapamil resulted in a 24 increase in plasma concentrations of almotriptan No dose adjustment is necessary Coadministration of almotriptan and the potent CYP3A4 inhibitor ketoconazole 400 mg q d for 3 days resulted in an approximately 60 increase in the area under the plasma concentration time curve and maximal plasma concentrations of almotriptan Although the interaction between almotriptan and other potent CYP3A4 inhibitors e g itraconazole ritonavir and erythromycin has not been studied increased exposures to almotriptan may be expected when almotriptan is used concomitantly with these medications AXERT is not known to interfere with commonly employed clinical laboratory tests Because alosetron is metabolized by a variety of hepatic CYP drug metabolizing enzymes inducers or inhibitors of these enzymes may change the clearance of alosetron Fluvoxamine is a known strong inhibitor of CYP1A2 and also inhibits CYP3A4 CYP2C9 and CYP2C19 In a pharmacokinetic study 40 healthy female subjects received fluvoxamine in escalating doses from 50 to 200 mg per day for 16 days with coadministration of alosetron 1 mg on the last day Fluvoxamine increased mean alosetron plasma concentrations AUC approximately 6 fold and prolonged the half life by approximately 3 fold Concomitant administration of alosetron and fluvoxamine is contraindicated Concomitant administration of alosetron and moderate CYP1A2 inhibitors including quinolone antibiotics and cimetidine has not been evaluated but should be avoided unless clinically necessary because of similar potential drug interactions Ketoconazole is a known strong inhibitor of CYP3A4 In a pharmacokinetic study 38 healthy female subjects received ketoconazole 200 mg twice daily for 7 days with coadministration of alosetron 1 mg on the last day Ketoconazole increased mean alosetron plasma concentrations AUC by 29 Caution should be used when alosetron and ketoconazole are administered concomitantly Coadministration of alosetron and strong CYP3A4 inhibitors such as clarithromycin telithromycin protease inhibitors voriconazole and itraconazole has not been evaluated but should be undertaken with caution because of similar potential drug interactions The effect of induction or inhibition of other pathways on exposure to alosetron and its metabolites is not known In vitro human liver microsome studies and an in vivo metabolic probe study demonstrated that alosetron did not inhibit CYP enzymes 2D6 3A4 2C9 or 2C19 In vitro at total drug concentrations 27 fold higher than peak plasma concentrations observed with the 1 mg dosage alosetron inhibited CYP enzymes 1A2 60 and 2E1 50 In an in vivo metabolic probe study alosetron did not inhibit CYP2E1 but did produce 30 inhibition of both CYP1A2 and N acetyltransferase Although not studied with alosetron inhibition of N acetyltransferase may have clinically relevant consequences for drugs such as isoniazid procainamide and hydralazine The effect on CYP1A2 was explored further in a clinical interaction study with theophylline and no effect on metabolism was observed Another study showed that alosetron had no clinically significant effect on plasma concentrations of the oral contraceptive agents ethinyl estradiol and levonorgestrel CYP3A4 substrates A clinical interaction study was also conducted with alosetron and the CYP3A4 substrate cisapride No significant effects on cisapride metabolism or QT interval were noted The effect of alosetron on monoamine oxidases and on intestinal first pass secondary to high intraluminal concentrations have not been examined Based on the above data from in vitro and in vivo studies it is unlikely that alosetron will inhibit the hepatic metabolic clearance of drugs metabolized by the major CYP enzyme 3A4 as well as the CYP enzymes 2D6 2C9 2C19 2E1 or 1A2 Alosetron does not appear to induce the major cytochrome P450 CYP drug metabolizing enzyme 3A Alosetron also does not appear to induce CYP enzymes 2E1 or 2C19 It is not known whether alosetron might induce other enzymes The benzodiazepines including alprazolam produce additive CNS depressant effects when co administered with other psychotropic medications anticonvulsants antihistaminics ethanol and other drugs which themselves produce CNS depression The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31 and 20 respectively by the concomitant administration of alprazolam tablets in doses up to 4 mg day The clinical significance of these changes is unknown Drugs That Inhibit Alprazolam Metabolism Via Cytochrome P450 3A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A CYP 3A Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam Drugs Demonstrated to be CYP 3A Inhibitors of Possible Clinical Significance on the Basis of Clinical Studies Involving Alprazolam caution is recommended during coadministration with alprazolam Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46 decreased clearance by 21 increased half life by 17 and decreased measured psychomotor performance Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6 decreased clearance by 38 and increased half life by 58 Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18 decreased clearance by 22 and increased half life by 29 Drugs and other substances demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines caution is recommended during coadministration with alprazolam Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following diltiazem isoniazid macrolide antibiotics such as erythromycin and clarithromycin and grapefruit juice Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following sertraline and paroxetine Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following ergotamine cyclosporine amiodarone nicardipine and nifedipine Caution is recommended during the coadministration of any of these with alprazolam No drug interactions have been reported between Prostin VR Pediatric and the therapy standard in neonates with restricted pulmonary or systemic blood flow Standard therapy includes antibiotics such as penicillin and gentamicin vasopressors such as dopamine and isoproterenol cardiac glycosides and diuretics such as furosemide Caverject The potential for pharmacokinetic drug drug interactions between alprostadil and other agents has not been formally studied The interaction of Activase with other cardioactive or cerebroactive drugs has not been studied In addition to bleeding associated with heparin and vitamin K antagonists drugs that alter platelet function such as acetylsalicylic acid dipyridamole and Abciximab may increase the risk of bleeding if administered prior to during or after Activase therapy Use of Antithrombotics Aspirin and heparin have been administered concomitantly with and following infusions of Activase in the management of acute myocardial infarction or pulmonary embolism Because heparin aspirin or Activase may cause bleeding complications careful monitoring for bleeding is advised especially at arterial puncture sites The concomitant use of heparin or aspirin during the first 24 hours following symptom onset were prohibited in The NINDS t PA Stroke Trial The safety of such concomitant use with Activase for the management of acute ischemic stroke is unknown Concurrent administration of HEXALEN and antidepressants of the MAO inhibitor class may cause severe orthostatic hypotension Cimetidine an inhibitor of microsomal drug metabolism increased altretamines half life and toxicity in a rat model Data from a randomized trial of HEXALEN and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity however it adversely affected response duration suggesting that pyridoxine should not be administered with HEXALEN and or cisplatin 1 Careful observation is required when amantadine is administered concurrently with central nervous system stimulants Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinsons disease however it is not known if other phenothiazines produce a similar response Special consideration should be given to the administration of ETHYOL in patients receiving antihypertensive medications or other drugs that could cause or potentiate hypotension When amiloride HCl is administered concomitantly with an angiotensin converting enzyme inhibitor the risk of hyperkalemia may be increased Therefore if concomitant use of these agents is indicated because of demonstrated hypokalemia they should be used with caution and with frequent monitoring of serum potassium Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity Read circulars for lithium preparations before use of such concomitant therapy In some patients the administration of a non steroidal anti inflammatory agent can reduce the diuretic natriuretic and antihypertensive effects of loop potassium sparing and thiazide diuretics Therefore when MIDAMOR and non steroidal anti inflammatory agents are used concomitantly the patient should be observed closely to determine if the desired effect of the diuretic is obtained Since indomethacin and potassium sparing diuretics including MIDAMOR may each be associated with increased serum potassium levels the potential effects on potassium kinetics and renal function should be considered when these agents are administered concurrently Drug Laboratory Test Interactions Prolongation of the template bleeding time has been reported during continuous intravenous infusion of AMICAR at dosages exceeding 24 g day Platelet function studies in these patients have not demonstrated any significant platelet dysfunction However in vitro studies have shown that at high concentrations 7 4 mMol L or 0 97 mg mL and greater EACA inhibits ADP and collagen induced platelet aggregation the release of ATP and serotonin and the binding of fibrinogen to the platelets in a concentration response manner Following a 10 g bolus of AMICAR transient peak plasma concentrations of 4 6 mMol L or 0 60 mg mL have been obtained The concentration of AMICAR necessary to maintain inhibition of fibrinolysis is 0 99 mMol L or 0 13 mg mL Administration of a 5 g bolus followed by 1 to 1 25 g hr should achieve and sustain plasma levels of 0 13 mg mL Thus concentrations which have been obtained in vivo clinically in patients with normal renal function are considerably lower than the in vitro concentrations found to induce abnormalities in platelet function tests However higher plasma concentrations of AMICAR may occur in patients with severe renal failure Cytadren accelerates the metabolism of dexamethasone therefore if glucocorticoid replacement is needed hydrocortisone should be prescribed Aminoglutethimide diminishes the effect of coumarin and warfarin Renal clearance measurements of PAH cannot be made with any significant accuracy in patients receiving sulfonamides procaine or thiazolesulfone These compounds interfere with chemical color development essential to the analytical procedures Probenecid depresses tubular secretion of certain weak acids such as PAH Therefore patients receiving probenecid will have erroneously low ERPF and Tm PAH values There have been no formal studies of the interaction of LEVULAN KERASTICK for Topical Solution with any other drugs and no drug specific interactions were noted during any of the controlled clinical trials It is however possible that concomitant use of other known photosensitizing agents such as griseofulvin thiazide diuretics sulfonylureas phenothiazines sulfonamides and tetracyclines might increase the photosensitivity reaction of actinic keratoses treated with the LEVULAN KERASTICK for Topical Solution Aminosalicylic acid may decrease the amount of digoxin Lanoxin Lanoxicaps that gets absorbed into your body In the case that you are taking digoxin while taking aminosalicylic acid higher doses of digoxin may be needed Aminosalicylic acid may also decrease the absorption of vitamin B12 which can lead to a deficiency Therefore you may need to take a vitamin B12 supplement while taking aminosalicylic acid Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 CYP450 enzyme group specifically cytochromes P450 3A4 CYP3A4 and CYP2C8 The CYP3A4 isoenzyme is present in both the liver and intestines Amiodarone is also known to be an inhibitor of CYP3A4 Therefore amiodarone has the potential for interactions with drugs or substances that may be substrates inhibitors or inducers of CYP3A4 While only a limited number of in vivo drug drug interactions with amiodarone have been reported chiefly with the oral formulation the potential for other interactions should be anticipated This is especially important for drugs associated with serious toxicity such as other antiarrhythmics If such drugs are needed their dose should be reassessed and where appropriate plasma concentration measured In view of the long and variable half life of amiodarone potential for drug interactions exists not only with concomitant medication but also with drugs administered after discontinuation of amiodarone Since amiodarone is a substrate for CYP3A4 and CYP2C8 drugs substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone Reported examples include the following Protease Inhibitors Protease inhibitors are known to inhibit CYP3A4 to varying degrees A case report of one patient taking amiodarone 200 mg and indinavir 800 mg three times a day resulted in increases in amiodarone concentrations from 0 9 mg L to 1 3 mg L DEA concentrations were not affected There was no evidence of toxicity Monitoring for amiodarone toxicity and serial measurement of amiodarone serum concentration during concomitant protease inhibitor therapy should be considered Histamine H2 antagonists Cimetidine inhibits CYP3A4 and can increase serum amiodarone levels Other substances Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50 and Cmax by 84 resulting in increased plasma levels of amiodarone Grapefruit juice should not be taken during treatment with oral amiodarone This information should be considered when changing from intravenous amiodarone to oral amiodarone Amiodarone may suppress certain CYP450 enzymes including CYP1A2 CYP2C9 CYP2D6 and CYP3A4 This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes Reported examples of this interaction include the following Immunosuppressives Cyclosporine CYP3A4 substrate administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine despite reduction in dose of cyclosporine HMG CoA Reductase Inhibitors Simvastatin CYP3A4 substrate in combination with amiodarone has been associated with reports of myopathy rhabdomyolysis Cardiovasculars Cardiac glycosides In patients receiving digoxin therapy administration of oral amiodarone regularly results in an increase in serum digoxin concentration that may reach toxic levels with resultant clinical toxicity Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70 after one day On administration of oral amiodarone the need for digitalis therapy should be reviewed and the dose reduced by approximately 50 or discontinued If digitalis treatment is continued serum levels should be closely monitored and patients observed for clinical evidence of toxicity These precautions probably should apply to digitoxin administration as well Antiarrhythmics Other antiarrhythmic drugs such as quinidine procainamide disopyramide and phenytoin have been used concurrently with amiodarone There have been case reports of increased steady state levels of quinidine procainamide and phenytoin during concomitant therapy with amiodarone Phenytoin decreases serum amiodarone levels Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33 after two days Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n acetyl procainamide by 55 and 33 respectively Quinidine and procainamide doses should be reduced by one third when either is administered with amiodarone Plasma levels of flecainide have been reported to increase in the presence of oral amiodarone because of this the dosage of flecainide should be adjusted when these drugs are administered concomitantly In general any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone During transfer to oral amiodarone the dose levels of previously administered agents should be reduced by 30 to 50 several days after the addition of oral amiodarone The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established and discontinuation ordinarily should be attempted If the treatment is continued these patients should be particularly carefully monitored for adverse effects especially conduction disturbances and exacerbation of tachyarrhythmias as amiodarone is continued In amiodarone treated patients who require additional antiarrhythmic therapy the initial dose of such agents should be approximately half of the usual recommended dose Antihypertensives Amiodarone should be used with caution in patients receiving receptor blocking agents e g propranolol a CYP3A4 inhibitor or calcium channel antagonists e g verapamil a CYP3A4 substrate and diltiazem a CYP3A4 inhibitor because of the possible potentiation of bradycardia sinus arrest and AV block if necessary amiodarone can continue to be used after insertion of a pacemaker in patients with severe bradycardia or sinus arrest Anticoagulants Potentiation of warfarin type CYP2C9 and CYP3A4 substrate anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100 after 3 to 4 days the dose of the anticoagulant should be reduced by one third to one half and prothrombin times should be monitored closely Some drugs substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 enzyme induction This may lead to low amiodarone serum levels and potential decrease in efficacy Reported examples of this interaction include the following Antibiotics Rifampin is a potent inducer of CYP3A4 Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone Other substances including herbal preparations St John s Wort Hypericum perforatum induces CYP3A4 Since amiodarone is a substrate for CYP3A4 there is the potential that the use of St John s Wort in patients receiving amiodarone could result in reduced amiodarone levels Other reported interactions with amiodarone Fentanyl CYP3A4 substrate in combination with amiodarone may cause hypotension bradycardia and decreased cardiac output Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine CYP3A4 substrate given for local anesthesia Seizure associated with increased lidocaine concentrations has been reported with concomitant administration of intravenous amiodarone Dextromethorphan is a substrate for both CYP2D6 and CYP3A4 Amiodarone inhibits CYP2D6 Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t1 2 Disopyramide increases QT prolongation which could cause arrhythmia Fluoroquinolones macrolide antibiotics and azoles are known to cause QTc prolongation There have been reports of QTc prolongation with or without TdP in patients taking amiodarone when fluoroquinolones macrolide antibiotics or azoles were administered concomitantly Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol diltiazem and verapamil Volatile Anesthetic Agents In addition to the interactions noted above chronic 2 weeks oral Cordarone administration impairs metabolism of phenytoin dextromethorphan and methotrexate Electrolyte Disturbances Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being treated with Cordarone I V as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP Special attention should be given to electrolyte and acid base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 debrisoquin hydroxylase is reduced in a subset of the caucasian population about 7 10 of caucasians are so called poor metabolizers reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian African and other populations are not yet available Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants TCAs when given usual doses Depending on the fraction of drug metabolized by P450 2D6 the increase in plasma concentration may be small or quite large 8 fold increase in plasma AUC of the TCA In addition certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme quinidine cimetidine and many that are substrates for P450 2D6 many other antidepressants phenothiazines and the Type 1C antiarrhythmics propafenone and flecainide While all the selective serotonin reuptake inhibitors SSRIs e g fluoxetine sertraline and paroxetine inhibit P450 2D6 they may vary in the extent of inhibition The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved Nevertheless caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other Of particular importance sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine given the long half life of the parent and active metabolite at least 5 weeks may be necessary Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug Furthermore whenever one of these other drugs is withdrawn from co therapy an increased dose of tricyclic antidepressant may be required It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6 Monoamine Oxidase Inhibitors Guanethidine or similarly acting compounds thyroid medication alcohol barbiturates and other CNS depressants and disulfiram When amitriptyline HCl is given with anticholinergic agents or sympathomimetic drugs including epinephrine combined with local anesthetics close supervision and careful adjustment of dosages are required Hyperpyrexia has been reported when amitriptyline HCl is administered with anticholinergic agents or with neuroleptic drugs particularly during hot weather Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic type drugs Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants thereby delaying elimination and increasing steady state concentrations of these drugs Clinically significant effects have been reported with the tricyclic antidepressants when used concomitantly with cimetidine Increases in plasma levels of tricyclic antidepressants and in the frequency and severity of side effects particularly anticholinergic have been reported when cimetidine was added to the drug regimen Discontinuation of cimetidine in well controlled patients receiving tricyclic antidepressants and cimetidine may decrease the plasma levels and efficacy of the antidepressants Caution is advised if patients receive large doses of ethchlorvynol concurrently Transient delirium has been reported in patients who were treated with one gram of ethchlorvynol and 75 150 mg of amitriptyline HCl When administered concurrently the following drugs may interact with amphotericin B Antineoplastic agents may enhance the potential for renal toxicity bronchospasm and hypotension Antineoplastic agents e g nitrogen mustard etc should be given concomitantly only with great caution Corticosteroids and Corticotropin ACTH may potentiate amphotericin B induced hypokalemia which may predispose the patient to cardiac dysfunction Avoid concomitant use unless necessary to control side effects of amphotericin B If used concomitantly closely monitor serum electrolytes and cardiac function Digitalis glycosides amphotericin B induced hypokalemia may potentiate digitalis toxicity Serum potassium levels and cardiac function should be closely monitored and any deficit promptly corrected Flucytosine while a synergistic relationship with amphotericin B has been reported concomitant use may increase the toxicity of flucytosine by possibly increasing its cellular uptake and or impairing its renal excretion Imidazoles e g ketoconazole miconazole clotrimazole fluconazole etc in vitro and animal studies with the combination of amphotericin B and imidazoles suggest that imidazoles may induce fungal resistance to amphotericin B Combination therapy should be administered with caution especially in immunocompromised patients Other nephrotoxic medications agents such as aminoglycosides cyclosporine and pentamidine may enhance the potential for drug induced renal toxicity and should be used concomitantly only with great caution Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications Skeletal muscle relaxants amphotericin B induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants e g tubocurarine Serum potassium levels should be monitored and deficiencies corrected Leukocyte transfusions acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions When administered concurrently the following drugs may interact with ampicillin Allopurinol Increased possibility of skin rash particularly in hyperuricemic patients may occur Bacteriostatic Antibiotics Chloramphenicol erythromycins sulfonamides or tetracyclines may interfere with the bactericidal effect of penicillins This has been demonstrated in view however the clinical significance of this interaction is not well documented Oral Contraceptives May be less effective and increased breakthrough bleeding may occur Probenecid May decrease renal tubular secretion of ampicillin resulting in increased blood levels and or ampicillin toxicity Drug Laboratory Test Interaction After treatment with ampicillin a false positive reaction for glucose in the urine may occur with copper sulfate tests Benedicts solution Fehlings solution or Clinitest tablets but not with enzyme based tests such as Clinistix and Glucose Enzymatic Test Strip USP Amprenavir is metabolized in the liver by the cytochrome P450 enzyme system Amprenavir inhibits CYP3A4 Caution should be used when coadministering medications that are substrates inhibitors or inducers of CYP3A4 or potentially toxic medications that are metabolized by CYP3A4 Amprenavir does not inhibit CYP2D6 CYP1A2 CYP2C9 CYP2C19 CYP2E1 or uridine glucuronosyltransferase UDPGT HIV Protease Inhibitors The effect of amprenavir on total drug concentrations of other HIV protease inhibitors in subjects receiving both agents was evaluated using comparisons to historical data Indinavir steady state Cmax A C and Cmin were decreased by 22 38 and 27 respectively by concomitant amprenavir Similar decreases in Cmax and AUC were seen after the first dose Saquinavir steady state Cmax A C and Cmin were increased 21 decreased 19 and decreased 48 respectively by concomitant amprenavir Nelfinavir steady state Cmax A C and Cmin were increased by 12 15 and 14 respectively by concomitant amprenavir Methadone Coadministration of amprenavir and methadone can decrease plasma levels of methadone Coadministration of amprenavir and methadone as compared to a non matched historicalcontrol group resulted in a 30 27 and 25 decrease in serum amprenavir AUC Cmax andCmin respectively Amprenavir is an inhibitor of cytochrome P450 C P A metabolism and therefore should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4 There are other agents that may result in serious and or life threatening drug interactions Laboratory Tests The combination of Amprenavir and low dose ritonavir has been associated with elevations of cholesterol and triglycerides SGOT AST and SGPT ALT in some patients Appropriate laboratory testing should be considered prior to initiating combination therapy with Amprenavir and ritonavir and at periodic intervals or if any clinical signs or symptoms of hyperlipidemia or elevated liver function tests occur during therapy For comprehensive information concerning laboratory test alterations associated with ritonavir physicians should refer to the complete prescribing information for NORVIR ritonavir Taking amyl nitrite after drinking alcohol may worsen side effects and may cause severe hypotension and cardiovascular collapse Limited PK and or PD studies investigating possible interactions between anagrelide and other medicinal products have been conducted In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the PK properties of anagrelide nor does anagrelide affect the PK properties of digoxin or warfarin Although additional drug interaction studies have not been conducted the most common medications used concomitantly with anagrelide in clinical trials were aspirin acetaminophen furosemide iron ranitidine hydroxyurea and allopurinol There is no clinical evidence to suggest that anagrelide interacts with any of these compounds An in vivo interaction study in humans demonstrated that a single 1mg dose of anagrelide administered concomitantly with a single 900 mg dose of aspirin was generally well tolerated There was no effect on bleeding time PT or aPTT No clinically relevant pharmacokinetic interactions between anagrelide and acetylsalicylic acid were observed In that same study aspirin alone produced a marked inhibition in platelet aggregation ex vivo Anagrelide alone had no effect on platelet aggregation but did slightly enhance the inhibition of platelet aggregation by aspirin Anagrelide is metabolized at least in part by CYP1A2 It is known that CYP1A2 is inhibited by several medicinal products including fluvoxamine and such medicinal products could theoretically adversely influence the clearance of anagrelide Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other coadministered medicinal products sharing that clearance mechanism e g Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other coadministered medicinal products sharing that clearance mechanism e g theophylline Anagrelide is an inhibitor of cyclic AMP PDE III The effects of medicinal products with similar properties such as inotropes milrinone enoximone amrinone olprinone and cilostazol may be exacerbated by anagrelide There is a single case report which suggests that sucralfate may interfere with anagrelide absorption Food has no clinically significant effect on the bioavailability of anagrelide No drug drug interaction studies in human subjects have been conducted Toxicologic and toxicokinetic studies in rats did not demonstrate any alterations in the clearance or toxicologic profile of either methotrexate or Kineret when the two agents were administered together In a study in which patients with active RA were treated for up to 24 weeks with concurrent Kineret and etanercept therapy a 7 rate of serious infections was observed which was higher than that observed with etanercept alone 0 Two percent of patients treated concurrently with Kineret and etanercept developed neutropenia ANC 1 x 109 L Anastrozole inhibited in vitro metabolic reactions catalyzed by cytochromes P450 1A2 2C8 9 and 3A4 but only at relatively high concentrations Anastrozole did not inhibit P450 2A6 or the polymorphic P450 2D6 in human liver microsomes Anastrozole did not alter the pharmacokinetics of antipyrine Although there have been no formal interaction studies other than with antipyrine based on these in vivo and in vitro studies it is unlikely that co administration of a 1 mg dose of ARIMIDEX with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drugs An interaction study with warfarin showed no clinically significant effect of anastrozole on warfarin pharmacokinetics or anticoagulant activity At a median follow up of 33 months the combination of ARIMIDEX and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor positive subpopulation This treatment arm was discontinued from the trial Based on clinical and pharmacokinetic results from the ATAC trial tamoxifen should not be administered with anastrozole see CLINICAL PHARMACOLOGY Drug Interactions and CLINICAL PHARMACOLOGY Clinical Studies Adjuvant Treatment of Breast Cancer in Postmenopausal Women subsections Co administration of anastrozole and tamoxifen resulted in a reduction of anastrozole plasma levels by 27 compared with those achieved with anastrozole alone Estrogen containing therapies should not be used with ARIMIDEX as they may diminish its pharmacologic action Drug Laboratory Test Interactions No clinically significant changes in the results of clinical laboratory tests have been observed No clinically relevant drug drug interactions have been observed with drugs likely to be co administered with anidulafungin Caution should be observed when anileridine is coadministered with other opioids sedatives phenothiazines or anesthetics as these agents may increase respiratory and circulatory depression Addition or deletion of any drug from the therapeutic regimen of patients receiving oral anticoagulants may affect patient response to the anticoagulant Frequent determination of prothrombin time and close monitoring of the patient is essential to ascertain when adjustment of dosage of anticoagulant may be needed Because of the variability of individual patient response multiple interacting mechanisms with some drugs the dependency of the extent of the interaction on the dosage and duration of therapy and the possible administration of several interacting drugs simultaneously it is difficult to predict the direction and degree of the ultimate effect of concomitant medications on anticoagulant response For example since cholestyramine may reduce the gastrointestinal absorption of both the oral anticoagulants and vitamin K the net effects are unpredictable Chloral hydrate may cause an increased prothrombin response by displacing the anticoagulant from protein binding sites or a diminished prothrombin response through increased metabolism of the unbound drug by hepatic enzyme induction thus leading to inter patient variation in ultimate prothrombin effect An interacting drug which leads to a decrease in prothrombin time necessitating an increased dose of oral anticoagulant to maintain an adequate degree of anticoagulation may if abruptly discontinued increase the risk of subsequent bleeding Drugs that have been reported to diminish oral anticoagulant response ie decreased prothrom bin time response in man significantly include adrenocortical steroids alcohol antacids antihistamines barbiturates carbamazepine chloral hydrate chlordiazepoxide cholestyramine diet high in vitamin K diuretics ethchlorvynol glutethimide griseofulvin haloperidol meprobamate oral contraceptives paraldehyde primidone ranitidine rifampin unreliable prothrombin time determinations vitamin C Drugs that have been reported to diminish oral anticoagulant response ie decreased prothrom bin time response in man significantly include adrenocortical steroids alcohol antacids antihistamines barbiturates carbamazepine chloral hydrate chlordiazepoxide cholestyramine diet high in vitamin K diuretics ethchlorvynol glutethimide griseofulvin haloperidol meprobamate oral contraceptives paraldehyde primidone ranitidine rifampin unreliable prothrombin time determinations vitamin C warfarin sodium under dosage Drugs that reportedly may increase oral anticoagulant response ie increased prothrombin response in man include alcohol allopurinol aminosalicylic acid amiodarone anabolic steroids antibiotics bromelains chloral hydrate chlorpropamide chymotrypsin cimetidine cinchophen clofibrate dextran dextrothyroxine diazoxide dietary deficiencies diflunisal diuretics disulfiram drugs affecting blood elements ethacrynic acid fenoprofen glucagon hepatotoxic drugs ibuprofen indomethacin influenza virus vaccine inhalation anesthetics mefenamic acid methyldopa methylphenidate metronidazole miconazole monoamine oxidase inhibitors nalidixic acid naproxen oxolinic acid oxyphenbutazone pentoxifylline phenylbutazone phenyramidol phenytoin prolonged hot weather prolonged narcotics pyrazolones quinidine quinine ranitidine salicylates sulfinpyrazone sulfonamides long acting sulindac thyroid drugs tolbutamide triclofos sodium trimethoprim sulfamethoxazole unreliable prothrombin time determinations Drugs that reportedly may increase oral anticoagulant response ie increased prothrombin response in man include alcohol allopurinol aminosalicylic acid amiodarone anabolic steroids antibiotics bromelains chloral hydrate chlorpropamide chymotrypsin cimetidine cinchophen clofibrate dextran dextrothyroxine diazoxide dietary deficiencies diflunisal disulfiram drugs affecting blood elements ethacrynic acid fenoprofen glucagon hepatotoxic drugs ibuprofen indomethacin influenza virus vaccine inhalation anesthetics mefenamic acid methyldopa methylphenidate metronidazole miconazole monoamine oxidase inhibitors nalidixic acid naproxen oxolinic acid oxyphenbutazone pentoxifylline phenylbutazone phenyramidol phenytoin prolonged hot weather prolonged narcotics pyrazolones quinidine quinine ranitidine salicylates sulfinpyrazone sulfonamides long acting sulindac thyroid drugs tolbutamide triclofos sodium trimethoprim sulfamethoxazole unreliable prothrombin time determinations warfarin sodium overdosage Oral anticoagulants may potentiate the hypoglycemic action of hypoglycemic agents eg tolbutamide and chlorpropamide by inhibiting their metabolism in the liver Because oral anticoagulants may interfere with the hepatic metabolism of phenytoin toxic levels of the anticonvulsant may occur when an oral anticoagulant and phenytoin are administered concurrently Drugs that reduce the number of blood platelets by causing bone marrow depression such as antineoplastic agents or drugs which inhibit platelet function eg aspirin and other non steroidal anti inflammatory drugs dipyridamole hydrochloroquine clofibrate dextran may increase the bleeding tendency produced by anticoagulants without altering prothrombin time determinations The beneficial effects on arterial thrombus formation from combined therapy with antiplatelet and anticoagulant medication must be weighed against an increased risk of inducing hemorrhage Increased and decreased prothrombin time responses have been reported Drug Laboratory Test Interferences Dicumarol and indanedione anticoagulants including anisindione or their metabolites may color alkaline urine red orange which may interfere with spectrophotometrically determined urinary laboratory tests The color reverses when the test sample is acidified in vitro to a pH below 4 5HT3 Antagonists Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron the concomitant use of apomorphine with drugs of the 5HT3 antagonist class including for example ondansetron granisetron dolasetron palonosetron and alosetron is contraindicated Antihypertensive Medications and Vasodilators The following adverse events were experienced more commonly in patients receiving concomitant antihypertensive medications or vasodilators n 94 compared to patients not receiving these concomitant drugs n 456 hypotension 10 vs 4 myocardial infarction 3 vs 1 serious pneumonia 5 vs 3 serious falls 9 vs 3 and bone and joint injuries 6 vs 2 The mechanism underlying many of these events is unknown but may represent increased hypotension Dopamine Antagonists Since apomorphine is a dopamine agonist it is possible that dopamine antagonists such as the neuroleptics phenothiazines butyrophenones thioxanthenes or metoclopramide may diminish the effectiveness of APOKYN Patients with major psychotic disorders treated with neuroleptics should be treated with dopamine agonists only if the potential benefits outweigh the risks Drugs Prolonging the QT QTc Interval Caution should be exercised when prescribing apomorphine concomitantly with drugs that prolong the QT QTc interval Drug Laboratory Test Interactions There are no known interactions between APOKYN and laboratory tests Apraclonidine should not be used in patients receiving MAO inhibitors Although no specific drug interactions with topical glaucoma drugs or systemic medications were identified in clinical studies of IOPIDINE 0 5 Ophthalmic Solution the possibility of an additive or potentiating effect with CNS depressants alcohol barbiturates opiates sedatives anesthetics should be considered Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine It is not known whether the concurrent use of these agents with apraclonidine can lead to a reduction in IOP lowering effect No data on the level of circulating catecholamines after apraclonidine withdrawal are available Caution however is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines An additive hypotensive effect has been reported with the combination of systemic clonidine and neuroleptic therapy Systemic clonidine may inhibit the production of catecholamines in response to insulin induced hypoglycemia and mask the signs and symptoms of hypoglycemia Since apraclonidine may reduce pulse and blood pressure caution in using drugs such as beta blockers ophthalmic and systemic antihypertensives and cardiac glycosides is advised Patients using cardiovascular drugs concurrently with IOPIDINE 0 5 Ophthalmic Solution should have pulse and blood pressures frequently monitored Caution should be exercised with simultaneous use of clonidine and other similar pharmacologic agents Aprepitant is a substrate a moderate inhibitor and an inducer of CYP3A4 Aprepitant is also an inducer of CYP2C9 Effect of aprepitant on the pharmacokinetics of other agents As a moderate inhibitor of CYP3A4 aprepitant can increase plasma concentrations of coadministered medicinal products that are metabolized through CYP3A4 Aprepitant has been shown to induce the metabolism of S warfarin and tolbutamide which are metabolized through CYP2C9 Coadministration of Aprepitant with these drugs or other drugs that are known to be metabolized by CYP2C9 such as phenytoin may result in lower plasma concentrations of these drugs Aprepitant is unlikely to interact with drugs that are substrates for the P glycoprotein transporter as demonstrated by the lack of interaction of Aprepitant with digoxin in a clinical drug interaction study 5 HT3 antagonists In clinical drug interaction studies aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron or granisetron No clinical or drug interaction study was conducted with dolasetron Corticosteroids Dexamethasone Aprepitant when given as a regimen of 125mg with dexamethasone coadministered orally as 20 mg on Day 1 and Aprepitant when given as 80 mg day with dexamethasone coadministered orally as 8 mg on Days 2 through 5 increased the AUC of dexamethasone a CYP3A4 substrate by 2 2 fold on Days 1 and 5 The oral dexamethasone doses should be reduced by approximately 50 when coadministered with Aprepitant to achieve exposures of dexamethasone similar to those obtained when it is given without Aprepitant The daily dose of dexamethasone administered in clinical studies with Aprepitant reflects an approximate 50 reduction of the dose of dexamethasone Methylprednisolone Aprepitant when given as a regimen of 125 mg on Day 1 and 80 mg day on Days 2 and 3 increased the AUC of methylprednisolone a CYP3A4 substrate by 1 34 fold on Day 1 and by 2 5 fold on Day 3 when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3 The IV methylprednisolone dose should be reduced by approximately 25 and the oral methylprednisolone dose should be reduced by approximately 50 when coadministered with Aprepitant to achieve exposures of methylprednisolone similar to those obtained when it is given without Aprepitant Warfarin A single 125 mg dose of Aprepitant was administered on Day 1 and 80 mg day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy Although there was no effect of Aprepitant on the plasma AUC of R or S warfarin determined on Day 3 there was a 34 decrease in S warfarin a CYP2C9 substrate trough concentration accompanied by a 14 decrease in the prothrombin time reported as International Normalized Ratio or INR 5 days after completion of dosing with Aprepitant In patients on chronic warfarin therapy the prothrombin time INR should be closely monitored in the 2 week period particularly at 7 to 10 days following initiation of the 3 day regimen of Aprepitant with each chemotherapy cycle Tolbutamide Aprepitant when given as 125 mg on Day 1 and 80 mg day on Days 2 and 3 decreased the AUC of tolbutamide a CYP2C9 substrate by 23 on Day 4 28 on Day 8 and 15 on Day 15 when a single dose of tolbutamide 500 mg was admini stered orally prior to the administration of the 3 day regimen of Aprepitant and on Days 4 8 and 15 Oral contraceptives Aprepitant when given once daily for 14 days as a 100 mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone decreased the AUC of ethinyl estradiol by 43 and decreased the AUC of norethindrone by 8 therefore the efficacy of oral contraceptives during administration of Aprepitant may be reduced Although a 3 day regimen of Aprepitant given concomitantly with oral contraceptives has not been studied alternative or back up methods of contraception should be used Midazolam Aprepitant increased the AUC of midazolam a sensitive CYP3A4 substrate by 2 3 fold on Day 1 and 3 3 fold on Day 5 when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of Aprepitant 125 mg on Day 1 and 80 mg day on Days 2 through 5 The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 alprazolam triazolam should be considered when coadministering these agents with Aprepitant In another study with intravenous administration of midazolam Aprepitant was given as 125 mg on Day 1 and 80 mg day on Days 2 and 3 and midazolam 2 mg IV was given prior to the administration of the 3 day regimen of Aprepitant and on Days 4 8 and 15 Aprepitant increased the AUC of midazolam by 25 on Day 4 and decreased the AUC of midazolam by 19 on Day 8 relative to the dosing of Aprepitant on Days 1 through 3 These effects were not considered clinically important The AUC of midazolam on Day 15 was similar to that observed at baseline Effect of other agents on the pharmacokinefics of aprepitant Aprepitant is a substrate for CYP3A4 therefore coadministration of Aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant Consequently concomitant administration of Aprepitant with strong CYP3A4 inhibitors e g ketoconazole itraconazole nefazodone troleandomycin clarithromycin ritonavir nelfinavir should be approached with caution Because moderate CYP3A4 inhibitors e g diltiazem result in 2 fold increase in plasma concentrations of aprepitant concomitant administration should also be approached with caution Aprepitant is a substrate for CYP3A4 therefore coadministration of Aprepitant with drugs that strongly induce CYP3A4 activity e g rifampin carbamazepine phenytoin may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of Aprepitant Ketoconazole When a single 125 mg dose of Aprepitant was administered on Day5 of a Ketoconazole When a single 125 mg dose of Aprepitant was administered on Day5 of a 10 day regimen of 400 mg day of ketoconazole a strong CYP3A4 inhibitor the AUC of aprepitant increased approximately 5 fold and the mean terminal half life of aprepitant increased approximately 3 fold Concomitant administration of Aprepitant with strong CYP3A4 inhibitors should be approached cautiously Rifampin When a single 375 mg dose of Aprepitant was administered on Day9 of a 14 day regimen of 600 mg day of rifampin a strong CYP3A4 inducer the AUC of aprepitant decreased approximately 11 fold and the mean terminal half life decreased approximately 3 fold Coadministration of Aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of Aprepitant Additional interactions Diltiazem In patients with mild to moderate hypertension administration of aprepitant once daily as a tablet formulation comparable to 230 mg of the capsule formulation with diltiazem 120 mg 3 times daily for 5 days resulted in a 2 fold increase of aprepitant AUC and a simultaneous 1 7 fold increase of diltiazem AUC These pharmacokinetic effects did not result in clinically meaningful changes in ECG heart rate or blood pressure beyond those changes induced by diltiazem alone Paroxetine Coadministration of once daily doses of aprepitant as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation with paroxetine 20 mg once daily resulted in a decrease in AUC by approximately 25 and Cmax by approximately 20 of both aprepitant and paroxetine Beta adrenergic blocking agents concurrent use may blunt the response to arbutamine Beta adrenergic blocking agents should be withdrawn at least 48 hours before conducting an arbutamine mediated stress test Antiarrhythmic agents class I such as flecainide lidocaine or quinidine concurrent use with arbutamine may have a proarrhythmic effect Antidepressants tricyclic atropine or other anticholinergic agents or digitalis glycosides concurrent use with arbutamine may produce additive inotropic and or chronotropic effects Anticoagulants including coumarin derivatives indandione derivatives and platelet aggregation inhibitors such as nonsteroidal anti inflammatory drugs NSAIDs and aspirin may increase the risk of bleeding when administered concomitantly with ardeparin If additional adrenergic drugs are to be administered by any route they should be used with caution because the pharmacologically predictable sympathetic effects of BROVANA may be potentiated When paroxetine a potent inhibitor of CYP2D6 was co administered with BROVANA at steady state exposure to either drug was not altered Dosage adjustments of BROVANA are not necessary when the drug is given concomitantly with potent CYP2D6 inhibitors Concomitant treatment with methylxanthines aminophylline theophylline steroids or diuretics may potentiate any hypokalemic effect of adrenergic agonists The ECG changes and or hypokalemia that may result from the administration of non potassium sparing diuretics such as loop or thiazide diuretics can be acutely worsened by beta agonists especially when the recommended dose of the beta agonist is exceeded Although the clinical significance of these effects is not known caution is advised in the co administration of beta agonists with non potassium sparing diuretics BROVANA as with other beta2 agonists should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors tricyclic antidepressants or drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias The concurrent use of intravenously or orally administered methylxanthines e g aminophylline theophylline by patients receiving BROVANA has not been completely evaluated In two combined 12 week placebo controlled trials that included BROVANA doses of 15 mcg twice daily 25 mcg twice daily and 50 mcg once daily 54 of 873 BROVANA treated subjects received concomitant theophylline at study entry In a 12 month controlled trial that included a 50 mcg once daily BROVANA dose 30 of the 528 BROVANA treated subjects received concomitant theophylline at study entry In these trials heart rate and systolic blood pressure were approximately 2 3 bpm and 6 8 mm Hg higher respectively in subjects on concomitant theophylline compared with the overall population Beta adrenergic receptor antagonists beta blockers and BROVANA may interfere with the effect of each other when administered concurrently Beta blockers not only block the therapeutic effects of beta agonists but may produce severe bronchospasm in COPD patients Therefore patients with COPD should not normally be treated with beta blockers However under certain circumstances e g as prophylaxis after myocardial infarction there may be no acceptable alternatives to the use of beta blockers in patients with COPD In this setting cardioselective beta blockers could be considered although they should be administered with caution Heparin Since heparin is contraindicated in patients with heparin induced thrombocytopenia the co administration of Argatroban and heparin is unlikely for this indication However if Argatroban is to be initiated after cessation of heparin therapy allow sufficient time for heparins effect on the aPTT to decrease prior to initiation of Argatroban therapy Aspirin Acetaminophen Pharmacokinetic or pharmacodynamic drug drug interactions have not been demonstrated between Argatroban and concomitantly administered aspirin 162 5 mg orally given 26 and 2 hours prior to initiation of Argatroban 1 g kg min over 4 hours or acetaminophen 1000 mg orally given 12 6 and 0 hours prior to and 6 and 12 hours subsequent to initiation of Argatroban 1 5 g kg min over 18 hours Oral anticoagulant agents Pharmacokinetic drug drug interactions between Argatroban and warfarin 7 5 mg single oral dose have not been demonstrated However the concomitant use of Argatroban and warfarin 5 7 5 mg initial oral dose followed by 2 5 6 mg day orally for 6 10 days results in prolongation of the prothrombin time PT and International Normalized Ratio INR Thrombolytic agents The safety and effectiveness of Argatroban with thrombolytic agents have not been established Co administration Concomitant use of Argatroban with antiplatelet agents thrombolytics and other anticoagulants may increase the risk of bleeding Drug drug interactions have not been observed between Argatroban and digoxin or erythromycin Drug Drug Interactions Given the primary CNS effects of aripiprazole caution should be used when ABILIFY is taken in combination with other centrally acting drugs and alcohol Due to its 1 adrenergic receptor antagonism aripiprazole has the potential to enhance the effect of certain antihypertensive agents Potential for Other Drugs to Affect ABILIFY Aripiprazole is not a substrate of CYP1A1 CYP1A2 CYP2A6 CYP2B6 CYP2C8 CYP2C9 CYP2C19 or CYP2E1 enzymes Aripiprazole also does not undergo direct glucuronidation This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes or other factors like smoking is unlikely Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism Agents that induce CYP3A4 eg carbamazepine could cause an increase in aripiprazole clearance and lower blood levels Inhibitors of CYP3A4 eg ketoconazole or CYP2D6 eg quinidine fluoxetine or paroxetine can inhibit aripiprazole elimination and cause increased blood levels Ketoconazole Coadministration of ketoconazole 200 mg day for 14 days with a 15 mg single dose of aripiprazole increased the AUC of aripiprazole and its active metabolite by 63 and 77 respectively The effect of a higher ketoconazole dose 400 mg day has not been studied When concomitant administration of ketoconazole with aripiprazole occurs aripiprazole dose should be reduced to one half of its normal dose Other strong inhibitors of CYP3A4 itraconazole would be expected to have similar effects and need similar dose reductions weaker inhibitors erythromycin grapefruit juice have not been studied When the CYP3A4 inhibitor is withdrawn from the combination therapy aripiprazole dose should then be increased Quinidine Coadministration of a 10 mg single dose of aripiprazole with quinidine 166 mg day for 13 days a potent inhibitor of CYP2D6 increased the AUC of aripiprazole by 112 but decreased the AUC of its active metabolite dehydroaripiprazole by 35 Aripiprazole dose should be reduced to one half of its normal dose when concomitant administration of quinidine with aripiprazole occurs Other significant inhibitors of CYP2D6 such as fluoxetine or paroxetine would be expected to have similar effects and therefore should be accompanied by similar dose reductions When the CYP2D6 inhibitor is withdrawn from the combination therapy aripiprazole dose should then be increased Carbamazepine Coadministration of carbamazepine 200 mg BID a potent CYP3A4 inducer with aripiprazole 30 mg QD resulted in an approximate 70 decrease in Cmax and AUC values of both aripiprazole and its active metabolite dehydro aripiprazole When carbamazepine is added to aripiprazole therapy aripiprazole dose should be doubled Additional dose increases should be based on clinical evaluation When carbamazepine is withdrawn from the combination therapy aripiprazole dose should then be reduced No clinically significant effect of famotidine valproate or lithium was seen on the pharmacokinetics of aripiprazole see CLINICAL PHARMACOLOGY Drug Drug Interactions Potential for ABILIFY to Affect Other Drugs Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes In in vivo studies 10 to 30 mg day doses of aripiprazole had no significant effect on metabolism by CYP2D6 dextromethorphan CYP2C9 warfarin CYP2C19 omeprazole warfarin and CYP3A4 dextromethorphan substrates Additionally aripiprazole and dehydroaripiprazole did not show potential for altering CYP1A2 mediated metabolism in vitro Alcohol There was no significant difference between aripiprazole coadministered with ethanol and placebo coadministered with ethanol on performance of gross motor skills or stimulus response in healthy subjects As with most psychoactive medications patients should be advised to avoid alcohol while taking ABILIFY No formal assessments of pharmacokinetic drug drug interactions between TRISENOX and other agents have been conducted Caution is advised when TRISENOX is coadministered with other medications that can prolong the QT interval e g certain antiarrhythmics or thioridazine or lead to electrolyte abnormalities such as diuretics or amphotericin B Tissue culture and animal studies indicate that ELSPAR can diminish or abolish the effect of methotrexate on malignant cells 14 This effect on methotrexate activity persists as long as plasma asparagine levels are suppressed These results would seem to dictate against the clinical use of methotrexate with ELSPAR or during the period following ELSPAR therapy when plasma asparagine levels are below normal Uricosuric Agents Aspirin may decrease the effects of probenecid sulfinpyrazone and phenylbutazone Alcohol Has a synergistic effect with aspirin in causing gastrointestinal bleeding Corticosteroids Concomitant administration with aspirin may increase the risk of gastrointestinal ulceration and may reduce serum salicylate levels Pyrazolone Derivatives phenylbutazone oxyphenbutazone and possibly dipyrone Concomitant administration with aspirin may increase the risk of gastrointestinal ulceration Nonsteroidal Antiinflammatory Agents Aspirin is contraindicated in patients who are hypersensitive to nonsteroidal anti inflammatory agents Urinary Alkalinizers Decrease aspirin effectiveness by increasing the rate of salicylate renal excretion Phenobarbital Decreases aspirin effectiveness by enzyme induction Phenytoin Serum phenytoin levels may be increased by aspirin Propranolol May decrease aspirins anti inflammatory action by competing for the same receptors Antacids Enteric Coated Aspirin should not be given concurrently with antacids since an increase in the pH of the stomach may effect the enteric coating of the tablets Ketoconazole Itraconazole Macrolides Including Erythromycin Catecholamine depleting drugs eg reserpine may have an additive effect when given with beta blocking agents Patients treated with TENORMIN plus a catecholamine depletor should therefore be closely observed for evidence of hypotension and or marked bradycardia which may produce vertigo syncope or postural hypotension Calcium channel blockers may also have an additive effect when given with TENORMIN Beta blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine If the two drugs are coadministered the beta blocker should be withdrawn several days before the gradual withdrawal of clonidine If replacing clonidine by beta blocker therapy the introduction of beta blockers should be delayed for several days after clonidine administration has stopped Concomitant use of prostaglandin synthase inhibiting drugs eg indomethacin may decrease the hypotensive effects of beta blockers Information on concurrent usage of atenolol and aspirin is limited Data from several studies ie TIMI II ISIS 2 currently do not suggest any clinical interaction between aspirin and beta blockers in the acute myocardial infarction setting While taking beta blockers patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge either accidental diagnostic or therapeutic Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction Drug Drug Interactions Albuterol STRATTERA should be administered with caution to patients being treated with systemically administered oral or intravenous albuterol or other beta2 agonists because the action of albuterol on the cardiovascular system can be potentiated resulting in increases in heart rate and blood pressure CYP2D6 inhibitors Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4 hydroxyatomoxetine In EMs selective inhibitors of CYP2D6 increase atomoxetine steady state plasma concentrations to exposures similar to those observed in PMs Dosage adjustment of STRATTERA may be necessary when coadministered with CYP2D6 inhibitors e g paroxetine fluoxetine and quinidine In EM individuals treated with paroxetine or fluoxetine the AUC of atomoxetine is approximately 6 to 8 fold and Css max is about 3 to 4 fold greater than atomoxetine alone In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine Pressor agents Because of possible effects on blood pressure STRATTERA should be used cautiously with pressor agents The risk of myopathy during treatment with drugs of this class is increased with concurrent administration of cyclosporine fibric acid derivatives niacin nicotinic acid erythromycin azole antifungals Antacid When atorvastatin and Maalox TC suspension were coadministered plasma concentrations of atorvastatin decreased approximately 35 However LDL C reduction was not altered Antipyrine Because atorvastatin does not affect the pharmacokinetics of antipyrine interactions with other drugs metabolized via the same cytochrome isozymes are not expected Colestipol Plasma concentrations of atorvastatin decreased approximately 25 when colestipol and atorvastatin were coadministered However LDL C reduction was greater when atorvastatin and colestipol were coadministered than when either drug was given alone Cimetidine Atorvastatin plasma concentrations and LDL C reduction were not altered by coadministration of cimetidine Digoxin When multiple doses of atorvastatin and digoxin were coadministered steady state plasma digoxin concentrations increased by approximately 20 Patients taking digoxin should be monitored appropriately Erythromycin In healthy individuals plasma concentrations of atorvastatin increased approximately 40 with coadministration of atorvastatin and erythromycin a known inhibitor of cytochrome P450 3A4 Oral Contraceptives Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30 and 20 These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin Warfarin Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment Endocrine Function HMG CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might blunt adrenal and or gonadal steroid production Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve The effects of HMG CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients The effects if any on the pituitary gonadal axis in premenopausal women are unknown Caution should be exercised if an HMG CoA reductase inhibitor is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole spironolactone and cimetidine CNS Toxicity Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg kg day Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg kg day The 120 mg kg dose resulted in a systemic exposure approximately 16 times the human plasma area under the curve AUC 0 24 hours based on the maximum human dose of 80 mg day A single tonic convulsion was seen in each of 2 male dogs one treated at 10 mg kg day and one at 120 mg kg day in a 2 year study No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg kg day or in rats at doses up to 100 mg kg day These doses were 6 to 11 times mouse and 8 to 16 times rat the human AUC 0 24 based on the maximum recommended human dose of 80 mg day CNS vascular lesions characterized by perivascular hemorrhages edema and mononuclear cell infiltration of perivascular spaces have been observed in dogs treated with other members of this class A chemically similar drug in this class produced optic nerve degeneration Wallerian degeneration of retinogeniculate fibers in clinically normal dogs in a dose dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose Atovaquone is highly bound to plasma protein 99 9 Therefore caution should be used when administering MEPRON concurrently with other highly plasma protein bound drugs with narrow therapeutic indices as competition for binding sites may occur The extent of plasma protein binding of atovaquone in human plasma is not affected by the presence of therapeutic concentrations of phenytoin 15 mcg mL nor is the binding of phenytoin affected by the presence of atovaquone Rifampin Coadministration of rifampin and MEPRON Suspension results in a significant decrease in average steady state plasma atovaquone concentrations Alternatives to rifampin should be considered during the course of PCP treatment with MEPRON Rifabutin another rifamycin is structurally similar to rifampin and may possibly have some of the same drug interactions as rifampin No interaction trials have been conducted with MEPRON and rifabutin Drug Laboratory Test Interactions It is not known if MEPRON interferes with clinical laboratory test or assay results Drugs which may enhance the neuromuscular blocking action of TRACRIUM include enflurane isoflurane halothane certain antibiotics especially the aminoglycosides and polymyxins lithium magnesium salts procainamide Drugs which may enhance the neuromuscular blocking action of TRACRIUM include enflurane isoflurane halothane certain antibiotics especially the aminoglycosides and polymyxins lithium magnesium salts procainamide and quinidine If other muscle relaxants are used during the same procedure the possibility of a synergistic or antagonist effect should be considered The prior administration of succinylcholine does not enhance the duration but quickens the onset and may increase the depth of neuromuscular block induced by TRACRIUM TRACRIUM should not be administered until a patient has recovered from succinylcholine induced neuromuscular block When atropine and pralidoxime are used together the signs of atropinization flushing mydriasis tachycardia dryness of the mouth and nose may occur earlier than might be expected than when atropine is used alone because pralidoxime may potentiate the effect of atropine The following precautions should be kept in mind in the treatment of anticholinesterase poisoning although they do not bear directly on the use of atropine and pralidoxime Since barbiturates are potentiated by the anticholinesterases they should be used cautiously in the treatment of convulsions Auranofin should be avoided by patients with a history of serious reaction to any gold medication including Solganal and Myochrysine Auranofin should not be used together with penicillamine Depen Cuprimine another arthritis medication It should also be avoided in patients with blood liver or kidney diseases recent radiation treatment or uncontrolled diabetes Patients should report to their practitioners any new rashes itching mouth sores or unusual taste while taking auranofin Gold is excreted slowly from the body Safety and effectiveness in children has not been established No formal assessments of drug drug interactions between Vidaza and other agents have been conducted MAO inhibitors prolong and intensify the effects of antihistamines Concomitant use of antihistamines with alcohol tricyclic antidepressants barbiturates or other central nervous system depressants may have an additive effect When sympathomimetic drugs are given to patients receiving monoamine oxidase inhibitors hypertensive reactions including hypertensive crises may occur The antihypertensive effects of methyldopa mecamylamine reserpine and veratrum alkaloids may be reduced by sympathomimetics Beta adrenergic blocking agents may also interact with sympathomimetics Increased ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis Antacids increase the rate of absorption of pseudoephedrine while kaolin decreases it Use with Allopurinol The principal pathway for detoxification of azathioprine is inhibited by allopurinol Patients receiving azathioprine and allopurinol concomitantly should have a dose reduction of azathioprine to approximately 1 3 to 1 4 the usual dose Use with Other Agents Affecting Myelopoesis Drugs which may affect leukocyte production including co trimoxazole may lead to exaggerated leukopenia especially in renal transplant recipients Use with Angiotensln Converting Enzyme Inhibitors The use of angiotensin converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce severe leukopenia No information provided Co administration of nelfinavir at steady state with a single dose of azithromycin Co administration of nelfinavir at steady state with a single dose of azithromycin 2 x 600 mg tablets results in increased azithromycin serum concentrations Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir close monitoring for known side effects of azithromycin such as liver enzyme abnormalities and hearing impairment is warranted Azithromycin did not affect the prothrombin time response to a single dose of warfarin However prudent medical practice dictates careful monitoring of prothrombin time in all patients treated with azithromycin and warfarin concomitantly Concurrent use of macrolides and warfarin in clinical practice has been associated with increased anticoagulant effects Drug interaction studies were performed with azithromycin and other drugs likely to be co administered When used in therapeutic doses azithromycin had a modest effect on the pharmacokinetics of atorvastatin carbamazepine cetirizine didanosine efavirenz fluconazole indinavir midazolam rifabutin sildenafil theophylline intravenous and oral triazolam trimethoprim sulfamethoxazole or zidovudine Co administration with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin No dosage adjustment of either drug is recommended when azithromycin is co administered with any of the above agents Interactions with the drugs listed below have not been reported in clinical trials with azithromycin however no specific drug interaction studies have been performed to evaluate potential drug drug interaction Nonetheless they have been observed with macrolide products Until further data are developed regarding drug interactions when azithromycin and these drugs are used concomitantly careful monitoring of patients is advised Digoxin elevated digoxin concentrations Ergotamine or dihydroergotamine acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia Cyclosporine hexobarbital and phenytoin concentrations Laboratory Test Interactions There are no reported laboratory test interactions Repeat Treatment Studies evaluating the use of repeated courses of Zmax have not been conducted Azlocillin should not be administered concomitantly with amikacin ciprofloxacin gentamicin netilmicin or tobramycin Injection There is inadequate systematic experience with the use of baclofen injection in combination with other medications to predict specific drug drug interactions Interactions attributed to the combined use of baclofen injection and epidural morphine include hypotension and dyspnea SIDE EFFECTS KEMSTRO The most common adverse reaction during treatment with baclofen is transient drowsiness 10 63 In one controlled study of 175 patients transient drowsiness was observed in 63 of those receiving baclofen tablets compared to 36 of those in the placebo group Other common adverse reactions are dizziness 5 15 weakness 5 15 and fatigue 2 4 Others reported Neuropsychiatric Confusion 1 11 headache 4 8 insomnia 2 7 and rarely euphoria excitement depression hallucinations paresthesia muscle pain tinnitus slurred speech coordination disorder tremor rigidity dystonia ataxia blurred vision nystagmus strabismus miosis mydriasis diplopia dysarthria epileptic seizure Cardiovascular Hypotension 0 9 Rare instances of dyspnea palpitation chest pain syncope Gastrointestinal Nausea 4 12 constipation 2 6 and rarely dry mouth anorexia taste disorder abdominal pain vomiting diarrhea and positive test for occult blood in stool Genitourinary Urinary frequency 2 6 and rarely enuresis urinary retention dysuria impotence inability to ejaculate nocturia hematuria Other Instances of rash pruritus ankle edema excessive perspiration weight gain nasal congestion Some of the CNS and genitourinary symptoms may be related to the underlying disease rather than to drug therapy The following laboratory tests have been found to be abnormal in a few patients receiving baclofen increased SGOT elevated alkaline phosphatase and elevation of blood sugar The adverse experience profile seen with KEMSTROTM was similar to that seen with baclofen tablets No drug interaction studies have been conducted for COLAZAL however the use of orally administered antibiotics could theoretically interfere with the release of mesalamine in the colon No dose adjustment is necessary when Simulect is added to triple immunosuppression regimens including cyclosporine corticosteroids and either azathioprine or mycophenolate mofetil Three clinical trials have investigated Simulect use in combination with triple therapy regimens Pharmacokinetics were assessed in two of these trials Total body clearance of Simulect was reduced by an average 22 and 51 when azathioprine and mycophenolate mofetil respectively were added to a regimen consisting of cyclosporine USP MODIFIED and corticosteroids Nonetheless the range of individual Simulect clearance values in the presence of azathioprine 12 57 mL h or mycophenolate mofetil 7 54 mL h did not extend outside the range observed with dual therapy 10 78 mL h The following medications have been administered in clinical trials with Simulect with no increase in adverse reactions ATG ALG azathioprine corticosteroids cyclosporine mycophenolate mofetil and muromonab CD3 It is not known if REGRANEX Gel interacts with other topical medications applied to the ulcer site The use of REGRANEX Gel with other topical drugs has not been studied Albuterol Antihistamines antidiabetic drugs diuretics digitalis Diuretics Patients on diuretics especially those in whom diuretic therapy was recently instituted may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Lotensin The possibility of hypotensive effects with Lotensin can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Lotensin If this is not possible the starting dose should be reduced Potassium Supplements and Potassium Sparing Diuretics Lotensin can attenuate potassium loss caused by thiazide diuretics Potassium sparing diuretics spironolactone amiloride triamterene and others or potassium supplements can increase the risk of hyperkalemia Therefore if concomitant use of such agents is indicated they should be given with caution and the patient s serum potassium should be monitored frequently Oral Anticoagulants Interaction studies with warfarin and acenocoumarol failed to identify any clinically important effects on the serum concentrations or clinical effects of these anticoagulants Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended If a diuretic is also used the risk of lithium toxicity may be increased Other No clinically important pharmacokinetic interactions occurred when Lotensin was administered concomitantly with hydrochlorothiazide chlorthalidone furosemide digoxin propranolol atenolol naproxen or cimetidine Lotensin has been used concomitantly with beta adrenergic blocking agents calcium channel blocking agents diuretics digoxin and hydralazine without evidence of clinically important adverse interactions Benazepril like other ACE inhibitors has had less than additive effects with beta adrenergic blockers presumably because both drugs lower blood pressure by inhibiting parts of the renin angiotensin system May interact with the following cholestyramine colestipol use with thiazide diuretics may prevent the diuretic from working properly Bentiromide may interact with acetaminophen e g Tylenol chloramphenicol e g Chloromycetin local anesthetics e g benzocaine and lidocaine para aminobenzoic acid PABA containing preparations e g sunscreens and some multivitamins procainamide e g Pronestyl sulfonamides sulfa medicines thiazide diuretics use of these medicines during the test period will affect the test results and pancreatic supplements use of pancreatic supplements may give false test results May interact with other creams lotions or skin medicines when placed on the same areas of your skin that you are using bentoquatam No information is available Hypertensive crises have resulted when sympathomimetic amines have been used concomitantly within14 days following use of monoamine oxidase inhibitors DIDREX should not be used concomitantly with other CNS stimulants Amphetamines may decrease the hypotensive effect of antihypertensives Amphetamines may enhance the effects of tricyclic antidepressants Urinary alkalinizing agents increase blood levels and decrease excretion of amphetamines Urinary acidifying agents decrease blood levels and increase excretion of amphetamines Benzthiazide may interact with alcohol blood thinners decongestant drugs allergy cold and sinus medicines diabetic drugs lithium norepinephrine NSAIDs like Aleve or Ibuprofen and high blood pressure medications Antipsychotic drugs such as phenothiazines or haloperidol tricyclic antidepressants Nitrates The concomitant use of Bepridil with long and short acting nitrates has been safely tolerated in patients with stable angina pectoris Sublingual nitroglycerin may be taken if necessary for the control of acute angina attacks during Bepridil therapy Beta blocking Agents The concomitant use of Bepridil and beta blocking agents has been well tolerated in patients with stable angina Available data are not sufficient however to predict the effects of concomitant medication on patients with impaired ventricular function or cardiac conduction abnormalities Digoxin In controlled studies in healthy volunteers bepridil hydrochloride either had no effect one study or was associated with modest increases about 30 two studies in steady state serum digoxin concentrations Limited clinical data in angina patients receiving concomitant bepridil hydrochloride and digoxin therapy indicate no discernible changes in serum digoxin levels Available data are neither sufficient to rule out possible increases in serum digoxin with concomitant treatment in some patients nor other possible interactions particularly in patients with cardiac conduction abnormalities Also see WARNINGS Congestive Heart Failure Oral Hypoglycemics Bepridil has been safely used in diabetic patients without significantly lowering their blood glucose levels or altering their need for insulin or oral hypoglycemic agents General Interactions Certain drugs could increase the likelihood of potentially serious adverse effects with bepridil hydrochloride In general these are drugs that have one or more pharmacologic activities similar to bepridil hydrochloride including anti arrhythmic agents such as quinidine and procainamide cardiac glycosides and tricyclic anti depressants Anti arrhythmics and tricyclic anti depressants could exaggerate the prolongation of the QT interval observed with bepridil hydrochloride Cardiac glycosides could exaggerate the depression of AV nodal conduction observed with bepridil hydrochloride APRD00513 IN txt The following drugs have been coadministered with Kerlone and have not altered its pharmacokinetics cimetidine nifedipine chlorthalidone and hydrochlorothiazide Concomitant administration of Kerlone with the oral anticoagulant warfarin has been shown not to potentiate the anticoagulant effect of warfarin Catecholamine depleting drugs e g reserpine may have an additive effect when given with beta blocking agents Patients treated with a beta adrenergic receptor blocking agent plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia which may produce vertigo syncope or postural hypotension Should it be decided to discontinue therapy in patients receiving beta blockers and clonidine concurrently the beta blocker should be discontinued slowly over several days before the gradual withdrawal of clonidine Literature reports suggest that oral calcium antagonists may be used in combination with beta adrenergic blocking agents when heart function is normal but should be avoided in patients with impaired cardiac function Hypotension AV conduction disturbances and left ventricular failure have been reported in some patients receiving beta adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen Hypotension was more likely to occur if the calcium antagonist were a dihydropyridine derivative e g nifedipine while left ventricular failure and AV conduction disturbances including complete heart block were more likely to occur with either verapamil or diltiazem Risk of Anaphylactic Reaction Although it is known that patients on beta blockers may be refractory to epinephrine in the treatment of anaphylactic shock beta blockers can in addition interfere with the modulation of allergic reaction and lead to an increased severity and or frequency of attacks Severe allergic reactions including anaphylaxis have been reported in patients exposed to a variety of allergens either by repeated challenge or accidental contact and with diagnostic or therapeutic agents while receiving beta blockers Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction Special care is required if this drug is given to patients receiving ganglion blocking compounds because a critical fall in blood pressure may occur Usually severe abdominal symptoms appear before there is such a fall in the blood pressure No formal drug interaction studies with anti neoplastic agents have been conducted In Study 1 patients with colorectal cancer were given irinotecan 5 FU leucovorin bolus IFL with or without AVASTIN Irinotecan concentrations were similar in patients receiving bolus IFL alone and in combination with AVASTIN The concentrations of SN38 the active metabolite of irinotecan were on average 33 higher in patients receiving bolus IFL in combination with AVASTIN when compared with bolus IFL alone In Study 1 patients receiving bolus IFL plus AVASTIN had a higher incidence of Grade 3 4 diarrhea and neutropenia Due to high inter patient variability and limited sampling the extent of the increase in SN38 levels in patients receiving concurrent irinotecan and AVASTIN is uncertain No formal studies to evaluate drug interactions with bexarotene have been conducted Bexarotene oxidative metabolites appear to be formed by cytochrome P450 3A4 On the basis of the metabolism of bexarotene by cytochrome P450 3A4 ketoconazole itraconazole erythromycin gemfibrozil grapefruit juice and other inhibitors of cytochrome P450 3A4 would be expected to lead to an increase in plasma bexarotene concentrations Furthermore rifampin phenytoin phenobarbital and other inducers of cytochrome P450 3A4 may cause a reduction in plasma bexarotene concentrations Concomitant administration of Targretin capsules and gemfibrozil resulted in substantial increases in plasma concentrations of bexarotene probably at least partially related to cytochrome P450 3A4 inhibition by gemfibrozil Under similar conditions bexarotene concentrations were not affected by concomitant atorvastatin administration Concomitant administration of gemfibrozil with Targretin capsules is not recommended When Bezalip or Bezalip retard is used at the same time as other medicines or substances the following interactions must be taken into account Bezalip and Bezalip retard may enhance the action of anticoagulants of the coumarin type For this reason the dose of the anticoagulant should be reduced by 30 50 at the start of treatment with Bezalip or Bezalip retard and then titrated according to the blood clotting parameters The action of sulphonylureas and insulin may be enhanced by Bezalip or Bezalip retard This may be due to an improved glucose utilization with simultaneous reduction in insulin requirement In isolated cases a pronounced though reversible impairment of renal function accompanied by a corresponding increase in the serum creatinine level has been reported in organ transplant patients receiving immuno suppressant therapy and concomitant bezafibrate Accordingly renal function should be closely monitored in these patients and in the event of relevant significant changes in laboratory parameters bezafibrate should if necessary be discontinued When Bezalip or Bezalip retard is used concurrently with anion exchange resins e g cholestryramine an interval of at least 2 hours should be maintained between the two medicines since the absorption of Bezalip or Bezalip retard is impaired Perhexiline hydrogen maleate or MAO inhibitors with hepatotoxic potential must not be administered together with Bezalip or Bezalip retard In vitro studies have shown CASODEX can displace coumarin anticoagulants such as warfarin from their protein binding sites It is recommended that if CASODEX is started in patients already receiving coumarin anticoagulants prothrombin times should be closely monitored and adjustment of the anticoagulant dose may be necessary No Information Provided Drug Interactions The central anticholinergic syndrome can occur when anticholinergic agents such as AKINETON are administered concomitantly with drugs that have secondary anticholinergic actions e g certain narcotic analgesics such as meperidine the phenothiazines and other antipsychotics tricyclic antidepressants certain antiarrhythmics such as the quinidine salts and antihistamines ZEBETA should not be combined with other beta blocking agents Patients receiving catecholamine depleting drugs such as reserpine or guanethidine should be closely monitored because the added beta adrenergic blocking action of ZEBETA may produce excessive reduction of sympathetic activity In patients receiving concurrent therapy with clonidine if therapy is to be discontinued it is suggested that ZEBETA be discontinued for several days before the withdrawal of clonidine ZEBETA should be used with care when myocardial depressants or inhibitors of AV conduction such as certain calcium antagonists particularly of the phenylalkylamine verapamil and benzothiazepine diltiazem classes or antiarrhythmic agents such as disopyramide are used concurrently Concurrent use of rifampin increases the metabolic clearance of ZEBETA resulting in a shortened elimination half life of ZEBETA However initial dose modification is generally not necessary Pharmacokinetic studies document no clinically relevant interactions with other agents given concomitantly including thiazide diuretics digoxin and cimetidine There was no effect of ZEBETA on prothrombin time in patients on stable doses of warfarin Risk of Anaphylactic Reaction While taking beta blockers patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge either accidental diagnostic or therapeutic Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions Use of MAO inhibitors may cause an excessive increase in blood pressure and heart stimulation If you are also using a steroid inhaler take bitolterol first and then wait about 15 minutes before using the steroid inhaler This allows bitolterol to open air passages increasing the effectiveness of the steroid Angiomax does not exhibit binding to plasma proteins other than thrombin or red blood cells In clinical trials in patients undergoing PTCA PCI co administration of Angiomax with heparin warfarin thrombolytics or glycoprotein IIb IIIa inhibitors was associated with increased risks of major bleeding events compared to patients not receiving these concomitant medications There is no experience with co administration of Angiomax and plasma expanders such as dextran Angiomax should be used with caution in patients with disease states associated with an increased risk of bleeding Immunogenicity Re exposure In in vitro studies Angiomax exhibited no platelet aggregation response against sera from patients with a history of HIT HITTS Among 494 subjects who received Angiomax in clinical trials and were tested for antibodies 2 subjects had treatment emergent positive bivalirudin antibody tests Neither subject demonstrated clinical evidence of allergic or anaphylactic reactions and repeat testing was not performed Nine additional patients who had initial positive tests were negative on repeat testing Certain antibiotic cisplatin cyclosporine diuretic foscarnet and vaccines No formal drug interaction studies have been conducted with VELCADE In vitro studies with human liver microsomes indicate that bortezomib is primarily a substrate for cytochrome P450 3A4 2C19 and 1A2 Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy During clinical trials hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication Drug Laboratory Test Interactions None known Bosentan is metabolized by CYP2C9 and CYP3A4 Inhibition of these isoenzymes may increase the plasma concentration of bosentan Bosentan is an inducer of CYP3A4 and CYP2C9 Consequently plasma concentrations of drugs metabolized by these two isoenzymes will be decreased when TRACLEER is co administered Bosentan had no relevant inhibitory effect on any CYP isoenzymes tested CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 Consequently TRACLEER is not expected to increase the plasma concentrations of drugs metabolized by these enzymes Hormonal Contraceptives Including Oral Injectable Transdermal and Implantable Contraceptives An interaction study demonstrated that co administration of bosentan and the oral hormonal contraceptive Ortho Novum produced average decreases of norethindrone and ethinyl estradiol levels of 14 and 31 respectively However decreases in exposure were as much as 56 and 66 respectively in individual subjects Therefore hormonal contraceptives including oral injectable transdermal and implantable forms may not be reliable when TRACLEER is co administered Women should practice additional methods of contraception and not rely on hormonal contraception alone when taking TRACLEER Specific interaction studies have demonstrated the following Cyclosporine A During the first day of concomitant administration trough concentrations of bosentan were increased by about 30 fold Steady state bosentan plasma concentrations were 3 to 4 fold higher than in the absence of cyclosporine A The concomitant administration of bosentan and cyclosporine A is contraindicated Co administration of bosentan decreased the plasma concentrations of cyclosporine A a CYP3A4 substrate by approximately 50 Tacrolimus Co administration of tacrolimus and bosentan has not been studied in man Co administration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals Caution should be exercised if tacrolimus and bosentan are used together Glyburide An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant therapy with glyburide Therefore the concomitant administration of TRACLEER and glyburide is contraindicated and alternative hypoglycemic agents should be considered Co administration of bosentan decreased the plasma concentrations of glyburide by approximately 40 The plasma concentrations of bosentan were also decreased by approximately 30 Bosentan is also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by CYP2C9 or CYP3A4 The possibility of worsened glucose control in patients using these agents should be considered Ketoconazole Co administration of bosentan 125 mg b i d and ketoconazole a potent CYP3A4 inhibitor increased the plasma concentrations of bosentan by approximately 2 fold No dose adjustment of bosentan is necessary but increased effects of bosentan should be considered Simvastatin and Other Statins Co administration of bosentan decreased the plasma concentrations of simvastatin a CYP3A4 substrate and its active hydroxy acid metabolite by approximately 50 The plasma concentrations of bosentan were not affected Bosentan is also expected to reduce plasma concentrations of other statins that have significant metabolism by CYP3A4 such as lovastatin and atorvastatin The possibility of reduced statin efficacy should be considered Patients using CYP3A4 metabolized statins should have cholesterol levels monitored after TRACLEER is initiated to see whether the statin dose needs adjustment Warfarin Co administration of bosentan 500 mg b i d for 6 days decreased the plasma concentrations of both S warfarin a CYP2C9 substrate and R warfarin a CYP3A4 substrate by 29 and 38 respectively Clinical experience with concomitant administration of bosentan and warfarin in patients with pulmonary arterial hypertension did not show clinically relevant changes in INR or warfarin dose baseline vs end of the clinical studies and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan and placebo treated patients Digoxin Nimodipine and Losartan Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine and losartan has no significant effect on plasma levels of bosentan Co administration of BOTOX and aminoglycosides or other agents interfering with neuromuscular transmission e g curare like compounds should only be performed with caution as the effect of the toxin may be potentiated The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin Co administration of MYOBLOC and aminoglycosides or other agents interfering with neuromuscular transmission e g curare like compounds should only be performed with caution as the effect of the toxin may be potentiated The effect of administering different botulinum neurotoxin serotypes at the same time or within less than 4 months of each other is unknown However neuromuscular paralysis may be potentiated by co administration or overlapping administration of different botulinum toxin serotypes Digitalis toxicity may be aggravated by the initial release of norepinephrine caused by Bretylium Tosylate Injection The pressor effects of catecholamines such as dopamine or norepinephrine are enhanced by Bretylium Tosylate When catecholamines are administered dilute solutions should be used and blood pressure should be monitored closely Although there is little published information on concomitant administration of lidocaine and Bretylium Tosylate these drugs are often administered concurrently without any evidence of interactions resulting in adverse effects or diminished efficacy Although specific drug interaction studies have not been conducted with ALPHAGAN P the possibility of an additive or potentiating effect with CNS depressants alcohol barbiturates opiates sedatives or anesthetics should be considered Alpha agonists as a class may reduce pulse and blood pressure Caution in using concomitant drugs such as beta blockers ophthalmic and systemic anti hypertensives and or cardiac glycosides is advised Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine It is not known whether the concurrent use of these agents with ALPHAGAN P in humans can lead to resulting interference with the IOP lowering effect No data on the level of circulating catecholamines after ALPHAGAN P administration are available Caution however is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines AZOPT brinzolamide ophthalmic suspension 1 contains a carbonic anhydrase inhibitor Acid base and electrolyte alterations were not reported in the clinical trials with brinzolamide However in patients treated with oral carbonic anhydrase inhibitors rare instances of drug interactions have occurred with high dose salicylate therapy Therefore the potential for such drug interaction should be considered in patients receiving AZOPT brinzolamide ophthalmic suspension 1 The risk of using bromocriptine mesylate in combination with other drugs has not been systematically evaluated but alcohol may potentiate the side effects of bromocriptine mesylate Bromocriptine mesylate may interact with dopamine antagonists butyrophenones and certain other agents Compounds in these categories result in a decreased efficacy of bromocriptine mesylate phenothiazines haloperidol metoclopramide pimozide Concomitant use of bromocriptine mesylate with other ergot alkaloids is not recommended Dexbrompheniramine can interact with alcohol or other CNS depressants may potentiate the CNS depressant effects of either these medications or antihistamines anticholinergics or other medications with anticholinergic activity anticholinergic effects may be potentiated when these medications are used concurrently with antihistamines and monoamine oxidase MAO inhibitors concurrent use with antihistamines may prolong and intensify the anticholinergic and CNS depressant effects of antihistamines This drug may interact with alcohol or other CNS depressants may potentiate the CNS depressant effects of either these medications or antihistamines anticholinergics or other medications with anticholinergic activity anticholinergic effects may be potentiated when these medications are used concurrently with antihistamines and monoamine oxidase MAO inhibitors concurrent use with antihistamines may prolong and intensify the anticholinergic and CNS depressant effects of antihistamines Concomitant oral administration of ketoconazole a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa caused an eight fold increase of the systemic exposure to oral budesonide If treatment with inhibitors of CYP3A4 activity such as ketoconazole intraconazole ritonavir indinavir saquinavir erythromycin etc is indicated reduction of the budesonide dose should be considered After extensive intake of grapefruit juice which inhibits CYP3A4 activity predominantly in the intestinal mucosa the systemic exposure for oral budesonide increased about two times As with other drugs primarily being metabolized through CYP3A4 ingestion of grapefruit or grapefruit juice should be avoided in connection with budesonide administration Drugs with ototoxic potential Especially in the presence of impaired renal function the use of parenterally administered bumetanide in patients to whom aminoglycoside antibiotics are also being given should be avoided except in life threatening conditions Drugs with nephrotoxic potential There has been no experience on the concurrent use of bumetanide with drugs known to have a nephrotoxic potential Therefore the simultaneous administration of these drugs should be avoided Lithium Lithium should generally not be given with diuretics such as bumetanide because they reduce its renal clearance and add a high risk of lithium toxicity Probenecid Pretreatment with probenecid reduces both the natriuresis and hyperreninemia produced by bumetanide This antagonistic effect of probenecid on bumetanide natriuresis is not due to a direct action on sodium excretion but is probably secondary to its inhibitory effect on renal tubular secretion of bumetanide Thus probenecid should not be administered concurrently with bumetanide Indomethacin Indomethacin blunts the increases in urine volume and sodium excretion seen during bumetanide treatment and inhibits the bumetanide induced increase in plasma renin activity Concurrent therapy with bumetanide is thus not recommended Antihypertensives Bumetanide may potentiate the effect of various antihypertensive drugs necessitating a reduction in the dosage of these drugs Digoxin Interaction studies in humans have shown no effect on digoxin blood levels Anticoagulants Interaction studies in humans have shown bumetanide to have no effect on warfarin metabolism or on plasma prothrombin activity The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe prolonged hypertension Concurrent use of these agents should generally be avoided In situations in which concurrent therapy is necessary careful patient monitoring is essential Concurrent administration of vasopressor drugs and of ergot type oxytocic drugs may cause severe persistent hypertension or cerebrovascular accidents Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine Buprenorphine is metabolized to norbuprenorphine by cytochrome CYP 3A4 Because CYP 3A4 inhibitors may increase plasma concentrations of buprenorphine patients already on CYP 3A4 inhibitors such as azole antifungals e g ketoconazole macrolide antibiotics e g erythromycin and HIV protease inhibitors e g ritonavir indinavir and saquinavir should have their dose of SUBUTEX or SUBOXONE adjusted Based on anecdotal reports there may be an interaction between buprenorphine and benzodiazepines There have been a number of reports in the post marketing experience of coma and death associated with the concomitant intravenous misuse of buprenorphine and benzodiazepines by addicts In many of these cases buprenorphine was misused by self injection of crushed SUBUTEX tablets SUBUTEX and SUBOXONE should be prescribed with caution to patients on benzodiazepines or other drugs that act on the central nervous system regardless of whether these drugs are taken on the advice of a physician or are taken as drugs of abuse Patients should be warned of the potential danger of the intravenous self administration of benzodiazepines while under treatment with SUBOXONE or SUBUTEX Few systemic data have been collected on the metabolism of WELLBUTRIN following concomitant administration with other drugs or alternatively the effect of concomitant administration of WELLBUTRIN on the metabolism of other drugs Because bupropion is extensively metabolized the coadministration of other drugs may affect its clinical activity In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme Therefore the potential exists for a drug interaction between WELLBUTRIN and drugs that affect the CYP2B6 isoenzyme e g orphenadrine and cyclophosphamide The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers Following oral administration of two 150 mg sustained release tablets with and without 800 mg of cimetidine the pharmacokinetics of bupropion and hydroxybupropion were unaffected However there were 16 and 32 increases in the AUC and Cmax respectively of the combined moieties of threohydrobupropion and erythrohydrobupropion While not systematically studied certain drugs may induce the metabolism of bupropion e g carbamazepine phenobarbital phenytoin Animal data indicated that bupropion may be an inducer of drug metabolizing enzymes in humans In one study following chronic administration of bupropion 100 mg 3 times daily to 8 healthy male volunteers for 14 days there was no evidence of induction of its own metabolism Nevertheless there may be the potential for clinically important alterations of blood levels of coadministered drugs Drugs Metabolized by Cytochrome P450IID6 CYP2D6 Many drugs including most antidepressants SSRIs many tricyclics beta blockers antiarrhythmics and antipsychotics are metabolized by the CYP2D6 isoenzyme Although bupropion is not metabolized by this isoenzyme bupropion and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme in vitro In a study of 15 male subjects ages 19 to 35 years who were extensive metabolizers of the CYP2D6 isoenzyme daily doses of bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the Cmax AUC and t1 2 of desipramine by an average of approximately 2 5 and 2 fold respectively The effect was present for at least 7 days after the last dose of bupropion Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied Therefore co administration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including certain antidepressants e g nortriptyline imipramine desipramine paroxetine fluoxetine sertraline antipsychotics e g haloperidol risperidone thioridazine beta blockers e g metoprolol and Type 1C antiarrhythmics e g propafenone flecainide should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6 the need to decrease the dose of the original medication should be considered particularly for those concomitant medications with a narrow therapeutic index MAO Inhibitors Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine Levodopa and Amantadine Limited clinical data suggest a higher incidence of adverse experiences in patients receiving bupropion concurrently with either levodopa or amantadine Administration of WELLBUTRIN Tablets to patients receiving either levodopa or amantadine concurrently should be undertaken with caution using small initial doses and small gradual dose increases Drugs that Lower Seizure Threshold Concurrent administration of WELLBUTRIN and agents e g antipsychotics other antidepressants theophylline systemic steroids etc that lower seizure threshold should be undertaken only with extreme caution Low initial dosing and small gradual dose increases should be employed Nicotine Transdermal System Alcohol In post marketing experience there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with WELLBUTRIN The consumption of alcohol during treatment with WELLBUTRIN should be minimized or avoided also see a href bupropz od htm CI CONTRAINDICATIONS It is recommended that buspirone hydrochloride not be used concomitantly with MAO inhibitors Because the effects of concomitant administration of buspirone HCl with most other psychotropic drugs have not been studied the concomitant use of buspirone HCl with other CNS active drugs should be approached with caution There is one report suggesting that the concomitant use of trazodone hydrochloride Desyrel and buspirone HCl may have caused 3 to 6 fold elevations on SGPT ALT in a few patients In a similar study attempting to replicate this finding no interactive effect on hepatic transaminases was identified In a study in normal volunteers concomitant administration of buspirone HCl and haloperidol resulted in increased serum haloperidol concentrations The clinical significance of this finding is not clear In vitro buspirone does not displace tightly bound drugs like phenytoin propranolol and warfarin from serum proteins However there has been one report of prolonged prothrombin time when buspirone was added to the regimen of a patient treated with warfarin The patient was also chronically receiving phenytoin phenobarbital digoxin and levothyroxine sodium In vitro buspirone may displace less firmly bound drugs like digoxin The clinical significance of this property is unknown Itraconazole decreases busulfan clearance by up to 25 and may produce AUCs 1500 M min in some patients Fluconazole and the 5 HT3 antiemetics ondansetron Zofran and granisetron Kytril have all been used with BUSULFEX Phenytoin increases the clearance of busulfan by 15 or more possibly due to the induction of glutathione S transferase Since the pharmacokinetics of BUSULFEX were studied in patients treated with phenytoin the clearance of BUSULFEX at the recommended dose may be lower and exposure AUC higher in patients not treated with phenytoin Because busulfan is eliminated from the body via conjugation with glutathione use of acetaminophen prior to 72 hours or concurrent with BUSULFEX may result in reduced busulfan clearance based upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues Interactions may occur with the following adrenocorticoids cortisone like medicine anticoagulants blood thinners carbamazepine corticotropin barbiturates may decrease the effects of these medicines central nervous system CNS depressants using these medicines with barbiturates may result in increased CNS depressant effects divalproex sodium valproic acid using these medicines with barbiturates may change the amount of either medicine that you need to take and oral contraceptives containing estrogens barbiturates may decrease the effectiveness of these oral contraceptives and you may need to change to a different type of birth control The CNS effects of butalbital may be enhanced by monoamine oxidase MAO inhibitors Butalbital acetaminophen and caffeine may enhance the effects of other narcotic analgesics alcohol general anesthetics tranquilizers such as chlordiazepoxide sedative hypnotics or other CNS depressants causing increased CNS depression Drug Laboratory Test Interactions Acetaminophen may produce false positive test results for urinary 5 hydroxyindoleacetic acid Potential drug interactions between Mentax butenafine HCl cream Cream 1 and other drugs have not been systematically evaluated Concurrent use of butorphanol with central nervous system depressants e g alcohol barbiturates tranquilizers and antihistamines may result in increased central nervous system depressant effects When used concurrently with such drugs the dose of butorphanol should be the smallest effective dose and the frequency of dosing reduced as much as possible when administered concomitantly with drugs that potentiate the action of opioids In healthy volunteers the pharmacokinetics of a 1 mg dose of butorphanol administered as STADOL NS were not affected by the coadministration of a single 6 mg subcutaneous dose of sumatriptan However in another study in healthy volunteers the pharmacokinetics of butorphanol were significantly altered 29 decrease in AUC and 38 decrease in Cmax when a 1 mg dose of STADOL NS was administered 1 minute after a 20 mg dose of sumatriptan nasal spray The two drugs were administered in opposite nostrils When the STADOL NS was administered 30 minutes after the sumatriptan nasal spray the AUC of butorphanol increased 11 and Cmax decreased 18 In neither case were the pharmacokinetics of sumatriptan affected by coadministration with STADOL NS These results suggest that the analgesic effect of STADOL NS may be diminished when it is administered shortly after sumatriptan nasal spray but by 30 minutes any such reduction in effect should be minimal The safety of using STADOL NS and IMITREX sumatriptan Nasal Spray during the same episode of migraine has not been established However it should be noted that both products are capable of producing transient increases in blood pressure The pharmacokinetics of a 1 mg dose of butorphanol administered as STADOL NS were not affected by the coadministration of cimetidine 300 mg QID Conversely the administration of STADOL NS 1 mg butorphanol QID did not alter the pharmacokinetics of a 300 mg dose of cimetidine It is not known if the effects of butorphanol are altered by concomitant medications that affect hepatic metabolism of drugs erythromycin etc but physicians should be alert to the possibility that a smaller initial dose and longer intervals between doses may be needed The fraction of STADOL NS absorbed is unaffected by the concomitant administration of a nasal vasoconstrictor oxymetazoline but the rate of absorption is decreased Therefore a slower onset can be anticipated if STADOL NS is administered concomitantly with or immediately following a nasal vasoconstrictor No information is available about the use of butorphanol concurrently with MAO inhibitors DOSTINEX should not be administered concurrently with D2 antagonists such as phenothiazines butyrophenones thioxanthines or metoclopramide Cytochrome P450 1A2 CYP1A2 is known to be the major enzyme involved in the metabolism of caffeine Therefore caffeine has the potential to interact with drugs that are substrates for CYP1A2 inhibit CYP1A2 or induce CYP1A2 Few data exist on drug interactions with caffeine in preterm neonates Based on adult data lower doses of caffeine may be needed following coadministration of drugs which are reported to decrease caffeine elimination e g cimetidine and ketoconazole and higher caffeine doses may be needed following coadministration of drugs that increase caffeine elimination e g phenobarbital and phenytoin Caffeine administered concurrently with ketoprofen reduced the urine volume in 4 healthy volunteers The clinical significance of this interaction in preterm neonates is not known Interconversion between caffeine and theophylline has been reported in preterm neonates The concurrent use of these drugs is not recommended Interactions for vitamin D analogues Vitamin D2 Vitamin D3 Calcitriol and Calcidiol Cholestyramine Cholestyramine has been reported to reduce intestinal absorption of fat soluble vitamins as such it may impair intestinal absorption of any of vitamin D Phenytoin Phenobarbital The coadministration of phenytoin or phenobarbital will not affect plasma concentrations of vitamin D but may reduce endogenous plasma levels of calcitriol ergocalcitriol by accelerating metabolism Since blood level of calcitriol ergocalcitriol will be reduced higher doses of Rocaltrol may be necessary if these drugs are administered simultaneously Thiazides Thiazides are known to induce hypercalcemia by the reduction of calcium excretion in urine Some reports have shown that the concomitant administration of thiazides with vitamin D causes hypercalcemia Therefore precaution should be taken when coadministration is necessary Digitalis Vitamin D dosage must be determined with care in patients undergoing treatment with digitalis as hypercalcemia in such patients may precipitate cardiac arrhythmias Ketoconazole Ketoconazole may inhibit both synthetic and catabolic enzymes of vitamin D Reductions in serum endogenous vitamin D concentrations have been observed following the administration of 300 mg day to 1200 mg day ketoconazole for a week to healthy men However in vivo drug interaction studies of ketoconazole with vitamin D have not been investigated Corticosteroids A relationship of functional antagonism exists between vitamin D analogues which promote calcium absorption and corticosteroids which inhibit calcium absorption Phosphate Binding Agents Since vitamin D also has an effect on phosphate transport in the intestine kidneys and bones the dosage of phosphate binding agents must be adjusted in accordance with the serum phosphate concentration Vitamin D The coadministration of any of the vitamin D analogues should be avoided as this could create possible additive effects and hypercalcemia Calcium Supplements Uncontrolled intake of additional calcium containing preparations should be avoided Magnesium Magnesium containing preparations eg antacids may cause hypermagnesemia and should therefore not be taken during therapy with vitamin D by patients on chronic renal dialysis Interactions for vitamin D analogues Vitamin D2 Vitamin D3 Calcitriol and Calcidiol Cholestyramine Cholestyramine has been reported to reduce intestinal absorption of fat soluble vitamins as such it may impair intestinal absorption of any of vitamin D Phenytoin Phenobarbital The coadministration of phenytoin or phenobarbital will not affect plasma concentrations of vitamin D but may reduce endogenous plasma levels of calcitriol ergocalcitriol by accelerating metabolism Since blood level of calcitriol ergocalcitriol will be reduced higher doses of Rocaltrol may be necessary if these drugs are administered simultaneously Thiazides Thiazides are known to induce hypercalcemia by the reduction of calcium excretion in urine Some reports have shown that the concomitant administration of thiazides with vitamin D causes hypercalcemia Therefore precaution should be taken when coadministration is necessary Digitalis Vitamin D dosage must be determined with care in patients undergoing treatment with digitalis as hypercalcemia in such patients may precipitate cardiac arrhythmias Ketoconazole Ketoconazole may inhibit both synthetic and catabolic enzymes of vitamin D Reductions in serum endogenous vitamin D concentrations have been observed following the administration of 300 mg day to 1200 mg day ketoconazole for a week to healthy men However in vivo drug interaction studies of ketoconazole with vitamin D have not been investigated Corticosteroids A relationship of functional antagonism exists between vitamin D analogues which promote calcium absorption and corticosteroids which inhibit calcium absorption Phosphate Binding Agents Since vitamin D also has an effect on phosphate transport in the intestine kidneys and bones the dosage of phosphate binding agents must be adjusted in accordance with the serum phosphate concentration Vitamin D The coadministration of any of the vitamin D analogues should be avoided as this could create possible additive effects and hypercalcemia Calcium Supplements Uncontrolled intake of additional calcium containing preparations should be avoided Magnesium Magnesium containing preparations eg antacids may cause hypermagnesemia and should therefore not be taken during therapy with vitamin D by patients on chronic renal dialysis Concomitant use with other calcium containing medicines including antacids may cause too much calcium in the blood or urine which may increase the chance of side effects Using calcium acetate with digitalis glycosides heart medicine may cause hypercalcemia too much calcium in the blood which could increase the chance of developing an irregular heartbeat May interact with cefamandole naftate cephalothin sodium magnesium sulfate prednisolone sodium succinate and prochlorperazine edisylate No significant drug interactions have been reported in studies of candesartan cilexetil given with other drugs such as glyburide nifedipine digoxin warfarin hydrochlorothiazide and oral contraceptives in healthy volunteers or given with enalapril to patients with heart failure NYHA class II and III Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes interactions with drugs that inhibit or are metabolized by those enzymes would not be expected Lithium Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors and with some angiotensin II receptor antagonists An increase in serum lithium concentration has been reported during concomitant administration of lithium with ATACAND so careful monitoring of serum lithium levels is recommended during concomitant use Antacid The effect of an aluminum hydroxide and magnesium hydroxide containing antacid Maalox on the pharmacokinetics of capecitabine was investigated in 12 cancer patients There was a small increase in plasma concentrations of capecitabine and one metabolite 5 DFCR there was no effect on the 3 major metabolites 5 DFUR 5 FU and FBAL Coumarin Anticoagulants Altered coagulation parameters and or bleeding have been reported in patients taking capecitabine concomitantly with coumarin derivative anticoagulants such as warfarin and phenprocoumon Patients taking coumarin derivative anticoagulants concomitantly with capecitabine should be monitored regularly for alterations in their coagulation parameters PT or INR Leucovorin The concentration of 5 fluorouracil is increased and its toxicity may be enhanced by leucovorin Deaths from severe enterocolitis diarrhea and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil Hypotension Patients on Diuretic Therapy Patients on diuretics and especially those in whom diuretic therapy was recently instituted as well as those on severe dietary salt restriction or dialysis may occasionally experience a precipitous reduction of blood pressure usually within the first hour after receiving the initial dose of captopril The possibility of hypotensive effects with captopril can be minimized by either discontinuing the diuretic or increasing the salt intake approximately one week prior to initiation of treatment with captopril captopril tablets USP or initiating therapy with small doses 6 25 or 12 5 mg Alternatively provide medical supervision for at least one hour after the initial dose If hypotension occurs the patient should be placed in a supine position and if necessary receive an intravenous infusion of normal saline This transient hypotensive response is not a contraindication to further doses which can be given without difficulty once the blood pressure has increased after volume expansion Agents Having Vasodilator Activity Data on the effect of concomitant use of other vasodilators in patients receiving captopril for heart failure are not available therefore nitroglycerin or other nitrates as used for management of angina or other drugs having vasodilator activity should if possible be discontinued before starting captopril If resumed during captopril therapy such agents should be administered cautiously and perhaps at lower dosage Agents Causing Renin Release Captopril s effect will be augmented by antihypertensive agents that cause renin release For example diuretics e g thiazides may activate the renin angiotensin aldosterone system Agents Affecting Sympathetic Activity The sympathetic nervous system may be especially important in supporting blood pressure in patients receiving captopril alone or with diuretics Therefore agents affecting sympathetic activity e g ganglionic blocking agents or adrenergic neuron blocking agents should be used with caution Beta adrenergic blocking drugs add some further antihypertensive effect to captopril but the overall response is less than additive Agents Increasing Serum Potassium Since captopril decreases aldosterone production elevation of serum potassium may occur Potassium sparing diuretics such as spironolactone triamterene or amiloride or potassium supplements should be given only for documented hypokalemia and then with caution since they may lead to a significant increase of serum potassium Salt substitutes containing potassium should also be used with caution Inhibitors Of Endogenous Prostaglandin Synthesis It has been reported that indomethacin may reduce the antihypertensive effect of captopril especially in cases of low renin hypertension Other nonsteroidal anti inflammatory agents e g aspirin may also have this effect Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy These drugs should be coad ministered with caution and frequent monitoring of serum lithium levels is recommended If a diuretic is also used it may increase the risk of lithium toxicity Cardiac Glycosides In a study of young healthy male subjects no evidence of a direct pharmacokinetic captopril digoxin interaction could be found Loop Diuretics Furosemide administered concurrently with captopril does not alter the pharmacokinetics of captopril in renally impaired hypertensive patients Allopurinol In a study of healthy male volunteers no significant pharmacokinetic interaction occurred when captopril and allopurinol were administered concomitantly for 6 days Drug Laboratory Test Interaction Captopril may cause a false positive urine test for acetone Clinically meaningful drug interactions have occurred with concomitant medications and include but are not limited to the following Agents Highly Bound to Plasma Protein Carbamazepine is not highly bound to plasma proteins therefore administration of EQUETROTM to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug Agents that Inhibit Cytochrome P450 Isoenzymes and or Epoxide Hydrolase Carbamazepine is metabolized mainly by cytochrome P450 CYP 3A4 to the active carbamazepine 10 11 epoxide which is further metabolized to the trans diol by epoxide hydrolase Therefore the potential exists for interaction between carbamazepine and any agent that inhibits CYP3A4 and or epoxide hydrolase Agents that are CYP3A4 inhibitors that have been found or are expected to increase plasma levels of EQUETROTM are the following Acetazolamide azole antifungals cimetidine clarithromycin 1 dalfopristin danazol delavirdine diltiazem erythromycin 1 fluoxetine fluvoxamine grapefruit juice isoniazid itraconazole ketoconazole loratadine nefazodone niacinamide nicotinamide protease inhibitors propoxyphene quinine quinupristin troleandomycin valproate 1 verapamil zileuton Thus if a patient has been titrated to a stable dosage of EQUETROTM and then begins a course of treatment with one of these CYP3A4 or epoxide hydrolase inhibitors it is reasonable to expect that a dose reduction for EQUETROTM may be necessary Agents that Induce Cytochrome P450 Isoenzymes Carbamazepine is metabolized by CYP3A4 Therefore the potential exists for interaction between carbamazepine and any agent that induces CYP3A4 Agents that are CYP inducers that have been found or are expected to decrease plasma levels of EQUETROTM are the following Cisplatin doxorubicin HCL felbamate rifampin phenobarbital Phenytoin 2 primidone methsuximide and theophylline Thus if a patient has been titrated to a stable dosage on EQUETROTM and then begins a course of treatment with one of these CYP3A4 inducers it is reasonable to expect that a dose increase for EQUETROTM may be necessary Agents with Decreased Levels in the Presence of Carbamazepine due to Induction of Cytochrome P450 Enzymes Carbamazepine is known to induce CYP1A2 and CYP3A4 Therefore the potential exists for interaction between carbamazepine and any agent metabolized by one or more of these enzymes Agents that have been found or are expected to have decreased plasma levels in the presence of EQUETROTM due to induction of CYP enzymes are the following Acetaminophen alprazolam amitriptyline bupropion buspirone citalopram clobazam clonazepam clozapine cyclosporin delavirdine desipramine diazepam dicumarol doxycycline ethosuximide felbamate felodipine glucocorticoids haloperidol itraconazole lamotrigine levothyroxine lorazepam methadone midazolam mirtazapine nortriptyline olanzapine oral contraceptives 3 oxcarbazepine Phenytoin 4 praziquantel protease inhibitors quetiapine risperidone theophylline topiramate tiagabine tramadol triazolam valproate warfarin 5 ziprasidone and zonisamide Thus if a patient has been titrated to a stable dosage on one of the agents in this category and then begins a course of treatment with EQUETROTM it is reasonable to expect that a dose increase for the concomitant agent may be necessary Agents with Increased Levels in the Presence of Carbamazepine EQUETROTM increases the plasma levels of the following agents Clomipramine HCl Phenytoin 6 and primidone Thus if a patient has been titrated to a stable dosage on one of the agents in this category and then begins a course of the treatment with EQUETROTM it is reasonable to expect that a dose decrease for the concomitant agent may be necessary Pharmacological Pharmacodynamic Interactions with Carbamazepine Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects Given the anticonvulsant properties of carbamazepine EQUETROTM may reduce the thyroid function as has been reported with other anticonvulsants Additionally anti malarial drugs such as chloroquine and mefloquine may antagonize the activity of carbamazepine Thus if a patient has been titrated to a stable dosage on one of the agents in this category and then begins a course of treatment with EQUETROTM it is reasonable to expect that a dose adjustment may be necessary Because of its primary CNS effect caution should be used when EQUETROTM is taken with other centrally acting drugs and alcohol Geocillin carbenicillin indanyl sodium blood levels may be increased and prolonged by concurrent administration of probenecid Caution should be exercised when the following drugs are administered concomitantly with LODOSYN Carbidopa given with levodopa or carbidopa levodopa combination products For patients receiving monoamine oxidase inhibitors see CONTRAINDICATIONS Dopamine D2 receptor antagonists e g phenothiazines butyrophenones risperidone and isoniazid may reduce the therapeutic effects of levodopa In addition the beneficial effects of levodopa in Parkinsons disease have been reported to be reversed by phenytoin and papaverine Patients taking these drugs with LODOSYN and levodopa or carbidopa levodopa combination products should be carefully observed for loss of therapeutic response Iron salts may reduce the bioavailability of carbidopa and levodopa The clinical relevance is unclear Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties Iodine or iodine excess may decrease the effect of Carbimazole and an iodine deficiency can increase the effect of Carbimazole Serum concentration of digoxin and digitoxin may increase when patients take antithyroid agents A decrease of the dosage may be necessary when patient becomes euthyroid Antithyroid agents may decrease thyroidal uptake of sodium iodide I131 a rebound in uptake may occur up to 5 days after sudden withdrawal of Carbimazole Patients response to oral anticoagulants may be affected by his her thyroid and metabolic status An evaluation of prothrombin time and an adjustment of anticoagulant dosage are recommended Antihistamines may enhance the effects of tricyclic antidepressants barbiturates alcohol and other CNS depressants MAO inhibitors prolong and intensify the anticholinergic effects of antihistamines Sympathomimetic amines may reduce the antihypertensive effects of reserpine veratrum alkaloids methyldopa and mecamylamine Effects of sympathomimetics are increased with MAO inhibitors and beta adrenergic blockers The renal effects of nephrotoxic compounds may be potentiated by Carboplatin HEMABATE may augment the activity of other oxytocic agents Concomitant use with other oxytocic agents is not recommended Ocupress should be used with caution in patients who are receiving a beta adrenergic blocking agent orally because of the potential for additive effects on systemic beta blockade Close observation of the patient is recommended when a beta blocker is administered to patients receiving catecholamine depleting drugs such as reserpine because of possible additive effects and the production of hypotension and or marked bradycardia which may produce vertigo syncope or postural hypotension Inhibitors of CYP2D6 poor metabolizers of debrisoquin Interactions of carvedilol with strong inhibitors of CYP2D6 such as quinidine fluoxetine paroxetine and propafenone have not been studied but these drugs would be expected to increase blood levels of the R enantiomer of carvedilol Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up titration presumably resulting from vasodilating effects of the higher concentrations of the a blocking R enantiomer Catecholamine depleting Agents Patients taking both agents with b blocking properties and a drug that can deplete catecholamines e g reserpine and monoamine oxidase inhibitors should be observed closely for signs of hypotension and or severe bradycardia Clonidine Concomitant administration of clonidine with agents with b blocking properties may potentiate blood pressure and heart rate lowering effects When concomitant treatment with agents with b blocking properties and clonidine is to be terminated the b blocking agent should be discontinued first Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage Cyclosporine Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection In about 30 of patients the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range while in the remainder no adjustment was needed On the average for the group the dose of cyclosporine was reduced about 20 in these patients Due to wide interindividual variability in the dose adjustment required it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate Digoxin Digoxin concentrations are increased by about 15 when digoxin and carvedilol are administered concomitantly Both digoxin and COREG slow AV conduction Therefore increased monitoring of digoxin is recommended when initiating adjusting or discontinuing COREG Inducers and Inhibitors of Hepatic Metabolism Rifampin reduced plasma concentrations of carvedilol by about 70 Cimetidine increased AUC by about 30 but caused no change in Cmax Calcium Channel Blockers Isolated cases of conduction disturbance rarely with hemodynamic compromise have been observed when COREG is co administered with diltiazem As with other agents with b blocking properties if COREG is to be administered orally with calcium channel blockers of the verapamil or diltiazem type it is recommended that ECG and blood pressure be monitored Insulin or Oral Hypoglycemics Agents with b blocking properties may enhance the blood sugar reducing effect of insulin and oral hypoglycemics Therefore in patients taking insulin or oral hypoglycemics regular monitoring of blood glucose is recommended Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P450 CYP system In clinical studies caspofungin did not induce the CYP3A4 metabolism of other drugs Caspofungin is not a substrate for P glycoprotein and is a poor substrate for cytochrome P450 enzymes Clinical studies in healthy volunteers show that the pharmacokinetics of CANCIDAS are not altered by itraconazole amphotericin B mycophenolate nelfinavir or tacrolimus CANCIDAS has no effect on the pharmacokinetics of itraconazole amphotericin B or the active metabolite of mycophenolate CANCIDAS reduced the blood AUC0 12 of tacrolimus by approximately 20 peak blood concentration Cmax by 16 and 12 hour blood concentration C12hr by 26 in healthy subjects when tacrolimus 2 doses of 0 1 mg kg 12 hours apart was administered on the 10th day of CANCIDAS 70 mg daily as compared to results from a control period in which tacrolimus was administered alone For patients receiving both therapies standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended In two clinical studies cyclosporine one 4 mg kg dose or two 3 mg kg doses increased the AUC of caspofungin by approximately 35 CANCIDAS did not increase the plasma levels of cyclosporine There were transient increases in liver ALT and AST when CANCIDAS and cyclosporine were co administered A drug drug interaction study with rifampin in healthy volunteers has shown a 30 decrease in caspofungin trough concentrations Patients on rifampin should receive 70 mg of CANCIDAS daily In addition results from regression analyses of patient pharmacokinetic data suggest that co administration of other inducers of drug clearance efavirenz nevirapine phenytoin dexamethasone or carbamazepine with CANCIDAS may result in clinically meaningful reductions in caspofungin concentrations It is not known which drug clearance mechanism involved in caspofungin disposition may be inducible When CANCIDAS is co administered with inducers of drug clearance such as efavirenz nevirapine phenytoin dexamethasone or carbamazepine use of a daily dose of 70 mg of CANCIDAS should be considered Drug Laboratory Test Interactions Positive direct Coombs tests have been reported during treatment with the cephalosporin antibiotics In hematologic studies or in transfusion cross matching procedures when anti globulin tests are performed on the minor side or in Coombs testing of newborns whose mothers have received cephalosporin antibiotics before parturition it should be recognized that a positive Coombs test may be due to the drug Probenecid may decrease renal tubular secretion of cephalosporins when used concurrently resulting in increased and more prolonged cephalosporin blood levels Drug Laboratory Test Interactions A false positive reaction for glucose in the urine may occur with Benedicts solution Fehlings solution or with CLINITEST tablets but not with enzyme based tests such as CLINISTIX Positive direct and indirect antiglobulin Coombs tests have occurred these may also occur in neonates whose mothers received cephalosporins before delivery Antacids aluminum or magnesium containing Concomitant administration of 300 mg cefdinir capsules with 30 mL Maalox TC suspension reduces the rate Cmax and extent AUC of absorption by approximately 40 Time to reach Cmax is also prolonged by 1 hour There are no significant effects on cefdinir pharmacokinetics if the antacid is administered 2 hours before or 2 hours after cefdinir If antacids are required during OMNICEF therapy OMNICEF should be taken at least 2 hours before or after the antacid Probenecid As with other b lactam antibiotics probenecid inhibits the renal excretion of cefdinir resulting in an approximate doubling in A C a 54 increase in peak cefdinir plasma levels and a 50 prolongation in the apparent elimination half life Iron Supplements and Foods Fortified With Iron Concomitant administration of cefdinir with a therapeutic iron supplement containing 60 mg of elemental iron as FeSO4 or vitamins supplemented with 10 mg of elemental iron reduced extent of absorption by 80 and 31 respectively If iron supplements are required during OMNICEF therapy OMNICEF should be taken at least 2 hours before or after the supplement The effect of foods highly fortified with elemental iron primarily iron fortified breakfast cereals on cefdinir absorption has not been studied Concomitantly administered iron fortified infant formula 2 2 mg elemental iron 6 oz has no significant effect on cefdinir pharmacokinetics Therefore OMNICEF for Oral Suspension can be administered with iron fortified infant formula There have been rare reports of reddish stools in patients who have received cefdinir in Japan The reddish color is due to the formation of a nonabsorbable complex between cefdinir or its breakdown products and iron in the gastrointestinal tract Drug Laboratory Test Interactions A false positive reaction for ketones in the urine may occur with tests using nitroprusside but not with those using nitroferricyanide The administration of cefdinir may result in a false positive reaction for glucose in urine using Clinitest Benedict s solution or Fehlings solution It is recommended that glucose tests based on enzymatic glucose oxidase reactions such as Clinistix or Tes Tape be used Cephalosporins are known to occasionally induce a positive direct Coombs test Oral Contraceptives Multiple doses of cefditoren pivoxil had no effect on the pharmacokinetics of ethinyl estradiol the estrogenic component in most oral contraceptives Although the clinical significance is not known it is not recommended that cefditoren pivoxil be taken concomitantly with antacids H2 Receptor Antagonists Co administration of a single dose of intravenously administered famotidine 20 mg reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered following a meal as evidenced by a 27 decrease in mean Cmax and a 22 decrease in mean AUC Although the clinical significance is not known it is not recommended that cefditoren pivoxil be taken concomitantly with H2 receptor antagonists Probenecid As with other b lactam antibiotics co administration of probenecid with cefditoren pivoxil resulted in an increase in the plasma exposure of cefditoren with a 49 increase in mean Cmax a 122 increase in mean AUC and a 53 increase in half life Drug Laboratory Test Interactions Cephalosporins are known to occasionally induce a positive direct Coombs test A false positive reaction for glucose in the urine may occur with copper reduction tests Benedicts or Fehlings solution or with CLINITEST tablets but not with enzyme based tests for glycosuria e g CLINISTIX TES TAPE As a false negative result may occur in the ferricyanide test it is recommended that either the glucose oxidase or hexokinase method be used to determine blood plasma glucose levels in patients receiving cefditoren pivoxil Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with MAXIPIME because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibiotics Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide Drug Laboratory Test Interactions The administration of cefepime may result in a false positive reaction for glucose in the urine when using Clinitest tablets It is recommended that glucose tests based on enzymatic glucose oxidase reactions such as Clinistix or Tes Tape be used Carbamazepine Elevated carbamazepine levels have been reported in postmarketing experience when SUPRAX is administered concomitantly Drug monitoring may be of assistance in detecting alterations in carbamazepine plasma concentrations Warfarin and Anticoagulants Increased prothrombin time with or without clinical bleeding has been reported when cefixime is administered concomitantly Drug Laboratory Test Interactions A false positive reaction for ketones in the urine may occur with tests using nitroprusside but not with those using nitroferricyanide The administration of SUPRAX may result in a false positive reaction for glucose in the urine using Clinitest Benedict s solution or Fehling s solution It is recommended that glucose tests based on enzymatic glucose oxidase reactions such as Clinistix or Tes Tape be used A false positive direct Coombs test has been reported during treatment with other cephalosporin antibiotics therefore it should be recognized that a positive Coombs test may be due to the drug Increased nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics Drug Laboratory Test Interactions Cephalosporins including cefotaxime sodium are known to occasionally induce a positive direct Coombs test Increases in serum creatinine have occurred when CEFOTAN was given alone If CEFOTAN and an aminoglycoside are used concomitantly renal function should be carefully monitored because nephrotoxicity may be potentiated Drug Laboratory Test Interactions The administration of CEFOTAN may result in a false positive reaction for glucose in the urine using Clinitest Benedicts solution or Fehlings solution It is recommended that glucose tests based on enzymatic glucose oxidase be used As with other cephalosporins high concentrations of cefotetan may interfere with measurement of serum and urine creatinine levels by Jaffe reaction and produce false increases in the levels of creatinine reported Increased nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics Drug Laboratory Test Interactions As with cephalothin high concentrations of cefoxitin 100 micrograms mL may interfere with measurement of serum and urine creatinine levels by the Jaff reaction and produce false increases of modest degree in the levels of creatinine reported Serum samples from patients treated with cefoxitin should not be analyzed for creatinine if withdrawn within 2 hours of drug administration High concentrations of cefoxitin in the urine may interfere with measurement of urinary 17 hydroxy corticosteroids by the Porter Silber reaction and produce false increases of modest degree in the levels reported A false positive reaction for glucose in the urine may occur This has been observed with CLINITEST reagent tablets Registered trademark of Ames Company Division of Miles Laboratories Inc Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporin antibiotics Concomitant administration of probenecid doubled the AUC for cefprozil The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid Nephrotoxicity has been reported following concomitant administration of cephalosporins with aminoglycoside antibiotics or potent diuretics such as furosemide Renal function should be carefully monitored especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged because of the potential nephrotoxicity and ototoxicity of aminoglycosidic antibiotics Nephrotoxicity and ototoxicity were not noted when ceftazidime was given alone in clinical trials Chloramphenicol has been shown to be antagonistic to beta lactam antibiotics including ceftazidime based on in vitro studies and time kill curves with enteric gram negative bacilli Due to the possibility of antagonism in vivo particularly when bactericidal activity is desired this drug combination should be avoided Drug Laboratory Test Interactions The administration of ceftazidime may result in a false positive reaction for glucose in the urine when using CLINITEST tablets Benedicts solution or Fehlings solution It is recommended that glucose tests based on enzymatic glucose oxidase reactions such as CLINISTIX or TES TAPE be used Theophylline Twelve healthy male volunteers were administered one 200 mg ceftibuten capsule twice daily for 6 days With the morning dose of ceftibuten on day 6 each volunteer received a single intravenous infusion of theophylline 4 mg kg The pharmacokinetics of theophylline were not altered The effect of ceftibuten on the pharmacokinetics of theophylline administered orally has not been investigated Antacids or H 2 receptor antagonists The effect of increased gastric pH on the bioavailability of ceftibuten was evaluated in 18 healthy adult volunteers Each volunteer was administered one 400 mg ceftibuten capsule A single dose of liquid antacid did not affect the C max or AUC of ceftibuten however 150 mg of ranitidine q12h for 3 days increased the ceftibuten C max by 23 and ceftibuten AUC by 16 The clinical relevance of these increases is not known Drug Laboratory Test Interactions There have been no chemical or laboratory test interactions with ceftibuten noted to date False positive direct Coombs tests have been reported during treatment with other cephalosporins Therefore it should be recognized that a positive Coombs test could be due to the drug The results of assays using red cells from healthy subjects to determine whether ceftibuten would cause direct Coombs reactions in vitro showed no positive reaction at ceftibuten concentrations as high as 40 g mL Although the occurrence has not been reported with Cefizox nephrotoxicity has been reported following concomitant administration of other cephalosporins and aminoglycosides Drug Laboratory Test Interactions A false positive reaction for glucose in the urine may occur with copper reduction tests Benedict s or Fehling s solution or with Clinitest tablets but not with enzyme based tests for glycosuria As a false negative result may occur in the ferricyanide test it is recommended that either the glucose oxidase or hexokinase method be used to determine blood plasma glucose levels in patients receiving cefuroxime Cefuroxime does not interfere with the assay of serum and urine creatinine by the alkaline picrate method General Significant interactions may occur when celecoxib is administered together with drugs that inhibit P450 2C9 Celecoxib metabolism is predominantly mediated via cytochrome P450 2C9 in the liver Co administration of celecoxib with drugs that are known to inhibit 2C9 should be done with caution In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9 2C19 or 3A4 In vitro studies also indicate that celecoxib although not a substrate is an inhibitor of cytochrome P450 2D6 Therefore there is a potential for an in vivo drug interaction with drugs that are metabolized by P450 2D6 Clinical studies with celecoxib have identified potentially significant interactions with fluconazole and lithium Experience with nonsteroidal anti inflammatory drugs NSAIDs suggests the potential for interactions with furosemide and ACE inhibitors The effects celecoxib on the pharmacokinetics and or pharmacodynamics of glyburide ketoconazole methotrexate phenytoin tolbutamide and warfarin have been studied in vivo and clinically important interactions have not been found ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme ACE inhibitors This interaction should be given consideration in patients taking CELEBREX concomitantly with ACE inhibitors Furosemide Clinical studies as well as post marketing observations have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients This response has been attributed to inhibition of renal prostaglandin synthesis Aspirin CELEBREX can be used with low dose aspirin However concomitant administration of aspirin with CELEBREX may result in an increased rate of GI ulceration or other complications compared to use of CELEBREX alone Because of its lack of platelet effects CELEBREX is not a substitute for aspirin for cardiovascular prophylaxis Fluconazole Concomitant administration of fluconazole at 200 mg QD resulted in a two fold increase in celecoxib plasma concentration This increase is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole see CLINICAL PHARMACOLOGY Pharmacokinetics Metabolism CELEBREX should be introduced at the lowest recommended dose in patients receiving fluconazole Lithium In a study conducted in healthy subjects mean steady state lithium plasma levels increased approximately 17 in subjects receiving lithium 450 mg BID with CELEBREX 200 mg BID as compared to subjects receiving lithium alone Patients on lithium treatment should be closely monitored when CELEBREX is introduced or withdrawn Methotrexate In an interaction study of rheumatoid arthritis patients taking methotrexate CELEBREX did not have a significant effect on the pharmacokinetics of methotrexate Warfarin The effect of celecoxib on the anti coagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of 2 5 mg of warfarin In these subjects celecoxib did not alter the anticoagulant effect of warfarin as determined by prothrombin time However caution should be used when administering CELEBREX with warfarin since these patients are at increased risk of bleeding complications Metformin In healthy subjects given single 500 mg doses of cephalexin and metformin plasma metformin mean cmax and AUC increased by an average of 34 and 24 respectively and metformin mean renal clearance decreased by 14 No information is available about the interaction of cephalexin and metformin following multiple doses of either drug Although not observed in this study adverse effects could potentially arise from co administration of cephalexin and metformin by inhibition of tubular secretion via organic cationic transporter systems Accordingly careful patient monitoring and dose adjustment of metformin is recommended in patients concomitantly taking cephalexin and metformin Probenecid As with other b lactams the renal excretion of cephalexin is inhibited by probenecid Drug Laboratory Test Interactions As a result of administration of Keflex a false positive reaction for glucose in the urine may occur This has been observed with Benedict s and Fehling s solutions and also with Clinitest tablets Immunosuppressive Drugs Fibric Acid Derivatives Niacin Nicotinic Acid Erythromycin Azole Antifungals Skeletal Muscle ANTACID Magnesium Aluminum Hydroxide Cerivastatin plasma concentrations were not affected by co administration of antacid CIMETlDINE Cerivastatin plasma concentrations were not affected by co administration of cimetidine CHOLESTYRAMINE The influence of the bile acidsequestering agent cholestyramine on the pharmacokinetits of cerivastatin sodium was evaluated in 12 healthy males in 2 separate randomized crossover studies In the first study concomitant administration of 0 2 mg cerivastatin sodium and 12 g cholestyramine resulted in decreases of more than 22 for AUC and 40 for Cmax when compared to dosing cerivastatin sodium alone However in the second study administration of 12 g cholestyramine 1 hour before the evening meal and 0 3 mg cerivastatin sodium approximately 4 hours after the same evening meal resulted in a decrease in the cerivastatin AUC of less than 8 and a decrease in Cmax of about 30 when compared to dosing cerivastatin sodium alone Therefore it would be expected that a dosing schedule of cerivastatin sodium given at bedtime and cholestyramine given before the evening meal would not result in a significant decrease in the clinical effect of cerivastatin sodium DIGOXIN Plasma digoxin levels and digoxin clearance at steady state were not affected by co administration of 0 2 mg cerivastatin sodium Cerivastatin plasma concentrations were also not affected by co administration of digoxin WARFARIN Co administration of warfarin and cerivastatin to healthy volunteers did not result in any changes in prothrombin time or clotting factor VII when compared to co administration of warfarin and placebo The AUC and Cmax of both the R and S isomers of warfarin were unaffected by concurrent dosing of 0 3 mg cerivastatin sodium Co administration of warfarin and cerivastatin did not alter the pharmacokinetics of cerivastatin sodium ERYTHROMYCIN In hypercholesterolemic patients steady state cerivastatin AUC and Cmax increased approximately 50 and 24 respectively after 10 days with co administration of erythromycin a known inhibitor of cytochrome P450 3A4 OTHER CONCOMITANT THERAPY Although specific interaction studies were not performed in clinical studies cerivastatin sodium was used concomitantly with angiotensin converting enzyme ACE inhibitors betablockers calcium channel blockers diuretics and nonsteroidal anti inflammatory drugs NSAIDs without evidence of clinically significant adverse interactions Pharmacokinetic interaction studies with cetirizine in adults were conducted with pseudoephedrine antipyrine ketoconazole erythromycin and azithromycin No interactions were observed In a multiple dose study of theophylline 400 mg once daily for 3 days and cetirizine 20 mg once daily for 3 days a 16 decrease in the clearance of cetirizine was observed The disposition of theophylline was not altered by concomitant cetirizine administration Drug Drug Interactions No clinically significant drug interactions have been found with theophylline at a low dose azithromycin pseudoephedrine ketoconazole or erythromycin There was a small decrease in the clearance of cetirizine caused by a 400 mg dose of theophylline it is possible that larger theophylline doses could have a greater effect No formal drug interaction studies have been performed with Cetrotide A drug interaction study was performed in which ERBITUX was administered in combination with irinotecan There was no evidence of any pharmacokinetic interactions between ERBITUX and irinotecan Cevimeline should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances Drugs with parasympathomimetic effects administered concurrently with cevimeline can be expected to have additive effects Cevimeline might interfere with desirable antimuscarinic effects of drugs used concomitantly Drugs which inhibit CYP2D6 and CYP3A3 4 also inhibit the metabolism of cevimeline Cevimeline should be used with caution in individuals known or suspected to be deficient in CYP2D6 activity based on previous experience as they may be at a higher risk of adverse events In an in vitro study cytochrome P450 isozymes 1A2 2A6 2C9 2C19 2D6 2E1 and 3A4 were not inhibited by exposure to cevimeline There are no known drug drug interactions with chlorambucil Although clinical studies have not established a cause and effect relationship physicians should be aware that variable effects an blood coagulation have been reported very rarely in patients receiving oral anticoagulants and chlordiazepoxide The concomitant use of alcohol or other central nervous system depressants may have an additive effect The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors tricyclic antidepressants or phenothiazines may produce severe prolonged hypotension or hypertension Concurrent use of these agents should generally be avoided In situations when concurrent therapy is necessary careful patient monitoring is essential Concurrent administration of vasopressor drugs for the treatment of hypotension related to obstetric blocks and ergot type oxytocic drugs may cause severe persistent hypertension or cerebrovascular accidents The para aminobenzoic acid metabolite of chloroprocaine inhibits the action of sulfonamides Therefore chloroprocaine should not be used in any condition in which a sulfonamide drug is being employed Antacids and kaolin Antacids and kaolin can reduce absorption of chloroquine an interval of at least 4 hours between intake of these agents and chloroquine should be observed Cimetidine Cimetidine can inhibit the metabolism of chloroquine increasing its plasma level Concomitant use of cimetidine should be avoided Ampicillin In a study of healthy volunteers chloroquine significantly reduced the bioavailability of ampicillin An interval of at least two hours between intake of this agent and chloroquine should be observed Cyclosporin After introduction of chloroquine oral form a sudden increase in serum cyclosporin level has been reported Therefore close monitoring of serum cyclosporin level is recommended and if necessary chloroquine should be discontinued When given concurrently the following drugs may interact with thiazide diuretics Alcohol barbiturates or narcotics Potentiation of otthostatic hypotension may occur Antidiabetic drugs Oral agents and insulin Dosage adjustment of the antidiabetic drug may be required Other antihypertensive drugs Additive effect or potentiation Cholestyramine and colestipol resins Cholestytamine and colestipol resins have the potential of binding thiazide diuretics and reducing diuretic absorption from the gastrointestinal tract Corticosteroids ACTH Intensified electrolyte depletion particularly hypokalemia Pressor amines e g norepinephrine Possible decreased response to pressor amines but not sufficient to preclude their use Skeletal muscle relaxants nondepolarizing e g tubocurarine Possible increased responsiveness to the muscle relaxant Lithium Generally should not be given with diuretics Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity Refer to the package insert for lithium preparations before use of such preparations with chlorothiazide Non steroidal Anti inflammatory Drugs In some patients the administration of a non steroidal anti inflammatory agent can reduce the diuretic natriuretic and antihypertensive effects of loop potassium sparing and thiazide diuretics Therefore when chlorothiazide and non steroidal anti inflammatory agents are used concomitantly the patient should be observed closely to determine if the desired effect of the diuretic is obtained Drug Laboratory Test Interactions Thiazides should be discontinued before carrying out tests for parathyroid function Chlorotrianisene may interact with antidepressants aspirin barbiturates bromocriptine calcium supplements corticosteroids corticotropin cyclosporine dantrolene nicotine somatropin tamoxifen and warfarin May interact with skin products or shampoos for dandruff or psoriasis Substrate of CYP2D6 minor 3A4 major Inhibits CYP2D6 weak Increased toxicity CNS depression CNS depressants MAO inhibitors tricyclic antidepressants phenothiazines CYP3A4 inhibitors May increase the levels effects of chlorpheniramine Example inhibitors include azole antifungals ciprofloxacin clarithromycin diclofenac doxycycline erythromycin imatinib isoniazid nefazodone nicardipine propofol protease inhibitors quinidine and verapamil The concurrent use of two or more drugs with anticholinergic activity such as an antipsychotic drug eg chlorpromazine an antiparkinsonian drug eg trihexyphenidyl and or a tricyclic antidepressant eg amitriptyline commonly results in excessive anticholinergic effects including dry mouth and associated dental complications blurred vision and in patients exposed to high temperature and humidity hyperpyrexia Interactions may also occur with the following anti depressants anti anxiety drugs drugs used to treat an overactive thyroid beta blockers e g propranolol sparfloxacin grepafloxacin guanethidine guanadrel metrizamide cabergoline lithium narcotic pain medication e g codeine drugs used to aid sleep drowsiness causing antihistamines e g diphenhydramine any other drugs that may make you drowsy The hypoglycemic action of sulfonylurea may be potentiated by certain drugs including nonsteroidal anti inflammatory agents and other drugs that are highly protein bound salicylates sulfonamides chloramphenicol probenecid coumarins monoamine oxidase inhibitors and beta adrenergic blocking agents When such drugs are administered to a patient receiving DIABINESE the patient should be observed closely for hypoglycemia When such drugs are withdrawn from a patient receiving DIABINESE the patient should be observed closely for loss of control Certain drugs tend to produce hyperglycemia and may lead to loss of control These drugs include the thiazides and other diuretics corticosteroids phenothiazines thyroid products estrogens oral contraceptives phenytoin nicotinic acid sympathomimetics calcium channel blocking drugs and isoniazid When such drugs are administered to a patient receiving DIABINESE the patient should be closely observed for loss of control When such drugs are withdrawn from a patient receiving DIABINESE the patient should be observed closely for hypoglycemia Since animal studies suggest that the action of barbiturates may be prolonged by therapy with chlorpropamide barbiturates should be employed with caution In some patients a disulfiram like reaction may be produced by the ingestion of alcohol A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported Whether this interaction also occurs with the intravenous topical or vaginal preparations of miconazole is not known Chlorprothixene may increase the plasma level of concomitantly given lithium In order to avoid lithium intoxication lithium plasma levels should be monitored closely If chlorprothixene is given concomitantly with opioids the opioid dose should be reduced by approx 50 because chlorprothixene amplifies the therapeutic actions and side effects of opioids massively Avoid the concomitant use of chlorprothixene and tramadol Ultram Massive seizures may be encountered with this combination Consider additive sedative effects and confusional states to emerge if chlorprothixene is given with benzodiazepines or barbituates Choose particular low doses of these drugs Exert particular caution in combining chlorprothixene with other anticholinergic drugs tricyclic antidepressants and antiparkinsonian agents Particularly the elderly may develop delirium high fever severe obstipation even ileus and glaucoma Chlorthalidone may add to or potentiate the action of other antihypertensive drugs Potentiation occurs with ganglionic peripheral adrenergic blocking drugs Medication such as digitalis may also influence serum electrolytes Warning signs irrespective of cause are dryness of mouth thirst weakness lethargy drowsiness restlessness muscle pains or cramps muscular fatigue hypotension oliguria tachycardia and gastrointestinal disturbances such as nausea and vomiting Insulin requirements in diabetic patients may be increased decreased or unchanged Higher dosage of oral hypoglycemic agents may be required Latent diabetes mellitus may become manifest during chlorthalidone administration Chlorthalidone and related drugs may increase the responsiveness to tubocurarine Chlorthalidone and related drugs may decrease arterial responsiveness to norepinephrine This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use The concomitant use of alcohol or other central nervous system depressants may have an additive effect Interactions for vitamin D analogues Vitamin D2 Vitamin D3 Calcitriol and Calcidiol Cholestyramine Cholestyramine has been reported to reduce intestinal absorption of fat soluble vitamins as such it may impair intestinal absorption of any of vitamin D Phenytoin Phenobarbital The coadministration of phenytoin or phenobarbital will not affect plasma concentrations of vitamin D but may reduce endogenous plasma levels of calcitriol ergocalcitriol by accelerating metabolism Since blood level of calcitriol ergocalcitriol will be reduced higher doses of Rocaltrol may be necessary if these drugs are administered simultaneously Thiazides Thiazides are known to induce hypercalcemia by the reduction of calcium excretion in urine Some reports have shown that the concomitant administration of thiazides with vitamin D causes hypercalcemia Therefore precaution should be taken when coadministration is necessary Digitalis Vitamin D dosage must be determined with care in patients undergoing treatment with digitalis as hypercalcemia in such patients may precipitate cardiac arrhythmias Ketoconazole Ketoconazole may inhibit both synthetic and catabolic enzymes of vitamin D Reductions in serum endogenous vitamin D concentrations have been observed following the administration of 300 mg day to 1200 mg day ketoconazole for a week to healthy men However in vivo drug interaction studies of ketoconazole with vitamin D have not been investigated Corticosteroids A relationship of functional antagonism exists between vitamin D analogues which promote calcium absorption and corticosteroids which inhibit calcium absorption Phosphate Binding Agents Since vitamin D also has an effect on phosphate transport in the intestine kidneys and bones the dosage of phosphate binding agents must be adjusted in accordance with the serum phosphate concentration Vitamin D The coadministration of any of the vitamin D analogues should be avoided as this could create possible additive effects and hypercalcemia Calcium Supplements Uncontrolled intake of additional calcium containing preparations should be avoided Magnesium Magnesium containing preparations eg antacids may cause hypermagnesemia and should therefore not be taken during therapy with vitamin D by patients on chronic renal dialysis Cholestyramine resin may delay or reduce the absorption of concomitant oral medication such as phenylbutazone warfarin thiazide diuretics acidic or propranolol basic as well as tetracycline penicillin G phenobarbital thyroid and thyroxine preparations estrogens and progestins and digitalis Interference with the absorption of oral phosphate supplements has been observed with another positively charged bile acid sequestrant Cholestyramine resin may interfere with the pharmacokinetics of drugs that undergo enterohepatic circulation The discontinuance of cholestyramine resin could pose a hazard to health if a potentially toxic drug such as digitalis has been filtrated to a maintenance level while the patient was taking cholestyramine resin Because cholestyramine binds bile acids cholestyramine resin may interfere with normal fat digestion and absorption and thus may prevent absorption of fat soluble vitamins such as A D E and K When cholestyramine resin is given for long periods of time concomitant supplementation with water miscible or parenteral forms of fat soluble vitamins should be considered SINCE CHOLESTYRAMINE RESIN MAY BIND OTHER DRUGS GIVEN CONCURRENTLY IT IS RECOMMENDED THAT PATIENTS TAKE OTHER DRUGS AT LEAST 1 HOUR BEFORE OR 4 TO 6 HOURS AFTER CHOLESTYRAMINE RESIN OR AT AS GREAT AN INTERVAL AS POSSIBLE TO AVOID IMPEDING THEIR ABSORPTION Based on in vitro studies in human liver microsomes des ciclesonide appears to have no inhibitory or induction potential on the metabolism of other drugs metabolized by CYP 450 enzymes The inhibitory potential of ciclesonide on CYP450 isoenzymes has not been studied In vitro studies demonstrated that the plasma protein binding of des ciclesonide was not affected by warfarin or salicylic acid indicating no potential for protein binding based drug interactions In a drug interaction study co administration of orally inhaled ciclesonide and oral erythromycin an inhibitor of cytochrome P450 3A4 had no effect on the pharmacokinetics of either des ciclesonide or erythromycin In another drug interaction study co administration of orally inhaled ciclesonide and oral ketoconazole a potent inhibitor of cytochrome P450 3A4 increased the exposure AUC of des ciclesonide by approximately 3 6 fold at steady state while levels of ciclesonide remained unchanged Therefore ketoconazole should be administered with caution with intranasal ciclesonide Probenecid Probenecid is known to interact with the metabolism or renal tubular excretion of many drugs e g acetaminophen acyclovir angiotensin converting enzyme inhibitors aminosalicylic acid barbiturates benzodiazepines bumetanide clofibrate methotrexate famotidine furosemide nonsteroidal anti inflammatory agents theophylline and zidovudine Concomitant medications should be carefully assessed Zidovudine should either be temporarily discontinued or decreased by 50 when coadministered with probenecid on the day of VISTIDE infusion Nephrotoxic agents Concomitant administration of VISTIDE and agents with nephrotoxic potential e g intravenous aminoglycosides e g tobramycin gentamicin and amikacin amphotericin B foscarnet intravenous pentamidine vancomycin and non steroidal anti inflammatory agents is contraindicated Such agents must be discontinued at least seven days prior to starting therapy with VISTIDE Since PLETAL is extensively metabolized by cytochrome P 450 isoenzymes caution should be exercised when PLETAL is coadministered with inhibitors of C P A such as ketoconazole and erythromycin or inhibitors of CYP2C19 such as omeprazole Pharmacokinetic studies have demonstrated that omeprazole and erythromycin significantly increased the systemic exposure of cilostazol and or its major metabolites Population pharmacokinetic studies showed higher concentrations of cilostazol among patients concurrently treated with diltiazem an inhibitor of C P A Pletal does not however appear to cause increased blood levels of drugs metabolized by CYP3A4 as it had no effect on lovastatin a drug with metabolism very sensitive to C P A inhibition Tagamet apparently through an effect on certain microsomal enzyme systems has been reported to reduce the hepatic metabolism of warfarin type anticoagulants phenytoin propranolol nifedipine chlordiazepoxide diazepam certain tricyclic antidepressants lidocaine theophylline and metronidazole thereby delaying elimination and increasing blood levels of these drugs Clinically significant effects have been reported with the warfarin anticoagulants therefore close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when Tagamet is administered concomitantly Interaction with phenytoin lidocaine and theophylline has also been reported to produce adverse clinical effects However a crossover study in healthy subjects receiving either Tagamet 300 mg q i d or 800 mg h s concomitantly with a 300 mg b i d dosage of theophylline Theo Dur Key Pharmaceuticals Inc demonstrated less alteration in steady state theophylline peak serum levels with the 800 mg h s regimen particularly in subjects aged 54 years and older Data beyond 10 days are not available Note All patients receiving theophylline should be monitored appropriately regardless of concomitant drug therapy Dosage of the drugs mentioned above and other similarly metabolized drugs particularly those of low therapeutic ratio or in patients with renal and or hepatic impairment may require adjustment when starting or stopping concomitantly administered Tagamet to maintain optimum therapeutic blood levels Alteration of pH may affect absorption of certain drugs e g ketoconazole If these products are needed they should be given at least 2 hours before cimetidine administration Additional clinical experience may reveal other drugs affected by the concomitant administration of Tagamet and or Drug Laboratory Test Interactions See CLINICAL PHARMACOLOGY Pharmacokinetics and Drug Interactions Effect of Sensipar on other drugs Drugs metabolized by cytochrome P450 2D6 CYP2D6 Sensipar is a strong in vitro inhibitor of CYP2D6 Therefore dose adjustments of concomitant medications that are predominantly metabolized by CYP2D6 and have a narrow therapeutic index e g flecainide vinblastine thioridazine and most tricyclic antidepressants may be required Amitriptyline Concurrent administration of 25 mg or 100 mg cinacalcet with 50 mg amitriptyline increased amitriptyline exposure and nortriptyline active metabolite exposure by approximately 20 in CYP2D6 extensive metabolizers Effect of other drugs on Sensipar Sensipar is metabolized by multiple cytochrome P450 enzymes primarily CYP3A4 CYP2D6 and CYP1A2 Ketoconazole Sensipar is metabolized in part by CYP3A4 Co administration of ketoconazole a strong inhibitor of CYP3A4 increased cinacalcet exposure following a single 90 mg dose of Sensipar by 2 3 fold Dose adjustment of Sensipar may be required and PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor e g ketoconazole erythromycin itraconazole see DOSAGE AND ADMINISTRATION Elevated plasma levels of theophylline have been reported with concomitant use of some quinolones There have been reports of theophylline related side effects in patients on concomitant theophylline quinolone therapy Therefore monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required Quinolones have also been shown to interfere with the metabolism of caffeine This may lead to reduced clearance of caffeine and a prolongation of its plasma half life Although this interaction has not been reported with cinoxacin caution should be exercised when cinoxacin is given concomitantly with caffeine containing products Antacids or sucralfate substantially interfere with the absorption of some quinolones resulting in low urine levels Also concomitant administration of quinolones with products containing iron multivitamins containing zinc or Videx didanosine chewable buffered tablets or the pediatric powder for oral solution may result in low urine levels Quinolones including cinoxacin may enhance the effects of oral anticoagulants such as warfarin or its derivatives When these products are administered concomitantly prothrombin time or other suitable coagulation tests should be closely monitored Seizures have been reported in patients taking another quinolone class antimicrobial and the nonsteroidal anti inflammatory drug fenbufen concurrently Animal studies also suggest an increased potential for seizures when these 2 drugs are given concomitantly Fenbufen is not approved in the United States at this time Physicians are provided this information to increase awareness of the potential for serious interactions when cinoxacin and certain nonsteroidal anti inflammatory agents are administered concomitantly Elevated cyclosporine serum levels have been reported with the concomitant use of quinolones and cyclosporine Some quinolones including ciprofloxacin have also been shown to interfere with the metabolism of caffeine This may lead to reduced clearance of caffeine and a prolongation of its serum half life Some quinolones including ciprofloxacin have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly Glyburide The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has on rare occasions resulted in severe hypoglycemia Histamine H2 receptor antagonists Histamine H2 receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin Methotrexate Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially leading to increased plasma levels of methotrexate This might increase the risk of methotrexate toxic reactions Therefore patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated Multivalent Cation Containing Products Concurrent administration of a quinolone including ciprofloxacin with multivalent cation containing products such as magnesium or aluminum antacids sucralfate VIDEX chewable buffered tablets or pediatric powder or products containing calcium iron or zinc may substantially decrease the absorption of ciprofloxacin resulting in serum and urine levels considerably lower than desired Proquin XR should be administered at least 4 hours before or 2 hours after these products This time window is different than for other oral formulations of ciprofloxacin which are usually administered 2 hours before or 6 hours after antacids Non steroidal anti inflammatory drugs but not aspirin These drugs in combination with very high doses of quinolones have been shown to provoke convulsions in pre clinical studies Omeprazole The rate and extent of absorption of ciprofloxacin was bioequivalent when Proquin XR was given alone or when Proquin XR was given 2 hours after omeprazole at the dose that maximally suppresses gastric acid secretion Omeprazole should be taken as directed and Proquin XR should be taken with a main meal of the day preferably the evening meal Phenytoin Altered serum levels of phenytoin increased and decreased have been reported in patients receiving concomitant ciprofloxacin Probenecid Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in serum Theophylline As with some other quinolones concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half life This may result in increased risk of theophylline related adverse reactions If concomitant use cannot be avoided serum levels of theophylline should be monitored and dosage adjustments made as appropriate Warfarin Quinolones have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives When these products are administered concomitantly prothrombin time or other suitable coagulation tests should be monitored Cisapride is metabolized mainly via the cytochrome P450 3A4 enzyme In some cases where serious ventricular arrhythmias QT prolongation and torsades de pointes have occurred when cisapride was taken in conjunction with one of the cytochrome P450 3A4 inhibitors elevated blood cisapride levels were noted at the time of the QT prolongation Antibiotics In vitro and or in vivo data show that clarithromycin erythromycin and troleandomycin markedly inhibit the metabolism of cisapride which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG Anticholinergics Concurrent administration of certain anticholinergic compounds such as belladonna alkaloids and dicyclomine would be expected to compromise the beneficial effects of cisapride Anticoagulants Oral In patients receiving oral anticoagulants the coagulation times were increased in some cases It is advisable to check coagulation time within the first few days after the start and discontinuation of cisapride therapy with an appropriate adjustment of the anticoagulant dose if necessary Antidepressants In vitro data indicate that nefazodone inhibits the metabolism of cisapride which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG Antifungals In vitro and or in vivo data indicate that fluconazole itraconazole and oral ketoconazole markedly inhibit the metabolism of cisapride which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG Human pharmacokinetic data indicate that oral ketoconazole markedly inhibits the metabolism of cisapride resulting in a mean eight fold increase in AUC of cisapride A study in 14 normal male and female volunteers suggests that coadministration of cisapride and ketoconazole can result in prolongation of the QT interval on the ECG H2 Receptor Antagonists Cimetidine coadministration leads to an increased peak plasma concentration and AUC of cisapride there is no effect on cisapride absorption when it is coadministered with ranitidine The gastrointestinal absorption of cimetidine and ranitidine is accelerated when they are coadministered with cisapride Protease Inhibitors In vitro data indicate that indinavir and ritonavir markedly inhibit the metabolism of cisapride which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG Other Coadministration of grapefruit juice with cisapride increases the bioavailability of cisapride and concomitant use should be avoided Cisapride should not be used concomitantly with other drugs known to prolong the QT interval certain antiarrhythmics including those of Class IA such as quinidine and procainamide and Class III such as sotalol tricyclic antidepressants such as amitriptyline certain tetracyclic antidepressants such as maprotiline certain antipsychotic medications such as sertindole astemizole bepridil sparfloxacin and terodiline The preceding lists of drugs are not comprehensive The acceleration of gastric emptying by cisapride could affect the rate of absorption of other drugs Patients receiving narrow therapeutic ratio drugs or other drugs that require careful titration should be followed closely if plasma levels are being monitored they should be reassessed Administration of 0 1 mg kg 2 x ED95 NIMBEX at 10 or 95 recovery following an intubating dose of succinylcholine 1 mg kg produced 95 neuromuscular block The time to onset of maximum block following NIMBEX is approximately 2 minutes faster with prior administration of succinylcholine Prior administration of succinylcholine had no effect on the duration of neuromuscular block following initial or maintenance bolus doses of NIMBEX Infusion requirements of NIMBEX in patients administered succinylcholine prior to infusions of NIMBEX were comparable to or slightly greater than when succinylcholine was not administered The use of NIMBEX before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied Although not studied systematically in clinical trials no drug interactions were observed when vecuronium pancuronium or atracurium were administered following varying degrees of recovery from single doses or infusions of NIMBEX Isoflurane or enflurane administered with nitrous oxide oxygen to achieve 1 25 MAC Minimum Alveolar Concentration may prolong the clinically effective duration of action of initial and maintenance doses of NIMBEX and decrease the required infusion rate of NIMBEX The magnitude of these effects may depend on the duration of administration of the volatile agents Fifteen to 30 minutes of exposure to 1 25 MAC isoflurane or enflurane had minimal effects on the duration of action of initial doses of NIMBEX and therefore no adjustment to the initial dose should be necessary when NIMBEX is administered shortly after initiation of volatile agents In long surgical procedures during enflurane or isoflurane anesthesia less frequent maintenance dosing lower maintenance doses or reduced infusion rates of NIMBEX may be necessary The average infusion rate requirement may be decreased by as much as 30 to 40 In clinical studies propofol had no effect on the duration of action or dosing requirements for NIMBEX Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as NIMBEX include certain antibiotics e g aminoglycosides tetracyclines bacitracin polymyxins lincomycin clindamycin colistin and sodium colistemethate magnesium salts lithium local anesthetics procainamide and quinidine Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine While the effects of chronic phenytoin or carbamazepine therapy on the action of NIMBEX are unknown slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher Drug Laboratory Test Interactions None known Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy Central nervous system depressant CNS drugs including alcohol antidepressants antihistamines antipsychotics blood pressure medications reserpine methyldopa beta blockers motion sickness medications muscle relaxants narcotics sedatives sleeping pills and tranquilizers There are no known drug interactions with LEUSTATIN Injection Caution should be exercised if LEUSTATIN Injection is administered before after or in conjunction with other drugs known to cause immunosuppression or myelosuppression The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia present in these patients In controlled clinical trials of AUGMENTIN XR 22 patients received concomitant allopurinol and AUGMENTIN XR No rashes were reported in these patients However this sample size is too small to allow for any conclusions to be drawn regarding the risk of rashes with concomitant AUGMENTIN XR and allopurinol use In common with other broad spectrum antibiotics AUGMENTIN XR may reduce the efficacy of oral contraceptives Additive CNS depression may occur when antihistamines are administered concomitantly with other CNS depressants including barbiturates tranquilizers and alcohol Patients receiving antihistamines should be advised against the concurrent use of other CNS depressant drugs Monoamine oxidase MAO inhibitors prolong and intensify the anticholinergic effects of antihistamines Amantadine tricyclic antidepressants and MAOIs may increase anticholinergic effect of clidinium Clidinium may decrease the effect of phenothiazines levodopa and ketoconazole Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents Therefore it should be used with caution in patients receiving such agents Antagonism has been demonstrated between clindamycin and erythromycin in vitro Because of possible clinical significance these two drugs should not be administered concurrently Alcohol increases bioavailability by 50 cimetidine and valproates No separate information available Although no clinical drug drug interaction studies have been conducted to date on the basis of the in vitro studies cytochrome p450 inhibitors and inducers are unlikely to affect the metabolism of clofarabine The effect of clofarabine on the metabolism of cytochrome p450 substrates has not been studied Drug Laboratory Tests Interactions There are no known clinically significant interactions of CLOLAR with other medications or laboratory tests No formal drug laboratory test interaction studies have been conducted with CLOLAR Preliminary data which suggest that dapsone may inhibit the anti inflammatory activity of Lamprene have not been confirmed If leprosy associated inflammatory reactions develop in patients being treated with dapsone and clofazimine it is still advisable to continue treatment with both drugs Caution should be exercised when anticoagulants are given in conjunction with Atromid S Usually the dosage of the anticoagulant should be reduced by one half depending on the individual case to maintain the prothrombin time at the desired level to prevent bleeding complications Frequent prothrombin determinations are advisable until it has been determined definitely that the prothrombin level has been stabilized Atromid S may displace acidic drugs such as phenytoin or tolbutamide from their binding sites Caution should be exercised when treating patients with either of these drugs or other highly protein bound drugs and Atromid S The hypoglycemic effect of tolbutamide has been reported to increase when Atromid S is given concurrently Fulminant rhabdomyolysis has been seen as early as three weeks after initiation of combined therapy with another fibrate and lovastatin but may be seen after several months For these reasons it is felt that in most subjects who have had an unsatisfactory lipid response to either drug alone the possible benefits of combined therapy with lovastatin and a fibrate do not outweigh the risks of severe myopathy rhabdomyolysis and acute renal failure While it is not known whether this interaction occurs with fibrates other than gemfibrozil myopathy and rhabdomyolysis have occasionally been associated with the use of fibrates alone including clofibrate Therefore the combined use of lovastatin with fibrates should generally be avoided Drug interactions with clomiphene citrate tablets USP have not been documented The risks of using Anafranil in combination with other drugs have not been systematically evaluated Given the primary CNS effects of Anafranil caution is advised in using it concomitantly with other CNS active drugs Anafranil should not be used with MAO inhibitors Close supervision and careful adjustment of dosage are required when Anafranil is administered with anticholinergic or sympathomimetic drugs Several tricyclic antidepressants have been reported to block the pharmacologic effects of guanethidine clonidine or similar agents and such an effect may be anticipated with CMI because of its structural similarity to other tricyclic antidepressants The plasma concentration of CMI has been reported to be increased by the concomitant administration of haloperidol plasma levels of several closely related tricyclic antidepressants have been reported to be increased by the concomitant administration of methylphenidate or hepatic enzyme inhibitors e g cimetidine fluoxetine and decreased by the concomitant administration of hepatic enzyme inducers e g barbiturates phenytoin and such an effect may be anticipated with CMI as well Administration of CMI has been reported to increase the plasma levels of phenobarbital if given concomitantly Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 debrisoquin hydroxylase is reduced in a subset of the aucasian population about 7 10 of Caucasians are so called poor metabolizers reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian African and other populations are not yet available Poor metabolizers have higher than expected lasma concentrations of tricyclic antidepressants TCAs when given usual doses Depending on the fraction of drug metabolized by P450 2D6 the increase in plasma concentration may be small or quite large 8 fold increase in plasma AUC of the TCA In addition certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers An individual who is stable on a given dose of TCAmay become abruptly toxic when given one of these inhibiting drugs as concomitant therapy The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme quinidine cimetidine and many that are substrates for P450 2D6 many other antidepressants phenothiazines and the Type 1C antiarrhythmics propafenone and flecainide While all the selective serotonin reuptake inhibitors SSRIs e g fluoxetine sertraline paroxetine and fluvoxamine inhibit P450 2D6 they may vary in the extent of inhibition Fluvoxamine has also been shown to inhibit P450 1A2 an isoform also involved in TCAmetabolism The extent to which SSRI TCAinteractions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved Nevertheless caution is indicated in the co administration of TCAs with any of the SSRIs and also in switching from one class to the other Of particular importance sufficient time must elapse before initiating TCAtreatment in a patient being withdrawn from fluoxetine given the long half life of the parent and active metabolite at least 5 weeks may be necessary Concomitant use of agents in the tricyclic antidepressant class which includes Anafranil with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant agent or the other drug Furthermore whenever one of these drugs is withdrawn from co therapy an increased dose of tricyclic antidepressant agent may be required It is desirable to monitor TCAplasma levels whenever an agent of the tricyclic antidepressant class including Anafranil is going to be co administered with another drug known to be an inhibitor of P450 2D6 and or P450 1A2 Because Anafranil is highly bound to serum protein the administration of Anafranil to patients taking other drugs that are highly bound to protein e g warfarin digoxin may cause an increase in plasma concentrations of these drugs potentially resulting in adverse effects Conversely adverse effects may result from displacement of protein bound Anafranil by other highly bound drugs Effect of Clonazepam on the Pharmacokinetics of Other Drugs Clonazepam does not appear to alter the pharmacokinetics of phenytoin carbamazepine or phenobarbital The effect of clonazepam on the metabolism of other drugs has not been investigated Effect of Other Drugs on the Pharmacokinetics of Clonazepam Literature reports suggest that ranitidine an agent that decreases stomach acidity does not greatly alter clonazepam pharmacokinetics In a study in which the 2 mg clonazepam orally disintegrating tablet was administered with and without propantheline an anticholinergic agent with multiple effects on the GI tract to healthy volunteers the AUC of clonazepam was 10 lower and the Cmax of clonazepam was 20 lower when the orally disintegrating tablet was given with propantheline compared to when it was given alone Fluoxetine does not affect the pharmacokinetics of clonazepam Cytochrome P 450 inducers such as phenytoin carbamazepine and phenobarbital induce clonazepam metabolism causing an approximately 30 decrease in plasma clonazepam levels Although clinical studies have not been performed based on the involvement of the cytochrome P 450 3A family in clonazepam metabolism inhibitors of this enzyme system notably oral antifungal agents should be used cautiously in patients receiving clonazepam Pharmacodynamic Interactions The CNS depressant action of the benzodiazepine class of drugs may be potentiated by alcohol narcotics barbiturates nonbarbiturate hypnotics antianxiety agents the phenothiazines thioxanthene and butyrophenone classes of antipsychotic agents monoamine oxidase inhibitors and the tricyclic antidepressants and by other anticonvulsant drugs Tablet If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants the effect of clonidine may be reduced thus necessitating an increase in dosage Clonidine hydrochloride may enhance the CNS depressive effects of alcohol barbiturates or other sedatives Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats Epidural Injection Clonidine may potentiate the CNS depressive effect of alcohol barbiturates or other sedating drugs Narcotic analgesics may potentiate the hypotensive effects of clonidine Tricyclic antidepressants may antagonize the hypotensive effects of clonidine The effects of tricyclic antidepressants on clonidines analgesic actions are not known Beta blockers may exacerbate the hypertensive response seen with clonidine withdrawl Also due to the potential for additive effects such as bradycardia and AV block caution is warranted in patients receiving clonidine with agents known to affect sinus node function or AV nodal conduction e g digitalis calcium channel blockers and beta blockers There is one reported case of a patient with acute delirium associated with the simultaneous use of fluphenazine and oral clonidine Symptoms resolved when clonidine was withdrawn and recurred when the patient was rechallenged with clonidine Epidural clonidine may prolong the duration of pharmacologic effects of epidural local anesthetics including both sensory and motor blockade Aspirin warfarin heparin NSAIDs If TRANXENE is to be combined with other drugs acting on the central nervous system careful consideration should be given to the pharmacology of the agents to be employed Animal experience indicates that clorazepate dipotassium prolongs the sleeping time after hexobarbital or after ethyl alcohol increases the inhibitory effects of chlorpromazine but does not exhibit monoamine oxidase inhibition Clinical studies have shown increased sedation with concurrent hypnotic medications The actions of the benzodiazepines may be potentiated by barbiturates narcotics phenothiazines monoamine oxidase inhibitors or other antidepressants If TRANXENE tablets are used to treat anxiety associated with somatic disease states careful attention must be paid to possible drug interaction with concomitant medication In bioavailability studies with normal subjects the concurrent administration of antacids at therapeutic levels did not significantly influence the bioavailability of TRANXENE tablets The risks of using Clozapine in combination with other drugs have not been systematically evaluated Pharmacodynamic related Interactions The mechanism of Clozapine induced agranulocytosis is unknown nonetheless the possibility that causative factors may interact synergistically to increase the risk and or severity of bone marrow suppression warrants consideration Therefore Clozapine should not be used with other agents having a well known potential to suppress bone marrow function Given the primary CNS effects of Clozapine caution is advised in using it concomitantly with other CNS active drugs or alcohol Orthostatic hypotension in patients taking clozapine can in rare cases approximately 1 case per 3 000 patients be accompanied by profound collapse and respiratory and or cardiac arrest Some of the cases of collapse respiratory arrest cardiac arrest during initial treatment occurred in patients who were being administered benzodiazepines similar events have been reported in patients taking other psychotropic drugs or even Clozapine by itself Although it has not been established that there is an interaction between Clozapine and benzodiazepines or other psychotropics caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug Clozapine may potentiate the hypotensive effects of antihypertensive drugs and the anticholinergic effects of atropine type drugs The administration of epinephrine should be avoided in the treatment of drug induced hypotension because of a possible reverse epinephrine effect Pharmacokinetic related Interactions Clozapine is a substrate for many CYP 450 isozymes in particular 1A2 2D6 and 3A4 The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized Nevertheless caution should be used in patients receiving concomitant treatment with other drugs that are either inhibitors or inducers of these enzymes Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine Phenytoin nicotine and rifampin may decrease Clozapine plasma levels resulting in a decrease in effectiveness of a previously effective Clozapine dose Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine Cimetidine caffeine and erythromycin may increase plasma levels of Clozapine potentially resulting in adverse effects Although concomitant use of Clozapine and carbamazepine is not recommended it should be noted that discontinuation of concomitant carbamazepine administration may result in an increase in Clozapine plasma levels In a study of schizophrenic patients who received clozapine under steady state conditions fluvoxamine or paroxetine was added in 16 and 14 patients respectively After 14 days of co administration mean trough concentrations of clozapine and its metabolites N desmethylclozapine and clozapine N oxide were elevated with fluvoxamine by about three fold compared to baseline concentrations Paroxetine produced only minor changes in the levels of clozapine and its metabolites However other published reports describe modest elevations less than two fold of clozapine and metabolite concentrations when clozapine was taken with paroxetine fluoxetine and sertraline Therefore such combined treatment should be approached with caution and patients should be monitored closely when Clozapine is combined with these drugs particularly with fluvoxamine A reduced Clozapine dose should be considered A subset 3 10 of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isozyme P450 2D6 Such individuals are referred to as poor metabolizers of drugs such as debrisoquin dextromethorphan the tricyclic antidepressants and clozapine These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses In addition certain drugs that are metabolized by this isozyme including many antidepressants clozapine selective serotonin reuptake inhibitors and others may inhibit the activity of this isozyme and thus may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system leading to drug interaction Concomitant use of clozapine with other drugs metabolized by cytochrome P450 2D6 may require lower doses than usually prescribed for either clozapine or the other drug Therefore co administration of clozapine with other drugs that are metabolized by this isozyme including antidepressants phenothiazines carbamazepine and Type 1C antiarrhythmics e g propafenone flecainide and encainide or that inhibit this enzyme e g quinidine should be approached with caution The risk of a potential interaction between NovoSeven and coagulation factor concentrates has not been adequately evaluated in preclinical or clinical studies Simultaneous use of activated prothrombin complex concentrates or prothrombin complex concentrates should be avoided Although the specific drug interaction was not studied in a clinical trial there have been more than 50 episodes of concomitant use of antifibrinolytic therapies i e tranexamic acid aminocaproic acid and NovoSeven NovoSeven should not be mixed with infusion solutions until clinical data are available to direct this use Codeine in combination with other narcotic analgesics general anesthetics phenothiazines tranquilizers sedative hypnotics or other CNS depressants including alcohol has additive depressant effects When s c combination therapy is contemplated the dosage of one or both agents should be reduced Colchicine is inhibited by acidifying agents The action of colchicine is potentiated by alkalinizing agents Colchicine may increase sensitivity to the CNS depressants Response to sympathomimetic agents may be enhanced by colchicine WelChol has been studied in several human drug interaction studies in which it was administered with a meal and the test drug WelChol was found to have no significant effect on the bioavailability of digoxin lovastatin metoprolol quinidine valproic acid and warfarin WelChol decreased the Cmax and AUC of sustained release verapamil Calan SR by approximately 31 and 11 respectively Since there is a high degree of variability in the bioavailability of verapamil the clinical significance of this finding is unclear In clinical studies coadministration of WelChol with atorvastatin lovastatin or simvastatin did not interfere with the lipid lowering activity of the HMG CoA reductase inhibitor Other drugs have not been studied When administering other drugs for which alterations in blood levels could have a clinically significant effect on safety or efficacy physicians should consider monitoring drug levels or effects Since colestipol hydrochloride is an anion exchange resin it may have a strong affinity for anions other than the bile acids In vitro studies have indicated that colestipol hydrochloride binds a number of drugs Therefore COLESTlD Tablets may delay or reduce the absorption of concomitant oral medication The interval between the administration of COLESTID Tablets and any other medication should be as long as possible Patients should take other drugs at least one hour before or four hours after COLESTID Tablets to avoid impeding their absorption Repeated doses of colestipol hydrochloride given prior to a single dose of propranolol in human trials have been reported to decrease propranolol absorption However in a follow up study in normal subjects single dose administration of colestipol hydrochloride and propranolol and twice a day administration for 5 days of both agents did not affect the extent of propranolol absorption but had a small yet statistically significant effect on its rate of absorption the time to reach maximum concentration was delayed approximately 30 minutes Effects on the absorption of other beta blockers have not been determined Therefore patients on propranolol should be observed when COLESTID Tablets are either added or deleted from a therapeutic regimen Studies in humans show that the absorption of chlorothiazide as reflected in urinary excretion is markedly decreased even when administered one hour before colestipol hydrochloride The absorption of tetracycline furosemide penicillin G hydrochlorothiazide and gemfibrozil was significantly decreased when given simultaneously with colestipol hydrochloride these drugs were not tested to determine the effect of administration one hour before colestipol hydrochloride No depressant effect on blood levels in humans was noted when colestipol hydrochloride was administered with any of the following drugs aspirin clindamycin clofibrate methyldopa nicotinic acid niacin tolbutamide phenytoin or warfarin Particular caution should be observed with digitalis preparations since there are conflicting results for the effect of colestipol hydrochloride on the availability of digoxin and digitoxin The potential for binding of these drugs if given concomitantly is present Discontinuing colestipol hydrochloride could pose a hazard to health if a potentially toxic drug that is significantly bound to the resin has been titrated to a maintenance level while the patient was taking colestipol hydrochloride Bile acid binding resins may also interfere with the absorption of oral phosphate supplements and hydrocortisone Certain other antibiotics aminoglycosides and polymyxin have also been reported to interfere with the nerve transmission at the neuromuscular junction Based on this reported activity they should not be given concomitantly with Coly Mycin M Parenteral except with the greatest caution Curariform muscle relaxants eg tubocurarine and other drugs including ether succinylcholine gallamine decamethonium and sodium citrate potentiate the neuromuscular blocking effect and should be used with extreme caution in patients being treated with Coly Mycin M Parenteral Sodium cephalothin may enhance the nephrotoxicity of Coly Mycin M Parenteral The concomitant use of sodium cephalothin and Coly Mycin M Parenteral should be avoided Digoxin Coadministration of digoxin a P glycoprotein substrate with oral conivaptan resulted in a reduction in clearance and an increase in digoxin Cmax and AUC values Therefore if digoxin is administered with VAPRISOL the clinician should be alert to the possibility of increases in digoxin levels DRUG LABORATORY TEST INTERACTIONS 1 Accelerated prothrombin time partial thromboplastin time and platelet aggregation time increased platelet count increased factors II VII antigen VIII antigen VIII coagulant activity IX X XII VII X complex II VII X complex and beta thromboglobulin decreased levels of anti factor Xa and antithrombin III decreased antithrombin III activity increased levels of fibrinogen and fibrinogen activity increased plasminogen antigen and activity 2 Increased thyroid binding globulin TBG levels leading to increased circulating total thyroid hormone levels as measured by protein bound iodine PBI T4 levels by column or by radioimmunoassay or T3 levels by radioimmunoassay T3 resin uptake is decreased reflecting the elevated TBG Free T4 and free T3 concentrations are unaltered Patients on thyroid replacement therapy may require higher doses of thyroid hormone 3 Other binding proteins may be elevated in serum i e corticosteroid binding globulin CBG sex hormone binding globulin SHBG leading to increased total circulating corticosteroids and sex steroids respectively Free hormone concentrations may be decreased Other plasma proteins may be increased angiotensinogen renin substrate alpha 1 antitrypsin ceruloplasmin 4 Increased plasma HDL and HDL2 cholesterol subfraction concentrations reduced LDL cholesterol concentration increased triglyceride levels 5 Impaired glucose tolerance 6 Reduced response to metyrapone test Corticotropin may accentuate the electrolyte loss associated with diuretic therapy The pharmacokinetic interactions listed below are potentially clinically important Drugs that induce hepatic enzymes such as phenobarbital phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance Therefore the dose of corticosteroid should be titrated to avoid steroid toxicity Corticosteroids may increase the clearance of chronic high dose aspirin This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn Aspirin should be used cautiously in conjunction with cortico steroids in patients suffering from hypopro thrombinemia The effect of corticosteroids on oral anticoagulants is variable There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids Therefore coagulation indices should be monitored to maintain the desired anticoagulant effect Corticotropin may accentuate the electrolyte loss associated with diuretic therapy Drug Interaction During Pregnancy Cromolyn sodium and isoproterenol were studied following subcutaneous injections in pregnant mice Cromolyn sodium alone in doses up to 540 mg kg day approximately 340 times the maximum recommended daily inhalation dose in adults on a mg m2 basis did not cause significant increases in resorptions or major malformations Isoproterenol alone at a dose of 2 7 mg kg day approximately 7 times the maximum recommended daily inhalation dose in adults on a mg m2 basis increased both resorptions and malformations The addition of 540 mg kg day of cromolyn sodium approximately 340 times the maximum recommended daily inhalation dose in adults on a mg m2 basis to 2 7 mg kg day of isoproterenol approximately 7 times the maximum recommended daily inhalation dose in adults on a mg m2 basis appears to have increased the incidence of both resorptions and malformations None known Persons taking most antibiotics methotrexate and pyrimethamine invalidate folic acid and vitamin B12 diagnostic blood assays Colchicine para aminosalicylic acid and heavy alcohol intake for longer than 2 weeks may produce malabsorption of vitamin B12 FLEXERIL may have life threatening interactions with MAO inhibitors FLEXERIL may enhance the effects of alcohol barbiturates and other CNS depressants Tricyclic antidepressants may block the antihypertensive action of guanethidine and similarly acting compounds Tricyclic antidepressants may enhance the seizure risk in patients taking tramadol Cyclopentolate may interfere with the anti glaucoma action of carbachol or pilocarpine also concurrent use of this medication may antagonise the anti glaucoma and miotic actions of ophthalmic cholinesterase inhibitors The rate of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic administration of high doses of phenobarbital The physician should be alert for possible combined drug actions desirable or undesirable involving cyclophosphamide even though cyclophosphamide has been used successfully concurrently with other drugs including other cytotoxic drugs Cyclophosphamide treatment which causes a marked and persistent inhibition of cholinesterase activity potentiates the effect of succinylcholine chloride If a patient has been treated with cyclophosphamide within 10 days of general anesthesia the anesthesiologist should be alerted May interact with wthionamide Trecator SC and isoniazid Nydrazid MAO inhibitors prolong and intensify the anticholinergic effects of antihistamines Antihistamines may have additive effects with alcohol and other CNS depressants e g hypnotics sedatives tranquilizers antianxiety agents No drug interactions have been reported Steady state plasma digitoxin concentrations did not appear to change Therefore monitoring of plasma digoxin levels may be indicated in patients receiving similar combination chemotherapy regimens The utilization of digitoxin for such patients may be considered as an alternative Also flucytosine Drug LaboratoryTest Interactions Dactinomycin may interfere with bioassay procedures for the determination of antibacterial drug levels Dantrium is metabolized by the liver and it is theoretically possible that its metabolism may be enhanced by drugs known to induce hepatic microsomal enzymes However neither phenobarbital nor diazepam appears to affect Dantrium metabolism Binding to plasma protein is not significantly altered by diazepam diphenylhydantoin or phenylbutazone Binding to plasma proteins is reduced by warfarin and clotibrate and increased by tolbutamide Cardiovascular collapse in patients treated simultaneously with varapamil and dantrolene sodium is rare The combination of therapeutic doses of intravenous dantrolene sodium and verapamil in halothane a chloralose anesthetized swine has resulted in ventricular fibrillation and cardiovascular collapse in association with marked hyperkalemia It is recommended that the combination of intravenous dantrolene sodium and calcium channel blockers such as verapamil not be used together during the management of malignant hyperthermia crisis until the relevance of these findings to humans is established Administration of dantrolene may potentiate vecuronium induced neuromuscular block A drug drug interaction study evaluated the effect of the use of ACZONE Gel 5 in combination with double strength 160 mg 800 mg trimethoprim sulfamethoxazole TMP SMX During co administration systemic levels of TMP and SMX were essentially unchanged Notably systemic exposure AUC0 12 of dapsone hydroxylamine DHA was more than doubled in the presence of TMP SMX Exposure from the proposed topical dose is about 1 of that from the 100 mg oral dose even when co administered with TMP SMX Certain concomitant medications such as rifampin anticonvulsants St John s wort may increase the formation of dapsone hydroxylamine a metabolite of dapsone associated with hemolysis With oral dapsone treatment folic acid antagonists such as pyrimethamine have been noted to possibly increase the likelihood of hematologic reactions Warfarin Concomitant administration of daptomycin 6 mg kg once every 24 hours for 5 days and warfarin 25 mg single oral dose had no significant effect on the pharmacokinetics of either drug and the INR was not significantly altered HMG CoA Reductase Inhibitors Inhibitors of HMG CoA reductase may cause myopathy which is manifested as muscle pain or weakness associated with elevated levels of CPK There were no reports of skeletal myopathy in a placebo controlled Phase I trial in which 10 healthy subjects on stable simvastatin therapy were treated concurrently with daptomycin 4 mg kg once every 24 hours for 14 days Experience with co administration of HMG CoA reductase inhibitors and Fentanyl in patients is limited therefore consideration should be given to temporarily suspending use of HMG CoA reductase inhibitors in patients receiving Fentanyl Drug Laboratory Test Interactions There are no reported drug laboratory test interactions No formal drug interaction studies of Aranesp have been performed The daily dose of ENABLEX should not exceed 7 5 mg when coadministered with potent CYP3A4 inhibitors e g ketoconazole itraconazole ritonavir nelfinavir clarithromycin and nefazadone Caution should be taken when ENABLEX is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window such as flecainide thioridazine and tricyclic antidepressants see CLINICAL PHARMACOLOGY The concomitant use of ENABLEX with other anticholinergic agents may increase the frequency and or severity of dry mouth constipation blurred vision and other anticholinergic pharmacological effects Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to effects on gastrointestinal motility Drug Laboratory Test Interactions Interactions between darifenacin and laboratory tests have not been studied Drugs that may increase dasatinib plasma concentrations CYP3A4 Inhibitors Dasatinib is a CYP3A4 substrate Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 eg ketoconazole itraconazole erythromycin clarithromycin ritonavir atazanavir indinavir nefazodone nelfinavir saquinavir telithromycin may increase exposure to dasatinib and should be avoided In patients receiving treatment with SPRYCEL close monitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided Drugs that may decrease dasatinib plasma concentrations CYP3A4 Inducers Drugs that induce CYP3A4 activity may decrease dasatinib plasma concentrations In patients in whom CYP3A4 inducers eg dexamethasone phenytoin carbamazepine rifampicin phenobarbital are indicated alternative agents with less enzyme induction potential should be used If SPRYCEL must be administered with a CYP3A4 inducer a dose increase in SPRYCEL should be considered St Johns wort Hypericum perforatum may decrease SPRYCEL plasma concentrations unpredictably Patients receiving SPRYCEL should not take St Johns wort Antacids Nonclinical data demonstrate that the solubility of dasatinib is pH dependent Simultaneous administration of SPRYCEL with antacids should be avoided If antacid therapy is needed the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL H2 Blockers Proton Pump Inhibitors Long term suppression of gastric acid secretion by H2 blockers or proton pump inhibitors eg famotidine and omeprazole is likely to reduce dasatinib exposure The concomitant use of H2 blockers or proton pump inhibitors with SPRYCEL is not recommended The use of antacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving SPRYCEL therapy Drugs that may have their plasma concentration altered by dasatinib CYP3A4 Substrates Dasatinib is a time dependent inhibitor of CYP3A4 Therefore CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil astemizole terfenadine cisapride cyclosporine fentanyl pimozide quinidine sirolimus tacrolimus or ergot alkaloids ergotamine dihydroergotamine should be administered with caution in patients receiving SPRYCEL Hepatic Impairment There are currently no clinical studies with SPRYCEL in patients with impaired liver function clinical studies have excluded patients with ALT and or AST 2 5 times the upper limit of the normal range and or total bilirubin 2 times the upper limit of the normal range Metabolism of dasatinib is mainly hepatic Caution is recommended in patients with hepatic impairment Renal Impairment There are currently no clinical studies with SPRYCEL in patients with impaired renal function clinical studies have excluded patients with serum creatinine concentration 1 5 times the upper limit of the normal range Dasatinib and its metabolites are minimally excreted via the kidney Since the renal excretion of unchanged dasatinib and its metabolites is 4 a decrease in total body clearance is not expected in patients with renal insufficiency Use of Cerubidine in a patient who has previously received doxorubicin increases the risk of cardiotoxicity Cerubidine should not be used in patients who have previously received the recommended maximum cumulative doses of doxorubicin or Cerubidine Cyclophosphamide used concurrently with Cerubidine may also result in increased cardiotoxicity Dosage reduction of Cerubidine may be required when used concurrently with other myelosuppressive agents Hepatotoxic medications such as high dose methotrexate may impair liver function and increase the risk of toxicity Potentially fatal drug interactions may occur when coadministered with digoxin as this may enhance cardiovascular depression and bradyarrhythmias may occur Anticholinesterases neostgmine physostigmine lignocaine quinine procainamide can enhance toxicity and cause cardio respiratory depression In addition neuromuscular blocking action is enhanced by general anesthetics local anesthetics like lidocaine procaine beta blockers metaclopramide lithium carbonate and terbutaline Drug interaction studies with decitabine have not been conducted In vitro studies in human liver microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes In vitro metabolism studies have suggested that decitabine is not a substrate for the human liver cytochrome P450 enzymes As plasma protein binding of decitabine is negligible 1 interactions due to displacement of more highly protein bound drugs from plasma proteins are not expected The concomitant administration of Exjade and aluminum containing antacid preparations has not been formally studied Although deferasirox has a lower affinity for aluminum than for iron Exjade should not be taken with aluminum containing antacid preparations In healthy volunteers Exjade had no effect on the pharmacokinetics of digoxin The effect of digoxin on Exjade pharmacokinetics has not been studied The concomitant administration of Exjade and vitamin C has not been formally studied Doses of vitamin C up to 200 mg were allowed in clinical studies without negative consequences The interaction of Exjade with hydroxyurea has not been formally studied No inhibition of deferasirox metabolism by hydroxyurea is expected based on the results of an in vitro study Exjade should not be combined with other iron chelator therapies as safety of such combinations has not been established Drug Food Interactions The bioavailability AUC of deferasirox was variably increased when taken with a meal Deferasirox should be taken on an empty stomach 30 minutes before eating Exjade tablets for oral suspension can be dispersed in water orange juice or apple juice Antiacid clarithromycin Didanosine Fluconazole Fluoxetine Indanavir Ketoconazole Phenytoin Phenobarbitol carbamazepine Rifabutin Rifampin Ritanovir Saquinavir Possible drug interactions of HUMORSOL with succinylcholine or with other anticholinesterase agents Because the tetracyclines have been shown to depress plasma prothrombin activity patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage Since bacteriostatic drugs such as the tetracycline class of antibiotics may interfere with the bactericidal action of penicillins it is not advisable to administer these drugs concomitantly Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective Breakthrough bleeding has been reported No clinical drug interaction studies have been conducted However in a single in vivo rodent study denileukin diftitox had no effect on P450 levels Taking a rauwolfia alkaloid while you are taking or within 2 weeks of taking MAO inhibitors may increase the risk of central nervous system depression or may cause a severe high blood pressure reaction No clinically significant adverse interactions with commonly used preanesthetic drugs or drugs used during anesthesia muscle relaxants intravenous agents and local anesthetic agents were reported in clinical trials The effect of desflurane on the disposition of other drugs has not been determined Like isoflurane desflurane does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine 1 Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 debrisoquin hydroxylase is reduced in a subset of the caucasian population about 7 to 10 of caucasians are so called poor metabolizers reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian African and other populations are not yet available Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants TCAs when given usual doses Depending on the traction of drug metabolized by P450 2D6 the increase in plasma concentration may be small or quite large 8 fold increase in plasma AUC of the TCA In addition certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble p o metabolizers An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme quinidine cimetidine and many that are substrates for P450 2D6 many other antidepressants phenothiazines and the Type 1C antiarrhythrnics propatenone and flecainide While all the selective serotonin reuptake inhibitors SSRIs e g fluoxetine seriraline and paroxetine inhibit P450 2D6 they may vary in the extent of inhibition The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved Nevertheless caution is indicated in the co administration of T A with any of the SSRIs and also in switching from one class to the other Of particular importance sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine given the long half life of the parent and active metabolite at least 5 weeks may be necessary Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug Furthermore whenever one of these other drugs is withdrawn from co therapy an increased dose of tricyclic antidepressant may be required It is desirable to monitor TCA plasma levels whenever a TCA is going to be co administered with another drug known to be an inhibitor of P450 2D6 2 Close supervision and careful adjustment of dosage are required when this drug is given concomitantly with anticholinergic or sympathomimetic drugs 3 Clinical experience in the concurrent administration of ECT and antidepressant drugs is limited Thus if such treatment is essential the possibility of increased risk relative to benefits should be considered 4 If desipramine hydrochloride is to be combined with other psychotropic agents such as tranquilizers or sedative hypnotics careful consideration should be given to the pharmacology of the agents employed since the sedative effects of desipramine and benzodiazepines e g chlordiazepoxide or diazepam are additive Both the sedative and anticholinergic effects of the major tranquilizers are also additive to those of desipramine 5 Concurrent administration of cimetidine and tricyclic antidepressants can produce clinically significant increases in the plasma levels of the tricyclic antidepressants Conversely decreases in plasma levels of the tricyclic antidepressants have been reported upon discontinuation of cimetidine which may result in the loss of the therapeutic efficacy of the tricyclic antidepressant 6 There have been greater than two fold increases of previously stable plasma levels of tricyclic antidepressants when fluoxetine has been administered in combination with these agents In two controlled crossover clinical pharmacology studies in healthy male n 12 in each study a nd female n 12 in each study volunteers desloratadine 7 5 mg 1 5 times the daily dose once daily was coadministered with erythromycin 500 mg every 8 hours or ketoconazole 200 mg every 12 hours for 10 days In three separate controlled parallel group clinical pharmacology studies desloratadine at the clinical dose of 5 mg has been coadministered with azithromycin 500 mg followed by 250 mg once daily for 4 days n 18 or with fluoxetine 20 mg once daily for 7 days after a 23 day pretreatment period with fluoxetine n 18 or with cimetidine 600 mg every 12 hours for 14 days n 18 under steady state conditions to normal healthy male and female volunteers Although increased plasma concentrations C max and AUC 0 24 hrs of desloratadine and 3 hydroxydesloratadine were observed there were no clinically relevant changes in the safety profile of desloratadine as assessed by electrocardiographic parameters including the corrected QT interval clinical laboratory tests vital signs and adverse events Table 1 Changes in Desloratadine and 3 Hydroxydesloratadine Pharmacokinetics in Healthy Male and Female Volunteers Desloratadine 3 Hydroxydesloratadine C max AUC 0 24 hrs C max AUC 0 24 hrs Erythromycin 500 mg Q8h 24 14 43 40 Ketoconazole 200 mg Q12h 45 39 43 72 Azithromycin 500 mg day 1 250 mg QD 4 days 15 5 15 4 Fluoxetine 20 mg QD 15 0 17 13 Cimetidine 600 mg Q12h 12 19 11 3 Although the pressor activity of Desmopressin is very low compared to its antidiuretic activity large doses of Desmopressin Tablets should be used with other pressor agents only with careful patient monitoring Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin A similar association though less marked has been suggested with barbiturates phenyl butazone phenytoin sodium carbamazepine and possibly with griseofulvin ampicillin and tetracyclines 72 No specific information available Aminoglutethimide Aminoglutethimide may diminish adrenal suppression by corticosteroids Amphotericin B injection and potassium depleting agents When corticosteroids are administered concomitantly with potassium depleting agents e g amphotericin B diuretics patients should be observed closely for development of hypokalemia In addition there have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure Antibiotics Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance Anticholinesterases Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis If possible anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy Anticoagulants oral Co administration of corticosteroids and warfarin usually results in inhibition of response to warfarin although there have been some conflicting reports Therefore coagulation indices should be monitored frequently to maintain the desired anticoagulant effect Antidiabetics Because corticosteroids may increase blood glucose concentrations dosage adjustments of antidiabetic agents may be required Antitubercular drugs Serum concentrations of isoniazid may be decreased Cholestyramine Cholestyramine may increase the clearance of corticosteroids Cyclosporine Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently Convulsions have been reported with this concurrent use Dexamethasone suppression test DST False negative results in the dexamethasone suppression test DST in patients being treated with indomethacin have been reported Thus results of the DST should be interpreted with caution in these patients Digitalis glycosides Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia Ephedrine Ephedrine may enhance the metabolic clearance of corticosteroids resulting in decreased blood levels and lessened physiologic activity thus requiring an increase in corticosteroid dosage Estrogens including oral contraceptives Estrogens may decrease the hepatic metabolism of certain corticosteroids thereby increasing their effect Hepatic Enzyme Inducers Inhibitors and Substrates Drugs which induce cytochrome P450 3A4 CYP 3A4 enzyme activity e g barbiturates phenytoin carbamazepine rifampin may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased Drugs which inhibit CYP 3A4 e g ketoconazole macrolide antibiotics such as erythromycin have the potential to result in increased plasma concentrations of corticosteroids Dexamethasone is a moderate inducer of CYP 3A4 Co administration with other drugs that are metabolized by CYP 3A4 e g indinavir erythromycin may increase their clearance resulting in decreased plasma concentration Ketoconazole Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60 leading to increased risk of corticosteroid side effects In addition ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal Nonsteroidal anti inflammatory agents NSAIDS Concomitant use of aspirin or other nonsteroidal antiinflammatory agents and corticosteroids increases the risk of gastrointestinal side effects Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia The clearance of salicylates may be increased with concurrent use of corticosteroids Phenytoin In post marketing experience there have been reports of both increases and decreases in phenytoin levels with dexamethasone co administration leading to alterations in seizure control Skin tests Corticosteroids may suppress reactions to skin tests Thalidomide Co administration with thalidomide should be employed cautiously as toxic epidermal necrolysis has been reported with concomitant use Vaccines Patients on corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible Dexbrompheniramine can interact with alcohol or other CNS depressants may potentiate the CNS depressant effects of either these medications or antihistamines anticholinergics or other medications with anticholinergic activity anticholinergic effects may be potentiated when these medications are used concurrently with antihistamines and monoamine oxidase MAO inhibitors concurrent use with antihistamines may prolong and intensify the anticholinergic and CNS depressant effects of antihistamines In patients receiving nonselective monoamine oxidase inhibitors MAOIs e g selegiline hydrochloride in combination with serotoninergic agents e g fluoxetine fluvoxamine paroxetine sertraline venlafaxine there have been reports of serious sometimes fatal reactions Because dexfenfluramine is a serotonin releaser and reuptake inhibitor dexfenfluramine should not be used concomitantly with a MAO inhibitor At least 14 days should elapse between discontinuation of a MAO inhibitor and initiation of treatment with dexfenfluramine At least 3 weeks should elapse between discontinuation of dexfenfluramine and initiation of treatment with a MAO inhibitor A rare but serious constellation of symptoms termed serotonin syndrome has been reported with the concomitant use of selective serotonin reuptake inhibitors SSRIs and agents for migraine therapy such as Imitrex sumatriptan succinate and dihydroergotamine The syndrome requires immediate medical attention and may include one or more of the following symptoms excitement hypomania restlessness loss of consciousness confusion disorientation anxiety agitation motor weakness myoclonus tremor hemiballismus hyperreflexia ataxia dysarthria incoordination hyperthermia shivering pupillary dilation diaphoresis emesis and tachycardia Dexfenfluramine should not be administered with other serotoninergic agents The appropriate interval between administration of these agents and dexfenfluramine has not been established The use of dexfenfluramine with other CNS active drugs has not been systematically evaluated consequently caution is advised if dexfenfluramine and such drugs are prescribed concurrently General In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance Anesthetics Sedatives Hypnotics Opioids Co administration of PRECEDEX with anesthetics sedatives hypnotics and opioids is likely to lead to an enhancement of effects Specific studies have confirmed these effects with sevoflurane isoflurane propofol alfentanil and midazolam No pharmacokinetic interactions between dexmedetomidine and isoflurane propofol alfentanil and midazolam have been demonstrated However due to possible pharmacodynamic interactions when co administered with PRECEDEX a reduction in dosage of PRECEDEX on the concomitant anesthetic sedative hypnotic or opioid may be required Neuromuscular Blockers In one study of 10 healthy volunteers administration of PRECEDEX for 45 minutes at a plasma concentration of 1 one ng mL resulted in no clinically meaningful increases in the magnitude or neuromuscular blockade associated with rocuronium administration ZINECARD does not influence the pharmacokinetics of doxorubicin Carcinogenesis Mutagenesis Impairment of Fertility No long term carcinogenicity studies have been carried out with dexrazoxane in animals Dexrazoxane was not mutagenic in the Ames test but was found to be clastogenic to human lymphocytes in vitro and to mouse bone marrow erythrocytes in vivo micronucleus test The possible adverse effects of ZINECARD on the fertility of humans and experimental animals male or female have not been adequately studied Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg kg weekly for 6 weeks in rats 1 3 the human dose on a mg m 2 basis and as low as 20 mg kg weekly for 13 weeks in dogs approximately equal to the human dose on a mg m 2 basis Acidifying agents Gastrointestinal acidifying agents guanethidine reserpine glutamic acid HCl ascorbic acid fruit juices etc lower absorption of amphetamines Urinary acidifying agents ammonium chloride sodium acid phosphate etc increase the concentration of the ionized species of the amphetamine molecule thereby increasing urinary excretion Both groups of agents lower blood levels and efficacy of amphetamines Adrenergic blockers Adrenergic blockers are inhibited by amphetamines Alkalinizing agents Gastrointestinal alkalinizing agents sodium bicarbonate etc increase absorption of amphetamines Urinary alkalinizing agents acetazolamide some thiazides increase the concentration of the non ionized species of the amphetamine molecule thereby decreasing urinary excretion Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines Antidepressants tricyclic Amphetamines may enhance the activity of tricyclic or sympathomimetic agents d amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d amphetamine in the brain cardiovascular effects can be potentiated MAO inhibitors MAOI antidepressants as well as a metabolite of furazolidone slow amphetamine metabolism This slowing potentiates amphetamines increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings this can cause headaches and other signs of hypertensive crisis A variety of neurological toxic effects and malignant hyperpyrexia can occur sometimes with fatal results Antihistamines Amphetamines may counteract the sedative effect of antihistamines Antihypertensives Amphetamines may antagonize the hypotensive effects of antihypertensives Chlorpromazine Chlorpromazine blocks dopamine and norepinephrine reuptake thus inhibiting the central stimulant effects of amphetamines and can be used to treat amphetamine poisoning Ethosuximide Amphetamines may delay intestinal absorption of ethosuximide Haloperidol Haloperidol blocks dopamine and norepinephrine reuptake thus inhibiting the central stimulant effects of amphetamines Lithium carbonate The stimulatory effects of amphetamines may be inhibited by lithium carbonate Meperidine Amphetamines potentiate the analgesic effect of meperidine Methenamine therapy Urinary excretion of amphetamines is increased and efficacy is reduced by acidifying agents used in methenamine therapy Norepinephrine Amphetamines enhance the adrenergic effect of norepinephrine Phenobarbital Amphetamines may delay intestinal absorption of phenobarbital co administration of phenobarbital may produce a synergistic anticonvulsant action Phenytoin Amphetamines may delay intestinal absorption of phenytoin co administration of phenytoin may produce a synergistic anticonvulsant action Propoxyphene In cases of propoxyphene overdosage amphetamine CNS stimulation is potentiated and fatal convulsions can occur Veratrum alkaloids Amphetamines inhibit the hypotensive effect of veratrum alkaloids Drug Laboratory Test Interactions Amphetamines can cause a significant elevation in plasma corticosteroid levels This increase is greatest in the evening Amphetamines may interfere with urinary steroid determinations Additive depressant effect when used with general anesthetics sedatives antianxiety drugs hypnotics alcohol and other opiate analgesics May interact with thyroid medication e g levothyroxine iodine containing products antacids H2 antagonists e g famotidine ranitidine and proton pump inhibitors e g lansoprazole omeprazole This product can affect the results of certain lab tests Caution is advised in patients receiving concomitant high dose aspirin and carbonic anhydrase inhibitors as anorexia tachypnea lethargy and coma have been rarely reported due to a possible drug interaction Aspirin Concomitant administration of diclofenac and aspirin is not recommended because diclofenac is displaced from its binding sites during the concomitant administration of aspirin resulting in lower plasma concentrations peak plasma levels and AUC values Anticoagulants While studies have not shown diclofenac to interact with anticoagulants of the warfarin type caution should be exercised nonetheless since interactions have been seen with other NSAIDs Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet function as well concurrent therapy with all NSAIDs including diclofenac and warfarin requires close monitoring of patients to be certain that no change in their anticoagulant dosage is required Digoxin Methotrexate Cyclosporine Diclofenac like other NSAIDs may affect renal prostaglandins and increase the toxicity of certain drugs Ingestion of diclofenac may increase serum concentrations of digoxin and methotrexate and increase cyclosporine s nephrotoxicity Patients who begin taking diclofenac or who increase their diclofenac dose or any other NSAID while taking digoxin methotrexate or cyclosporine may develop toxicity characteristics for these drugs They should be observed closely particularly if renal function is impaired In the case of digoxin serum levels should be monitored Lithium Diclofenac decreases lithium renal clearance and increases lithium plasma levels In patients taking diclofenac and lithium concomitantly lithium toxicity may develop Oral Hypoglycemics Diclofenac does not alter glucose metabolism in normal subjects nor does it alter the effects of oral hypoglycemic agents There are rare reports however from marketing experiences of changes in effects of insulin or oral hypoglycemic agents in the presence of diclofenac that necessitated changes in the doses of such agents Both hypo and hyperglycemic effects have been reported A direct causal relationship has not been established but physicians should consider the possibility that diclofenac may alter a diabetic patient s response to insulin or oral hypoglycemic agents Diuretics Diclofenac and other NSAIDs can inhibit the activity of diuretics Concomitant treatment with potassium sparing diuretics may be associated with increased serum potassium levels Other Drugs In small groups of patients 7 10 interaction study the concomitant administration of azathioprine gold chloroquine D penicillamine prednisolone doxycycline or digitoxin did not significantly affect the peak levels and AUC values of diclofenac Phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment following the initiation of diclofenac therapy Protein Binding In vitro diclofenac interferes minimally or not at all with the protein binding of salicylic acid 20 decrease in binding tolbutamide prednisolone 10 decrease in binding or warfarin Benzylpenicillin ampicillin oxacillin chlortetracycline doxycycline cephalothin erythromycin and sulfamethoxazole have no influence in vitro on the protein binding of diclofenac in human serum Drug Laboratory Test Interactions Effect on Blood Coagulation Diclofenac increases platelet aggregation time but does not affect bleeding time plasma thrombin clotting time plasma fibrinogen or factors V and VII to XII Statistically significant changes in prothrombin and partial thromboplastin times have been reported in normal volunteers The mean changes were observed to be less than 1 second in both instances however and are unlikely to be clinically important Diclofenac is a prostaglandin synthetase inhibitor however and all drugs that inhibit prostaglandin synthesis interfere with platelet function to some degree therefore patients who may be adversely affected by such an action should be carefully observed Tetracycline a bacteriostatic antibiotic may antagonize the bactercidal effect of penicillin and concurrent use of these drugs should be avoided The following agents may increase certain actions or side effects of anticholinergic drugs amantadine antiarrhythmic agents of class e g quinidine antihistamines antipsychotic agents e g phenothiazines benzodiazepines MAO inhibitors narcotic analgesics e g meperidine nitrates and nitrites sympathomimetic agents tricyclic antidepressants and other drugs having anticholinergic activity Anticholinergics antagonize the effects of antiglaucoma agents Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corti costeroids Anticholinergic agents may affect gastrointestinal absorption of various drugs such as slowly dissolving dosage forms of digoxin increased serum digoxin concentrations may result Anticholinergic drugs may antagonize the effects of the drugs that alter gastrointestinal motility such as metoclopramide Because antacids may interfere with the absorption of anticholinergic agents simultaneous use of these drugs should be avoided The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion Coadministration of VIDEX with drugs that are known to cause pancreatitis may increase the risk of this toxicity see WARNINGS and should be done with extreme caution only if other alternatives are not available and only if clearly indicated Neuropathy has occurred more frequently in patients with a history of neuropathy or neurotoxic drug therapy including stavudine and these patients may be at increased risk of neuropathy during VIDEX therapy see ADVERSE REACTIONS Allopurinol The AUC of didanosine was increased about 4 fold when allopurinol at 300 mg day was coadministered with a single 200 mg dose of VIDEX to two patients with renal impairment CLcr 15 and 18 mL min The effects of allopurinol on didanosine pharmacokinetics in subjects with normal renal function are not known Antacids Concomitant administration of antacids containing magnesium or aluminum with VIDEX Chewable Dispersible Buffered Tablets or Pediatric Powder for Oral Solution may potentiate adverse events associated with the antacid components Drugs Whose Absorption Can Be Affected by the Level of Acidity in the Stomach Drugs such as ketoconazole and itraconazole should be administered at least 2 hours prior to dosing with VIDEX Ganciclovir Administration of VIDEX 2 hours prior to or concurrent with oral ganciclovir was associated with a 111 114 increase in the steady state AUC of didanosine n 12 A 21 17 decrease in the steady state AUC of ganciclovir was observed when VIDEX was administered 2 hours prior to ganciclovir but not when the two drugs were administered simultaneously n 12 Quinolone Antibiotics VIDEX should be administered at least 2 hours after or 6 hours before dosing with ciprofloxacin because plasma concentrations of ciprofloxacin are decreased when administered with antacids containing magnesium calcium or aluminum In eight HIV infected patients the steady state AUC of ciprofloxacin was decreased an average of 26 95 CI 14 37 when ciprofloxacin was administered 2 hours prior to a marketed chewable dispersible tablet formulation of VIDEX The AUC of ciprofloxacin was decreased an average of 15 fold in 12 healthy subjects given ciprofloxacin and didanosine placebo tablets concurrently In a single subject given one dose of ciprofloxacin 2 hours after a dose of didanosine placebo tablets a greater than 50 reduction in the AUC of ciprofloxacin was observed Plasma concentrations of quinolone antibiotics are decreased when administered with antacids containing magnesium calcium or aluminum The optimal dosing interval for coadministration with VIDEX should be determined by consulting the appropriate quinolone package insert Interactions with Other Antiretroviral Drugs Significant decreases in the AUC of delavirdine 20 and indinavir 84 occurred following simultaneous administration of these agents with VIDEX To avoid this interaction delavirdine or indinavir should be given 1 hour prior to dosing with VIDEX The pharmacokinetics of nelfinavir are not altered to a clinically significant degree when it is administered with a light meal 1 hour after VIDEX Drug Laboratory Test Interactions Certain endocrine and liver function tests may be affected by estrogen containing oral contraceptives The following similar changes may be expected with larger doses of estrogen Increased sulfobromophthalein retention Increased prothrombin and factors VII VIII IX and X decreased antithrombin 3 increased norepinephrine induced platelet aggregability Increased thyroid binding globulin TBG leading to in creased circulating total thyroid hormone as measured by PBI T4 by column or T4 by radioimmunoassay Free T3 resin uptake is decreased reflecting the elevated TBG free T4 concentration is unaltered Impaired glucose tolerance Decreased pregnanediol excretion Reduced response to metyrapone test Reduced serum folate concentration Increased serum triglyceride and phospholipid concentration Antidiabetic drug requirements i e insulin may be altered Concurrent use with general anesthetics may result in arrhythmias The pressor effects of diethylpropion and those of other drugs may be additive when the drugs are used concomitantly conversely diethylpropion may interfere with antihypertensive drugs i e guanethidine a methyldopa Concurrent use of phenothiazines may antagonize the anorectic effect of diethylpropion May interact anticoagulants altered hypo prothrombinemic effect barbiturates rifampin and other inducers of hepatic microsomal enzyme oxidation system decreased effect of diethylstilbestrol corticosteroids increased effect of corticosteroids Oral Anticoagulants In some normal volunteers the concomitant administration of diflunisal and warfarin acenocoumarol or phenprocoumon resulted in prolongation of prothrombin time This may occur because diflunisal competitively displaces coumarins from protein binding sites Accordingly when diflunisal is administered with oral anticoagulants the prothrombin time should be closely monitored during and for several days after concomitant drug administration Adjustment of dosage of oral anticoagulants may be required Tolbutamide In diabetic patients receiving diflunisal and tolbutamide no significant effects were seen on tolbutamide plasma levels or fasting blood glucose Hydrochlorothiazide In normal volunteers concomitant administration of diflunisal and hydrochlorothiazide resulted in significantly increased plasma levels of hydrochlorothiazide Diflunisal decreased the hyperuricemic effect of hydrochlorothiazide Furosemide In normal volunteers the concomitant administration of diflunisal and furosemide had no effect on the diuretic activity of furosemide Diflunisal decreased the hyperuricemic effect of furosemide Antacids Concomitant administration of antacids may reduce plasma levels of diflunisal This effect is small with occasional doses of antacids but may be clinically significant when antacids are used on a continuous schedule Acetaminophen In normal volunteers concomitant administration of diflunisal and acetaminophen resulted in an approximate 50 increase in plasma levels of acetaminophen Acetaminophen had no effect on plasma levels of diflunisal Since acetaminophen in high doses has been associated with hepatotoxicity concomitant administration of diflunisal and acetaminophen should be used cautiously with careful monitoring of patients Concomitant administration of diflunisal and acetaminophen in dogs but not in rats at approximately 2 times the recommended maximum human therapeutic dose of each 40 to 52 mg kg day of diflunisal acetaminophen resulted in greater gastrointestinal toxicity than when either drug was administered alone The clinical significance of these findings has not been established Methotrexate Caution should be used if diflunisal is administered concomitantly with methotrexate Nonsteroidal anti inflammatory drugs have been reported to decrease the tubular secretion of methotrexate and to potentiate its toxicity Cyclosporine Administration of nonsteroial anti inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine induced toxicity possibly due to decreased synthesis of renal prostacyclin NSAIDs should be used with caution in patients taking cyclosporine and renal function should be carefully monitored Nonsteroidal Anti Inflammatory Drugs The administration of diflunisal to normal volunteers receiving indomethacin decreased the renal clearance and significantly increased the plasma levels of indomethacin In some patients the combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage Therefore indomethacin and diflunisal should not be used concomitantly The concomitant use of diflunisal tablets and other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity with little or no increase in efficacy The following information was obtained from studies in normal volunteers Aspirin In normal volunteers a small decrease in diflunisal levels was observed when multiple doses of diflunisal and aspirin were administered concomitantly Sulindac The concomitant administration of diflunisal and sulindac in normal volunteers resulted in lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one third Naproxen The concomitant administration of diflunisal and naproxen in normal volunteers had no effect on the plasma levels of naproxen but significantly decreased the urinary excretion of naproxen and its glucuronide metabolite Naproxen had no effect on plasma levels of diflunisal Drug laboratory Test Interactions Serum Salicylate Assays Caution should be used in interpreting the results of serum salicylate assays when diflunisal is present Salicylate levels have been found to be falsely elevated with some assay methods Potassium depleting diuretics are a major contributing factor to digitalis toxicity Calcium particularly if administered rapidly by the intravenous route may produce serious arrhythmias in digitalized patients Quinidine verapamil amiodarone propafenone indomethacin itraconazole alprazolam and spironolactone raise the serum digoxin concentration due to a reduction in clearance and or in volume of distribution of the drug with the implication that digitalis intoxication may result Erythromycin and clarithromycin and possibly other macrolide antibiotics and tetracycline may increase digoxin absorption in patients who inactivate digoxin by bacterial metabolism in the lower intestine so that digitalis intoxication may result The risk of this interaction may be reduced if digoxin is given as capsules Propantheline and diphenoxylate by decreasing gut motility may increase digoxin absorption Antacids kaolin pectin sulfasalazine neomycin cholestyramine certain anticancer drugs and metoclopramide may interfere with intestinal digoxin absorption resulting in unexpectedly low serum concentrations Rifampin may decrease serum digoxin concentration especially in patients with renal dysfunction by increasing the non renal clearance of digoxin There have been inconsistent reports regarding the effects of other drugs e g quinine penicillamine on serum digoxin concentration Thyroid administration to a digitalized hypothyroid patient may increase the dose requirement of digoxin Concomitant use of digoxin and sympathomimetics increases the risk of cardiac arrhythmias Succinylcholine may cause a sudden extrusion of potassium from muscle cells and may thereby cause arrhythmias in digitalized patients Although beta adrenergic blockers or calcium channel blockers and digoxin may be useful in combination to control atrial fibrillation their additive effects on AV node conduction can result in advanced or complete heart block Due to the considerable variability of these interactions the dosage of digoxin should be individualized when patients receive these medications concurrently Furthermore caution should be exercised when combining digoxin with any drug that may cause a significant deterioration in renal function since a decline in glomerular filtration or tubular secretion may impair the excretion of digoxin Vasoconstrictors D H E 45 dihydroergotamine mesylate Injection USP should not be used with peripheral vasoconstrictors because the combination may cause synergistic elevation of blood pressure Sumatriptan Sumatriptan has been reported to cause coronary artery vasospasm and its effect could be additive with D H E 45 dihydroergotamine mesylate Injection USP Sumatriptan and D H E 45 dihydroergotamine mesylate Injection USP should not be taken within 24 hours of each other Beta Blockers Although the results of a clinical study did not indicate a safe problem associated with the administration of D H E 45 dihydroergotamine mesylate Injection USP to subjects already receiving propranolol there have been reports that propranolol may potentiate the vasoconstrictive action of ergotamine by blocking the vasodilating property of epinephrine Nicotine Nicotine may provoke vasoconstriction in some patients predisposing to a greater ischemic response to ergot therapy Macrolide Antibiotics e g erythromycin and troleandomycin Agents of the ergot alkaloid class of which D H E 45 dihydroergotamine mesylate Injection USP is a member have been shown to interact with antibiotics of the macrolide class resulting in increased plasma levels of unchanged alkaloids and peripheral vasoconstriction Vasospastic reactions have been reported with therapeutic doses of ergotamine containing drugs when co administered with these antibiotics SSRIs Weakness hyperreflexia and incoordination have been reported rarely when 5 HT1 agonists have been co administered with SSRIs e g fluoxetine fluvoxamine paroxetine sertraline There have been no reported cases from spontaneous reports of drug interaction between SSRIs and D H E 45 dihydroergotamine mesylate Injection USP Oral Contraceptives The effect of oral contraceptives on the pharmacokinetics of D H E 45 dihydroergotamine mesylate Injection USP has not been studied Administration of thiazide diuretics to hypoparathyroid patients who are concurrently being treated with dihydrotachysterol may cause hypercalcemia Due to the potential for additive effects caution and careful titration are warranted in patients receiving diltiazem hydrochloride concomitantly with other agents known to affect cardiac contractility and or conduction Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta blockers or digitalis concomitantly with Tiazac As with all drugs care should be exercised when treating patients with multiple medications Diltiazem is both a substrate and an inhibitor of the cytochrome P 450 3A4 enzyme system Other drugs that are specific substrates inhibitors or inducers of the enzyme system may have a significant impact on the efficacy and side effect profile of diltiazem Patients taking other drugs that are substrates of CYP450 3A4 especially patients with renal and or hepatic impairment may require dosage adjustment when starting or stopping concomitantly administered diltiazem in order to maintain optimum therapeutic blood levels Beta Blockers Controlled and uncontrolled domestic studies suggest that concomitant use of diltiazem hydrochloride and beta blockers is usually well tolerated but available data are not sufficient to predict the effects of concomitant treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities Administration of diltiazem hydrochloride concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects and bioavailability of propranolol was increased approximately 50 In vitro propranolol appears to be displaced from its binding sites by diltiazem If combination therapy is initiated or withdrawn in conjunction with propranolol an adjustment in the propranolol dose may be warranted Cimetidine A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels 58 and AUC 53 after a 1 week course of cimetidine 1200 mg day and a single dose of diltiazem 60mg Ranitidine produced smaller nonsignificant increases The effect may be mediated by cimetidines known inhibition of hepatic cytochrome P 450 the enzyme system responsible for the first pass metabolism of diltiazem Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine An adjustment in the diltiazem dose may be warranted Digitalis Administration of diltiazem hydrochloride with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20 Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease Since there have been conflicting results regarding the effect of digoxin levels it is recommended that digoxin levels be monitored when initiating adjusting and discontinuing diltiazem hydrochloride therapy to avoid possible over or under digitalization Anesthetics The depression of cardiac contractility conductivity and automaticity as well as the vascular dilation associated with anesthetics may be potentiated by calcium channel blockers When used concomitantly anesthetics and calcium channel blockers should be titrated carefully Cyclosporine A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients In renal and cardiac transplant recipients a reduction of cyclosporine dose ranging from 15 to 48 was necessary to maintain cyclosporine trough concentrations similar to those seen prior to the addition of diltiazem If these agents are to be administered concurrently cyclosporine concentrations should be monitored especially when diltiazem therapy is initiated adjusted or discontinued The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated Carbamazepine Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine 40 to 72 increase resulting in toxicity in some cases Patients receiving these drugs concurrently should be monitored for a potential drug interaction Benzodiazepines Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3 4 fold and the Cmax by 2 fold compared to placebo The elimination half life of midazolam and triazolam also increased 1 5 2 5 fold during coadministration with diltiazem These pharmacokinetic effects seen during diltiazem coadministration can result in increased clinical effects e g prolonged sodation of both midazolam and triazolam Lovastatin In a ten subject study coadministration of diltiazem 120 mg bid with lovastatin resulted in a 3 4 times increase in mean lovastatin AUC and Cmax vs lovastatin alone no change in pravastatin AUC and Cmax was observed during diltiazem coadministration Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin Rifampin Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible and alternative therapy considered Dimenhydrinate may decrease emetic response to apomorphine Oxytocin or other oxytocics concurrent use with dinoprost may result in uterine hypertonus possibly causing uterine rupture or cervical laceration especially in the absence of adequate cervical dilatation although combinations are sometimes used for therapeutic advantage when used concurrently patient should be closely monitored PROSTIN E2 may augment the activity of other oxytocic drugs Concomitant use with other oxytocic agents is not recommended Diphenhydramine hydrochloride has additive effects with alcohol and other CNS depressants hypnotics sedatives tranquilizers etc MAO inhibitors prolong and intensify the anticholinergic drying effects of antihistamines CNS depression producing medications concurrent use may potentiate the effects of either these medications or diphenidol anticholinergics or other medications with anticholinergic activity anticholinergic effects may be potentiated when these medications are used concurrently with diphenidol apomorphine prior ingestion of diphenidol may decrease the emetic response to apomorphine in the treatment of poisoning Known drug interactions include barbiturates tranquilizers and alcohol Diphenoxylate HCl and atropine sulfate may interact with MAO inhibitors In studies with male rats diphenoxylate hydrochloride was found to inhibit the hepatic microsomal enzyme system at a dose of 2 mg kg day Therefore diphenoxylate has the potential to prolong the biological half lives of drugs for which the rate of elimination is dependent on the microsomal drug metabolizing enzyme system This drug may interact with alcohol or other CNS depressants may potentiate the CNS depressant effects of either these medications or antihistamines anticholinergics or other medications with anticholinergic activity anticholinergic effects may be potentiated when these medications are used concurrently with antihistamines and monoamine oxidase MAO inhibitors concurrent use with antihistamines may prolong and intensify the anticholinergic and CNS depressant effects of antihistamines No pharmacokinetic drug drug interaction studies were conducted with PERSANTINE dipyridamole USP Tablets The following information was obtained from the literature Adenosine Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine Adjustment of adenosine dosage may be necessary Cholinesterase Inhibitors Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors thereby potentially aggravating myasthenia gravis Terfenadine In a prospective study involving six healthy male volunteers dirithromycin did not affect the metabolism of terfenadine These six volunteers received terfenadine alone 60 mg twice daily for 8 days followed by terfenadine in combination with dirithromycin 500 mg once daily for 10 days Both drugs were thus dosed to steady state The pharmacokinetics of terfenadine and its acid metabolite and the electrocardiographic QT c interval were measured during both periods with terfenadine alone and with terfenadine plus dirithromycin In five men terfenadine levels were undetectable 5 ng mL throughout the study in one man the C max of terfenadine was 8 1 ng mL with terfenadine alone and 7 2 ng mL with terfenadine plus dirithromycin The mean C max T max and AUC of the acid metabolite of terfenadine were not significantly changed The mean QT c interval msec was 369 with terfenadine alone and 367 with terfenadine plus dirithromycin Also in vitro experiments demonstrated a lack of interaction between dirithromycin and terfenadine Thus the interaction observed between erythromycin and terfenadine is not expected for dirithromycin Serious cardiac dysrhythmias some resulting in death have occurred in patients receiving terfenadine concomitantly with other macrolide antibiotics In addition most macrolides are contraindicated in patients receiving terfenadine therapy who have pre existing cardiac abnormalities arrhythmia bradycardia QT c interval prolongation ischemic heart disease congestive heart failure etc or electrolyte disturbances Theophylline Following co administration of two 250 mg dirithromycin tablets administered once daily with 200 mg theophylline tablets administered twice daily for 10 days to 14 healthy subjects the steady state plasma concentration of theophylline was not significantly altered In general most patients treated with dirithromycin who are receiving concomitant theophylline therapy may not require empiric adjustment of theophylline dosage or monitoring of theophylline plasma concentrations However theophylline plasma concentrations should be monitored with dosage adjustment as appropriate in patients whose pulmonary disease requires maintaining a given theophylline plasma concentration for optimal pulmonary function or in patients with theophylline concentrations at the higher end of the therapeutic range Antacids or H 2 receptor antagonists When dirithromycin is administered immediately following antacids or H 2 receptor antagonists the absorption of dirithromycin is slightly enhanced The following drug interactions have been reported with erythromycin products It is presently not known whether these same drug interactions occur with dirithromycin Until further data are available regarding the potential interaction of dirithromycin with these compounds caution should be used during coadministration Triazolam Erythromycin has been reported to decrease the clearance of triazolam and thus may increase the pharmacologic effect of triazolam Digoxin Concomitant administration of erythromycin and digoxin has been reported to result in elevated digoxin serum levels Anticoagulants There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants were used concomitantly Increased anticoagulation effects due to a drug interaction with erythromycin may be more pronounced in the elderly Ergotamine Concurrent use of erythromycin and ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia Other drugs Drug interactions have been reported with concomitant administration of erythromycin and other medications including cyclosporine hexobarbital carbamazepine alfentanil disopyramide phenytoin bromocriptine valproate astemizole and lovastatin If phenytoin or other hepatic enzyme inducers are taken concurrently with Norpace or Norpace CR lower plasma levels of disopyramide may occur Monitoring of disopyramide plasma levels is recommended in such concurrent use to avoid ineffective therapy Other antiarrhythmic drugs eg quinidine procainamide lidocaine propranolol have occasionally been used concurrently with Norpace Excessive widening of the QRS complex and or prolongation of the Q T interval may occur in these situations In healthy subjects no significant drug drug interaction was observed when Norpace was coadministered with either propranolol or diazepam Concomitant administration of Norpace and quinidine resulted in slight increases in plasma disopyramide levels and slight decreases in plasma quinidine levels Norpace does not increase serum digoxin levels Patients taking disopyramide phosphate and erythromycin concomitantly may develop increased serum concentrations of disopyramide resulting in excessive widening of the QRS complex and or prolongation of the Q T interval Patients taking disopyramide phosphate and hepatic enzyme inhibitors concomitantly should be closely monitored Until data on possible interactions between verapamil and disopyramide phosphate are obtained disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration Disulfiram appears to decrease the rate at which certain drugs are metabolized and therefore may increase the blood levels and the possibility of clinical toxicity of drugs given concomitantly DISULFIRAM SHOULD BE USED WITH CAUTION IN THOSE PATIENTS REVEIVING PHENYTOIN AND ITS CONGENERS SINCE THE CONCOMITANT ADMINISTRATION OF THESE TWO DRUGS CAN LEAD TO PHENYTOIN INTOXICATION PRIOR TO ADMINISTERING DISULFIRAM TO A PATIENT ON PHENYTOIN THERAPY A BASELINE PHENYTOIN SERUM LEVEL SHOULD BE OBTAINED SUBSEQUENT TO INITIATION OF DISULFIRAM THERAPY SERUM LEVELS OF PHENYTOIN SHOULD BE DETERMINED ON DIFFERENT DAYS FOR EVIDENCE OF AN INCREASE OR FOR A CONTINUING RISE IN LEVELS INCREASED PHENYTOIN LEVELS SHOULD BE TREATED WITH APPROPRIATE DOSAGE ADJUSTMENT It may be necessary to adjust the dosage of oral anticoagulants upon beginning or stopping disulfiram since disulfiram may prolong prothrombin time Patients taking isoniazid when disulfiram is given should be observed for the appearance of unsteady gait or marked changes in mental status the disulfiram should be discontinued if such signs appear In rats simultaneous ingestion of disulfiram and nitrite in the diet for 78 weeks has been reported to cause tumors and it has been suggested that disulfiram may react with nitrites in the rat stomach to form a nitrosamine which is tumorigenic Disulfiram alone in the rat s diet did not lead to such tumors The relevance of this finding to humans is not known at this time Animal studies indicate that dobutamine may be ineffective if the patient has recently received a b blocking drug In such a case the peripheral vascular resistance may increase Preliminary studies indicate that the concomitant use of dobutamine and nitroprusside results in a higher cardiac output and usually a lower pulmonary wedge pressure than when either drug is used alone There was no evidence of drug interactions in clinical studies in which dobutamine was administered concurrently with other drugs including digitalis preparations furosemide spironolactone lidocaine glyceryl trinitrate isosorbide dinitrate morphine atropine heparin protamine potassium chloride folic acid and acetaminophen There have been no formal clinical studies to evaluate the drug interactions of TAXOTERE with other medications In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce inhibit or are metabolized by cytochrome P450 3A4 such as cyclosporine terfenadine ketoconazole erythromycin and troleandomycin Caution should be exercised with these drugs when treating patients receiving TAXOTERE as there is a potential for a significant interaction Drug Laboratory Test Interactions None known Drug Drug Interactions Cimetidine Concomitant use of cimetidine is contraindicated Cimetidine at 400 mg BID the usual prescription dose co administered with TIKOSYN 500 mcg BID for 7 days has been shown to increase dofetilide plasma levels by 58 Cimetidine at doses of 100 mg BID OTC dose resulted in a 13 increase in dofetilide plasma levels 500 mcg single dose No studies have been conducted at intermediate doses of cimetidine If a patient requires TIKOSYN and anti ulcer therapy it is suggested that omeprazole ranitidine or antacids aluminum and magnesium hydroxides be used as alternatives to cimetidine as these agents have no effect on the pharmacokinetic profile of TIKOSYN Verapamil Concomitant use of verapamil is contraindicated Co administration of TIKOSYN with verapamil resulted in increases in dofetilide peak plasma levels of 42 although overall exposure to dofetilide was not significantly increased In an analysis of the supraventricular arrhythmia and DIAMOND patient populations the concomitant administration of verapamil with dofetilide was associated with a higher occurrence of torsade de pointes Ketoconazole Concomitant use of ketoconazole is contraindicated Ketoconazole at 400 mg daily the maximum approved prescription dose co administered with TIKOSYN 500 mcg BID for 7 days has been shown to increase dofetilide Cmax by 53 in males and 97 in females and AUC by 41 in males and 69 in females Trimethoprim Alone or in Combination with Sulfamethoxazole Concomitant use of trimethoprim alone or in combination with sulfamethoxazole is contraindicated Hydrochlorothiazide HCTZ Alone or in Combination with Triamterene Concomitant use of HCTZ alone or in combination with triamterene is contraindicated HCTZ 50 mg QD or HCTZ triamterene 50 100 mg QD was co administered with TIKOSYN 500 mcg BID for 5 days following 2 days of diuretic use at half dose In patients receiving HCTZ alone dofetilide AUC increased by 27 and Cmax by 21 However the pharmacodynamic effect increased by 197 QTc increase over time and by 95 maximum QTc increase However the pharmacodynamic effect increased by 190 QTc increase over time and by 84 Maximum QTc increase The pharmacodynamic effects can be explained by a combination of the increase in dofetilide exposure and the reductions in serum potassium In the DIAMOND trials 1252 patients were treated with TIKOSYN and diuretics concomitantly of whom 493 died compared to 508 deaths among the 1248 patients receiving placebo and diuretics Of the 229 patients who had potassium depleting diuretics added to their concomitant medications in the DIAMOND trials the patients on TIKOSYN had a non significantly reduced relative risk for death of 0 68 95 CI 0 376 1 230 Potential Drug Interactions Dofetilide is eliminated in the kidney by cationic secretion Inhibitors of renal cationic secretion are contraindicated with TIKOSYN In addition drugs that are actively secreted via this route e g triamterene metformin and amiloride should be co administered with care as they might increase dofetilide levels Dofetilide is metabolized to a small extent by the CYP3A4 isoenzyme of the cytochrome P450 system Inhibitors of the CYP3A4 isoenzyme could increase systemic dofetilide exposure Inhibitors of this isoenzyme e g macrolide antibiotics azole antifungal agents protease inhibitors serotonin reuptake inhibitors amiodarone cannabinoids diltiazem grapefruit juice nefazadone norfloxacin quinine zafirlukast should be cautiously coadministered with TIKOSYN as they can potentially increase dofetilide levels Dofetilide is not an inhibitor of CYP3A4 nor of other cytochrome P450 isoenzymes e g CYP2C9 CYP2D6 and is not expected to increase levels of drugs metabolized by CYP3A4 Other Drug Interaction Information Digoxin Studies in healthy volunteers have shown that TIKOSYN does not affect the pharmacokinetics of digoxin In patients the concomitant administration of digoxin with dofetilide was associated with a higher occurrence of torsade de pointes It is not clear whether this represents an interaction with TIKOSYN or the presence of more severe structural heart disease in patients on digoxin structural heart disease is a known risk factor for arrhythmia No increase in mortality was observed in patients taking digoxin as concomitant medication Other Drugs In healthy volunteers amlodipine phenytoin glyburide ranitidine omeprazole hormone replacement therapy a combination of conjugated estrogens and medroxyprogesterone antacid aluminum and magnesium hydroxides and theophylline did not affect the pharmacokinetics of TIKOSYN In addition studies in healthy volunteers have shown that TIKOSYN does not affect the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of propranolol 40 mg twice daily phenytoin theophylline or oral contraceptives Population pharmacokinetic analyses were conducted on plasma concentration data from 1445 patients in clinical trials to examine the effects of concomitant medications on clearance or volume of distribution of dofetilide Concomitant medications were grouped as ACE inhibitors oral anticoagulants calcium channel blockers beta blockers cardiac glycosides inducers of CYP3A4 substrates and inhibitors of CYP3A4 substrates and inhibitors of P glycoprotein nitrates sulphonylureas loop diuretics potassium sparing diuretics thiazide diuretics substrates and inhibitors of tubular organic cation transport and QTc prolonging drugs Differences in clearance between patients on these medications at any occasion in the study and those off medications varied between 16 and 3 The mean clearances of dofetilide were 16 and 15 lower in patients on thiazide diuretics and inhibitors of tubular organic cation transport respectively The potential for clinically significant drug drug interactions posed by dolasetron and hydrodolasetron appears to be low for drugs commonly used in chemotherapy or surgery because hydrodolasetron is eliminated by multiple routes Blood levels of hydrodolasetron increased 24 when dolasetron was coadministered with cimetidine nonselective inhibitor of cytochrome P 450 for 7 days and decreased 28 with coadministration of rifampin potent inducer of cytochrome P 450 for 7 days Dolasetron has been safely coadministered with drugs used in chemotherapy and surgery As with other agents which prolong ECG intervals caution should be exercised in patients taking drugs which prolong ECG intervals particularly QTc In patients taking furosemide nifedipine diltiazem ACE inhibitors verapamil glyburide propranolol and various chemotherapy agents no effect was shown on the clearance of hydrodolasetron Clearance of hydrodolasetron decreased by about 27 when dolasetron mesylate was administered intravenously concomitantly with atenolol Dolasetron does not influence anesthesia recovery time in patients Dolasetron mesylate did not inhibit the antitumor activity of four chemotherapeutic agents cisplatin 5 fluorouracil doxorubicin cyclophosphamide in four murine models Drugs that inhibit or Induce CYP 2D6 and CYP 3A4 may affect the concentration on Aricept Because dopamine is metabolized by monoamine oxidase MAO inhibition of this enzyme prolongs and potentiates the effect of dopamine Patients who have been treated with MAO inhibitors within two to three weeks prior to the administration of dopamine HCl should receive initial doses of dopamine HCl no greater than one tenth 1 10 of the usual dose Concurrent administration of low dose dopamine HCl and diuretic agents may produce an additive or potentiating effect on urine flow Tricyclic antidepressants may potentiate the cardiovascular effects of adreneric agents Cardiac effects of dopamine are antagonized by beta adrenergic blocking agents such as propranolol and metoprolol The peripheral vasoconstriction caused by high doses of dopamine HCl is antagonized by alpha adrenergic blocking agents Dopamine induced renal and mesenteric vasodilation is not antagonized by either alpha or beta adrenergic blocking agents Butyrophenones such as haloperidol and phenothiazines can suppress the dopaminergic renal and mesenteric vasodilation induced with low dose dopamine infusion Cyclopropane or halogenated hydrocarbon anesthetics increase cardiac autonomic irritability and may sensitize the myocardium to the action of certain intravenously administered catecholamines such as dopamine This interaction appears to be related both to pressor activity and to beta adrenergic stimulating properties of these catecholamines and may produce ventricular arrhythmias and hypertension Therefore EXTREME CAUTION should be exercised when administering dopamine HCl to patients receiving cyclopropane or halogenated hydrocarbon anesthetics It has been reported that results of studies in animals indicate that dopamine induced ventricular arrhythmias during anesthesia can be reversed by propranolol The concomitant use of vasopressors vasoconstricting agents such as ergonovine and some oxytocic drugs may result in severe hypertension Administration of phenytoin to patients receiving dopamine HCl has been reported to lead to hypotension and bradycardia It is suggested that in patients receiving dopamine HCl alternatives to phenytoin should be used if anticonvulsant therapy is needed Clinical trials have indicated that Pulmozyme can be effectively and safely used in conjunction with standard cystic fibrosis therapies including oral inhaled and or parenteral antibiotics bronchodilators enzyme supplements vitamins oral or inhaled corticosteroids and analgesics No formal drug interaction studies have been performed Although acid base and electrolyte disturbances were not reported in the clinical trials with dorzolamide these disturbances have been reported with oral carbonic anhydrase inhibitors and have in some instances resulted in drug interactions e g toxicity associated with high dose salicylate therapy Therefore the potential for such drug interactions should be considered in patients receiving dorzolamide Prior administration of succinylcholine has no clinically important effect on the neuromuscular blocking action of NUROMAX The use of NUROMAX before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied There are no clinical data on concomitant use of NUROMAX and other nondepolarizing neuromuscular blocking agents Isoflurane enflurane and halothane decrease the ED50 of NUROMAX by 30 to 45 These agents may also prolong the clinically effective duration of action by up to 25 Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as NUROMAX include certain antibiotics e g aminoglycosides tetracyclines bacitracin polymyxins lincomycin clindamycin colistin and sodium colistimethate magnesium salts lithium local anesthetics procainamide and quinidine As with some other nondepolarizing neuromuscular blocking agents the time of onset of neuromuscular block induced by NUROMAX is lengthened and the duration of block is shortened in patients receiving phenytoin or carbamazepine Administration of doxapram to patients who are receiving sympathomimetic or monoamine oxidase inhibiting drugs may result in an additive pressor effect In patients who have received muscle relaxants doxapram may temporarily mask the residual effects of muscle relaxant drugs In patients who have received general anesthesia utilizing a volatile agent known to sensitize the myocardium to catecholamines administration of doxapram should be delayed until the volatile agent has been excreted in order to lessen the potential for arrhythmias including ventricular tachycardia and ventricular fibrillation Most 98 of plasma doxazosin is protein bound In vitro data in human plasma indicate that doxazosin mesylate has no effect on protein binding of digoxin warfarin phenytoin or indomethacin There is no information on the effect of other highly plasma protein bound drugs on doxazosin binding Doxazosin mesylate has been administered without any evidence of an adverse drug interaction to patients receiving thiazide diuretics beta blocking agents and nonsteroidal anti inflammatory drugs In a placebo controlled trial in normal volunteers the administration of a single 1 mg dose of doxazosin on day 1 of a four day regimen of oral cimetidine 400 mg twice daily resulted in a 10 increase in mean AUC of doxazosin p 0 006 and a slight but not statistically significant increase in mean Cmax and mean half life of doxazosin The clinical significance of this increase in doxazosin AUC is unknown In clinical trials doxazosin mesylate tablets have been administered to patients on a variety of concomitant medications while no formal interaction studies have been conducted no interactions were observed Doxazosin mesylate tablets have been used with the following drugs or drug classes 1 Analgesic anti inflammatory e g acetaminophen aspirin codeine and codeine combinations ibuprofen indomethacin 2 Antibiotics e g erythromycin trimethoprim and sulfamethoxazole amoxicillin 3 Antihistamines e g chlorpheniramine 4 Cardiovascular agents e g atenolol hydrochlorothiazide propranolol 5 Corticosteroids 6 Gastrointestinal agents e g antacids 7 Hypoglycemics and endocrine drugs 8 Sedatives and tranquilizers e g diazepam 9 Cold and flu remedies Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 debrisoquin hydroxylase is reduced in a subset of the Caucasian population about 7 10 of Caucasians are so called poor metabolizers reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian African and other populations are not yet available Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants TCAs when given usual doses Depending on the fraction of drug metabolized by P450 2D6 the increase in plasma concentration may be small or quite large 8 fold increase in plasma AUC of the TCA In addition certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme quinidine cimetidine and many that are substrates for P450 2D6 many other antidepressants phenothiazines and the Type 1C antiarrhythmics propafenone and flecainide While all the selective serotonin reuptake inhibitors SSRIs e g citalopram escitalopram fluoxetine sertraline and paroxetine inhibit P450 2D6 they may vary in the extent of inhibition The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved Nevertheless caution is indicated in the co administration of TCAs with any of the SSRIs and also in switching from one class to the other Of particular importance sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine given the long half life of the parent and active metabolite at least 5 weeks may be necessary Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug Furthermore whenever one of these other drugs is withdrawn from co therapy an increased dose of tricyclic antidepressant may be required It is desirable to monitor TCA plasma levels whenever a TCA is going to be co administered with another drug known to be an inhibitor of P450 2D6 Doxepin is primarily metabolized by CYP2D6 with CYP1A2 and CYP3A4 as minor pathways Inhibitors or substrates of CYP2D6 i e quinidine selective serotonin reuptake inhibitors SSRIs may increase the plasma concentration of doxepin when administered concomitantly The extent of interaction depends on the variability of effect on CYP2D6 The clinical significance of this interaction with doxepin has not been systematically evaluated MAO Inhibitors Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors Therefore MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with SINEQUAN The exact length of time may vary and is dependent upon the particular MAO inhibitor being used the length of time it has been administered and the dosage involved Cimetidine Cimetidine has been reported to produce clinically significant fluctuations in steady state serum concentrations of various tricyclic antidepressants Serious anticholinergic symptoms i e severe dry mouth urinary retention and blurred vision have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated Additionally higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy discontinuation of cimetidine has been reported to decrease established steady state serum tricyclic antidepressant levels and compromise their therapeutic effects Alcohol It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional SINEQUAN overdosage This is especially important in patients who may use alcohol excessively Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide 1 gm day 11 days after the addition of doxepin 75 mg day No formal drug interaction studies have been conducted with DOXIL Until specific compatibility data are available it is not recommended that DOXIL be mixed with other drugs DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl Because tetracyclines have been shown to depress plasma prothrombin activity patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage Since bacteriostatic drugs may interfere with the bactericidal action of penicillin it is advisable to avoid giving tetracyclines in conjunction with penicillin Absorption of tetracyclines is impaired by antacids containing aluminum calcium or magnesium and iron containing preparations Absorption of tetracycline is impaired by bismuth subsalicylate Barbiturates carbamazepine and phenytoin decrease the half life of doxycycline The concurrent use of tetracycline and Penthrane methoxyflurane has been reported to result in fatal renal toxicity Concurrent use of tetracycline may render oral contraceptives less effective Drug Laboratory Test Interactions False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test Potential drug interactions for doxylamine include increased sedation if doxylamine is combined with other CNS depressant drugs Antihistamines may partially counteract the anticoagulation effects of heparin or warfarin Doxylamine may enhance the effects of epinephrine Androgens may increase sensitivity to oral anticoagulahts Dosage of the anticoagulant may require reduction in order to maintain satisfactory therapeutic hypoprothrombinemia Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone In diabetic patients the metabolic effects of androgens may decrease blood glucose and therefore insulin requirements Other CNS depressant drugs e g barbiturates tranquilizers opioids and general anesthetics have additive or potentiating effects with INAPSINE When patients have received such drugs the dose of INAPSINE required will be less than usual Following the administration of INAPSINE the dose of other CNS depressant drugs should be reduced Drug interaction studies with Xigris have not been performed in patients with severe sepsis However since there is an increased risk of bleeding with Xigris caution should be employed when Xigris is used with other drugs that affect hemostasis Approximately 2 3 of the patients in the Phase 3 study received either prophylactic low dose heparin unfractionated heparin up to 15 000 units day or prophylactic doses of low molecular weight heparins as indicated in the prescribing information for the specific products Concomitant use of prophylactic low dose heparin did not appear to affect safety however its effects on the efficacy of Xigris have not been evaluated in an adequate and well controlled clinical trial Drug Laboratory Test Interaction Because Xigris may affect the APTT assay Xigris present in plasma samples may interfere with one stage coagulation assays based on the APTT such as factor VIII IX and XI assays This interference may result in an apparent factor concentration that is lower than the true concentration Xigris present in plasma samples does not interfere with one stage factor assays based on the PT such as factor II V VII and X assays Potential for Other Drugs to Affect Duloxetine Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism Inhibitors of CYP1A2 Concomitant use of duloxetine with fluvoxamine an inhibitor of CYP1A2 results in approximately a 6 fold increase in AUC and about a 2 5 fold increase in Cmax of duloxetine Some quinolone antibiotics would be expected to have similar effects and these combinations should be avoided Inhibitors of CYP2D6 Because CYP2D6 is involved in duloxetine metabolism concomitant use of duloxetine with potent inhibitors of CYP2D6 may result in higher concentrations of duloxetine Paroxetine 20 mg QD increased the concentration of duloxetine 40 mg QD by about 60 and greater degrees of inhibition are expected with higher doses of paroxetine Similar effects would be expected with other potent CYP2D6 inhibitors e g fluoxetine quinidine Potential for Duloxetine to Affect Other Drugs Drugs Metabolized by CYP1A2 In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity and it is unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates Drugs Metabolized by CYP2D6 Duloxetine is a moderate inhibitor of CYP2D6 When duloxetine was administered at a dose of 60 mg BID in conjunction with a single 50 mg dose of desipramine a CYP2D6 substrate the AUC of desipramine increased 3 fold Therefore co administration of Duloxetine with other drugs that are extensively metabolized by this isozyme and which have a narrow therapeutic index including certain antidepressants tricyclic antidepressants TCAs such as nortriptyline amitriptyline and imipramine phenothiazines and Type 1C antiarrhythmics e g propafenone flecainide should be approached with caution Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co administered with Duloxetine Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine Duloxetine and thioridazine should not be co administered Drugs Metabolized by CYP3A Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity Duloxetine May Have a Clinically Important Interaction with the Following Other Drugs Alcohol When Duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide Duloxetine did not increase the impairment of mental and motor skills caused by alcohol In the Duloxetine clinical trials database three Duloxetine treated patients had liver injury as manifested by ALT and total bilirubin elevations with evidence of obstruction Substantial intercurrent ethanol use was present in each of these cases and this may have contributed to the abnormalities seen CNS Acting Drugs Given the primary CNS effects of Duloxetine it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs including those with a similar mechanism of action Potential for Interaction with Drugs that Affect Gastric Acidity Duloxetine has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5 5 In extremely acidic conditions Duloxetine unprotected by the enteric coating may undergo hydrolysis to form naphthol Caution is advised in using Duloxetine in patients with conditions that may slow gastric emptying e g some diabetics Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine However co administration of Duloxetine with aluminum and magnesium containing antacids 51 mEq or Duloxetine with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption Synergism between xanthine bronchodilators e g theophylline ephedrine and other sympathomimetic bronchodilators has been reported This should be considered whenever these agents are prescribed concomitantly Concurrent administration of dyphylline and probenecid which competes for tubular secretion has been shown to increase the plasma half life of dyphylline Phospholine Iodide potentiates other cholinesterase inhibitors such as succinylcholine or organophosphate and carbamate insecticides Patients undergoing systemic anticholinesterase treatment should be warned of the possible additive effects of Phospholine Iodide Drug interaction studies have not been performed with Soliris There is no known drug interference with standard clinical laboratory tests Steroids enhance the renal toxicity of edetate calcium disodium in animals 7 Edetate calcium disodium interferes with the action of zinc insulin preparations by chelating the zinc 7 Care should be given when administering this drug to patients with symptoms of myasthenic weakness who are also on anticholinesterase drugs Since symptoms of anticholinesterase overdose cholinergic crisis may mimic underdosage myasthenic weakness their condition may be worsened by the use of this drug No formal drug interaction studies have been performed with RAPTIVA RAPTIVA should not be used with other immunosuppressive drugs Acellular live and live attenuated vaccines should not be administered during RAPTIVA treatment Drug Laboratory Test Interactions Increases in lymphocyte counts related to the pharmacologic mechanism of action are frequently observed during RAPTIVA treatment Efavirenz has been shown in vivo to induce CYP3A4 Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when coadministered with SUSTIVA efavirenz In vitro studies have demonstrated that efavirenz inhibits 2C9 2C19 and 3A4 isozymes in the range of observed efavirenz plasma concentrations Coadministration of efavirenz with drugs primarily metabolized by these isozymes may result in altered plasma concentrations of the coadministered drug Therefore appropriate dose adjustments may be necessary for these drugs Drugs which induce CYP3A4 activity eg phenobarbital rifampin rifabutin would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations Drug interactions with SUSTIVA are summarized in Table 5 Table 5a Drugs That Should Not Be Coadministered With SUSTIVA Drug Class Drugs Within Class Not To Be Coadministered With SUSTIVA Antihistamines Benzodiazepines GI Motility Agents Anti Migraine Antifungal astemizole midazolam triazolam cisapride ergot derivatives voriconazole Established Drug Interactions Drug Name Effect Clinical Comment Atazanavir atazanavir When coadministered with SUSTIVA in treatment naive patients the recommended dose of atazanavir is 300 mg with ritonavir 100 mg and SUSTIVA 600 mg all once daily Dosing recommendations for SUSTIVA and atazanavir in treatment experienced patients have not been established Established Drug Interactions continued Drug Name Effect Clinical Comment Clarithromycin clarithromycin concentration Plasma concentrations decreased by SUSTIVA clinical significance unknown In uninfected volunteers 46 developed rash while receiving SUSTIVA and clarithromycin No dose adjustment of SUSTIVA is recommended when given with clarithromycin Alternatives to clarithromycin such as azithromycin should be considered Other macrolide antibiotics such as erythromycin have not been studied in combination with SUSTIVA 14 OH metabolite concentration Indinavir indinavir concentration The optimal dose of indinavir when given in combination with SUSTIVA is not known Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA When indinavir at an increased dose 1000 mg every 8 hours was given with SUSTIVA 600 mg once daily the indinavir AUC and Cmin were decreased on average by 33 46 and 39 57 respectively compared to when indinavir 800 mg every 8 hours was given alone Lopinavir ritonavir lopinavir concentration A dose increase of lopinavir ritonavir to 533 133 mg 4 capsules or 6 5 mL twice daily taken with food is recommended when used in combination with SUSTIVA Methadone methadone concentration Coadministration in HIV infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal Methadone dose was increased by a mean of 22 to alleviate withdrawal symptoms Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms Ethinyl estradiol ethinyl estradiol concentration Plasma concentrations increased by SUSTIVA efavirenz clinical significance unknown Because the potential interaction of efavirenz with oral contraceptives has not been fully characterized a reliable method of barrier contraception should be used in addition to oral contraceptives Rifabutin rifabutin concentration Increase daily dose of rifabutin by 50 Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week Rifampin efavirenz concentration Clinical significance of reduced efavirenz concentrations unknown Ritonavir ritonavir concentration Combination was associated with a higher frequency of adverse clinical experiences eg dizziness nausea paresthesia and laboratory abnormalities elevated liver enzymes Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir efavirenz concentration Saquinavir saquinavir concentration Should not be used as sole protease inhibitor in combination with SUSTIVA Sertraline sertraline concentration Increases in sertraline dose should be guided by clinical response Other Potentially Clinically Significant Drug or Herbal Product Interactions With SUSTIVAb Anticoagulants Warfarin Plasma concentrations and effects potentially increased or decreased by SUSTIVA Anticonvulsants Phenytoin Phenobarbital Carbamazepine Potential for reduction in anticonvulsant and or efavirenz plasma levels periodic monitoring of anticonvulsant plasma levels should be conducted Antifungals Itraconazole Ketoconazole Drug interaction studies with SUSTIVA and these imidazole and triazole antifungals have not been conducted SUSTIVA has the potential to decrease plasma concentrations of itraconazole and ketoconazole Anti HIV protease inhibitors Saquinavir ritonavir combination No pharmacokinetic data are available Amprenavir SUSTIVAhas the potential to decrease serum concentrations of amprenavir Non nucleoside reverse transcriptase inhibitors No studies have been performed with other NNRTIs St John s wort Hypericum perforatum Expected to substantially decrease plasma levels of efavirenz has not been studied in combination with SUSTIVA a See Tables 1 and 2 b This table is not all inclusive Other Drugs Based on the results of drug interaction studies no dosage adjustment is recommended when SUSTIVA efavirenz is given with the following aluminum magnesium hydroxide antacids azithromycin cetirizine famotidine fluconazole lamivudine lorazepam nelfinavir paroxetine and zidovudine Specific drug interaction studies have not been performed with SUSTIVA and NRTIs other than lamivudine and zidovudine Clinically significant interactions would not be expected since the NRTIs are metabolized via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways The potential for drug interactions with EMTRIVA has been studied in combination with indinavir stavudine famciclovir and tenofovir disoproxil fumarate There were no clinically significant drug interactions for any of these drugs Hypotension Patients on Diuretic Therapy Patients on diuretics and especially those in whom diuretic therapy was recently instituted may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril or enalaprilat The possibility of hypotensive effects with enalapril or enalaprilat can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril or enalaprilat If it is necessary to continue the diuretic provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour Agents Causing Renin Release The antihypertensive effect of enalapril and enalapril IV is augmented by antihypertensive agents that cause renin release e g diuretics Non steroidal Anti inflammatory Agents In some patients with compromised renal function who are being treated with nonsteroidal anti inflammatory drugs the co administration of enalapril may result in a further deterioration of renal function These effects are usually reversible In a clinical pharmacology study indomethacin or sulindac was administered to hypertensive patients receiving VASOTEC In this study there was no evidence of a blunting of the antihypertensive action of VASOTEC However reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors Other Cardiovascular Agents Enalapril and enalapril IV have been used concomitantly with beta adrenergic blocking agents methyldopa nitrates calcium blocking agents hydralazine prazosin and digoxin without evidence of clinically significant adverse interactions Enalapril IV has been used concomitantly with digitalis without evidence of clinically significant adverse reactions Agents Increasing Serum Potassium Enalapril and enalapril IV attenuate potassium loss caused by thiazide type diuretics Potassium sparing diuretics e g spironolactone triamterene or amiloride potassium supplements or potassium containing salt substitutes may lead to significant increases in serum potassium Therefore if concomitant use of these agents is indicated because of demonstrated hypokalemia they should be used with caution and with frequent monitoring of serum potassium Potassium sparing agents should generally not be used in patients with heart failure receiving enalapril Lithium Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium including ACE inhibitors It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium The action of nondepolarizing relaxants is augmented by Enflurane Less than the usual amounts of these medicines should be used If the usual amounts of nondepolarizing relaxants are given the time for recovery from neuromuscular blockade will be longer in the presence of Enflurane than when halothane or nitrous oxide with a balanced technique are used CYP450 Metabolized Drugs Results from in vitro and in vivo studies suggest that enfuvirtide is unlikely to have significant drug interactions with concomitantly administered drugs metabolized by CYP450 enzymes Antiretroviral Agents No drug interactions with other antiretroviral medications have been identified that would warrant alteration of either the enfuvirtide dose or the dose of the other antiretroviral medication Bismuth Bismuth subsalicylate given concomitantly with enoxacin or 60 minutes following enoxacin administration decreased enoxacin bioavailability by approximately 25 Thus concomitant administration of enoxacin and bismuth subsalicylate should be avoided Caffeine Enoxacin is a potent inhibitor of the cytochrome P 450 isozymes responsible for the metabolism of methylxanthines In a multiple dose study enoxacin caused a dose related increase in the mean elimination half life of caffeine thereby decreasing the clearance of caffeine by up to 80 and leading to a five fold increase in the AUC and the half life of caffeine Trough plasma enoxacin levels were also 20 higher when caffeine and enoxacin were administered concomitantly Caffeine related adverse effects have occurred in patients consuming caffeine while on therapy with enoxacin Cyclosporine Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with other members of the quinolone class Digoxin Enoxacin may raise serum digoxin levels in some individuals If signs and symptoms suggestive of digoxin toxicity occur when enoxacin and digoxin are given concomitantly physicians are advised to obtain serum digoxin levels and adjust digoxin doses appropriately Non steroidal anti inflammatory agents Seizures have been reported in patients taking enoxacin concomitantly with the nonsteroidal anti inflammatory drug fenbufen Animal studies also suggest an increased potential for seizures when these two drugs are given concomitantly Fenbufen is not approved in the United States at this time Sucralfate and antacids Quinolones form chelates with metal cations Therefore administration of quinolones with antacids containing calcium magnesium or aluminum with sucralfate with divalent or trivalent cations such as iron or with multivitamins containing zinc may substantially interfere with drug absorption and result in insufficient plasma and tissue quinolone concentrations Antacids containing aluminum hydroxide and magnesium hydroxide reduce the oral absorption of enoxacin by 75 The oral bioavailability of enoxacin is reduced by 60 with coadministration of ranitidine These agents should not be taken for 8 hours before or for 2 hours after enoxacin administration Theophylline Enoxacin is a potent inhibitor of the cytochrome P 450 isozymes responsible for the metabolism of methylxanthines Enoxacin interferes with the metabolism of theophylline resulting in a 42 to 74 dose related decrease in theophylline clearance and a subsequent 260 to 350 increase in serum theophylline levels Theophylline related adverse effects have occurred in patients when theophylline and enoxacin were coadministered Warfarin Quinolones including enoxacin decrease the clearance of R warfarin the less active isomer of racemic warfarin Enoxacin does not affect the clearance of the active S isomer and changes in clotting time have not been observed when enoxacin and warfarin were coadministered Nevertheless the prothrombin time or other suitable coagulation test should be monitored when warfarin or its derivatives and enoxacin are given concomitantly Unless really needed agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of Lovenox Injection therapy These agents include medications such as anticoagulants platelet inhibitors including acetylsalicylic acid sali cylates NSAIDs including ketorolac tromethamine dipyridamole or sulfinpyrazone If co administration is essential conduct close clinical and laboratory monitoring In vitro studies of human CYP enzymes showed that entacapone inhibited the CYP enzymes 1A2 2A6 2C9 2C19 2D6 2E1 and 3A only at very high concentrations IC50 from 200 to over 1000 uM an oral 200 mg dose achieves a highest level of approximately 5 uM in people these enzymes would therefore not be expected to be inhibited in clinical use Protein Binding Entacapone is highly protein bound 98 In vitro studies have shown no binding displacement between entacapone and other highly bound drugs such as warfarin salicylic acid phenylbutazone and diazepam Drugs Metabolized by Catechol O methyltransferase COMT Hormone levels Levodopa is known to depress prolactin secretion and increase growth hormone levels Treatment with entacapone coadministered with levodopa dopa decarboxylase inhibitor does not change these effects No interaction was noted with the MAO B inhibitor selegiline in two multiple dose interaction studies when entacapone was coadministered with a levodopa dopa decarboxylase inhibitor n 29 More than 600 Parkinsons disease patients in clinical trials have used selegiline in combination with entacapone and levodopa dopa decarboxylase inhibitor As most entacapone excretion is via the bile caution should be exercised when drugs known to interfere with biliary excretion glucuronidation and intestinal beta glucuronidase are given concurrently with entacapone These include probenecid cholestyramine and some antibiotics e g erythromycin rifamipicin ampicillin and chloramphenicol No interaction with the tricyclic antidepressant imipramine was shown in a single dose study with entacapone without coadministered levodopa dopa decarboxylase inhibitor Since entecavir is primarily eliminated by the kidneys coadministration of BARACLUDE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug Coadministration of entecavir with lamivudine adefovir dipivoxil or tenofovir disoproxil fumarate did not result in significant drug interactions The effects of coadministration of BARACLUDE with other drugs that are renally eliminated or are known to affect renal function have not been evaluated and patients should be monitored closely for adverse events when BARACLUDE is coadministered with such drugs None Reported Epinephrine should be used cautiously in patients with hyperthyroidism hypertension and cardiac arrhythmias All vasopressors should be used cautiously in patients taking monoamine oxidase MAO inhibitors Epinephrine should not be administered concomitantly with other sympathomimetic drugs such as isoproterenol because of possible additive effects and increased toxicity Combined effects may induce serious cardiac arrhythmias They may be administered alternately when the preceding effect of other such drug has subsided Administration of epinephrine to patients receiving cyclopropane or halogenated hydrocarbon general anesthetics such as halothane which sensitize the myocardium may induce cardiac arrhythmia When encountered such arrhythmias may respond to administration of a beta adrenergic blocking drug Epinephrine also should be used cautiously with other drugs e g digitalis glycosides that sensitize the myocardium to the actions of sympathomimetic drugs Diuretic agents may decrease vascular response to pressor drugs such as epinephrine Epinephrine may antagonize the neuron blockade produced by guanethidine resulting in decreased antihypertensive effect and requiring increased dosage of the latter ELLENCE when used in combination with other cytotoxic drugs may show on treatment additive toxicity especially hematologic and gastrointestinal effects Concomitant use of ELLENCE with other cardioactive compounds that could cause heart failure e g calcium channel blockers requires close monitoring of cardiac function throughout treatment There are few data regarding the coadministration of radiation therapy and epirubicin In adjuvant trials of epirubicin containing CEF 120 or FEC 100 chemotherapies breast irradiation was delayed until after chemotherapy was completed This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature A small number of patients received epirubicin based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities It is likely that use of epirubicin with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation Administration of ELLENCE after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation Epirubicin is extensively metabolized by the liver Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism pharmacokinetics therapeutic efficacy and or toxicity Cimetidine increased the AUC of epirubicin by 50 Cimetidine treatment should be stopped during treatment with ELLENCE Drug Laboratory Test Interactions There are no known interactions between ELLENCE and laboratory tests Inhibitors of CYP3A4 Eplerenone metabolism is predominantly mediated via CYP3A4 A pharmacokinetic study evaluating the administration of a single dose of INSPRA 100 mg with ketoconazole 200 mg BID a potent inhibitor of the CYP3A4 pathway showed a 1 7 fold increase in Cmax of eplerenone and a 5 4 fold increase in AUC of eplerenone INSPRA should not be used with drugs described as strong inhibitors of CYP3A4 in their labeling Administration of eplerenone with other CYP3A4 inhibitors e g erythromycin 500 mg BID verapamil 240 mg QD saquinavir 1200 mg TID fluconazole 200 mg QD resulted in increases in Cmax of eplerenone ranging from 1 4 to 1 6 fold and AUC from 2 0 to 2 9 fold ACE Inhibitors and Angiotensin II Receptor Antagonists Congestive Heart Failure Post Myocardial Infarction In EPHESUS 3020 91 patients receiving INSPRA 25 to 50 mg also received ACE inhibitors or angiotensin II receptor antagonists ACEI ARB Rates of patients with maximum potassium levels 5 5 mEq L were similar regardless of the use of ACEI ARB ACE Inhibitors and Angiotensin II Receptor Antagonists Hypertension In clinical studies of patients with hypertension the addition of INSPRA 50 to 100 mg to ACE inhibitors and angiotensin II receptor antagonists increased mean serum potassium slightly about 0 09 0 13 mEq L In a study in diabetics with microalbuminuria INSPRA 200 mg combined with the ACE inhibitor enalapril 10 mg increased the frequency of hyperkalemia serum potassium 5 5 mEq L from 17 on enalapril alone to 38 Lithium A drug interaction study of eplerenone with lithium has not been conducted Serum lithium levels should be monitored frequently if INSPRA is administered concomitantly with lithium Nonsteroidal Anti Inflammatory Drugs NSAIDs A drug interaction study of eplerenone with an NSAID has not been conducted The administration of other potassium sparing antihypertensives with NSAIDs has been shown to reduce the antihypertensive effect in some patients and result in severe hyperkalemia in patients with impaired renal function Therefore when INSPRA and NSAIDs are used concomitantly patients should be observed to determine whether the desired effect on blood pressure is obtained No evidence of interaction of PROCRIT with other drugs was observed in the course of clinical trials Additional reductions in blood pressure may occur when FLOLAN is administered with diuretics antihypertensive agents or other vasodilators When other antiplatelet agents or anticoagulants are used concomitantly there is the potential for FLOLAN to increase the risk of bleeding However patients receiving infusions of FLOLAN in clinical trials were maintained on anticoagulants without evidence of increased bleeding In clinical trials FLOLAN was used with digoxin diuretics anticoagulants oral vasodilators and supplemental oxygen In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide or digoxin in whom therapy with FLOLAN was initiated apparent oral clearance values for furosemide n 23 and digoxin n 30 were decreased by 13 and 15 respectively on the second day of therapy and had returned to baseline values by day 87 The change in furosemide clearance value is not likely to be clinically significant However patients on digoxin may show elevations of digoxin concentrations after initiation of therapy with FLOLAN which may be clinically significant in patients prone to digoxin toxicity Eprosartan has been shown to have no effect on the pharmacokinetics of digoxin and the pharmacodynamics of warfarin and glyburide Thus no dosing adjustments are necessary during concomitant use with these agents Because eprosartan is not metabolized by the cytochrome P450 system inhibitors of CYP450 enzyme would not be expected to affect its metabolism and ketoconazole and fluconazole potent inhibitors of CYP3A and 2C9 respectively have been shown to have no effect on eprosartan pharmacokinetics Ranitidine also has no effect on eprosartan pharmacokinetics Eprosartan up to 400 mg b i d or 800 mg q d doses have been safely used concomitantly with a thiazide diuretic hydrochlorothiazide Eprosartan doses of up to 300 mg b i d have been safely used concomitantly with sustained release calcium channel blockers sustained release nifedipine with no clinically significant adverse interactions Enoxaparin dosed as a 1 0 mg kg subcutaneous injection q12h for four doses did not alter the pharmacokinetics of eptifibatide or the level of platelet aggregation in healthy adults Mineral oil interferes with the absorption of fat soluble vitamins including vitamin D preparations Administration of thiazide diuretics to hypoparathyroid patients who are concurrently being treated with ergocalciferol may cause hypercalcemia No reported interactions The effects of ERGOMAR may be potentiated by triacetyloleandomycin which inhibits the metabolism of ergotamine The pressor effects of ERGOMAR and other vasoconstrictor drugs can combine to cause dangerous hypertension Co treatment with the potent CYP3A4 inhibitor ketoconazole increases erlotinib AUC by 2 3 Caution should be used when administering or taking TARCEVA with ketoconazole and other strong CYP3A4 inhibitors such as but not limited to atazanavir clarithromycin indinavir itraconazole nefazodone nelfinavir ritonavir saquinavir telithromycin troleandomycin TAO and voriconazole Pre treatment with the CYP3A4 inducer rifampicin decreased erlotinib AUC by about 2 3 Alternate treatments lacking CYP3A4 inducing activity should be considered If an alternative treatment is unavailable a TARCEVA dose greater than 150 mg should be considered for NSCLC patients and greater than 100 mg considered for pancreatic cancer patients If the TARCEVA dose is adjusted upward the dose will need to be reduced upon discontinuation of rifampicin or other inducers Other CYP3A4 inducers include but are not limited to rifabutin rifapentine phenytoin carbamazepine phenobarbital and St Johns Wort Hepatotoxicity Asymptomatic increases in liver transaminases have been observed in TARCEVA treated patients therefore periodic liver function testing transaminases bilirubin and alkaline phosphatase should be considered Dose reduction or interruption of TARCEVA should be considered if changes in liver function are severe Patients with Hepatic Impairment In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver Therefore erlotinib exposure may be increased in patients with hepatic dysfunction Elevated International Normalized Ratio and Potential Bleeding International Normalized Ratio INR elevations and infrequent reports of bleeding events including gastrointestinal and non gastrointestinal bleedings have been reported in clinical studies some associated with concomitant warfarin administration Patients taking warfarin or other coumarin derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR When ertapenem is co administered with probenecid 500 mg p o every 6 hours probenecid competes for active tubular secretion and reduces the renal clearance of ertapenem Based on total ertapenem concentrations probenecid increased the AUC by 25 and reduced the plasma and renal clearances by 20 and 35 respectively The half life increased from 4 0 to 4 8 hours Because of the small effect on half life the coadministration with probenecid to extend the half life of ertapenem is not recommended In vitro studies indicate that ertapenem does not inhibit P glycoprotein mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P glycoprotein mediated transport In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following six cytochrome p450 CYP isoforms 1A2 2C9 2C19 2D6 2E1 and 3A4 Drug interactions caused by inhibition of P glycoprotein mediated drug clearance or CYP mediated drug clearance with the listed isoforms are unlikely Other than with probenecid no specific clinical drug interaction studies have been conducted Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase in serum theophylline levels and potential theophylline toxicity In case of theophylline toxicity and or elevated serum theophylline levels the dose of theophylline should be reduced while the patient is receiving concomitant erythromycin therapy Concomitant administration of erythromycin and digoxin has been reported to result in elevated digoxin serum levels There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants were used concomitantly Increased anticoagulation effects due to interactions of erythromycin with various oral anticoagulents may be more pronounced in the elderly Concurrent use of erythromycin and ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia Erythromycin has been reported to decrease the clearance of triazolam and midazolam and thus may increase the pharmacologic effect of these benzodiazepines The use of erythromycin in patients concurrently taking drugs metabolized by the cytochrome P450 system may be associated with elevations in serum levels of these other drugs There have been reports of interactions of erythromycin with carbamazepine cyclosporine tacrolimus hexobarbital phenytoin alfentanil cisapride disopyramide lovastatin bromocriptine valproate terfenadine and astemizole Serum concentrations of drugs metabolized by the cytochrome P450 system should be monitored closely in patients concurrently receiving erythromycin Erythromycin has been reported to significantly alter the metabolism of nonsedating antihistamines terfenadine and astemizole when taken concomitantly Rare cases of serious cardiovascular adverse events including electrocardiographic QT QTc interval prolongation cardiac arrest torsades de pointes and other ventricular arrhythmias have been observed In addition deaths have been reported rarely with concomitant administration of terfenadine and erythromycin There have been postmarketing reports of drug interactions when erythromycin is coadministered with cisapride resulting in QT prolongation cardiac arrythmias ventricular tachycardia ventricular fibrulation and torsades de pointes most like due to inhibition of hepatic metabolism of cisapride by erythromycin Fatalities have been reported Patients receiving concomitant lovastatin and erythromycin should be carefully monitored cases of rhabdomyolysis have been reported in seriously ill patients CNS Drugs Given the primary CNS effects of escitalopram caution should be used when it is taken in combination with other centrally acting drugs Alcohol Although LEXAPRO did not potentiate the cognitive and motor effects of alcohol in a clinical trial as with other psychotropic medications the use of alcohol by patients taking LEXAPRO is not recommended Monoamine Oxidase Inhibitors MAOIs Drugs That Interfere With Hemostasis NSAIDs Aspirin Warfarin etc Serotonin release by platelets plays an important role in hemostasis Epidemiological studies of the case control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding Thus patients should be cautioned about the use of such drugs concurrently with LEXAPRO Cimetidine In subjects who had received 21 days of 40 mg day racemic citalopram combined administration of 400 mg day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43 and 39 respectively The clinical significance of these findings is unknown Digoxin In subjects who had received 21 days of 40 mg day racemic citalopram combined administration of citalopram and digoxin single dose of 1 mg did not significantly affect the pharmacokinetics of either citalopram or digoxin Lithium Coadministration of racemic citalopram 40 mg day for 10 days and lithium 30 mmol day for 5 days had no significant effect on the pharmacokinetics of citalopram or lithium Nevertheless plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice Because lithium may enhance the serotonergic effects of escitalopram caution should be exercised when LEXAPRO and lithium are coadministered Pimozide and Celexa In a controlled study a single dose of pimozide 2 mg co administered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone Racemic citalopram did not alter the mean AUC or Cmax of pimozide The mechanism of this pharmacodynamic interaction is not known Sumatriptan There have been rare postmarketing reports describing patients with weakness hyperreflexia and incoordination following the use of a selective serotonin reuptake inhibitor SSRI and sumatriptan If concomitant treatment with sumatriptan and an SSRI e g fluoxetine fluvoxamine paroxetine sertraline citalopram escitalopram is clinically warranted appropriate observation of the patient is advised Theophylline Combined administration of racemic citalopram 40 mg day for 21 days and the CYP1A2 substrate theophylline single dose of 300 mg did not affect the pharmacokinetics of theophylline The effect of theophylline on the pharmacokinetics of citalopram was not evaluated Warfarin Administration of 40 mg day racemic citalopram for 21 days did not affect the pharmacokinetics of warfarin a CYP3A4 substrate Prothrombin time was increased by 5 the clinical significance of which is unknown Carbamazepine Combined administration of racemic citalopram 40 mg day for 14 days and carbamazepine titrated to 400 mg day for 35 days did not significantly affect the pharmacokinetics of carbamazepine a CYP3A4 substrate Although trough citalopram plasma levels were unaffected given the enzyme inducing properties of carbamazepine the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered Triazolam Combined administration of racemic citalopram titrated to 40 mg day for 28 days and the CYP3A4 substrate triazolam single dose of 0 25 mg did not significantly affect the pharmacokinetics of either citalopram or triazolam Ketoconazole Combined administration of racemic citalopram 40 mg and ketoconazole 200 mg decreased the Cmax and AUC of ketoconazole by 21 and 10 respectively and did not significantly affect the pharmacokinetics of citalopram Ritonavir Combined administration of a single dose of ritonavir 600 mg both a CYP3A4 substrate and a potent inhibitor of CYP3A4 and escitalopram 20 mg did not affect the pharmacokinetics of either ritonavir or escitalopram CYP3A4 and 2C19 Inhibitors In vitro studies indicated that CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of escitalopram However coadministration of escitalopram 20 mg and ritonavir 600 mg a potent inhibitor of CYP3A4 did not significantly affect the pharmacokinetics of escitalopram Because escitalopram is metabolized by multiple enzyme systems inhibition of a single enzyme may not appreciably decrease escitalopram clearance Drugs Metabolized by Cytochrome P4502D6 In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6 In addition steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple dose administration of citalopram suggesting that coadministration with escitalopram of a drug that inhibits CYP2D6 is unlikely to have clinically significant effects on escitalopram metabolism However there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram i e coadministration of escitalopram 20 mg day for 21 days with the tricyclic antidepressant desipramine single dose of 50 mg a substrate for CYP2D6 resulted in a 40 increase in Cmax and a 100 increase in AUC of desipramine The clinical significance of this finding is unknown Nevertheless caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6 Metoprolol Administration of 20 mg day LEXAPRO for 21 days in healthy volunteers resulted in a 50 increase in Cmax and 82 increase in AUC of the beta adrenergic blocker metoprolol given in a single dose of 100 mg Increased metoprolol plasma levels have been associated with decreased cardioselectivity Coadministration of LEXAPRO and metoprolol had no clinically significant effects on blood pressure or heart rate Electroconvulsive Therapy ECT There are no clinical studies of the combined use of ECT and escitalopram Concomitant Administration with Racemic Citalopram Citalopram Since escitalopram is the active isomer of racemic citalopram Celexa the two agents should not be coadministered Catecholamine depleting drugs e g reserpine may have an additive effect when given with beta blocking agents Patients treated concurrently with BREVIBLOC esmolol HCl and a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia which may result in vertigo syncope or postural hypotension A study of interaction between BREVIBLOC and warfarin showed that concomitant administration of BREVIBLOC and warfarin does not alter warfarin plasma levels BREVIBLOC concentrations were equivocally higher when given with warfarin but this is not likely to be clinically important When digoxin and BREVIBLOC were concomitantly administered intravenously to normal volunteers there was a 10 20 increase in digoxin blood levels at some time points Digoxin did not affect BREVIBLOC pharmacokinetics When intravenous morphine and BREVIBLOC were concomitantly administered in normal subjects no effect on morphine blood levels was seen but BREVIBLOC steady state blood levels were increased by 46 in the presence of morphine No other pharmacokinetic parameters were changed The effect of BREVIBLOC on the duration of succinylcholine induced neuromuscular blockade was studied in patients undergoing surgery The onset of neuromuscular blockade by succinylcholine was unaffected by BREVIBLOC but the duration of neuromuscular blockade was prolonged from 5 minutes to 8 minutes Although the interactions observed in these studies do not appear to be of major clinical importance BREVIBLOC should be titrated with caution in patients being treated concurrently with digoxin morphine succinylcholine or warfarin While taking beta blockers patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge either accidental diagnostic or therapeutic Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction Caution should be exercised when considering the use of BREVIBLOC and verapamil in patients with depressed myocardial function Fatal cardiac arrests have occurred in patients receiving both drugs Additionally BREVIBLOC should not be used to control supraventricular tachycardia in the presence of agents which are vasoconstrictive and inotropic such as dopamine epinephrine and norepinephrine because of the danger of blocking cardiac contractility when systemic vascular resistance is high Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4 In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2 2A6 2C9 2D6 2E1 and 3A4 No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin warfarin quinidine clarithromycin or amoxicillin Post marketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy Increases in INR and prothrombin time may lead to abnormal bleeding and even death Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time Esomeprazole may potentially interfere with CYP2C19 the major esomeprazole metabolizing enzyme Coadministration of esomeprazole 30 mg and diazepam a CYP2C19 substrate resulted in a 45 decrease in clearance of diazepam Increased plasma levels of diazepam were observed 12 hours after dosing and onwards However at that time the plasma levels of diazepam were below the therapeutic interval and thus this interaction is unlikely to be of clinical relevance Esomeprazole inhibits gastric acid secretion Therefore esomeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability eg ketoconazole iron salts and digoxin Coadministration of oral contraceptives diazepam phenytoin or quinidine did not seem to change the pharmacokinetic profile of esomeprazole Concomitant administration of clarithromycin with pimozide is contraindicated If ProSom is given concomitantly with other drugs acting on the central nervous system careful consideration should be given to the pharmacology of all agents The action of the benzodiazepines may be potentiated by anticonvulsants antihistamines alcohol barbiturates monoamine oxidase inhibitors narcotics phenothiazines psychotropic medications or other drugs that produce CNS depression Smokers have an increased clearance of benzodiazepines as compared to nonsmokers this was seen in studies with estazolam While no in vivo drug drug interaction studies were conducted between estazolam and inducers of CYP3A compounds that are potent CYP3A inducers such as carbamazepine phenytoin rifampin and barbiturates would be expected to decrease estazolam concentrations Estazolam Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A CYP3A The metabolism of estazolam to the major circulating metabolite 4 hydroxy estazolam and the metabolism of other triazolobenzodiazepines is catalyzed by CYP3A Consequently estazolam should be avoided in patients receiving ketoconazole and itraconazole which are very potent inhibitors of CYP3A With drugs inhibiting CYP3A to a lesser but still significant degree estazolam should be used only with caution and consideration of appropriate dosage reduction The following are examples of drugs known to inhibit the metabolism of other related benzodiazepines presumably through inhibition of CYP3A nefazodone fluvoxamine cimetidine diltiazem isoniazide and some macrolide antibiotics Drug Interaction with Fluoxetine A multiple dose study was conducted to assess the effect of fluoxetine 20 mg BID on the pharmacokinetics of estazolam 2 mg QHS after seven days The pharmacokinetics of estazolam Cmax and AUC were not affected during multiple dose fluoxetine suggesting no clinically significant pharmacokinetic interaction Estazolam Interaction with Other Drugs that are Metabolized by Cytochrome P450 CYP At clinically relevant concentrations in vitro studies indicate that estazolam 0 6 M was not inhibitory towards the major cytochrome P450 isoforms CYP1A2 CYP2A6 CYP2C9 CYP2C19 CYP2D6 CYP2E1 and CYP3A Therefore based on these in vitro data estazolam is very unlikely to inhibit the biotransformation of other drugs metabolized by these CYP isoforms D Drug and Laboratory Test Interactions 1 Accelerated prothrombin time partial thromboplastin time and platelet aggregation time increased platelet count increased factors II VII antigen VIII antigen VIII coagulant activity IX X XII VII X complex II VII X complex and beta thromboglobulin decreased levels of anti factor Xa and antithrombin III decreased antithrombin III activity increased levels of fibrinogen and fibrinogen activity increased plasminogen antigen and activity 2 Increased thyroid binding globulin TBG leading to increased circulating total thyroid hormone levels as measured by protein bound iodine PBI T4 levels by column or by radioimmunoassay or T3 levels by radioimmunoassay T3 resin uptake is decreased reflecting the elevated TBG Free T4 and T3 concentrations are unaltered Patients on thyroid replacement therapy may require higher doses of thyroid hormone 3 Other binding proteins may be elevated in serum i e corticosteroid binding globulin CBG sex hormone binding globulin SHBG leading to increased total circulating corticosteroids and sex steroids respectively Free hormone concentrations may be decreased Other plasma proteins may be increased angiotensinogen renin substrate alpha 1 antitrypsin ceruloplasmin 4 Increased plasma HDL and HDL2 cholesterol subfraction concentrations reduced LDL cholesterol concentration increased triglyceride levels 5 Impaired glucose tolerance 6 Reduced response to metyrapone test Milk milk products and calcium rich foods or drugs may impair the absorption of EMCYT CNS Active Drugs Ethanol An additive effect on psychomotor performance was seen with coadministration of eszopiclone and ethanol 0 70 g kg for up to 4 hours after ethanol administration Paroxetine Coadministration of single doses of eszopiclone 3 mg and paroxetine 20 mg daily for 7 days produced no pharmacokinetic or pharmacodynamic interaction Lorazepam Coadministration of single doses of eszopiclone 3 mg and lorazepam 2 mg did not have clinically relevant effects on the pharmacodynamics or pharmacokinetics of either drug Olanzapine Coadministration of eszopiclone 3 mg and olanzapine 10 mg produced a decrease in DSST scores The interaction was pharmacodynamic there was no alteration in the pharmacokinetics of either drug Drugs That Inhibit CYP3A4 Ketoconazole CYP3A4 is a major metabolic pathway for elimination of eszopiclone The AUC of eszopiclone was increased 2 2 fold by coadministration of ketoconazole a potent inhibitor of CYP3A4 400 mg daily for 5 days Cmax and t1 2 were increased 1 4 fold and 1 3 fold respectively Other strong inhibitors of CYP3A4 e g itraconazole clarithromycin nefazodone troleandomycin ritonavir nelfinavir would be expected to behave similarly Drugs That Induce CYP3A4 Rifampicin Racemic zopiclone exposure was decreased 80 by concomitant useof rifampicin a potent inducer of CYP3A4 A similar effect would be expected with eszopiclone Drugs Highly Bound To Plasma Protein Eszopiclone is not highly bound to plasma proteins 52 59 bound therefore the disposition of eszopiclone is not expected to be sensitive to alterations in protein binding Administration of eszopiclone 3 mg to a patient taking another drug that is highly protein bound would not be expected to cause an alteration in the free concentration of either drug Drugs With A Narrow Therapeutic Index Digoxin A single dose of eszopiclone 3 mg did not affect the pharmacokinetics of digoxin measured at steady state following dosing of 0 5 mg twice daily for one day and 0 25 mg daily for the next 6 days Warfarin Eszopiclone 3 mg administered daily for 5 days did not affect the pharmacokinetics of R or S warfarin nor were there any changes in the pharmacodynamic profile prothrombin time following a single 25 mg oral dose of warfarin Specific drug interaction studies have not been conducted with ENBREL However it was observed that the pharmacokinetics of ENBREL was unaltered by concomitant methotrexate in rheumatoid arthritis patients In a study in which patients with active RA were treated for up to 24 weeks with concurrent ENBREL and anakinra therapy a 7 rate of serious infections was observed which was higher than that observed with ENBREL alone 0 Two percent of patients treated concurrently with ENBREL and anakinra developed neutropenia ANC 1 x 109 L Patients in a clinical study who were on established therapy with sulfasalazine to which ENBREL was added were noted to develop a mild decrease in mean neutrophil counts in comparison to groups treated with either ENBREL CI or sulfasalazine alone The clinical significance of this observation is unknown Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity Read circulars for lithium preparations before use of such concomitant therapy EDECRIN may increase the ototoxic potential of other drugs such as aminoglycoside and some cephalosporin antibiotics Their concurrent use should be avoided A number of drugs including ethacrynic acid have been shown to displace warfarin from plasma protein a reduction in the usual anticoagulant dosage may be required in patients receiving both drugs In some patients the administration of a non steroidal antiinflammatory agent can reduce the diuretic natriuretic and antihypertensive effects of loop potassium sparing and thiazide diuretics Therefore when EDECRIN and non steroidal anti inflammatory agents are used concomitantly the patient should be observed closely to determine if the desired effect of the diuretic is obtained The results of a study of coadministration of ethambutol 50 mg kg with an aluminum hydroxide containing antacid to 13 patients with tuberculosis showed a reduction of mean serum concentrations and urinary excretion of ethambutol of approximately 20 and 13 respectively suggesting that the oral absorption of ethambutol may be reduced by these antacid products It is recommended to avoid concurrent administration of ethambutol with aluminum hydroxide containing antacids for at least 4 hours following ethambutol administration Dicumarol and warfarin may decrease hypoprothrombinemic effect Other depressasnts such as alcohol barbiturates and MAOIs may enhance CNS depression when administered with ethchlorvynol May interact with addictive medications especially central nervous system CNS depressants with habituating potential prolonged concurrent use may increase the risk of habituation alcohol or CNS depression producing medications concurrent use may increase the CNS depressant effects of either these medications or ethinamate Certain endocrine and liver function tests may be affected by estrogen containing oral contraceptives The following similar changes may be expected with larger doses of estrogen Increased sulfobromophthalein retention increased prothrombin and factors VII VIII IX and X decreased antithrombin 3 increased norepinephrine induced platel et aggregation increased thyroid binding globulin TBG leading to increased circulating total thyroid hormone as measured by PBI T4 by column or T4 by radioimmunoassay Free T3 resin uptake is decreased reflecting the elevated TBG free T4 concentration is unaltered impaired glucose tolerance decreased pregnanediol excretion reduced response to metyrapone test reduced serum folate concentration increased serum triglyceride and phospholipid concentration Trecator has been found to temporarily raise serum concentrations of isoniazid Trecator may potentiate the adverse effects of other antituberculous drugs administered concomitantly In particular convulsions have been reported when ethionamide is administered with cycloserine and special care should be taken when the treatment regimen includes both of these drugs Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported Ethopropazine may interact with alcohol or other CNS depressants causing increased sedative effects It may also interact with amantadine or other anticholinergic drugs or MAOIs which may intensify the anticholinergic action Ethopropazine can interact with chlorpromazine increasing the metabolism of chlorpromazine Since Zarontin ethosuximide may interact with concurrently administered antiepileptic drugs periodic serum level determinations of these drugs may be necessary eg ethosuximide may elevate phenytoin serum levels and valproic acid has been reported to both increase and decrease ethosuximide levels PEGANONE used in combination with other drugs known to adversely affect the hematopoietic system should be avoided if possible Considerable caution should be exercised if PEGANONE is administered concurrently with Phenurone phenacemide since paranoid symptoms have been reported during therapy with this combination A two way interaction between the hydantoin antiepileptic phenytoin and the coumarin anticoagulants has been suggested Presumably phenytoin acts as a stimulator of coumarin metabolism and has been reported to cause decreased serum levels of the coumarin anticoagulants and increased prothrombin proconvertin concentrations Conversely the coumarin anticoagulants have been reported to increase the serum levels and prolong the serum half life of phenytoin by inhibiting its metabolism Although there is no documentation of such a similar interaction between ethotoin and the coumarin anticoagulants may occur Caution is therefore advised when administering PEGANONE to patients receiving coumarin anticoagulants Ethoxzolamide may increase the action of tricyclics amphetamines procainamide and quinidine It may increase excretion of barbiturates lithium and ASA and may also increase the toxicity of salicylates Coadministration of ethoxzolamide with other diuretics amphotericin B and corticosteroids may cause hypokalemia Ethinyl estradiol Substrate of CYP3A4 major 3A5 7 minor Inhibits CYP1A2 weak 2B6 weak 2C19 weak 3A4 weak Acetaminophen May increase plasma concentration of synthetic estrogens possibly by inhibiting conjugation Combination hormonal contraceptives may also decrease the plasma concentration of acetaminophen Acitretin Interferes with the contraceptive effect of microdosed progestin containing minipill preparations The effect on other progestational contraceptives eg implants injectables is unknown Aminoglutethimide May increase CYP metabolism of progestins leading to possible decrease in contraceptive effectiveness Use of a nonhormonal contraceptive product is recommended Antibiotics ampicillin tetracycline Pregnancy has been reported following concomitant use however pharmacokinetic studies have not shown consistent effects with these antibiotics on plasma concentrations of synthetic steroids Use of a nonhormonal contraceptive product is recommended Anticoagulants Combination hormonal contraceptives may increase or decrease the effects of coumarin derivatives Combination hormonal contraceptives may also increase risk of thromboembolic disorders Anticonvulsants carbamazepine felbamate phenobarbital phenytoin topiramate Increase the metabolism of ethinyl estradiol and or some progestins leading to possible decrease in contraceptive effectiveness Use of a nonhormonal contraceptive product is recommended Ascorbic acid Doses of ascorbic acid vitamin C 1 g day have been reported to increase plasma concentration of synthetic estrogens by 47 possibly by inhibiting conjugation clinical implications are unclear Atorvastatin Atorvastatin increases the AUC for norethindrone and ethinyl estradiol Benzodiazepines Combination hormonal contraceptives may decrease the clearance of some benzodiazepines alprazolam chlordiazepoxide diazepam and increase the clearance of others lorazepam oxazepam temazepam Clofibric acid Combination hormonal contraceptives may increase the clearance of clofibric acid Cyclosporine Combination hormonal contraceptives may inhibit the metabolism of cyclosporine leading to increased plasma concentrations monitor cyclosporine levels CYP3A4 inducers CYP3A4 inducers may decrease the levels effects of ethinyl estradiol Example inducers include aminoglutethimide carbamazepine nafcillin nevirapine phenobarbital phenytoin and rifamycins Griseofulvin Griseofulvin may induce the metabolism of combination hormonal contraceptives causing menstrual changes pregnancies have been reported Use of barrier form of contraception is suggested while on griseofulvin therapy Morphine Combination hormonal contraceptives may increase the clearance of morphine Non nucleoside reverse transcriptase inhibitors NNRTIs Nevirapine may decrease plasma levels of combination hormonal contraceptives use of a nonhormonal contraceptive product is recommended No data for delavirdine incomplete data for efavirenz Prednisolone Ethinyl estradiol may inhibit the metabolism of prednisolone leading to increased plasma concentrations Protease inhibitors Amprenavir lopinavir nelfinavir and ritonavir have been shown to decrease plasma levels of combination hormonal contraceptives use of a nonhormonal contraceptive product is recommended Indinavir has been shown to increase plasma levels of combination hormonal contraceptives No data for saquinavir Rifampin Rifampin increases the metabolism of ethinyl estradiol and some progestins norethindrone resulting in decreased contraceptive effectiveness and increased menstrual irregularities Use of a nonhormonal contraceptive product is recommended Salicylic acid Combination hormonal contraceptives may increase the clearance of salicylic acid Selegiline Combination hormonal contraceptives may increase the serum concentration of selegiline Theophylline Ethinyl estradiol may inhibit the metabolism of theophylline leading to increased plasma concentrations Tricyclic antidepressants amitriptyline imipramine nortriptyline Metabolism may be inhibited by combination hormonal contraceptives increasing plasma levels of antidepressant use caution ETHANOL NUTRITION HERB INTERACTIONS Food CNS effects of caffeine may be enhanced if combination hormonal contraceptives are used concurrently with caffeine Grapefruit juice increases ethinyl estradiol concentrations and would be expected to increase progesterone serum levels as well clinical implications are unclear Herb Nutraceutical St Johns wort may decrease the effectiveness of combination hormonal contraceptives by inducing hepatic enzymes Avoid dong quai and black cohosh have estrogen activity Avoid saw palmetto red clover ginseng There have been isolated reports of patients experiencing increases in their prothrombin times when etidronate was added to warfarin therapy The majority of these reports concerned variable elevations in prothrombin times without clinically significant sequelae Although the relevance of these reports and any mechanism of coagulation alterations is unclear patients on warfarin should have their prothrombin time monitored ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors Antacids The concomitant administration of antacids has no apparent effect on the extent of absorption of Lodine However antacids can decrease the peak concentration reached by 15 to 20 but have no detectable effect on the time to peak Aspirin When Lodine is administered with aspirin its protein binding is reduced although the clearance of free etodolac is not altered The clinical significance of this interaction is not known however as with other NSAIDs concomitant administration of Lodine and aspirin is not generally recommended because of the potential of increased adverse effects Cyclosporine Digoxin Methotrexate Lodine like other NSAIDs through effects on renal prostaglandins may cause changes in the elimination of these drugs leading to elevated serum levels of cyclosporine digoxin methotrexate and increased toxicity Nephrotoxicity associated with cyclosporine may also be enhanced Patients receiving these drugs who are given Lodine or any other NSAID and particularly those patients with altered renal function should be observed for the development of the specific toxicities of these drugs Diuretics Etodolac has no apparent pharmacokinetic interaction when administered with furosemide or hydrochlorothiazide Nevertheless clinical studies as well as postmarketing observations have shown that Lodine can reduce the natriuretic effect of furosemide and thiazides in some patients This response has been attributed to inhibition of renal prostaglandin synthesis During concomitant therapy with NSAIDs the patient should be observed closely for signs of renal failure as well as to assure diuretic efficacy Glyburide Etodolac has no apparent pharmacokinetic interaction when administered with glyburide Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance The mean minimum lithium concentration increased 15 and the renal clearance was decreased by approximately 20 These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID Thus when NSAIDs and lithium are administered concurrently subjects should be observed carefully for signs of lithium toxicity Phenylbutazone Phenylbutazone causes increase by about 80 in the free fraction of etodolac Although in vivo studies have not been done to see if etodolac clearance is changed by coadministration of phenylbutazone it is not recommended that they be coadministered Phenytoin Etodolac has no apparent pharmacokinetic interaction when administered with phenytoin Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic such that users of both drugs together have a risk of serious GI bleeding higher than that of users of either drug alone Short term pharmacokinetic studies have demonstrated that concomitant administration of warfarin and Lodine etodolac capsules and tablets results in reduced protein binding of warfarin but there was no change in the clearance of free warfarin There was no significant difference in the pharmacodynamic effect of warfarin administered alone and warfarin administered with Lodine as measured by prothrombin time Thus concomitant therapy with warfarin and Lodine should not require dosage adjustment of either drug However caution should be exercised because there have been a few spontaneous reports of prolonged prothrombin times with or without bleeding in etodolac treated patients receiving concomitant warfarin therapy Drug Laboratory Test Interactions The urine of patients who take Lodine can give a false positive reaction for urinary bilirubin urobilin due to the presence of phenolic metabolites of etodolac Diagnostic dip stick methodology used to detect ketone bodies in urine has resulted in false positive findings in some patients treated with Lodine Generally this phenomenon has not been associated with other clinically significant events No dose relationship has been observed Lodine treatment is associated with a small decrease in serum uric acid levels In clinical trials mean decreases of 1 to 2 mg dL were observed in arthritic patients receiving etodolac 600 mg to 1000 mg day after 4 weeks of therapy These levels then remained stable for up to 1 year of therapy The following drug interactions have been reported with etomidate Drug Effect Probenecid Prolonged action of etomidate Diazoxide Hypotension Zimelidine etomidate antagonism Opioid analgesics Decreased antinociceptive action Aminophylline Etomidate antagonism Midazolam Synergism Etonogestrel may interact with the following medications acetaminophen Tylenol antibiotics such as ampicillin and tetracycline anticonvulsants Dilantin Phenobarbital Tegretol Trileptal Topamax Felbatol antifungals Gris PEG Nizoral Sporanox atorvastatin Lipitor clofibrate Atromid S cyclosporine Neoral Sandimmune HIV drugs classified as protease inhibitors Agenerase Crixivan Fortovase Invirase Kaletra Norvir Viracept morphine Astramorph Kadian MS Contin phenylbutazone prednisolone Prelone rifadin rifampin St Johns wort temazepam theophylline Theo Dur and vitamin C Caution should be exercised when administering ETOPOPHOS with drugs that are known to inhibit phosphatase activities e g levamisole hydrochloride High dose cyclosporin A resulting in concentrations above 2000 ng mL administered with oral etoposide has led to an 80 increase in etoposide exposure with a 38 decrease in total body clearance of etoposide compared to etoposide alone Exemestane is extensively metabolized by CYP 3A4 but coadministration of ketoconazole a potent inhibitor of CYP 3A4 has no significant effect on exemestane pharmacokinetics Significant pharmacokinetic interactions mediated by inhibition of CYP isoenzymes therefore appear unlikely Co medications that induce CYP 3A4 e g rifampicin phenytoin carbamazepine phenobarbital or St John s wort may significantly decrease exposure to exemestane Dose modification is recommended for patients who are also receiving a potent CYP 3A4 inducer Drug Laboratory Tests Interactions No clinically relevant changes in the results of clinical laboratory tests have been observed Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may result in increased plasma concentrations of penciclovir The conversion of 6 deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase Interactions with other drugs metabolized by this enzyme could potentially occur No drug interactions have been identified Studies with famotidine in man in animal models and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes e g cytochrome P450 system Compounds tested in man include warfarin theophylline phenytoin diazepam aminopyrine and antipyrine Indocyanine green as an index of hepatic drug extraction has been tested and no significant effects have been found The drug interaction data described in this section were obtained from controlled clinical trials and studies involving otherwise healthy adults with epilepsy Use in Conjunction with Other Antiepileptic Drugs The addition of Felbatol to antiepileptic drugs AEDs affects the steady state plasma concentrations of AEDs The net effect of these interactions is summarized in the following table AED AED Felbatol Coadministered Concentration Concentration Phenytoin Valproate Carbamazepine CBZ CBZ epoxide Phenobarbital Not administered but an active metabolite of carbamazepine No significant effect Specific Effects of Felbatol on Other Antiepileptic Drugs Phenytoin Felbatol causes an increase in steady state phenytoin plasma concentrations In 10 otherwise healthy subjects with epilepsy ingesting phenytoin the steadystate trough Cmin phenytoin plasma concentration was 17 5 micrograms mL The steady state Cmin increased to 21 5 micrograms mL when 1200 mg day of felbamate was coadministered Increasing the felbamate dose to 1800 mg day in six of these subjects increased the steady state phenytoin Cmin to 25 7 micrograms mL In order to maintain phenytoin levels limit adverse experiences and achieve the felbamate dose of 3600 mg day a phenytoin dose reduction of approximately 40 was necessary for eight of these 10 subjects In a controlled clinical trial a 20 reduction of the phenytoin dose at the initiation of Felbatol therapy resulted in phenytoin levels comparable to those prior to Felbatol administration Carbamazepine Felbatol causes a decrease in the steady state carbamazepine plasma concentrations and an increase in the steady state carbamazepine epoxide plasma concentration In nine otherwise healthy subjects with epilepsy ingesting carbamazepine the steady state trough Cmin carbamazepine concentration was 8 2 micrograms mL The carbamazepine steady state Cmin decreased 31 to 5 1 micrograms mL when felbamate 3000 mg day divided into three doses was coadministered Carbamazepine epoxide steady state Cmin concentrations increased 57 from 1 0 0 3 to 1 6 0 4 micrograms mL with the addition of felbamate In clinical trials similar changes in carbamazepine and carbamazepine epoxide were seen Valproate Felbatol causes an increase in steady state valproate concentrations In four subjects with epilepsy ingesting valproate the steady state trough Cmin valproate plasma concentration was 63 16 micrograms mL The steady state Cmin increased to 78 14 micrograms mL when 1200 mg day of felbamate was coadministered Increasing the felbamate dose to 2400 mg day increased the steadystate valproate Cmin to 96 25 micrograms mL Corresponding values for free valproate Cmin concentrations were 7 3 9 4 and 11 6 micrograms mL for 0 1200 and 2400 mg day Felbatol respectively The ratios of the AUCs of unbound valproate to the AUCs of the total valproate were 11 1 13 0 and 11 5 with coadministration of 0 1200 and 2400 mg day of Felbatol respectively Phenobarbital Coadministration of felbamate with phenobarbital causes an increase in phenobarbital plasma concentrations In 12 otherwise healthy male volunteers ingesting phenobarbital the steady state trough Cmin phenobarbital concentration was 14 2 micrograms mL The steady state Cmin concentration increased to 17 8 micrograms mL when 2400 mg day of felbamate was coadministered for one week Effects of Other Antiepileptic Drugs on Felbatol Phenytoin Phenytoin causes an approximate doubling of the clearance of Felbatol felbamate at steady state and therefore the addition of phenytoin causes an approximate 45 decrease in the steady state trough concentrations of Felbatol as compared to the same dose of Felbatol given as monotherapy Carbamazepine Carbamazepine causes an approximate 50 increase in the clearance of Felbatol at steady state and therefore the addition of carbamazepine results in an approximate 40 decrease in the steady state trough concentrations of Felbatol as compared to the same dose of Felbatol given as monotherapy Valproate Available data suggest that there is no significant effect of valproate on the clearance of Felbatol at steady state Therefore the addition of valproate is not expected to cause a clinically important effect on Felbatol felbamate plasma concentrations Phenobarbital It appears that phenobarbital may reduce plasma felbamate concentrations Steady state plasma felbamate concentrations were found to be 29 lower than the mean concentrations of a group of newly diagnosed subjects with epilepsy also receiving 2400 mg of felbamate a day Effects of Antacids on Felbatol The rate and extent of absorption of a 2400 mg dose of Felbatol as monotherapy given as tablets was not affected when coadministered with antacids Effects of Erythromycin on Felbatol The coadministration of erythromycin 1000 mg day for 10 days did not alter the pharmacokinetic parameters of Cmax Cmin AUC CI kg or tmax at felbamate daily doses of 3000 or 3600 mg day in 10 otherwise healthy subjects with epilepsy Effects of Felbatol on Low Dose Combination Oral Contraceptives A group of 24 nonsmoking healthy white female volunteers established on an oral contraceptive regimen containing 30 mg ethinyl estradiol and 75 mg gestodene for at least 3 months received 2400 mg day of felbamate from midcycle day 15 to midcycle day 14 of two consecutive oral contraceptive cycles Felbamate treatment resulted in a 42 decrease in the gestodene AUC 0 24 but no clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol No volunteer showed hormonal evidence of ovulation but one volunteer reported intermenstrual bleeding during felbamate treatment CYP3A4 Inhibitors Felodipine is metabolized by CYP3A4 Co administration of CYP3A4 inhibitors eg ketoconazole itraconazole erythromycin grapefruit juice cimetidine with felodipine may lead to several fold increases in the plasma levels of felodipine either due to an increase in bioavailability or due to a decrease in metabolism These increases in concentration may lead to increased effects lower blood pressure and increased heart rate These effects have been observed with co administration of itraconazole a potent CYP3A4 inhibitor Caution should be used when CYP3A4 inhibitors are co administered with felodipine A conservative approach to dosing felodipine should be taken The following specific interactions have been reported Itraconazole Co administration of another extended release formulation of felodipine with itraconazole resulted in approximately 8 fold increase in the AUC more than 6 fold increase in the Cmax and 2 fold prolongation in the half life of felodipine Erythromycin Co administration of felodipine PLENDIL with erythromycin resulted in approximately 2 5 fold increase in the AUC and Cmax and about 2 fold prolongation in the half life of felodipine Grapefruit juice Co administration of felodipine with grapefruit juice resulted in more than 2 fold increase in the AUC and Cmax but no prolongation in the half life of felodipine Cimetidine Co administration of felodipine with cimetidine a non specific CYP 450 inhibitor resulted in an increase of approximately 50 in the AUC and the Cmax of felodipine Beta Blocking Agents A pharmacokinetic study of felodipine in conjunction with metoprolol demonstrated no significant effects on the pharmacokinetics of felodipine The AUC and Cmax of metoprolol however were increased approximately 31 and 38 respectively In controlled clinical trials however beta blockers including metoprolol were concurrently administered with felodipine and were well tolerated Digoxin When given concomitantly with PLENDIL the pharmacokinetics of digoxin in patients with heart failure were not significantly altered Anticonvulsants In a pharmacokinetic study maximum plasma concentrations of felodipine were considerably lower in epileptic patients on long term anticonvulsant therapy eg phenytoin carbamazepine or phenobarbital than in healthy volunteers In such patients the mean area under the felodipine plasma concentration time curve was also reduced to approximately 6 of that observed in healthy volunteers Since a clinically significant interaction may be anticipated alternative antihypertensive therapy should be considered in these patients Tacrolimus Felodipine may increase the blood concentration of tacrolimus When given concomitantly with felodipine the tacrolimus blood concentration should be followed and the tacrolimus dose may need to be adjusted Other Concomitant Therapy In healthy subjects there were no clinically significant interactions when felodipine was given concomitantly with indomethacin or spironolactone Interaction with Food See CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism Fenfluramine may increase slightly the effect of antihypertensive drugs e g guanethidine methyldopa reserpine Other CNS depressant drugs should be used with caution in patients taking fenfluramine since the effects may be additive Oral Anticoagulants CAUTION SHOULD BE EXERCISED WHEN COUMARIN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH TRICOR THE DOSAGE OF THE ANTICOAGULANTS SHOULD BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME INR AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS FREQUENT PROTHROMBIN TIME INR DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE PROTHROMBIN TIME INR HAS STABILIZED HMG CoA reductase inhibitors The combined use of TRICOR and HMG CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination Resins Since bile acid sequestrants may bind other drugs given concurrently patients should take TRICOR at least 1 hour before or 4 6 hours after a bile acid binding resin to avoid impeding its absorption Cyclosporine Because cyclosporine can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine and because renal excretion is the primary elimination route of fibrate drugs including TRICOR there is a risk that an interaction will lead to deterioration The benefits and risks of using TRICOR with immunosuppressants and other potentially nephrotoxic agents should be carefully considered and the lowest effective dose employed Drug drug interactions In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome CYP P450 isoforms CYP3A4 CYP2D6 CYP2E1 or CYP1A2 They are weak inhibitors of CYP2C19 and CYP2A6 and mild to moderate inhibitors of CYP2C9 at therapeutic concentrations Potentiation of coumarin type anticoagulants has been observed with prolongation of the prothrombin time INR Bile acid sequestrants have been shown to bind other drugs given concurrently Therefore fenofibrate should be taken at least 1 hour before or 4 6 hours after a bile acid binding resin to avoid impeding its absorption Concomitant administration of fenofibrate equivalent to 145mg TRICOR with pravastatin 40 mg once daily for 10 days has been shown to increase the mean Cmax and AUC values for pravastatin by 36 range from 69 decrease to 321 increase and 28 range from 54 decrease to 128 increase respectively and for 3 hydroxy iso pravastatin by 55 range from 32 decrease to 314 increase and 39 range from 24 decrease to 261 increase respectively in 23 healthy adults A single dose of pravastatin had no clinically important effect on the pharmacokinetics of fenofibric acid Concomitant administration of fenofibrate equivalent to 145 mg TRICOR with atorvastatin 20 mg once daily for 10 days resulted in approximately 17 decrease range from 67 decrease to 44 increase in atorvastatin AUC values in 22 healthy males The atorvastatin Cmax values were not significantly affected by fenofibrate The pharmacokinetics of fenofibric acid were not significantly affected by atorvastatin Drug Interactions with Beta Blockers Concomitant use of fenoldopam with beta blockers should be avoided If the drugs are used together caution should be exercised because unexpected hypotension could result from beta blocker inhibition of the sympathetic reflex response to fenoldopam Drug Interactions General Although there have been no formal interaction studies intravenous fenoldopam has been administered safely with drugs such as digitalis and sublingual nitroglycerin There is limited experience with concomitant antihypertensive agents such as alpha blockers calcium channel blockers ACE inhibitors and diuretics both thiazide like and loop The coadministration of aspirin decreases the biologic half life of fenoprofen because of an increase in metabolic clearance that results in a greater amount of hydroxylated fenoprofen in the urine Although the mechanism of interaction between fenoprofen and aspirin is not totally known enzyme induction and displacement of fenoprofen from plasma albumin binding sites are possibilities Because Nalfon has not been shown to produce any additional effect beyond that obtained with aspirin alone and because aspirin increases the rate of excretion of Nalfon the concomitant use of Nalfon and salicylates is not recommended Chronic administration of phenobarbital a known enzyme inducer may be associated with a decrease in the plasma half life of fenoprofen When phenobarbital is added to or withdrawn from treatment dosage adjustment of Nalfon may be required In vitro studies have shown that fenoprofen because of its affinity for albumin may displace from their binding sites other drugs that are also albumin bound and this may lead to drug interaction Theoretically fenoprofen could likewise be displaced Patients receiving hydantoins sulfonamides or sulfonylureas should be observed for increased activity of these drugs and therefore signs of toxicity from these drugs In patients receiving coumarin type anticoagulants the addition of Nalfon to therapy could prolong the prothrombin time Patients receiving both drugs should be under careful observation Patients treated with Nalfon may be resistant to the effects of loop diuretics In patients receiving Nalfon and a steroid concomitantly any reduction in steroid dosage should be gradual in order to avoid the possible complications of sudden steroid withdrawal Agents Affecting Cytochrome P450 3A4 Isoenzyme System Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system CYP3A4 therefore potential interactions may occur when DURAGESIC is given concurrently with agents that affect CYP3A4 activity Coadminstration with agents that induce 3A4 activity may reduce the efficacy of DURAGESIC The concomitant use of transdermal fentanyl with ritonavir or other potent 3A4 inhibitors such as ketoconazole itraconazole troleandomycin clarithromycin nelfinavir and nefazadone may result in an increase in fentanyl plasma concentrations The concomitant use of other CYP3A4 inhibitors such as diltiazem and erythromycin with transdermal fentanyl may also result in an increase in fentanyl plasma concentrations which could increase or prolong adverse drug effects and may cause serious respiratory depression In this situation special patient care and observation are appropriate Central Nervous System Depressants The concomitant use of DURAGESIC fentanyl transdermal system with other central nervous system depressants including but not limited to other opioids sedatives hypnotics tranquilizers e g benzodiazepines general anesthetics phenothiazines skeletal muscle relaxants and alcohol may cause respiratory depression hypotension and profound sedation or potentially result in coma or death When such combined therapy is contemplated the dose of one or both agents should be significantly reduced MAO Inhibitors DURAGESIC is not recommended for use in patients who have received MAOI within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics Drug Interaction with Erythromycin and Ketoconazole Fexofenadine has been shown to exhibit minimal ca 5 metabolism However co administration of fexofenadine hydrochloride with either ketoconazole or erythromycin led to increased plasma concentrations of fexofenadine Fexofenadine had no effect on the pharmacokinetics of either erythromycin or ketoconazole In 2 separate studies fexofenadine hydrochloride 120 mg twice daily 240 mg total daily dose was co administered with either erythromycin 500 mg every 8 hours or ketoconazole 400 mg once daily under steady state conditions to healthy volunteers n 24 each study No differences in adverse events or QTc interval were observed when subjects were administered fexofenadine hydrochloride alone or in combination with either erythromycin or ketoconazole The findings of these studies are summarized in the following table Effects on steady state fexofenadine pharmacokinetics after 7 days of co administration with fexofenadine hydrochloride 120 mg every 12 hours two times the recommended twice daily dose in healthy volunteers n 24 Concomitant Drug cmaxSS Peak plasma concentration AUCss 0 12h Extent of systemic exposure Erythromycin 500 mg every 8 hrs 82 109 Ketoconazole 400 mg once daily 135 164 The changes in plasma levels were within the range of plasma levels achieved in adequate and well controlled clinical trials The mechanism of these interactions has been evaluated in in vitro in situ and in vivo animal models These studies indicate that ketoconazole or erythromycin co administration enhances fexofenadine gastrointestinal absorption This observed increase in the bioavailability of fexofenadine may be due to transport related effects such as p glycoprotein in vivo animal studies also suggest that in addition to enhancing absorption ketoconazole decreases fexofenadine gastrointestinal secretion while erythromycin may also decrease biliary excretion Drug Interactions with Antacids Administration of 120 mg of fexofenadine hydrochloride 2 x 60 mg capsule within 15 minutes of an aluminum and magnesium containing antacid Maalox decreased fexofenadine AUC by 41 and cmax by 43 ALLEGRA should not be taken closely in time with aluminum and magnesium containing antacids Interactions with Fruit Juices Fruit juices such as grapefruit orange and apple may reduce the bioavailability and exposure of fexofenadine This is based on the results from 3 clinical studies using histamine induced skin wheals and flares coupled with population pharmacokinetic analysis The size of wheal and flare were significantly larger when fexofenadine hydrochloride was administered with either grapefruit or orange juices compared to water Based on the literature reports the same effects may be extrapolated to other fruit juices such as apple juice The clinical significance of these observations is unknown In addition based on the population pharmacokinetics analysis of the combined data from grapefruit and orange juices studies with the data from a bioequivalence study the bioavailability of fexofenadine was reduced by 36 Therefore to maximize the effects of fexofenadine it is recommended that ALLEGRA should be taken with water Drug interactions between NEUPOGEN and other drugs have not been fully evaluated Drugs which may potentiate the release of neutrophils such as lithium should be used with caution No drug interactions of clinical importance have been identified Finasteride does not appear to affect the cytochrome P450 linked drug metabolizing enzyme system Compounds that have been tested in man include antipyrine digoxin propranolol theophylline and warfarin and no clinically meaningful interactions were found Other concomitant therapy Although specific interaction studies were not performed finasteride doses of 1 mg or more were concomitantly used in clinical studies with acetaminophen acetylsalicylic acid a blockers analgesics angiotensin converting enzyme ACE inhibitors anticonvulsants benzodiazepines beta blockers calcium channel blockers cardiac nitrates diuretics H2 antagonists HMG CoA reductase inhibitors prostaglandin synthetase inhibitors also referred to as NSAIDs and quinolone anti infectives without evidence of clinically significant adverse interactions Drug Laboratory Test Interactions Finasteride had no effect on circulating levels of cortisol thyroid stimulating hormone or thyroxine nor did it affect the plasma lipid profile e g total cholesterol low density lipoproteins high density lipoproteins and triglycerides or bone mineral density In studies with finasteride no clinically meaningful changes in luteinizing hormone LH follicle stimulating hormone FSH or prolactin were detected In healthy volunteers treatment with finasteride did not alter the response of LH and FSH to gonadotropin releasing hormone indicating that the hypothalamic pituitary testicular axis was not affected In clinical studies with PROPECIA finasteride 1 mg in men 18 41 years of age the mean value of serum prostate specific antigen PSA decreased from 0 7 ng mL at baseline to 0 5 ng mL at Month 12 Further in clinical studies with PROSCAR finasteride 5 mg when used in older men who have benign prostatic hyperplasia BPH PSA levels are decreased by approximately 50 These findings should be taken into account for proper interpretation of serum PSA when evaluating men treated with finasteride Drug Interactions TAMBOCOR has been administered to patients receiving digitalis preparations or beta adrenergic blocking agents without adverse effects During administration of multiple oral doses of TAMBOCOR to healthy subjects stabilized on a maintenance dose of digoxin a 13 19 increase in plasma digoxin levels occurred at six hours postdose In a study involving healthy subjects receiving TAMBOCOR and propranolol concurrently plasma flecainide levels were increased about 20 and propranolol levels were increased about 30 compared to control values In this formal interaction study TAMBOCOR and propranolol were each found to have negative inotropic effects when the drugs were administered together the effects were additive The effects of concomitant administration of TAMBOCOR and propranolol on the PR interval were less than additive In TAMBOCOR clinical trials patients who were receiving beta blockers concurrently did not experience an increased incidence of side effects Nevertheless the possibility of additive negative inotropic effects of beta blockers and flecainide should be recognized Flecainide is not extensively bound to plasma proteins In vitro studies with several drugs which may be administered concomitantly showed that the extent of flecainide binding to human plasma proteins is either unchanged or only slightly less Consequently interactions with other drugs which are highly protein bound e g anticoagulants would not be expected TAMBOCOR has been used in a large number of patients receiving diuretics without apparent interaction Limited data in patients receiving known enzyme inducers phenytoin phenobarbital carbamazepine indicate only a 30 increase in the rate of flecainide elimination In healthy subjects receiving cimetidine 1 gm daily for one week plasma flecainide levels increased by about 30 and half life increased by about 10 When amiodarone is added to flecainide therapy plasma flecainide levels may increase two fold or more in some patients if flecainide dosage is not reduced Drugs that inhibit cytochrome P450IID6 such as quinidine might increase the plasma concentrations of flecainide in patients that are on chronic flecainide therapy especially if these patients are extensive metabolizers There has been little experience with the coadministration of TAMBOCOR and either disopyramide or verapamil Because both of these drugs have negative inotropic properties and the effects of coadministration with TAMBOCOR are unknown neither disopyramide nor verapamil should be administered concurrently with TAMBOCOR unless in the judgment of the physician the benefits of this combination outweigh the risks There has been too little experience with the coadministration of TAMBOCOR with nifedipine or diltiazem to recommend concomitant use Combination Therapy Any form of therapy which adds to the stress of the patient interferes with nutrition or depresses bone marrow function will increase the toxicity of Floxuridine Cytosine arabinoside a cytostatic agent has been reported to inactivate the antifungal activity of flucytosine by competitive inhibition Drugs which impair glomerular filtration may prolong the biological half life of flucytosine Drug Laboratory Test Interactions Measurement of serum creatinine levels should be determined by the Jaffe reaction since Ancobon does not interfere with the determination of creatinine values by this method Most automated equipment for measurement of creatinine makes use of the Jaffe reaction The use of FLUDARA FOR INJECTION in combination with pentostatin is not recommended due to the risk of severe pulmonary toxicity When administered concurrently the following drugs may interact with adrenal corticosteroids Amphotericin B or potassium depleting diuretics benzothiadiazines and related drugs ethacrynic acid and furosemide enhanced hypokalemia Check serum potassium levels at frequent intervals use potassium supplements if necessary Digitalis glycosides enhanced possibility of arrhythmias or digitalis toxicity associated with hypokalemia Monitor serum potassium levels use potassium supplements if necessary Oral anticoagulants decreased prothrombin time response Monitor prothrombin levels and adjust anticoagulant dosage accordingly Antidiabetic drugs oral agents and insulin diminished antidiabetic effect Monitor for symptoms of hyperglycemia adjust dosage of antidiabetic drug upward if necessary Aspirin increased ulcerogenic effect decreased pharmacologic effect of aspirin Rarely salicylate toxicity may occur in patients who discontinue steroids after concurrent high dose aspirin therapy Monitor salicylate levels or the therapeutic effect for which aspirin is given adjust salicylate dosage accordingly if effect is altered Barbiturates phenytoin or rifampin increased metabolic clearance of fludrocortisone acetate because of the induction of hepatic enzymes Observe the patient for possible diminished effect of steroid and increase the steroid dosage accordingly Anabolic steroids particularly C 17 alkylated androgens such as oxymetholone methandrostenolone norethandrolone and similar compounds enhanced tendency toward edema Use caution when giving these drugs together especially in patients with hepatic or cardiac disease Vaccines neurological complications and lack of antibody response Estrogen increased levels of corticosteroid binding globulin thereby increasing the bound inactive fraction this effect is at least balanced by decreased metabolism of corticosteroids When estrogen therapy is initiated a reduction in corticosteroid dosage may be required and increased amounts may be required when estrogen is terminated Drug Laboratory Test Interactions Corticosteroids may affect the nitrobluetetrazolium test for bacterial infection and produce false negative results Interaction with central nervous system depressants other than benzodiazepines has not been specifically studied however no deleterious interactions were seen when ROMAZICON was administered after narcotics inhalational anesthetics muscle relaxants and muscle relaxant antagonists administered in conjunction with sedation or anesthesia Particular caution is necessary when using ROMAZICON in cases of mixed drug overdosage since the toxic effects such as convulsions and cardiac dysrhythmias of other drugs taken in overdose especially cyclic antidepressants may emerge with the reversal of the benzodiazepine effect by flumazenil The use of ROMAZICON is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period Although ROMAZICON exerts a slight intrinsic anticonvulsant effect its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients ROMAZICON blocks the central effects of benzodiazepines by competitive interaction at the receptor level The effects of nonbenzodiazepine agonists at benzodiazepine receptors such as zopiclone triazolopyridazines and others are also blocked by ROMAZICON The pharmacokinetics of benzodiazepines are unaltered in the presence of flumazenil and vice versa There is no pharmacokinetic interaction between ethanol and flumazenil Use in Ambulatory Patients The effects of ROMAZICON may wear off before a long acting benzodiazepine is completely cleared from the body In general if a patient shows no signs of sedation within 2 hours after a 1 mg dose of flumazenil serious resedation at a later time is unlikely An adequate period of observation must be provided for any patient in whom either long acting benzodiazepines such as diazepam or large doses of short acting benzodiazepines such as 10 mg of midazolam have been used Because of the increased risk of adverse reactions in patients who have been taking benzodiazepines on a regular basis it is particularly important that physicians query patients or their guardians carefully about benzodiazepine alcohol and sedative use as part of the history prior to any procedure in which the use of ROMAZICON is planned No information available Do not take this medicine with thioridizine or within 5 weeks of taking fluoxetine Talk to your doctor if you are taking certain antibiotics such as erythromycin clarithromycin or azithromycin This medicine should not be taken with MAO inhibitors Caution should be exercised when taking this medicine certain antibiotics such as erythromycin clarithromycin or azithromycin This medicine should not be taken with MAO inhibitors If you think you are taking an MAO inhibitor talk to your doctor or pharmacist Do not take this medicine with St Johns Wort because of the additive effects of sertonin This medication should not be taken with MAO inhibitors Your doctor or pharmacist can give you more information on MAO inhibitors Wait 5 weeks after stopping escitalopram before starting a non selective MAO inhibitor Wait 2 weeks after stopping an MAO inhibitor before starting escitalopram If you are taking medications for migraines such as Imitrex talk to your doctor before starting this medicine If you are taking a tricyclic antidepressant talk to your doctor before taking this medicine St John s Wort should be avoided while taking this medicine due to the additive effects of serotonin Tell your doctor if you are taking any of the following drugs blood thinners Coumadin other antidepressants metoprolol antihistamines carbamazepine Tegretol cimetidine Tagamet estrogens fluoxetine Prozac intraconazole Sporanox ketoconazole Nizoral levodopa lithium muscle relaxants birth control pills sleeping pills thyroid medications Androgens may increase sensitivity to oral anticoagulahts Dosage of the anticoagulant may require reduction in order to maintain satisfactory therapeutic hypoprothrombinemia Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone In diabetic patients the metabolic effects of androgens may decrease blood glucose and therefore insulin requirements Drug Interactions Flupenthixol may interact with some drugs like Monoamine oxidase inhibitors MAOI MAOI could theoretically affect flupenthixol pharmacodynamics Arecoline Eproxindine Ethanol Flupenthixol and Ethanol cause additive CNS depression Tricyclic antidepressants Flupenthixol increases the effect of Tricyclic antidepressants Antacids Administration of flurbiprofen to volunteers under fasting conditions or with antacid suspension yielded similar serum flurbiprofen time profiles in young subjects n 12 In geriatric subjects n 7 there was a reduction in the rate but not the extent of flurbiprofen absorption Anticoagulants Flurbiprofen like other nonsteroidal anti inflammatory drugs has been shown to affect bleeding parameters in patients receiving anti coagulants and serious clinical bleeding has been reported The physician should be cautious when administering flurbiprofen to patients taking anticoagulants Aspirin Concurrent administration of aspirin and flurbiprofen resulted in 50 lower serum flurbiprofen concentrations This effect of aspirin which also lowers serum concentrations of other nonsteroidal anti inflammatory drugs given with it has been demonstrated in patients with rheumatoid arthritis n 15 as well as normal volunteers n 16 Concurrent use of flurbiprofen and aspirin is therefore not recommended Beta adrenergic Blocking Agents The effect of flurbiprofen on blood pressure response to propranolol and atenolol was evaluated in men with mild uncomplicated hypertension n 10 Flurbiprofen pretreatment attenuated the hypotensive effect of a single dose of propranolol but not atenolol Flurbiprofen did not appear to affect the beta blocker mediated reduction in heart rate Flurbiprofen did not affect the pharmacokinetic profile of either drug and the mechanism under lying the interference with propranolols hypotensive effect is unknown Patients taking both flurbiprofen and a beta blocker should be monitored to ensure that a satisfactory hypotensive effect is achieved Cimetidine Ranitidine In normal volunteers n 9 pretreatment with cimetidine or ranitidine did not affect flurbiprofen pharmacokinetics except that a small 13 but statistically significant increase in the area under the serum concentration curve of flurbiprofen resulted with cimetidine Digoxin Studies of concomitant administration of flurbiprofen and digoxin to healthy men n 14 did not show a change in the steady state serum levels of either drug Diuretics Studies in normal volunteers have shown that flurbiprofen like other nonsteroidal anti inflammatory drugs can interfere with the effects of furosemide Although results have varied from study to study effects have been shown on furosemide stimulated diuresis natriuresis and kaliuresis Other nonsteroidal anti inflammatory drugs that inhibit prostaglandin synthesis have been shown to interfere with thiazide diuretics in some studies and with potassium sparing diuretics Patients receiving flurbiprofen and furosemide or other diuretics should be observed closely to determine if the desired effect is obtained Oral Hypoglycemic Agents In one study flurbiprofen was given to adult diabetics who were already receiving glyburide n 4 metformin n 2 chlorpropamide with phenformin n 3 or glyburide with phenformin n 6 Although there was a slight reduction in blood sugar concentrations during concomitant administration of flurbiprofen and hypoglycemic agents there were no signs or symptoms of hypoglycemia Increases in prothrombin time have been noted in patients receiving long term warfarin therapy after flutamide was initiated Therefore close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when EULEXIN Capsules are administered concomitantly with warfarin Potential for Interaction with Monoamine Oxidase Inhibitors In patients receiving another serotonin reuptake inhibitor drug in combination with monoamine oxidase inhibitors MAOI there have been reports of serious sometimes fatal reactions including hyperthermia rigidity myoclonus autonomic instability with possible rapid fluctuations of vital signs and mental status changes that include extreme agitation progressing to delirium and coma These reactions have also been reported in patients who have discontinued that drug and have been started on a MAOI Some cases presented with features resembling neuroleptic malignant syndrome Therefore it is recommended that Fluvoxamine Tablets not be used in combination with MAOIs or within 14 days of discontinuing treatment with a MAOI After stopping Fluvoxamine Tablets at least 2 weeks should be allowed before starting a MAOI Potential Terfenadine Astemizole and Cisapride Interactions Terfenadine astemizole and cisapride are all metabolized by the cytochrome P450IIIA4 isozyme and it has been demonstrated that ketoconazole a potent inhibitor of IIIA4 blocks the metabolism of these drugs resulting in increased plasma concentrations of parent drug Increased plasma concentrations of terfenadine astemizole and cisapride cause QT prolongation and have been associated with torsades de pointes type ventricular tachycardia sometimes fatal As noted below a sub for fluvoxamine in combination with alprazolam a drug that is known to be metabolized by the IIIA4 isozyme Although it has not been definitively demonstrated that fluvoxamine is a potent IIIA4 inhibitor it is likely to be given the substantial interaction of fluvoxamine with alprazolam Consequently it is recommended that fluvoxamine not be used in combination with either terbinafine astemizole or cisapride Other Potentially Important Drug Interactions Benzodiazepines Benzodiazepines metabolized by hepatic oxidation e g alprazolam midazolam triazolam elc should be used with caution because the clearance of these drugs is likely to be reduced by fluvoxamine The clearance of benzodiazepines metabolized by glucuronidation e g lorazepam oxazepam temazepam is unlikely to be affected by fluvoxamine Alprazolam When fluvoxamine maleate 100 mg qd and alprazolam 1 mg q d were co administered to steady state plasma concentration and other pharmacokinetics parameters AUC Cmax T1 2 of alprazolam were approximately twice those observed when alprazolam was administered alone oral clearance was reduced by about 50 The elevated plasma alprazolam concentrations resulted in decreased psychomotor performance and memory This interaction which has not been investigated using higher doses of fluvoxamine may be more pronounced if a 300 mg daily dose is co administered particularly since fluvoxamine exhibits non linear pharmacokinetics over the dosage range 100 300 mg If alprazolam is co administered with Fluvoxamine Tablets the initial alprazolam dosage should be at least halved and titration to the lowest effective dose is recommended No dosage adjustment is required for Fluvoxamine Tablets Diazepam The co administration of Fluvoxamine Tablets and diazepam is generally not advisable Because fluvoxamine reduces the clearance of both diazepam and its active metabolite N desmethyldiazepam there is a strong likelihood of substantial accumulation of both species during chronic co administration Evidence supporting the conclusion that it is inadvisable to co administer fluvoxamine and diazepam is derived from a study in which healthy volunteers taking 150 mg day of fluvoxamine were administered a single oral dose of 10 mg of diazepam In these subjects R B the clearance of diazepam was reduced by 65 and that of N desmethyldiazepam to a level that was too low to measure over the course of the 2 week long study It is likely that experience significantly underestimates the degree of accumulation that might occur with repealed diazepam administration Moreover as noted with alprazolam the effect of fluvoxamine may even be more pronounced when it is administered at higher doses Accordingly diazepam and fluvoxamine should not ordinarily be co administered Theophylline The effect of steady state fluvoxamine l50 mg bid on the pharmacokinetics of a single dose of Theophylline 375 mg as 442 mg aminophylline was evaluated in 12 healthy non smoking male volunteers The clearance of theophylline was decreased approximately 3 fold Therefore if theophylline is co administered with fluvoxamine maleate its dose should be reduced to one third of the usual daily maintenance dose and plasma concentrations of theophylline should to monitored No dosage adjustment is required for Fluvoxamine Tablets Warfarin When fluvoxamine maleate 50 mg tid was administered concomitantly with warfarin for two weeks warfarin plasma concentrations increased by 98 and prothrombin times were prolonged Thus patients receiving oral anticoagulants and Fluvoxamine Tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly No dosage adjustment is required for Fluvoxamine Tablets Medications that interfere with your bodys ability to use folate may also increase the need for this vitamin Medications can interfere with folate utilization including anticonvulsant medications such as phenytoin and primidone metformin sometimes prescribed to control blood sugar in type 2 diabetes sulfasalazine used to control inflammation associated with Crohns disease and ulcerative colitis triamterene a diuretic Methotrexate There has been concern about the interaction between vitamin B12 and folic acid Folic acid supplements can correct the anemia associated with vitamin B12 deficiency Unfortunately folic acid will not correct changes in the nervous system that result from vitamin B12 deficiency Permanent nerve damage could theoretically occur if vitamin B12 deficiency is not treated Therefore intake of supplemental folic acid should not exceed 1000 micrograms g sometimes mcg per day to prevent folic acid from masking symptoms of vitamin B12 deficiency It is important for older adults to be aware of the relationship between folic acid and vitamin B12 because they are at greater risk of having a vitamin B12 deficiency If you are 50 years of age or older ask your physician to check your B12 status before you take a supplement that contains folic acid No drug drug interaction studies have been performed Oral doses of Antizol 10 20 mg kg via alcohol dehydrogenase inhibition significantly reduced the rate of elimination of ethanol by approximately 40 given to healthy volunteers in moderate doses Similarly ethanol decreased the rate of elimination of Antizol by approximately 50 by the same mechanism Reciprocal interactions may occur with concomitant use of Antizol and drugs that increase or inhibit the cytochrome P450 system e g phenytoin carbamazepine cimetidine ketoconazole though this has not been studied In clinical studies performed with Fondaparinux the concomitant use of oral anticoagulants warfarin platelet inhibitors acetylsalicylic acid NSAIDs piroxicam and digoxin did not significantly affect the pharmacokinetics pharmacodynamics of fondaparinux sodium In addition Fondaparinux neither influenced the pharmacodynamics of warfarin acetylsalicylic acid piroxicam and digoxin nor the pharmacokinetics of digoxin at steady state Agents that may enhance the risk of hemorrhage should be discontinued prior to initiation of Fondaparinux therapy If co administration is essential close monitoring may be appropriate In an in vitro study in human liver microsomes inhibition of CYP2A6 hydroxylation of coumarin by fondaparinux 200 m m M i e 350 mg L was 17 28 Inhibition of the other isozymes evaluated CYPs 2A1 2C9 2C19 2D6 3A4 and 3E1 was 0 16 Since fondaparinux does not markedly inhibit CYP450s CYP1A2 CYP2A6 CYP2C9 CYP2C19 CYP2D6 CYP2E1 or CYP3A4 in vitro fondaparinux sodium is not expected to significantly interact with other drugs in vivo by inhibition of metabolism mediated by these isozymes Since fondaparinux sodium does not bind significantly to plasma proteins other than ATIII no drug interactions by protein binding displacement are expected Short Acting beta2 agonists Aerosol bronchodilators of the short acting adrenergic stimulant type may be used for relief of breakthrough symptoms while using formoterol However increasing use of such preparations to control symptoms indicates deterioration of asthma control and the need to reassess the patient s therapy Concomitant administration of other sympathomimetic agents may potentiate the undesirable effects of FORADIL Monoamine Oxidase Inhibitors and Tricyclic Antidepressants FORADIL should be administered with extreme caution in patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants because the action of formoterol on the cardiovascular system may be potentiated by these agents Corticosteroids Methylxanthines and Diuretics Concomitant treatment with xanthine derivatives steroids or diuretics may potentiate a possible hypokalemic effect of beta2 agonists Hypokalemia may increase susceptibility to cardiac arrhythmias in patients treated with digitalis adrenergic Blockers adrenergic blockers may weaken or antagonise the effect of FORADIL Therefore FORADIL should not be given together with adrenergic blockers including eye drops unless there are compelling reasons for their use Other Drugs Drugs such as quinidine disopyramide procainamide phenothiazines antihistamines and tricyclic antidepressants may be associated with QT interval prolongation and an increased risk of ventricular arrhythmia INFORMATION TO BE PROVIDED TO THE PATIENT OR GUARDIAN See illustrated Information For The Patient or Guardian section It is important that patients understand how to use FORADIL formoterol fumarate capsules with the supplied AerolizerTM inhalation device and how it should be used in relation to other asthma or COPD medications they are taking Patients Guardians should be given the following information i The recommended dosage one or two capsules twice daily morning and evening should not be exceeded ii FORADIL is not meant to relieve acute asthma or COPD symptoms and extra doses should not be used for that purpose Acute symptoms should be treated with a short acting inhaled beta2 agonist such as salbutamol the physician should provide the patient with such medication and instruct the patient in how it should be used iii The physician should be notified immediately if any of the following situations occur which may be a sign of seriously worsening asthma Decreased effectiveness of short acting inhaled beta2 agonists Need for more inhalations than usual of short acting inhaled beta2 agonists iv FORADIL should not be used as a substitute for oral or inhaled corticosteroids The dosage of these medications should not be changed and they should not be stopped without consulting the physician even if the patient feels better after initiating treatment with FORADIL v Patients should be cautioned regarding potential adverse cardiovascular effects such as palpitations or chest pain vi In patients receiving FORADIL other inhaled medications should be used only as directed by the physician vii Guardians of children who have been prescribed FORADIL should be alerted to the general concern regarding asthma therapy compliance especially neglect of anti inflammatory therapy and overuse of short acting beta2 agonists A possible drug interaction of FOSCAVIR and intravenous pentamidine has been described Concomitant treatment of four patients in the United Kingdom with FOSCAVIR and intravenous pentamidine may have caused hypocalcemia one patient died with severe hypocalcemia Toxicity associated with concomitant use of aerosolized pentamidine has not been reported Because of foscarnets tendency to cause renal impairment the use of FOSCAVIR should be avoided in combination with potentially nephrotoxic drugs such as aminoglycosides amphotericin B and intravenous pentamidine unless the potential benefits outweigh the risks to the patient Since FOSCAVIR decreases serum concentrations of ionized calcium concurrent treatment with other drugs known to influence serum calcium concentrations should be used with particular caution Ganciclovir The pharmacokinetics of foscarnet and ganciclovir were not altered in 13 patients receiving either concomitant therapy or daily alternating therapy for maintenance of CMV disease Metoclopramide When coadministered with MONUROL metoclopramide a drug which increases gastrointestinal motility lowers the serum concentration and urinary excretion of fosfomycin Other drugs that increase gastrointestinal motility may produce similar effects Cimetidine Cimetidine does not affect the pharmacokinetics of fosfomycin when coadministered with MONUROL Diuretics Patients on diuretics especially those with intravascular volume depletion may occasionally experience an excessive reduction of blood pressure after initiation of therapy with fosinopril sodium The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing salt intake prior to initiation of treatment with fosinopril sodium If this is not possible the starting dose should be reduced and the patient should be observed closely for several hours following an initial dose and until blood pressure has stabilized see DOSAGE AND ADMINISTRATION Potassium Supplements and Potassium Sparing Diuretics Fosinopril sodium can attenuate potassium loss caused by thiazide diuretics Potassium sparing diuretics spironolactone amiloride triamterene and others or potassium supplements can increase the risk of hyperkalemia Therefore if concomitant use of such agents is indicated they should be given with caution and the patients serum potassium should be monitored frequently Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended If a diuretic is also used the risk of lithium toxicity may be increased Antacids In a clinical pharmacology study coadministration of an antacid aluminum hydroxide magnesium hydroxide and simethicone with fosinopril reduced serum levels and urinary excretion of fosinoprilat as compared with fosinopril administered alone suggesting that antacids may impair absorption of fosinopril Therefore if concomitant administration of these agents is indicated dosing should be separated by 2 hours Other Neither fosinopril sodium nor its metabolites have been found to interact with food In separate single or multiple dose pharmacokinetic interaction studies with chlorthalidone nifedipine propanolol hydrochlorothiazide cimetidine metoclopramide propantheline digoxin and warfarin the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs In a study with concomitant administration of aspirin and fosinopril sodium the bioavailability of unbound fosinoprilat was not altered In a pharmacokinetic interaction study with warfarin bioavailability parameters the degree of protein binding and the anticoagulant effect measured by prothrombin time of warfarin were not significantly changed Drug Laboratory Test Interaction Fosinopril may cause a false low measurement of serum digoxin levels with the Digi Tab RIA Kit for Digoxin Other kits such as the Coat A Count RIA Kit may be used No drugs are known to interfere with the conversion of fosphenytoin to phenytoin Conversion could be affected by alterations in the level of phosphatase activity but given the abundance and wide distribution of phosphatases in the body it is unlikely that drugs would affect this activity enough to affect conversion of fosphenytoin to phenytoin Drugs highly bound to albumin could increase the unbound fraction of fosphenytoin Although it is unknown whether this could result in clinically significant effects caution is advised when administering Cerebyx with other drugs that significantly bind to serum albumin The pharmacokinetics and protein binding of fosphenytoin phenytoin and diazepam were not altered when diazepam and Cerebyx were concurrently administered in single submaximal doses The most significant drug interactions following administration of Cerebyx are expected to occur with drugs that interact with phenytoin Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement Phenytoin is metabolized by hepatic cytochrome P450 enzymes and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity Phenytoin is a potent inducer of hepatic drug metabolizing enzymes The most commonly occurring drug interactions are listed below Drugs that may increase plasma phenytoin concentrations include acute alcohol intake amiodarone chboramphenicol chlordiazepoxide cimetidine diazepam dicumarol disulfiram estrogens ethosuximide fluoxetine H2 antagonists halothane isoniazid methylphenidate phenothiazines phenylbutazone salicylates succinimides sulfonamides tolbutamide trazodone Drugs that may decrease plasma phenytoin concentrations include carbamazepine chronic alcohol abuse reserpine Drugs that may either increase or decrease plasma phenytoin concentrations include phenobarbital vaiproic acid and sodium valproate Similarly the effects of phenytoin on phenobarbital valproic acid and sodium plasma valproate concentrations are unpredictable Although not a true drug interaction tricyclic antidepressants may precipitate seizures in susceptible patients and Cerebyx dosage may need to be adjusted Drugs whose efficacy is impaired by phenytoin include anticoagulants corticosteroids coumarin digitoxin doxycycline estrogens furosemide oral contraceptives rifampin quinidine theophylline vitamin D Monitoring of plasma phenytoin concentrations may be helpful when possible drug interactions are suspected Drug Laboratory Test Interactions Phenytoin may decrease serum concentrations of 14 It may also produce artifactually low results in dexamethasone or metyrapone tests Phenytoin may also cause increased serum concentrations of glucose alkaline phosphatase and gamma glutamyl transpeptidase GGT Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following Cerebyx administration Ergot containing drugs have been reported to cause prolonged vasospastic reactions Due to a theoretical risk of a pharmacodynamic interaction use of ergotamine containing or ergot type medications like dihydroergotamine or methysergide and FROVA within 24 hours of each other should be avoided see a href frova od htm CI CONTRAINDICATIONS Concomitant use of other 5 HT1B 1D agonists within 24 hours of FROVA treatment is not recommended Selective serotonin reuptake inhibitors SSRIs e g fluoxetine fluvoxamine paroxetine sertraline have been reported rarely to cause weakness hyperreflexia and incoordination when coadministered with 5 HT1 agonists If concomitant treatment with frovatriptan and an SSRI is clinically warranted appropriate observation of the patient is advised Drug Laboratory Test Interactions FROVA is not known to interfere with commonly employed clinical laboratory tests Fulvestrant is metabolized by CYP 3A4 in vitro Clinical studies of the effect of strong CYP 3A4 inhibitors on the pharmacokinetics of fulvestrant have not been performed Carcinogenesis Mutagenesis and Impairment of Fertility A two year carcinogenesis study was conducted in female and male rats at intramuscular doses of 15 mg kg 30 days 10 mg rat 30 days and 10 mg rat 15 days These doses correspond to approximately 1 3 and 5 fold in females and 1 3 1 3 and 1 6 fold in males the systemic exposure AUC0 30 days achieved in women receiving the recommended dose of 250 mg month An increased incidence of benign ovarian granulosa cell tumors and testicular Leydig cell tumors was evident in females dosed at 10 mg rat 15 days and males dosed at 15 mg rat 30 days respectively Induction of such tumors is consistent with the pharmacology related endocrine feedback alterations in gonadotropin levels caused by an antiestrogen Fulvestrant was not mutagenic or clastogenic in multiple in vitro tests with and without the addition of a mammalian liver metabolic activation factor bacterial mutation assay in strains of Salmonella typhimurium and Escherichia coli in vitro cytogenetics study in human lymphocytes mammalian cell mutation assay in mouse lymphoma cells and in vivo micronucleus test in rat In female rats fulvestrant administered at doses 0 01 mg kg day approximately one hundredth of the human recommended dose based on body surface area BSA for 2 weeks prior to and for 1 week following mating caused a reduction in fertility and embryonic survival No adverse effects on female fertility and embryonic survival were evident in female animals dosed at 0 001 mg kg day approximately one thousandth of the human dose based on BSA Restoration of female fertility to values similar to controls was evident following a 29 day withdrawal period after dosing at 2 mg kg day twice the human dose based on BSA The effects of fulvestrant on the fertility of female rats appear to be consistent with its anti estrogenic activity The potential effects of fulvestrant on the fertility of male animals were not studied but in a 6 month toxicology study male rats treated with intramuscular doses of 15 mg kg 30 days 10 mg rat 30 days or 10 mg rat 15 days fulvestrant showed a loss of spermatozoa from the seminiferous tubules seminiferous tubular atrophy and degenerative changes in the epididymides Changes in the testes and epididymides had not recovered 20 weeks after cessation of dosing These fulvestrant doses correspond to approximately 2 3 and 3 fold the systemic exposure AUC0 30 days achieved in women Pregnancy Pregnancy Category D In studies in female rats at doses 0 01 mg kg day IM approximately one hundredth of the human recommended dose based on body surface area BSA fulvestrant caused a reversible reduction in female fertility as well as effects on embryo fetal development consistent with its anti estrogenic activity Fulvestrant caused an increased incidence of fetal abnormalities in rats tarsal flexure of the hind paw at 2 mg kg day IM twice the human dose on BSA and non ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses 0 1 mg kg day IM approximately one tenth of the human dose on BSA when administered during the period of organogenesis Rabbits failed to maintain pregnancy when dosed with 1 mg kg day fulvestrant IM twice the human dose on BSA during the period of organogenesis Further in rabbits dosed at 0 25 mg kg day about one half the human dose on BSA increases in placental weight and post implantation loss were observed but there were no observed effects on fetal development Fulvestrant was associated with an increased incidence of fetal variations in rabbits backwards displacement of the pelvic girdle and 27 pre sacral vertebrae at 0 25 mg kg day IM one half the human dose on BSA when administered during the period of organogenesis Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg kg day and above this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures Nursing Mothers Fulvestrant is found in rat milk at levels significantly higher approximately 12 fold than plasma after administration of 2 mg kg Drug exposure in rodent pups from fulvestrant treated lactating dams was estimated as 10 of the administered dose It is not known if fulvestrant is excreted in human milk Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from FASLODEX in nursing infants a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother Pediatric Use The safety and efficacy of FASLODEX in pediatric patients have not been established Geriatric Use When tumor response was considered by age objective responses were seen in 24 and 22 of patients under 65 years of age and in 16 and 11 of patients 65 years of age and older who were treated with FASLODEX in the European and North American trials respectively Furosemide may increase the ototoxic potential of aminoglycoside antibiotics especially in the presence of impaired renal function Except in life threatening situations avoid this combination Furosemide should not be used concomitantly with ethacrynic acid because of the possibility of ototoxicity Patients receiving high doses of salicylates concomitantly with furosemide as in rheumatic disease may experience salicylate toxicity at lower doses because of competitive renal excretory sites Furosemide has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action of succinylcholine Lithium generally should not be given with diuretics because they reduce lithiums renal clearance and add a high risk of lithium toxicity Furosemide may add to or potentiate the therapeutic effect of other antihypertensive drugs Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs Furosemide may decrease arterial responsiveness to norepinephrine However norepinephrine may still be used effectively Tablets Simultaneous administration of sucralfate and furosemide tablets may reduce the natriuretic and antihypertensive effects of furosemide Patients receiving both drugs should be observed closely to determine if the desired diuretic and or antihypertensive effect of furosemide is achieved The intake of furosemide and sucralfate should be separated by at least two hours Tablets Injection and Oral Solution One study in six subjects demonstrated that the combination of furosemide and acetylsalicylic acid temporarily reduced creatinine clearance in patients with chronic renal insufficiency There are case reports of patients who developed increased BUN serum creatinine and serum potassium levels and weight gain when furosemide was used in conjunction with NSAIDs Literature reports indicate that coadministration of indomethacin may reduce the natriuretic and antihypertensive effects of furosemide in some patients by inhibiting prostaglandin synthesis Indomethacin may also affect plasma renin levels aldosterone excretion and renin profile evaluation Patients receiving both indomethacin and furosemide should be observed closely to determine if the desired diuretic and or antihypertensive effect of furosemide is achieved In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes CYP1A2 CYP2A6 CYP2C9 CYP2C19 CYP2D6 CYP2E1 and CYP3A4 that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations Only at the highest concentration tested 171 g mL 1 mM was a slight degree of inhibition 14 30 of isoform CYP2A6 observed No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mg mL approximately 15 times the Cmax at 3600 mg day Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy Phenytoin In a single 400 mg and multiple dose 400 mg TID study of Neurontin in epileptic patients N 8 maintained on phenytoin monotherapy for at least 2 months gabapentin had no effect on the steady state trough plasma concentrations of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics Carbamazepine Steady state trough plasma carbamazepine and carbamazepine 10 11 epoxide concentrations were not affected by concomitant gabapentin 400 mg TID N 12 administration Likewise gabapentin pharmacokinetics were unaltered by carbamazepine administration Valproic Acid The mean steady state trough serum valproic acid concentrations prior to and during concomitant gabapentin administration 400 mg TID N 17 were not different and neither were gabapentin pharmacokinetic parameters affected by valproic acid Phenobarbital Estimates of steady state pharmacokinetic parameters for phenobarbital or gabapentin 300 mg TID N 12 are identical whether the drugs are administered alone or together Naproxen Coadministration N 18 of naproxen sodium capsules 250 mg with Neurontin 125 mg appears to increase the amount of gabapentin absorbed by 12 to 15 Gabapentin had no effect on naproxen pharmacokinetic parameters These doses are lower than the therapeutic doses for both drugs The magnitude of interaction within the recommended dose ranges of either drug is not known Hydrocodone Coadministration of Neurontin 125 to 500 mg N 48 decreases hydrocodone 10 mg N 50 Cmax and AUC values in a dose dependent manner relative to administration of hydrocodone alone Cmax and AUC values are 3 to 4 lower respectively after administration of 125 mg Neurontin and 21 to 22 lower respectively after administration of 500 mg Neurontin The mechanism for this interaction is unknown Hydrocodone increases gabapentin AUC values by 14 The magnitude of interaction at other doses is not known Morphine A literature article reported that when a 60 mg controlled release morphine capsule was administered 2 hours prior to a 600 mg Neurontin capsule N 12 mean gabapentin AUC increased by 44 compared to gabapentin administered without morphine Morphine pharmacokinetic parameter values were not affected by administration of Neurontin 2 hours after morphine The magnitude of interaction at other doses is not known Cimetidine In the presence of cimetidine at 300 mg QID N 12 the mean apparent oral clearance of gabapentin fell by 14 and creatinine clearance fell by 10 Thus cimetidine appeared to alter the renal excretion of both gabapentin and creatinine an endogenous marker of renal function This small decrease in excretion of gabapentin by cimetidine is not expected to be of clinical importance The effect of gabapentin on cimetidine was not evaluated Oral Contraceptive Based on AUC and half life multiple dose pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of tablets containing 2 5 mg of norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without coadministration of gabapentin 400 mg TID N 13 The Cmax of norethindrone was 13 higher when it was coadministered with gabapentin this interaction is not expected to be of clinical importance Antacid Maalox Maalox reduced the bioavailability of gabapentin N 16 by about 20 This decrease in bioavailability was about 5 when gabapentin was administered 2 hours after Maalox It is recommended that gabapentin be taken at least 2 hours following Maalox administration Effect of Probenecid Probenecid is a blocker of renal tubular secretion Gabapentin pharmacokinetic parameters without and with probenecid were comparable This indicates that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid Drug Laboratory Tests Interactions Because false positive readings were reported with the Ames N Multistix SG dipstick test for urinary protein when gabapentin was added to other antiepileptic drugs the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein LABORATORY TEST FINDINGS Asymptomatic transitory changes in serum iron have been observed The clinical significance is unknown Omniscan interferes with serum calcium measurements with some colorimetric complexometric methods commonly used in hospitals resulting in serum calcium concentrations lower than the true values Thus it is recommended not to use such methods for 12 24 hours after administration of Omniscan If such measurements are necessary the use of other methods is recommended All patients in whom this effect was observed remained asymptomatic No formal drug interaction studies have been conducted No drug interactions have been observed with the Vitrasert Implant There is limited experience with use of retinal tamponades in conjunction with the Vitrasert Implant Substances that are inducers of CYP3A4 activity increase the metabolism of gefitinib and decrease its plasma concentrations In patients receiving a potent CYP3A4 inducer such as rifampicin or phenytoin a dose increase to 500 mg daily should be considered in the absence of severe adverse drug reaction and clinical response and adverse events should be carefully monitored see CLINICAL PHARMACOLOGY Pharmacokinetics Drug Drug Interactions and DOSAGE AND ADMINISTRATION Dosage Adjustment sections International Normalized Ratio INR elevations and or bleeding events have been reported in some patients taking warfarin while on IRESSA therapy Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR Substances that are potent inhibitors of CYP3A4 activity eg ketoconazole and itraconazole decrease gefitinib metabolism and increase gefitinib plasma concentrations This increase may be clinically relevant as adverse experiences are related to dose and exposure therefore caution should be used when administering CYP3A4 inhibitors with IRESSA Drugs that cause significant sustained elevation in gastric pH histamine H2 receptor antagonists such as ranitidine or cimetidine may reduce plasma concentrations of IRESSA and therefore potentially may reduce efficacy Phase II clinical trial data where IRESSA and vinorelbine have been used concomitantly indicate that IRESSA may exacerbate the neutropenic effect of vinorelbine No specific drug interaction studies have been conducted For information on the pharmacokinetics of Gemzar and cisplatin in combination see Drug Interactions under CLINICAL PHARMACOLOGY section Clinical Laboratory increased creatine positive antinuclear phosphokinase antibody increased bilirubin increased liver transaminases AST SGOT ALT SGPT increased alkaline phophatase Hematopoietic anemia thrombocytopenia leukopenia bone marrow hypoplasia eosinophilia Immunologic angioedema anaphylaxis laryngeal edema Lupus like syndrome urticaria vasculitis Integumentary exfoliative dermatitis alopecia rash dermatitis pruritus Administration of repeat doses of FACTIVE had no effect on the repeat dose pharmacokinetics of theophylline digoxin or an ethinylestradiol levonorgestrol oral contraceptive product in healthy subjects Concomitant administration of FACTIVE and calcium carbonate cimetidine omeprazole or an estrogen progesterone oral contraceptive produced minor changes in the pharmacokinetics of gemifloxacin which were considered to be without clinical significance Concomitant administration of FACTIVE with probenecid resulted in a 45 increase in systemic exposure to gemifloxacin FACTIVE had no significant effect on the anticoagulant effect of warfarin in healthy subjects on stable warfarin therapy However because some quinolones have been reported to enhance the anticoagulant effects of warfarin or its derivatives in patients the prothrombin time or other suitable coagulation test should be closely monitored if a quinolone antimicrobial is administered concomitantly with warfarin or its derivatives Quinolones form chelates with alkaline earth and transition metals The absorption of oral gemifloxacin is significantly reduced by the concomitant administration of an antacid containing aluminum and magnesium Magnesium and or aluminum containing antacids products containing ferrous sulfate iron multivitamin preparations containing zinc or other metal cations or Videx didanosine chewable buffered tablets or the pediatric powder for oral solution should not be taken within 3 hours before or 2 hours after FACTIVE Sucralfate should not be taken within 2 hours of FACTIVE There have been no formal drug interaction studies performed with Mylotarg The potential for drug drug interaction with drugs affected by cytochrome P450 enzymes may not be ruled out Laboratory Test Interactions Mylotarg is not known to interfere with any routine diagnostic tests Interactions between COPAXONE and other drugs have not been fully evaluated Results from existing clinical trials suggest no significant interactions between COPAXONE and other therapies commonly used in MS patients including the concurrent use of corticosteroids for up to 28 days COPAXONE has not been formally evaluated in combination with Interferon beta However 10 patients who switched from therapy with Interferon beta to COPAXONE did not report any serious and unexpected adverse reactions thought to be related to treatment The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti inflammatory agents and other drugs that are highly protein bound salicylates sulfonamides chloramphenicol probenecid coumarins monoamine oxidase inhibitors and beta adrenergic blocking agents When such drugs are administered to a patient receiving MICRONASE the patient should be observed closely for hypoglycemia When such drugs are withdrawn from a patient receiving MICRONASE the patient should be observed closely for loss of control Certain drugs tend to produce hyperglycemia and may lead to loss of control These drugs include the thiazides and other diuretics corticosteroids phe nothiazines thyroid products estrogens oral contraceptives phenytoin nicotinic acid sympathomimet ics calcium channel blocking drugs and isoniazid When such drugs are administered to a patient receiving MICRONASE the patient should be closely observed for loss of control When such drugs are withdrawn from a patient receiving MICRONASE the patient should be observed closely for hypoglycemia A possible interaction between glyburide and ciprofloxacin a fluoroquinolone antibiotic has been reported resulting in a potentiation of the hypoglycemic action of glyburide The mechanism for this interaction is not known A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported Whether this interaction also occurs with the intravenous topical or vaginal preparations of miconazole is not known Metformin In a single dose interaction study in NIDDM subjects decreases in glyburide AUC and Cmax were observed but were highly variable The single dose nature of this study and the lack of correlation between glyburide blood levels and pharmaco dynamic effects makes the clinical significance of this interaction uncertain Coadministration of gly buride and metformin did not result in any changes in either metformin pharmacokinetics or pharmaco dynamics Many other medicines may increase or decrease the effects of glimepiride or affect your condition Before taking glimepiride tell your doctor if you are taking any of the following medicines aspirin or another salicylate such as magnesium choline salicylate Trilisate salsalate Disalcid others choline salicylate Arthropan magnesium salicylate Magan or bismuth subsalicylate Pepto Bismol a nonsteroidal anti inflammatory drug NSAID such as ibuprofen Motrin Advil Nuprin others ketoprofen Orudis Orudis KT Oruvail diclofenac Voltaren Cataflam etodolac Lodine indomethacin Indocin nabumetone Relafen oxaprozin Daypro and naproxen Anaprox Naprosyn Aleve a sulfa based drug such as sulfamethoxazole trimethoprim Bactrim Septra sulfisoxazole Gantrisin or sulfasalazine Azulfidine a monoamine oxidase inhibitor MAOI such as isocarboxazid Marplan tranylcypromine Parnate or phenelzine Nardil a beta blocker such as propranolol Inderal atenolol Tenormin acebutolol Sectral metoprolol Lopressor and others a diuretic water pill such as hydrochlorothiazide HCTZ Hydrodiuril chlorothiazide Diuril and others a steroid medicine such as prednisone Deltasone Orasone others methylprednisolone Medrol others prednisolone Prelone Pediapred others and others a phenothiazine such as chlorpromazine Thorazine fluphenazine Prolixin Permitil prochlorperazine Compazine promethazine Phenergan and others phenytoin Dilantin isoniazid Nydrazid rifampin Rifadin Rifamate or over the counter cough cold allergy or weight loss medications You may require a dosage adjustment or special monitoring if you are taking any of the medicines listed above Drugs other than those listed here may also interact with glimepiride or affect your condition Talk to your doctor and pharmacist before taking any prescription or over the counter medicines including herbal products Immediate and Extended Release Tablets The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti inflammatory agents some azoles and other drugs that are highly protein bound salicylates sulfonamides chloramphenicol probenecid coumarins monoamine oxidase inhibitors and beta adrenergic blocking agents When such drugs are administered to a patient receiving glipizide the patient should be observed closely for hypoglycemia When such drugs are withdrawn from a patient receiving glipizide the patient should be observed closely for loss of control In vitro binding studies with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact with salicylate or dicumarol However caution must be exercised in extrapolating these findings to the clinical situation and in the use of glipizide with these drugs Certain drugs tend to produce hyperglycemia and may lead to loss of control These drugs include the thiazides and other diuretics corticosteroids phenothiazines thyroid products estrogens oral contraceptives phenytoin nicotinic acid sympathomimetics calcium channel blocking drugs and isoniazid When such drugs are administered to a patient receiving glipizide the patient should be closely observed for loss of control When such drugs are withdrawn from a patient receiving glipizide the patient should be observed closely for hypoglycemia A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported Whether this interaction also occurs with the intravenous topical or vaginal preparations of miconazole is not known The effect of concomitant administration of fluconazole and glipizide has been demonstrated in a placebo controlled crossover study in normal volunteers All subjects received glipizide alone and following treatment with 100 mg of fluconazole as a single daily oral dose for seven days The mean percentage increase in the glipizide AUC after fluconazole administration was 56 9 range 35 to 81 The concurrent use of Robinul Injection with other anticholinergics or medications with anticholinergic activity such as phenothiazines antiparkinson drugs or tricyclic antidepressants may intensify the antimuscarinic effects and may result in an increase in anticholinergic side effects Concomitant administration of Robinul Injection and potassium chloride in a wax matrix may increase the severity of potassium chloride induced gastrointestinal lesions as a result of a slower gastrointestinal transit time The Factrel test should be conducted in the absence of other drugs which directly affect the pituitary secretion of the gonadotropins These would include a variety of preparations which contain androgens estrogens progestins or glucocorticoids The gonadotropin levels may be transiently elevated by spironolactone minimally elevated by levodopa and suppressed by oral contraceptives and digoxin The response to Factrel may be blunted by phenothiazines and dopamine antagonists which cause a rise in prolactin No formal drug drug interaction studies have been performed No confirmed interactions have been reported between ZOLADEX and other drugs Antacids Sucralfate Metal Cations Multivitamins Quinolones form chelates with alkaline earth and transition metal cations Administration of quinolones with antacids containing aluminum magnesium or calcium with sucralfate with metal cations such as iron or with multivitamins containing iron or zinc or with formulations containing divalent and trivalent cations such as VIDEX didanosine chewable buffered tablets or the pediatric powder for oral solution may substantially interfere with the absorption of quinolones resulting in systemic concentrations considerably lower than desired These agents should not be taken within 4 hours before or 4 hours after grepafloxacin administration Caffeine Theobromine Grepafloxacin like other quinolones may inhibit the metabolism of caffeine and theobromine These stimulants are commonly found in coffee and tea respectively In some patients this may lead to reduced clearance prolongation of plasma half life and enhanced effects of caffeine and theobromine Theophylline Grepafloxacin is a competitive inhibitor of the metabolism of theophylline Serum theophylline concentrations increase when grepafloxacin is initiated in a patient maintained on theophylline When initiating a multi day course of grepafloxacin in a patient maintained on theophylline the theophylline maintenance dose should be halved for the period of concurrent use of grepafloxacin and monitoring of serum theophylline concentrations should be initiated as a guide to further dosage adjustments Warfarin In subjects receiving warfarin no significant change in clotting time was observed when grepafloxacin was coadministered However because some quinolones have been reported to enhance the effects of warfarin or its derivatives prothrombin time or other suitable anticoagulation test should be monitored closely if a quinolone antimicrobial is administered with warfarin or its derivatives Drugs Metabolized by Cytochrome P450 Enzymes The drug interaction study evaluating the effect of grepafloxacin on theophylline indicates that grepafloxacin inhibits theophylline metabolism which is mediated by CYP1A2 While no clinical studies have been conducted to evaluate the effect of grepafloxacin on the metabolism of C P A substrates in vitro data suggest similar effects of grepafloxacin in CYP3A4 mediated metabolism and theophylline metabolism In addition other quinolones have been reported to decrease the CYP3A4 mediated metabolism of cyclosporine Other drugs metabolized by C P A include terfenadine astemizole cisapride midazolam and triazolam The clinical relevance of the potential effect of grepafloxacin on the metabolism of C P A substrates is not known Patients receiving concurrent administration of substrates of C P A were not excluded from clinical trials of grepafloxacin Nonsteroidal Anti inflammatory Drugs NSAIDs The concomitant administration of a nonsteroidal anti inflammatory drug with a quinolone may increase the risks of CNS stimulation and convulsions Antidiabetic Agents Disturbances of blood glucose including hyperglycemia and hypoglycemia have been reported in patients treated concomitantly with quinolones and an antidiabetic agent Therefore careful monitoring of blood glucose is recommended when these agents are coadministered Patients on warfarin type anticoagulant therapy may require dosage adjustment of the anticoagulant during and after griseofulvin therapy Concomitant use of barbiturates usually depresses griseofulvin activity and may necessitate raising the dosage The concomitant administration of griseofulvin has been reported to reduce the efficacy of oral contraceptives and to increase the incidence of breakthrough bleeding The use of codeine may result in additive CNS depressant effects when coadministered with alcohol antihistamines psychotropics or other drugs that produce CNS depression Serious toxicity may result if dextromethorphan is coadministered with monoamine oxidase inhibitors MAOIs The use of dextromethorphan hydrobromide may result in additive CNS depressant effects when coadministered with alcohol antihistamines psychotropics or other drugs that produce CNS depression http www rxlist com cgi generic3 guanethidine od htm The potential for increased sedation when guanfacine is given with other CNS depressant drug should be appreciated The administration of guanfacine concomitantly with known microsomal enzyme inducer phenobarbital or phenytoin to two patients with renal impairment reportedly resulted in significant reductions in elimination half life and plasma concentration In such cases therefore more frequent dosing may be required to achieve or maintain the desired hypotensive response Further if guanfacine is to be discontinued in such patients careful tapering of the dosage may be necessary in order to avoid rebound phenomena TCAs decrease the hypotensive effect of guanfacine Noncardioselective beta blockers nadolol porpranolol timolol may exacerbate rebound hypertension when guanfacine is withdrawn The beta blocker should be withdrawn first The gradual withdrawal of guafacine or a cardioselective beta blocker could be substituted Anticoagulants Ten patients who were stabilized on oral anticoagulants were given guanfacine 1 2 mg day for 4 weeks No changes were observed in the degree of anticoagulation In several well controlled studies guanfacine was administered together with diuretics with no drug interactions reported In the long term safety studies guanfacine was given concomitantly with many drugs without evidence of any interactions The principal drugs given number of patients in parentheses were cardiac glycosides 115 sedatives and hypnotics 103 coronary vasodilators 52 oral hypoglycemics 45 cough and cold preparations 45 NSAIDs 38 antihyperlipidemics 29 antigout drugs 24 oral contraceptives 18 bronchodilators 13 insulin 10 and beta blockers 10 Laboratory Test In clinical trials no clinically relevant laboratory test abnormalities were identified as causally related to drug during short term treatment with guanfacine Drug Laboratory Test Interactions No laboratory test abnormalities related to the use of guanfacine have been identified An encephalopathic syndrome characterized by weakness lethargy fever tremulousness and confusion extrapyramidal symptoms leukocytosis elevated serum enzymes BUN and FBS followed by irreversible brain damage has occurred in a few patients treated with lithium plus HALDOL A causal relationship between these events and the concomitant administration of lithium and HALDOL has not been established however patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear As with other antipsychotic agents it should be noted that HALDOL may be capable of potentiating CNS depressants such as anesthetics opiates and alcohol In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin plasma haloperidol levels were decreased by a mean of 70 and mean scores on the Brief Psychiatric Rating Scale were increased from baseline In 5 other schizophrenic patients treated with oral haloperidol and rifampin discontinuation of rifampin produced a mean 3 3 fold increase in haloperidol concentrations Thus careful monitoring of clinical status is warranted when rifampin is administered or discontinued in haloperidol treated patients FLUOTHANE augments the action of non depolarising muscle relaxants and the muscle relaxant effects of aminoglycosides FLUOTHANE may augment the hypotension caused by the ganglionic blocking effect of tubocurarine Caution should be exercised during the administration of adrenaline to patients anaesthetised with FLUOTHANE as arrhythmias may be precipitated For this reason the dose of adrenaline should be restricted and an antiarrhythmic agent administered as appropriate Caution should also be applied for other sympathomimetics and for aminophylline and theophylline and tricyclic antidepressants which may also precipitate arrhythmias Drug Interactions a Drugs Enhancing Heparin Effect Oral anticoagulants Heparin sodium may prolong the one stage prothrombin time Therefore when heparin sodium is given with dicumarol or warfarin sodium a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained Platelet inhibitors Drugs such as acetylsalicylic acid dextran phenylbutazone ibuprofen indomethacin dipyridamole hydroxychloroquine and others that interfere with platelet aggregation reactions the main hemostatic defense of heparinized patients may induce bleeding and should be used with caution in patients receiving heparin sodium The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III human in patients with hereditary antithrombin III deficiency Thus in order to avoid bleeding reduced dosage of heparin is recommended during treatment with antithrombin III human b Drugs Decreasing Heparin Effect Digitalis tetracyclines nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium Heparin Sodium Injection should not be mixed with doxorubicin droperidol ciprofloxacin or mitoxantrone since it has been reported that these drugs are incompatible with heparin and a precipitate may form Drug Laboratory Tests Interactions Hyperaminotransferasemia Significant elevations of aminotransferase SGOT S AST and SGPT S ALT levels have occurred in a high percentage of patients and healthy subjects who have received heparin sodium Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction liver disease and pulmonary emboli rises that might be caused by drugs heparin sodium should be interpreted with caution Opioids are strong central nervous system depressants but regular users develop physiological tolerance allowing gradually increased dosages In combination with other central nervous system depressants heroin may still kill even experienced users particularly if their tolerance to the drug has reduced or the strength of their usual dose has increased Toxicology studies of heroin related deaths reveal frequent involvement of other central nervous system depressants including alcohol benzodiazepines such as diazepam Valium and to a rising degree methadone Ironically benzodiazepines are often used in the treatment of heroin addiction while they cause much more severe withdrawal symptoms Cocaine sometimes proves to be fatal when used in combination with heroin No information available Barbiturates may decrease the effectiveness of oral contraceptives certain antibiotics quinidine theophylline corticosteroids anticoagulants and beta blockers MAO inhibitors should be used with caution in patients receiving hydralazine When other potent parental antihypertensive drugs such as diazoxide are used in combination with hydralazine patients should be continuously observed for several hours for any excessive fall in blood pressure Profound hypotensive episodes may occur when diazoxide infection and hydralazine are used concomitantly Beta blockers metoprolol propranolol serum concentrations and pharmacologic effects may be increased Monitor cardiovascular status Propranolol increases hydralazines serum concentrations Acebutolol atenolol and nadolol low hepatic clearance or no first pass metabolism are unlikely to be affected NSAIDs may decrease the hemodynamic effects of hydralazine avoid use if possible or closely monitor cardiovascular status at the end of drug interactions When given concurrently the following drugs may interact with thiazide diuretics Alcohol barbiturates or narcotics potentiation of orthostatic hypotension may occur Antidiabetic drugs oral agents and insulin dosage adjustment of the antidiabetic drug may be required Other antihypertensive drugs additive effect or potentiation Cholestyramine and colestipol resins Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent respectively Corticosteroids ACTH intensified electrolyte depletion particularly hypokalemia Pressor amines e g norepinephrine possible decreased response to pressor amines but not sufficient to preclude their use Skeletal muscle relaxants nondepolarizing e g tubocurarine possible increased responsiveness to the muscle relaxant Lithium generally should not be given with diuretics Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity Refer to the package insert for lithium preparations before use of such preparations with Hydrochlorothiazide Non steroidal Anti inflammatory Drugs In some patients the administration of a non steroidal anti inflammatory agent can reduce the diuretic natriuretic and antihypertensive effects of loop potassium sparing and thiazide diuretics Therefore when Hydrochlorothiazide and non steroidal anti inflammatory agents are used concomitantly the patient should be observed closely to determine if the desired effect of the diuretic is obtained Patients receiving other narcotic analgesics antipsychotics antianxiety agents or other CNS depressants including alcohol concomitantly with hydrocodone and acetaminophen tablets may exhibit an additive CNS depression When combined therapy is contemplated the dose of one or both agents should be reduced The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone The concurrent use of anticholinergics with hydrocodone may produce paralytic ileus No information available Anticoagulants oral Effects may be decreased when used concurrently with thiazide diuretics dosage adjustments may be necessary Antigout medications Thiazide diuretics may raise the level of blood uric acid dosage adjustment of antigout medications may be necessary to control hyperuricemia and gout Antihypertensive medications other especially diazoxide or preanesthetic and anesthetic agents used in surgery or skeletal muscle relaxants nondepolarizing used in surgery Effects may be potentiated when used concurrently with thiazide diuretics dosage adjustments may be necessary Amphotericin B or Corticosteroids or Corticotropin ACTH Concurrent use with thiazide diuretics may intensify electrolyte imbalance particularly hypokalemia Cardiac glycosides Concurrent use with thiazide diuretics may enhance the possibility of digitalis toxicity associated with hypokalemia Colestipol May inhibit gastrointestinal absorption of the thiazide diuretics administration 1 hour before or 4 hours after colestipol is recommended Hypoglycemics Thiazide diuretics may raise blood glucose levels for adult onset diabetics dosage adjustment of hypoglycemic medications may be necessary during and after thiazide diuretic therapy insulin requirements may be increased decreased or unchanged Lithium salts Concurrent use with thiazide diuretics is not recommended as they may provoke lithium toxicity because of reduced renal clearance Methenamine Effectiveness may be decreased when used concurrently with thiazide diuretics because of alkalinization of the urine Nonsteroidal anti inflammatory agents In some patients the steroidal anti inflammatory agent can reduce the diuretic natriuretic and antihypertensive effects of loop potassium sparing and thiazide diuretics Therefore when hydroflumethiazide and nonsteroidal anti inflammatory agents are used concomitantly the patient should be observed closely to determine if the desired effect of the diuretic is obtained Norepinephrine Thiazides may decrease arterial responsiveness to norepinephrine This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use Tubocurarine Thiazide drugs may increase the responsiveness to tubocurarine DIAGNOSTIC INTERFERENCE With expected physiologic effects Blood and urine glucose levels usually only in patients with a predisposition for glucose intolerance and Serum bilirubin levels by displacement from albumin binding and Serum calcium levels thiazide diuretics should be discontinued before parathyroid function tests are carried out and Serum uric acid levels may be increased Serum magnesium potassium and sodium levels may be decreased serum magnesium levels may increase in uremic patients Serum protein bound iodine PBI levels may be decreased Thiazides should be discontinued before carrying out tests for parathyroid function Patients receiving other narcotic analgesics general anesthetics phenothiazines tranquilizers sedative hypnotics tricyclic antidepressants or other CNS depressants including alcohol concomitantly with DILAUDID may exhibit an additive CNS depression When such combined therapy is contemplated the dose of one or both agents should be reduced No formal drug interaction studies have been conducted with Cyanokit Prospective studies on the potential for hydroxyurea to interact with other drugs have not been performed Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may increase the likelihood of bone marrow depression or other adverse events Since hydroxyurea may raise the serum uric acid level dosage adjustment of uricosuric medication may be necessary THE POTENTIATING ACTION OF HYDROXYZINE MUST BE CONSIDERED WHEN THE DRUG IS USED IN CONJUNCTION WITH CENTRAL NERVOUS SYSTEM DEPRESSANTS SUCH AS NARCOTICS NON NARCOTIC ANALGESICS AND BARBITURATES Therefore when central nervous system depressants are administered concomitantly with hydroxyzine their dosage should be reduced Since drowsiness may occur with use of this drug patients should be warned of this possibility and cautioned against driving a car or operating dangerous machinery while taking Atarax Patients should be advised against the simultaneous use of other CNS depressant drugs and cautioned that the effect of alcohol may be increased Additive adverse effects resulting from cholinergic blockade may occur when LEVSIN is administered concomitantly with other antimuscarinics amantadine haloperidol phenothiazines monoamine oxidase MAO inhibitors tricyclic antidepressants or some antihistamines Antacids may interfere with the absorption of LEVSIN Administer LEVSIN before meals antacids after meals Calcium Supplements Antacids Products containing calcium and other multivalent cations such as aluminum magnesium iron are likely to interfere with absorption of Ibandronate Ibandronate should be taken at least 60 minutes before any oral medications containing multivalent cations including antacids supplements or vitamins H2 Blockers and Proton Pump Inhibitors PPIs Of over 3500 patients enrolled in the Ibandronate osteoporosis Treatment and Prevention Studies 15 used anti peptic agents primarily H2 blockers and PPIs Among these patients the incidence of upper gastrointestinal adverse experiences in the patients treated with Ibandronate was similar to that in placebo treated patients Similarly of over 1600 patients enrolled in a study comparing once monthly with daily dosing regimens of ibandronate 14 of patients used anti peptic agents Among these patients the incidence of upper gastrointestinal adverse experiences in the patients treated with Ibandronate 150 mg once monthly was similar to that in patients treated with Ibandronate 2 5 mg once daily Aspirin Nonsteroidal Antiinflammatory Drugs NSAIDs In the large placebo controlled osteoporosis Treatment Study aspirin and nonsteroidal anti inflammatory drugs were taken by 62 of the 2946 patients Among aspirin or NSAID users the incidence of upper gastrointestinal adverse events in patients treated with ibandronate 2 5 mg daily 28 9 was similar to that in placebo treated patients 30 7 Similarly in the 1 year monthly comparison study aspirin and nonsteroidal anti inflammatory drugs were taken by 39 of the 1602 patients The incidence of upper gastrointestinal events in patients concomitantly taking aspirin or NSAIDs was similar in patients taking ibandronate 2 5 mg daily 21 7 and 150 mg once monthly 22 0 However since aspirin NSAIDs and bisphosphonates are all associated with gastrointestinal irritation caution should be exercised in the concomitant use of aspirin or NSAIDs with Ibandronate Drug Laboratory Test Interactions Bisphosphonates are known to interfere with the use of bone imaging agents Specific studies with ibandronate have not been performed No formal drug interaction studies have been performed with ZEVALIN Due to the frequent occurrence of severe and prolonged thrombocytopenia the potential benefits of medications which interfere with platelet function and or anticoagulation should be weighed against the potential increased risks of bleeding and hemorrhage Patients receiving medications that interfere with platelet function or coagulation should have more frequent laboratory monitoring for thrombocytopenia In addition the transfusion practices for such patients may need to be modified given the increased risk of bleeding Patients in clinical studies were prohibited from receiving growth factor treatment for 2 weeks prior to the ZEVALIN therapeutic regimen as well as for 2 weeks following completion of the regimen Coumarin Type Anticoagulants Several short term controlled studies failed to wshow that ibuprofen significantly affected prothrombin times or a variety of other clotting factors when administered to individuals on coumarin type anticoagulants However because bleeding has been reported when ibuprofen and other nonsteroidal anti inflammatory agents have been administered to patients on coumarin type anticoagulants the physician should be cautious when administering ibuprofen to patients on anticoagulants Aspirin Animal studies wshow that aspirin given with nonsteroidal anti inflammatory agents including ibuprofen yields a net decrease in anti inflammatory activity with lowered blood levels of the non aspirin drug Single dose bioavailability studies in normal volunteers have failed to wshow an effect of aspirin on ibuprofen blood levels Correlative clinical studies have not been performed Methotrexate Ibuprofen as well as other nonsteroidal anti inflammatory drugs probably reduces the tubular secretion of methotrexate based on in vitro studies in rabbit kidney slices This may indicate that ibuprofen could enhance the toxicity of methotrexate Caution should be used if ibuprofen is administered concomitantly with methotrexate H 2 Antagonists In studies with human volunteers co administration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations Furosemide Clinical studies as well as random observations have shown that ibuprofen can reduce the natriuretic effect of furosemide and thiazides in some patients This response has been attributed to inhibition of renal prostaglandin synthesis During concomitant therapy with ibuprofen the patient should be observed closely for signs of renal failure as well as to assure diuretic efficacy Lithium Ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in a study of eleven normal volunteers The mean minimum lithium concentration increased 15 and the renal clearance of lithium was decreased by 19 during this period of concomitant drug administration This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen Thus when ibuprofen and lithium are administered concurrently subjects should be observed carefully for signs of lithium toxicity Read circulars for lithium preparation before use of such concurrent therapy No specific pharmacokinetic or other formal drug interaction studies were conducted Digoxin Supraventricular arrhythmias may mask the cardiotoxicity associated with excessive digoxin levels Therefore it is advisable to be particularly cautious in patients whose plasma digoxin levels are above or suspected to be above the usual therapeutic range Coadministration of digoxin did not have effects on either the safety or efficacy of ibutilide in the clinical trials Calcium channel blocking agents Coadministration of calcium channel blockers did not have any effect on either the safety or efficacy of ibutilide in the clinical trials Beta adrenergic blocking agents Coadministration of beta adrenergic blocking agents did not have any effect on either the safety or efficacy of ibutilide in the clinical trials General No clinical drug interaction studies were performed No evaluation of EXTRANEALs effects on the cytochrome P450 system was conducted As with other dialysis solutions blood concentrations of dialyzable drugs may be reduced by dialysis Dosage adjustment of concomitant medications may be necessary In patients using cardiac glycosides digoxin and others plasma levels of calcium potassium and magnesium must be carefully monitored Insulin A clinical study in 6 insulin dependent diabetic patients demonstrated no effect of EXTRANEAL on insulin absorption from the peritoneal cavity or on insulins ability to control blood glucose when insulin was administered intraperitoneally with EXTRANEAL However appropriate monitoring of blood glucose should be performed when initiating EXTRANEAL in diabetic patients and insulin dosage should be adjusted if needed Heparin No human drug interaction studies with heparin were conducted In vitro studies demonstrated no evidence of incompatibility of heparin with EXTRANEAL Antibiotics No human drug interaction studies with antibiotics were conducted In vitro studies evaluating the minimum inhibitory concentration MIC of vancomycin cefazolin ampicillin ampicillin flucoxacillin ceftazidime gentamicin and amphotericin demonstrated no evidence of incompatibility of these antibiotics with EXTRANEAL Drug Laboratory Test Interactions Blood Glucose Blood glucose measurement must be done with a glucose specific method to prevent maltose interference with test results Since falsely elevated glucose levels have been observed with blood glucose monitoring devices and test strips that use glucose dehydrogenase pyrroloquinolinequinone GDH PQQ based methods GDH PQQ based methods should not be used to measure glucose levels in patients administered EXTRANEAL Serum Amylase An apparent decrease in serum amylase activity has been observed in patients administered EXTRANEAL Preliminary investigations indicate that icodextrin and its metabolites interfere with enzymatic based amylase assays resulting in inaccurately low values This should be taken into account when evaluating serum amylase levels for diagnosis or monitoring of pancreatitis in patients using EXTRANEAL Interactions may occur between EPA supplements and aspirin and other non steroidal anti inflammatory drugs and herbs such as garlic Allium sativum and ginkgo Ginkgo biloba Such interactions might be manifested by increased susceptibility to bruising nosebleeds hemoptysis hematemesis hematuria and blood in the stool Most who take EPA supplements and the above drugs or herbs do not suffer from these problems and if they occur they are rare If they do occur the EPA dose should be lowered or discontinued Conflicting results have been reported regarding the effects of EPA supplements on glycemic control in non diabetics with glucose intolerance and those with type 2 diabetes Some early studies indicated that EPA supplements might have detrimental effects in those groups Recent better designed studies have not reported these adverse effects There is no evidence that EPA supplements have detrimental effects on glucose tolerance insulin secretion or insulin resistance in non diabetic subjects Diabetics should discuss the use of these supplements with their physicians and note if the supplements affect their glycemic control Diabetics who take EPA supplements should be monitored by their physicians Other medicines Although certain medicines should not be used together at all in other cases two different medicines may be used together even if an interaction might occur In these cases your doctor may want to change the dose or other precautions may be necessary When you are using idoxuridine it is especially important that your health care professional know if you are using the following Eye product containing boric acid Boric acid may interact with the idoxuridine preparation causing a gritty substance to form or may interact with the preservative in the idoxuridine preparation causing a toxic effect in the eye The physician should be alert for possible combined drug actions desirable or undesirable involving ifosfamide even though ifosfamide has been used successfully concurrently with other drugs including other cytotoxic drugs In studies in normal volunteers there was no pharmacodynamic interaction between intravenous iloprost and either nifedipine diltiazem or captopril However iloprost has the potential to increase the hypotensive effect of vasodilators and antihypertensive agents Since iloprost inhibits platelet function there is a potential for increased risk of bleeding particularly in patients maintained on anticoagulants During clinical trials iloprost was used concurrently with anticoagulants diuretics cardiac glycosides calcium channel blockers analgesics antipyretics nonsteroidal antiinflammatories corticosteroids and other medications Intravenous infusion of iloprost had no effect on the pharmacokinetics of digoxin Acetylsalicylic acid did not alter the clearance pharmacokinetics of iloprost Although clinical studies have not been conducted in vitro studies of iloprost indicate that no relevant inhibition of cytochrome P450 drug metabolism would be expected Drugs that may alter imatinib plasma concentrations Drugs that may increase imatinib plasma concentrations Caution is recommended when administering Gleevec with inhibitors of the CYP3A4 family e g ketoconazole itraconazole erythromycin clarithromycin Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity may decrease metabolism and increase imatinib concentrations There is a significant increase in exposure to imatinib when Gleevec is coadministered with ketoconazole CYP3A4 inhibitor Drugs that may decrease imatinib plasma concentrations Substances that are inducers of CYP3A4 activity may increase metabolism and decrease imatinib plasma concentrations Co medications that induce CYP3A4 e g dexamethasone phenytoin carbamazepine rifampin phenobarbital or St Johns Wort may significantly reduce exposure to Gleevec Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Gleevec increased Gleevec oral dose clearance by 3 8 fold which significantly p 0 05 decreased mean cmax and AUC 0 8 In patients where rifampin or other CYP3A4 inducers are indicated alternative therapeutic agents with less enzyme induction potential should be considered Drugs that may have their plasma concentration altered by Gleevec Gleevec increases the mean cmax and AUC of simvastatin CYP3A4 substrate 2 and 3 5 fold respectively suggesting an inhibition of the CYP3A4 by Gleevec Particular caution is recommended when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window e g cyclosporine or pimozide Gleevec will increase plasmaconcentration of other CYP3A4 metabolized drugs e g triazolo benzodiazepines dihydropyridine calcium channel blockers certain HMG CoA reductase inhibitors etc Because warfarin is metabolized by CYP2C9 and CYP3A4 patients who require anticoagulation should receive low molecular weight or standard heparin in vitro Gleevec inhibits the cytochrome P450 isoenzyme CYP2D6 activity at similar concentrations that affect CYP3A4 activity Systemic exposure to substrates of CYP2D6 is expected to be increased when coadministered with Gleevec No specific studies have been performed and caution is recommended in vitro Gleevec inhibits acetaminophen O glucuronidation Ki value of 58 5 M at therapeutic levels Systemic exposure to acetaminophen is expected to be increased when coadministered with Gleevec No specific studies in humans have been performed and caution is recommended In occasional susceptible patients or in those receiving anticholinergic drugs including antiparkinsonism agents in addition the atropine like effects may become more pronounced e g paralytic ileus Close supervision and careful adjustment of dosage is required when this drug is administered concomitantly with anticholinergic drugs Avoid the use of preparations such as decongestants and local anesthetics which contain any sympathomimetic amine e g epinephrine norepinephrine since it has been reported that tricyclic antidepressants can potentiate the effects of catecholamines Caution should be exercised when imipramine hydrochloride is used with agents that lower blood pressure Imipramine hydrochloride may potentiate the effects of CNS depressant drugs The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors e g cimetidine fluoxetine and decrease by concomitant administration of hepatic enzyme inducers e g barbiturates phenytoin and adjustment of the dosage of imipramine may therefore be necessary Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 debrisoquin hydroxylase is reduced in a subset of the caucasian population about 7 to 10 of caucasians are so called poor metabolizers reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian African and other populations are not yet available Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants TCAs when given usual doses Depending on the fraction of drug metabolized by P450 2D6 the increase in plasma concentration may be small or quite large 8 fold increase in plasma AUC of the TCA In addition certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble p o metabolizers An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme quinidine cimetidine and many that are substrates for P450 2D6 many other antidepressants phenothiazines and the Type 1C antiarrhythmics propafenone and flecainide While all the selective serotonin reuptake inhibitors SSRIs e g fluoxetine sertraline and paroxetine inhibit P450 2D6 they may vary in the extent of inhibition The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved Nevertheless caution is indicated in the co administration of TCA5 with any of the SSRIs and also in switching from one class to the other Of particular importance sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine given the long half life of the parent and active metabolite at least 5 weeks may be necessary Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug Furthermore whenever one of these other drugs is withdrawn from cotherapy an increased dose of tricyclic antidepressant may be required It is desirable to monitor TCA plasma levels whenever a TCA is going to be co administered with another drug known to be an inhibitor of P450 2D6 No information available Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4 Coadministration of CRIXIVAN and drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of the other drug which could increase or prolong its therapeutic and adverse effects Indinavir is metabolized by CYP3A4 Drugs that induce CYP3A4 activity would be expected to increase the clearance of indinavir resulting in lowered plasma concentrations of indinavir Coadministration of CRIXIVAN and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir Table 8 Drugs That Should Not Be Coadministered with CRIXIVAN Drug Class Drug Name Clinical Comment Antiarrhythmics amiodarone CONTRAINDICATED due to potential for serious and or life threatening reactions such as cardiac arrhythmias Ergot derivatives dihydroergotamine ergonovine ergotamine methylergonovine CONTRAINDICATED due to potential for serious and or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues Sedative hypnotics midazolam triazolam CONTRAINDICATED due to potential for serious and or life threatening reactions such as prolonged or increased sedation or respiratory depression GI motility agents cisapride CONTRAINDICATED due to potential for serious and or life threatening reactions such as cardiac arrhythmias Neuroleptic pimozide CONTRAINDICATED due to potential for serious and or life threatening reactions such as cardiac arrhythmias Herbal products St John s wort Hypericum perforatum May lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors Antimycobacterial rifampin May lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors or other coadministered antiretroviral agents HMG CoA Reductase inhibitors lovastatin simvastatin Potential for serious reactions such as risk of myopathy including rhabdomyolysis Protease inhibitor atazanavir Both CRIXIVAN and atazanavir are associated with indirect unconjugated hyperbilirubinemia Combinations of these drugs have not been studied and coadministration of CRIXIVAN and atazanavir is not recommended Table 9 Established and Other Potentially Significant Drug Interactions Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Drug Name Effect Clinical Comment HIV Antiviral Agents Delavirdine indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours should be considered when taking delavirdine 400 mg three times a day Didanosine Indinavir and didanosine formulations containing buffer should be administered at least one hour apart on an empty stomach Efavirenz indinavir concentration The optimal dose of indinavir when given in combination with efavirenz is not known Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz Nelfinavir indinavir concentration The appropriate doses for this combination with respect to efficacy and safety have not been established Nevirapine indinavir concentration Indinavir concentrations may be decreased in the presence of nevirapine The appropriate doses for this combination with respect to efficacy and safety have not been established Ritonavir indinavir concentration ritonavir concentration The appropriate doses for this combination with respect to efficacy and safety have not been established Preliminary clinical data suggest that the incidence of nephrolithiasis is higher in patients receiving indinavir in combination with ritonavir than those receiving CRIXIVAN 800 mg q8h Saquinavir saquinavir concentration The appropriate doses for this combination with respect to efficacy and safety have not been established Other Agents Antiarrhythmics bepridil lidocaine systemic and quinidine antiarrhythmic agents concentration Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when coadministered with CRIXIVAN Anticonvulsants carbamazepine phenobarbital phenytoin indinavir concentration Use with caution CRIXIVAN may not be effective due to decreased indinavir concentrations in patients taking these agents concomitantly Calcium Channel Blockers Dihydropyridine e g felodipine nifedipine nicardipine dihydropyridine calcium channel blockers concentration Caution is warranted and clinical monitoring of patients is recommended Clarithromycin clarithromycin concentration indinavir concentration The appropriate doses for this combination with respect to efficacy and safety have not been established HMG CoA Reductase Inhibitor atorvastatin atorvastatin concentration Use lowest possible dose of atorvastatin with careful monitoring or consider HMG CoA reductase inhibitors that are not primarily metabolized by CYP3A4 such as pravastatin fluvastatin or rosuvastatin in combination with CRIXIVAN Immunosuppressants cyclosporine tacrolimus sirolimus immunosuppressant agents concentration Plasma concentrations may be increased by CRIXIVAN Itraconazole indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours is recommended when administering itraconazole concurrently Ketoconazole indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours should be considered Rifabutin indinavir concentration rifabutin concentration Dose reduction of rifabutin to half the standard dose and a dose increase of CRIXIVAN to 1000 mg three 333 mg capsules every 8 hours are recommended when rifabutin and CRIXIVAN are coadministered Sildenafil sildenafil concentration Sildenafil dose should not exceed a maximum of 25 mg in a 48 hour period in patients receiving concomitant indinavir therapy Tadalafil tadalafil concentration Tadalafil dose should not exceed a maximum of 10 mg in a 72 hour period in patients receiving concomitant indinavir therapy Vardenafil vardenafil concentration Vardenafil dose should not exceed a maximum of 2 5 mg in a 24 hour period in patients receiving concomitant indinavir therapy Note increase decrease In normal volunteers receiving indomethacin the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin In some patients combined use of INDOCIN and diflunisal has been associated with fatal gastrointestinal hemorrhage Therefore diflunisal and INDOCIN should not be used concomitantly In a study in normal volunteers it was found that chronic concurrent administration of 3 6 g of aspirin per day decreases indomethacin blood levels approximately 20 The concomitant use of INDOCIN with other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity with little or no increase in efficacy Clinical studies have shown that INDOCIN does not influence the hypoprothrombinemia produced by anticoagulants However when any additional drug including INDOCIN is added to the treatment of patients on anticoagulant therapy the patients should be observed for alterations of the prothrombin time In post marketing experience bleeding has been reported in patients on concomitant treatment with anticoagulants and INDOCIN Caution should be exercised when INDOCIN and anticoagulants are administered concomitantly When INDOCIN is given to patients receiving probenecid the plasma levels of indomethacin are likely to be increased Therefore a lower total daily dosage of INDOCIN may produce a satisfactory therapeutic effect When increases in the dose of INDOCIN are made they should be made carefully and in small increments Caution should be used if INDOCIN is administered simultaneously with methotrexate INDOCIN has been reported to decrease the tubular secretion of methotrexate and to potentiate its toxicity Administration of non steroidal anti inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine induced toxicity possibly due to decreased synthesis of renal prostacyclin NSAIDs should be used with caution in patients taking cyclosporine and renal function should be carefully monitored Capsules INDOCIN 50 mg t i d produced a clinically relevant elevation of plasma lithium and reduction in renal lithium clearance in psychiatric patients and normal subjects with steady state plasma lithium concentrations This effect has been attributed to inhibition of prostaglandin synthesis As a consequence when INDOCIN and lithium are given concomitantly the patient should be carefully observed for signs of lithium toxicity Read circulars for lithium preparations before use of such concomitant therapy In addition the frequency of monitoring serum lithium concentration should be increased at the outset of such combination drug treatment INDOCIN given concomitantly with digoxin has been reported to increase the serum concentration and prolong the half life of digoxin Therefore when INDOCIN and digoxin are used concomitantly serum digoxin levels should be closely monitored In some patients the administration of INDOCIN can reduce the diuretic natriuretic and antihypertensive effects of loop potassium sparing and thiazide diuretics Therefore when INDOCIN and INDOCIN Indomethacin diuretics are used concomitantly the patient should be observed closely to determine if the desired effect of the diuretic is obtained INDOCIN reduces basal plasma renin activity PRA as well as those elevations of PRA induced by furosemide administration or salt or volume depletion These facts should be considered when evaluating plasma renin activity in hypertensive patients It has been reported that the addition of triamterene to a maintenance schedule of INDOCIN resulted in reversible acute renal failure in two of four healthy volunteers INDOCIN and triamterene should not be administered together INDOCIN and potassium sparing diuretics each may be associated with increased serum potassium levels The potential effects of INDOCIN and potassium sparing diuretics on potassium kinetics and renal function should be considered when these agents are administered concurrently Most of the above effects concerning diuretics have been attributed at least in part to mechanisms involving inhibition of prostaglandin synthesis by INDOCIN Blunting of the antihypertensive effect of beta adrenoceptor blocking agents by non steroidal antiinflammatory drugs including INDOCIN has been reported Therefore when using these blocking agents to treat hypertension patients should be observed carefully in order to confirm that the desired therapeutic effect has been obtained INDOCIN can reduce the antihypertensive effects of captopril and losartan False negative results in the dexamethasone suppression test DST in patients being treated with INDOCIN have been reported Thus results of the DST should be interpreted with caution in these patients Concurrent administration of etanercept another TNF blocking agent and anakinra an interleukin 1 antagonist has been associated with an increased risk of serious infections and increased risk of neutropenia and no additional benefit compared to these medicinal products alone Other TNFa blocking agents including REMICADE used in combination with anakinra may also result in similar toxicities Specific drug interaction studies including interactions with MTX have not been conducted The majority of patients in rheumatoid arthritis or Crohn s disease clinical studies received one or more concomitant medications In rheumatoid arthritis concomitant medications besides MTX were nonsteroidal anti inflammatory agents folic acid corticosteroids and or narcotics Concomitant Crohn s disease medications were antibiotics antivirals corticosteroids 6 MP AZA and aminosalicylates In psoriatic arthritis clinical trials concomitant medications included MTX in approximately half of the patients as well as nonsteroidal anti inflammatory agents folic acid and corticosteroids Patients with Crohn s disease who received immunosuppressants tended to experience fewer infusion reactions compared to patients on no immunosuppressants Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of Crohn s disease including corticosteroids antibiotics metronidazole or ciprofloxacin and aminosalicylates A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring The following are examples of substances that may increase the blood glucose lowering effect and susceptibility to hypoglycemia oral antidiabetes products ACE inhibitors disopyramide fibrates fluoxetine MAO inhibitors propoxyphene salicylates somatostatin analog e g octreotide sulfonamide antibiotics The following are examples of substances that may reduce the blood glucose lowering effect of insulin corticosteroids danazol diuretics sympathomimetic agents e g epinephrine albuterol terbutaline isoniazid phenothiazine derivatives somatropin thyroid hormones estrogens progestogens e g in oral contraceptives Beta blockers clonidine lithium salts and alcohol may either potentiate or weaken the blood glucose lowering effect of insulin Pentamidine may cause hypoglycemia which may sometimes be followed by hyperglycemia In addition under the influence of sympatholytic medicinal products such as beta blockers clonidine guanethidine and reserpine the signs of hypoglycemia may be reduced or absent A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring The following are examples of substances that may increase the blood glucose lowering effect and susceptibility to hypoglycemia oral antidiabetic products ACE inhibitors disopyramide fibrates fluoxetine monoamine oxidase MAO inhibitors propoxyphene salicylates somatostatin analog e g octreotide sulfonamide antibiotics The following are examples of substances that may reduce the blood glucose lowering effect corticosteroids niacin danazol diuretics sympathomimetic agents e g epinephrine salbutamol terbutaline isoniazid phenothiazine derivatives somatropin thyroid hormones estrogens progestogens e g in oral contraceptives Beta blockers clonidine lithium salts and alcohol may either potentiate or weaken the blood glucose lowering effect of insulin Pentamidine may cause hypoglycemia which may sometimes be followed by hyperglycemia In addition under the influence of sympatholytic medicinal products such as beta blockers clonidine guanethidine and reserpine the signs of hypoglycemia may be reduced or absent Mixing of Insulins A clinical study in healthy male volunteers n 24 demonstrated that mixing NovoLog with NPH human insulin immediately before injection produced some attenuation in the peak concentration of NovoLog but that the time to peak and the total bioavailability of NovoLog were not significantly affected If NovoLog is mixed with NPH human insulin NovoLog should be drawn into the syringe first The injection should be made immediately after mixing Because there are no data on the compatibility of NovoLog and crystalline zinc insulin preparations NovoLog should not be mixed with these preparations The effects of mixing NovoLog with insulins of animal source or insulin preparations produced by other manufacturers have not been studied Mixtures should not be administered intravenously When used in external subcutaneous infusion pumps for insulin NovoLog should not be mixed with any other insulins or diluent No formal drug interaction studies have been conducted with Rebif Due to its potential to cause neutropenia and lymphopenia proper monitoring of patients is required if Rebif is given in combination with myelosuppressive agents Also the potential for hepatic injury should be considered when Rebif is used in combination with other products associated with hepatic injury or when new agents are added to the regimen of patients already on Rebif Interactions between Betaseron and other drugs have not been fully evaluated Although studies designed to examine drug interactions have not been done it was noted that corticosteroid or ACTH treatment of relapses for periods of up to 28 days has been administered to patients N 180 receiving Betaseron Betaseron administration to three cancer patients over a dose range of 0 025 mg to 2 2 mg led to a dose dependent inhibition of antipyrine elimination 14 The effect of alternate day administration of 0 25 mg of Betaseron on drug metabolism in MS patients is unknown ATROVENT Inhalation Aerosol has been used concomitantly with other drugs including sympathomimetic bronchodilators methylxanthines and steroids commonly used in the treatment of chronic obstructive pulmonary disease With the exception of albuterol there are no formal studies fully evaluating the interaction effects of ATROVENT Inhalation Aerosol and these drugs with respect to effectiveness Anticholinergic agents Although ipratropium bromide is minimally absorbed into the systemic circulation there is some potential for an additive interaction with concomitantly used anticholinergic medications Caution is therefore advised in the coadministration of ATROVENT Inhalation Aerosol with other anticholinergic containing drugs No significant drug drug pharmacokinetic or pharmacodynamic interactions have been found in interaction studies with hydrochlorothiazide digoxin warfarin and nifedipine In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP 2C9 substrates inhibitors sulphenazole tolbutamide and nifedipine However in clinical studies the consequences of concomitant irbesartan on the pharmacodynamics of warfarin were negligible Based on in vitro data no interaction would be expected with drugs whose metabolism is dependent upon cytochrome P450 isozymes 1A1 1A2 2A6 2B6 2D6 2E1 or 3A4 In separate studies of patients receiving maintenance doses of warfarin hydrochlorothiazide or digoxin irbesartan administration for 7 days had no effect on the pharmacodynamics of warfarin prothrombin time or pharmacokinetics of digoxin The pharmacokinetics of irbesartan were not affected by coadministration of nifedipine or hydrochlorothiazide The adverse effects of CAMPTOSAR such as myelosuppression and diarrhea would be expected to be exacerbated by other antineoplastic agents having similar adverse effects Patients who have previously received pelvic abdominal irradiation are at increased risk of severe myelosuppression following the administration of CAMPTOSAR The concurrent administration of CAMPTOSAR with irradiation has not been adequately studied and is not recommended Lymphocytopenia has been reported in patients receiving CAMPTOSAR and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of this effect However serious opportunistic infections have not been observed and no complications have specifically been attributed to lymphocytopenia Hyperglycemia has also been reported in patients receiving CAMPTOSAR Usually this has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of CAMPTOSAR It is probable that dexamethasone given as antiemetic prophylaxis contributed to hyperglycemia in some patients The incidence of akathisia in clinical trials of the weekly dosage schedule was greater 8 5 4 47 patients when prochlorperazine was administered on the same day as CAMPTOSAR than when these drugs were given on separate days 1 3 1 80 patients The 8 5 incidence of akathisia however is within the range reported for use of prochlorperazine when given as a premedication for other chemotherapies It would be expected that laxative use during therapy with CAMPTOSAR would worsen the incidence or severity of diarrhea but this has not been studied In view of the potential risk of dehydration secondary to vomiting and or diarrhea induced by CAMPTOSAR the physician may wish to withhold diuretics during dosing with CAMPTOSAR and certainly during periods of active vomiting or diarrhea Drug Laboratory Test Interactions There are no known interactions between CAMPTOSAR and laboratory tests Isocarboxazid should be administered with caution to patients receiving Antabuse disulfiram Wyeth Ayerst Laboratories In a single study rats given high intraperitoneal doses of an MAO inhibitor plus disulfiram experienced severe toxicity including convulsions and death Concomitant use of Isocarboxazid and other psychotropic agents is generally not recommended because of possible potentiating effects This is especially true in patients who may subject themselves to an overdosage of drugs If combination therapy is needed careful consideration should be given to the pharmacology of all agents to be used The monoamine oxidase inhibitory effects of Isocarboxazid may persist for a substantial period after discontinuation of the drug and this should be borne in mind when another drug is prescribed following Isocarboxazid To avoid potentiation the physician wishing to terminate treatment with Isocarboxazid and begin therapy with another agent should allow for an interval of 10 days May interact with the following beta adrenergic blocking agents these medicines may make your condition worse and prevent the adrenergic bronchodilators from working properly and disopyramide quinidine phenothiazines and procainamide these medicines may increase the risk of heart problems Isoflurane potentiates the muscle relaxant effect of all muscle relaxants most notably nondepolarizing muscle relaxants and MAC minimum alveolar concentration is reduced by concomitant administration of N 2O See CLINICAL PHARMACOLOGY Food Isoniazid should not be administered with food Studies have shown that the bioavailability of isoniazid is reduced significantly when administered with food Acetaminophen A report of severe acetaminophen toxicity was reported in a patient receiving Isoniazid It is believed that the toxicity may have resulted from a previously unrecognized interaction between isoniazid and acetaminophen and a molecular basis for this interaction has been proposed However current evidence suggests that isoniazid does induce P 450IIE1 a mixed function oxidase enzyme that appears to generate the toxic metabolites in the liver Furthermore it has been proposed that isoniazid resulted In induction of P 450IIE1 in the patients liver which in turn resulted in a greater proportion of the ingested acetaminophen being converted to the toxic metabolites Studies have demonstrated that pretreatment with isoniazid potentiates a cetaminophen hepatoxicity in rats Carbamazepine Isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels Carbamazepine levels should be determined prior to concurrent administration with isoniazid signs and symptoms of carbamazepine toxicity should be monitored closely and appropriate dosage adjustment of the anticonvulsant should be made Ketoconazole Potential interaction of Ketoconazole and Isoniazid may exist Phenytoin Isoniazid may increase serum levels of phenytoin To avoid phenytoin intoxication appropriate adjustment of the anticonvulsant should be made Therophylline A recent study has shown that concomitan administration of isoniazid and theophylline may cause elevated plasma levels of theophylline and in some instances a slight decrease in the elimination of isoniazid Since the therapeutic range of theophylline is narrow theophylline serum levels should be monitored closely and appropriate dosage adjustments of theophylline should be made Valproate A recent case study has shown a possible increase in the plasma level of valproate when co administered with isoniazid Plasma valproate concentration should be monitored when isoniazid and valproate are co administered and appropriate dosage adjustments of valproate should be made Isoproterenol hydrochloride injection and epinephrine should not be administered simultaneously because both drugs are direct cardiac stimulants and their combined effects may induce serious arrhythmias The drugs may however be administered alternately provided a proper interval has elapsed between doses ISUPREL should be used with caution if at all when potent inhalational anesthetics such as halothane are employed because of potential to sensitize the myocardium to effects of sympathomimetic amines The vasodilating effects of isosorbide dinitrate may be additive with those of other vasodilators Alcohol in particular has been found to exhibit additive effects of this variety The vasodilating effects of isosorbide mononitrate may be additive with those of other vasodilators Alcohol in particular has been found to exhibit additive effects of this variety Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination Dose adjustments of either class of agents may be necessary Vitamin A Because of the relationship of Accutane to vitamin A patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects Tetracyclines Concomitant treatment with Accutane and tetracyclines should be avoided because Accutane use has been associated with a number of cases of pseudotumor cerebri benign intracranial hypertension some of which involved concomitant use of tetracyclines Micro dosed Progesterone Preparations Micro dosed progesterone preparations minipills that do not contain an estrogen may be an inadequate method of contraception during Accutane therapy Although other hormonal contraceptives are highly effective there have been reports of pregnancy from women who have used combined oral contraceptives as well as topical injectable implantable insertable hormonal birth control products These reports are more frequent for women who use only a single method of contraception It is not known if hormonal contraceptives differ in their effectiveness when used with Accutane Therefore it is critically important for women of childbearing potential to select and commit to use 2 forms of effective contraception simultaneously at least 1 of which must be a primary form unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy Phenytoin Accutane has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme Phenytoin is known to cause osteomalacia No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Accutane Therefore caution should be exercised when using these drugs together Systemic Corticosteroids Systemic corticosteroids are known to cause osteoporosis No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Accutane Therefore caution should be exercised when using these drugs together Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives since some medications may decrease the effectiveness of these birth control products Accutane use is associated with depression in some patients Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns Wort Laboratory Tests Pregnancy Test Female patients of childbearing potential must have negative results from 2 urine or serum pregnancy tests with a sensitivity of at least 25 mIU mL before receiving the initial Accutane prescription The first test is obtained by the prescriber when the decision is made to pursue qualification of the patient for Accutane a screening test The second pregnancy test a confirmation test should be done during the first 5 days of the menstrual period immediately preceding the beginning of Accutane therapy For patients with amenorrhea the second test should be done at least 11 days after the last act of unprotected sexual intercourse without using 2 effective forms of contraception Each month of therapy the patient must have a negative result from a urine or serum pregnancy test A pregnancy test must be repeated each month prior to the female patient receiving each prescription Lipids Pretreatment and follow up blood lipids should be obtained under fasting conditions After consumption of alcohol at least 36 hours should elapse before these determinations are made It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to Accutane is established The incidence of hypertriglyceridemia is 1 patient in 4 on Accutane therapy Liver Function Tests Since elevations of liver enzymes have been observed during clinical trials and hepatitis has been reported pretreatment and follow up liver function tests should be performed at weekly or biweekly intervals until the response to Accutane has been established Glucose Some patients receiving Accutane have experienced problems in the control of their blood sugar In addition new cases of diabetes have been diagnosed during Accutane therapy although no causal relationship has been established CPK Some patients undergoing vigorous physical activity while on Accutane therapy have experienced elevated CPK levels however the clinical significance is unknown There have been rare postmarketing reports of rhabdomyolysis some associated with strenuous physical activity In a clinical trial of 217 pediatric patients 12 to 17 years with severe recalcitrant nodular acne transient elevations in CPK were observed in 12 of patients including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain arthralgia limb injury or muscle sprain In these patients approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks No cases of rhabdomyolysis were reported in this trial Nitroglycerin DynaCirc isradipine has been safely coadministered with nitroglycerin Hydrochlorothiazide A study in normal healthy volunteers has shown that concomitant administration of DynaCirc isradipine and hydrochlorothiazide does not result in altered pharmacoktnetics of either drug In a study in hypertensive patients addition of isradipine to existing hydrochlorothiazide therapy did not result in any unexpected adverse effects and isradipine had an additional antihypertensive effect Propranolol In a single dose study in normal volunteers coadministration of propranolol had a small effect on the rate but no effect on the extent of isradipine bioavailability Significant increases In AUC 27 and Cmax 58 and decreases in tmax 23 of propranolol were noted in this study However concomitant administration of 5 mg b i d isradipine and 40 mg b i d propranolol to healthy volunteers under steady state conditions had no relevant effect on either drug s bioavailability AUC and Cmax differences were 20 between isradipine given singly and in combination with propranolol and between propranolol given singly and in combination with isradipine Cimetidine In a study in healthy volunteers a one week course of cimetidine at 400 mg b i d with a single 5 mg dose of isradipine on the sixth day showed an increase in isradipine mean peak plasma concentrations 36 and significant increase in area under the curve 50 If isradipine therapy is initiated in a patient currently receiving cimetidine careful monitoring for adverse reactions is advised and downward dose adjustment may be required Rifampicin In a study in healthy volunteers a six day course of rifampicin at 600 mg day followed by a single 5 mg dose of isradipine resulted in a reduction in isradipine levels to below detectable limits If rifampicin therapy is required isradipine concentrations and therapeutic effects are likely to be markedly reduced or abolished as a consequence of increased metabolism and higher clearance of isradipine Warfarin In a study in healthy volunteers no clinically relevant pharmacokinetic or pharmacodynamic interaction between isradipine and racemic warfarin was seen when two single oral doses of warfarin 0 7 mg kg body weight were administered during 11 days of multipledose treatment with 5 mg b i d isradipine Neither racemic warfarin nor isradipine binding to plasma proteins in vitro was altered by the addition of the other drug Digoxin The concomitant administration of DynaCirc isradipine and digoxin in a single dose pharmacokinetic study did not affect renal nonrenal and total body clearance of digoxin Fentanyl Anesthesia Severe hypotension has been reported during fentanyl anesthesia with concomitant use of a beta blocker and a calcium channel blocker Even though such interactions have not been seen in clinical studies with DynaCirc isradipine an increased volume of circulating fluids might be required if such an interaction were to occur Both itraconazole and its major metabolite hydroxyitraconazole are inhibitors of the cytochrome P450 3A4 enzyme system Coadministration of Itraconazole and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both therapeutic and adverse effects Therefore unless otherwise specified appropriate dosage adjustments may be necessary Coadministration of terfenadine with Itraconazole has led to elevated plasma concentrations of terfenadine resulting in rare instances of life threatening cardiac dysrhythmias and one death Another oral azole antifungal ketoconazole inhibits the metabolism of astemizole resulting in elevated plasma concentrations of astemizole and its active metabolite desmethylastermizole which may prolong QT intervals In vitro data suggest that itraconazole when compared to ketoconazole has a less pronounced effect on the biotransformation system responsible for the metabolism of astemizole Based on the chemical resemblance of itraconazole and ketoconazole coadministration of astemizole with itraconazole is contraindicated Human pharmacokinetics data indicate that oral ketoconazole potently inhibits the metabolism of cisapride resulting in an eight fold increase in the mean AUC of cisapride Data suggest that coadministration of oral ketoconazole and cisapride can result in prolongation of the QT interval on the ECG In vitro data suggest that itraconazole also markedly inhibits the biotransformation system mainly responsible for the metabolism of cisapride therefore concomitant administration of Itraconazole with cisapride is contraindicated Coadministration of Itraconazole with oral midazolam or triazolam has resulted in elevated plasma concentrations of the latter two drugs This may potentiate and prolong hypnotic and sedative effects These agents should not be used in patients treated with Itraconazole If midazolam is administered parenterally special precaution is required since the sedative effect may be prolonged Coadministration of Itraconazole and cyclosporine tacrolimus or digoxin has led to increased plasma concentrations of the latter three drugs Cyclosporine tacrolimus and digoxin concentrations should be monitored at the initiation of Itraconazole therapy and frequently thereafter and the dose of these three drug products adjusted appropriately Rhabdomyolysis has been observed in patients receiving HMG CoA reductase inhibitors administered alone at recommended dosages or concomitantly with immunosuppressive drugs including cyclosporine When Itraconazole was coadministered with phenytoin rifampin or H2antagonists reduced plasma concentrations of itraconazole were reported The physician is advised to monitor the plasma concentrations of itraconazole when any of these drugs is taken concurrently and to increase the dose of Itraconazole if necessary Although no studies have been conducted concomitant administration of Itraconazole and phenytoin may alter the metabolism of phenytoin therefore plasma concentrations of phenytoin should also be monitored when it is given concurrently with Itraconazole It has been reported that Itraconazole enhances the anticoagulant effect of coumarin like drugs Therefore prothrombin time should be carefully monitored in patients receiving Itraconazole and coumarin like drugs simultaneously Plasma concentrations of azole antifungal agents are reduced when given concurrently with isoniazid Itraconazole plasma concentrations should be monitored when Itraconazole and isoniazid are coadministered Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents Blood glucose concentrations should be carefully monitored when Itraconazole and oral hypoglycemic agents are coadministered Tinnitus and decreased hearing have been reported in patients concomitantly receiving Itraconazole and quinidine Edema has been reported in patients concomitantly receiving Itraconazole and dihydropyridine calcium channel blockers Appropriate dosage adjustments may be necessary The results from a study in which eight HIV infected individuals were treated with zidovudine 8 0 4 mg kg day showed that the pharmacokinetics of zidovudine were not affected during concomitant administration of Itraconazole 100 mg b i d In vitro mixing of an aminoglycoside with beta lactamtype antibiotics penicillins or cephalosporins may result in a significant mutual inactivation Even when an aminoglycoside and a penicillin type drug are administered separately by different routes a reduction in aminoglycoside serum half life or serum levels has been reported in patients with impaired renal function and in some patients with normal renal function Usually such inactivation of the aminoglycoside is clinically significant only in patients with severely impaired renal function See Prolonged recovery time may occur if barbiturates and or narcotics are used concurrently with ketamine Ketamine is clinically compatible with the commonly used general and local anesthetic agents when an adequate respiratory exchange is maintained Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system Coadministration of NIZORAL Tablets and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both therapeutic and adverse effects Therefore unless otherwise specified appropriate dosage adjustments may be necessary The following drug interactions have been identified involving NIZORAL Tablets and other drugs metabolized by the cytochrome P450 3A4 enzyme system Ketoconazole tablets inhibit the metabolism of terfenadine resulting in an increased plasma concentration of terfenadine and a delay in the elimination of its acid metabolite The increased plasma concentration of terfenadine or its metabolite may result in prolonged QT intervals Pharmacokinetic data indicate that oral ketoconazole inhibits the metabolism of astemizole resulting in elevated plasma levels of astemizole and its active metabolite desmethylastemizole which may prolong QT intervals Coadministration of astemizole with ketoconazole tablets is therefore contraindicated Human pharmacokinetics data indicate that oral ketoconazole potently inhibits the metabolism of cisapride resulting in a mean eight fold increase in AUC of cisapride Data suggest that coadministration of oral ketoconazole and cisapride can result in prolongation of the QT interval on the ECG Therefore concomitant administration of ketoconazole tablets with cisapride is contraindicated Ketoconazole tablets may alter the metabolism of cyclosporine tacrolimus and methylprednisolone resulting in elevated plasma concentrations of the latter drugs Dosage adjustment may be required if cyclosporine tacrolimus or methylprednisolone are given concomitantly with NIZORAL Tablets Coadministration of NIZORAL Tablets with midazolam or triazolam has resulted in elevated plasma concentrations of the latter two drugs This may potentiate and prolong hypnotic and sedative effects especially with repeated dosing or chronic administration of these agents These agents should not be used in patients treated with NIZORAL Tablets If midazolam is administered parenterally special precaution is required since the sedative effect may be prolonged Rare cases of elevated plasma concentrations of digoxin have been reported It is not clear whether this was due to the combination of therapy It is therefore advisable to monitor digoxin concentrations in patients receiving ketoconazole When taken orally imidazole compounds like ketoconazole may enhance the anticoagulant effect of coumarin like drugs In simultaneous treatment with imidazole drugs and coumarin drugs the anticoagulant effect should be carefully titrated and monitored Because severe hypoglycemia has been reported in patients concomitantly receiving oral miconazole an imidazole and oral hypoglycemic agents such a potential interaction involving the latter agents when used concomitantly with ketoconazole tablets an imidazole can not be ruled out Concomitant administration of ketoconazole tablets with phenytoin may alter the metabolism of one or both of the drugs It is suggested to monitor both ketoconazole and phenytoin Concomitant administration of rifampin with ketoconazole tablets reduces the blood levels of the latter INH Isoniazid is also reported to affect ketoconazole concentrations adversely These drugs should not be given concomitantly After the coadministration of 200 mg oral ketoconazole twice daily and one 20 mg dose of loratadine to 11 subjects the AUC and Cmax of loratadine averaged 302 142 S D and 251 68 S D respectively of those obtained after co treatment with placebo The AUC and Cmax of descarboethoxyloratadine an active metabolite averaged 155 27 S D and 141 35 S D respectively However no related changes were noted in the QT0 on ECG taken at 2 6 and 24 hours after the coadministration Also there were no clinically significant differences in adverse events when loratadine was administered with or without ketoconazole Rare cases of a disulfiram like reaction to alcohol have been reported These experiences have been characterized by flushing rash peripheral edema nausea and headache Symptoms resolved within a few hours The following drug interactions were studied with ketoprofen doses of 200 mg day The possibility of increased interaction should be kept in mind when Orudis doses greater than 50 mg as a single dose or 200 mg of ketoprofen per day are used concomitantly with highly bound drugs 1 Antacids Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with the rate or extent of the absorption of ketoprofen administered as Orudis 2 Aspirin Ketoprofen does not alter aspirin absorption however in a study of 12 normal subjects concurrent administration of aspirin decreased ketoprofen protein binding and increased ketoprofen plasma clearance from 0 07 L kg h without aspirin to 0 11 L kg h with aspirin The clinical significance of these changes has not been adequately studied Therefore concurrent use of aspirin and ketoprofen is not recommended 3 Diuretic Hydrochlorothiazide given concomitantly with ketoprofen produces a reduction in urinary potassium and chloride excretion compared to hydrochlorothiazide alone Patients taking diuretics are at a greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition 4 Digoxin In a study in 12 patients with congestive heart failure where ketoprofen and digoxin were concomitantly administered ketoprofen did not alter the serum levels of digoxin 5 Warfarin In a short term controlled study in 14 normal volunteers ketoprofen did not significantly interfere with the effect of warfarin on prothrombin time Bleeding from a number of sites may be a complication of warfarin treatment and GI bleeding a complication of ketoprofen treatment Because prostaglandina play an important role in hemostasis and ketoprofen has an effect on platelet function as well concurent therapy with ketoprofen and warfarin requires close monitoring of patients on both drugs 6 Probenecid Probenecid increases both free and bound ketoprofen by reducing the plasma clearance of ketoprofen to about one third as well as decreasing its protein binding Therefore the combination of ketoprofen and probenecid is not recommended 7 Methotrexate Ketoprofen like other NSAIDs may cause changes in the elimination of methotrexate leading to elevated serum levels of the drug and increased toxicity 8 Lithium Nonsteroidal anti inflammatory agents have been reported to increase steadystate plasma lithium levels It is recommended that plasma lithium levels be monitored when ketoprofen is coadministered with lithium DRUG LABORATORY TEST INTERACTIONS EFFECT ON BLOOD COAGULATION Ketoprofen decreases platelet adhesion and aggregation Therefore it can prolong bleeding time by approximately 3 to 4 minutes from baseline values There is no significant change in platelet count prothrombin time partial thromboplastin time or thrombin time Ketorolac is highly bound to human plasma protein mean 99 2 Warfarin Digoxin Salicylate and Heparin The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine 99 5 control vs 99 3 when ketorolac plasma concentrations reach 5 to10 m g mL Ketorolac does not alter digoxin protein binding In vitro studies indicate that at therapeutic concentrations of salicylate 300 m g mL the binding of ketorolac was reduced from approximately 99 2 to 97 5 representing a potential twofold increase in unbound ketorolac plasma levels Therapeutic concentrations of digoxin warfarin ibuprofen naproxen piroxicam acetaminophen phenytoin andtolbutamide did not alter ketorolac tromethamine protein binding In a study involving 12 adult volunteers TORADOLORAL was coadministered with a single dose of 25 mg warfarin causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin In another study TORADOLIV IM was given with two doses of 5000 U of heparin to 11 healthy volunteers resulting in a mean template bleeding time of 6 4 minutes 3 2 to 11 4 min compared to a mean of 6 0 minutes 3 4 to 7 5 min for heparin alone and 5 1 minutes 3 5 to 8 5 min for placebo Although these results do not indicate a significant interaction between TORADOL and warfarin or heparin the administration of TORADOL to patients taking anticoagulants should be done extremely cautiously and patients should be closely monitored Furosemide TORADOL IV IM reduced the diuretic response to furosemide in normovolemic healthy subjects by approximately 20 mean sodium and urinary output decreased 17 Probenecid Concomitant administration of TORADOL ORAL and probenecid resulted in decreased clearance of ketorolac and significant increases in ketorolac plasma levels total AUC increased approximately threefold from 5 4 to 17 8 m g h mL and terminal half life increased approximately twofold from 6 6 to 15 1 hours Therefore concomitant use of TORADOL and probenecid is contraindicated Lithium Inhibition of renal lithium clearance leading to an increase in plasma lithium concentration has been reported with some prostaglandin synthesis inhibiting drugs The effect of TORADOL on plasma lithium has not been studied but cases of increased lithium plasma levels during TORADOL therapy have been reported Methotrexate Concomitant administration of methotrexate and some NSAIDs has been reported to reduce the clearance of methotrexate enhancing the toxicity of methotrexate The effect of TORADOL on methotrexate clearance has not been studied Nondepolarizing Muscle Relaxants In postmarketing experience there have been reports of a possible interaction between TORADOLIV IM and nondepolarizing muscle relaxants that resulted in apnea The concurrent use of TORADOL with muscle relaxants has not been formally studied ACE Inhibitors Concomitant use of ACE inhibitors may increase the risk of renal impairment particularly in volume depleted patients Antiepileptic Drugs Sporadic cases of seizures have been reported during concomitant use of TORADOL and antiepileptic drugs phenytoin carbamazepine Psychoactive Drugs Hallucinations have been reported when TORADOL was used in patients taking psychoactive drugs fluoxetine thiothixene alprazolam Morphine TORADOLIV IM has been administered concurrently with morphine in several clinical trials of postoperative pain without evidence of adverse interactions Do not mix TORADOL and morphine in the same syringe There is no evidence in animal or human studies that TORADOL induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs Cyclosporine L arginine may counteract the antinaturetic effect of cyclosporin Ibuprofen L arginine may increase the absorption of ibuprofen if taken concomitantly Organic nitrates L arginine supplements theoretically may potentiate the effects of organic nitrates if taken concomitantly Sildenafil citrate Theoretically L arginine supplements taken concomitantly with sildenafil citrate may potentiate the effects of the drug No drug nutritional supplement food or herb interactions are known Interacts with valproic acid No well known drug interactions with glutamic acid Human growth hormone Concomitant use of L glutamine and human growth hormone may enhance nutrient absorption in those with severe short bowel syndrome L glutamine has orphan drug status for this indication Indomethacin Concomitant use of L glutamine and indomethacin may ameliorate increased intestinal permeability caused by indomethacin The reported dose used for L glutamine was 21 grams daily taken in divided doses three times a day Further misoprostol is reported to have a synergistic effect with this combination in ameliorating intestinal permeability Methotrexate There is one report that methotrexate may decrease the possible effectiveness of supplemental L glutamine for chemotherapy induced mucositis In another report nine patients with breast cancer were reported to have decreased symptoms of methotrexate related toxicity when given supplemental L glutamine at a dose of 0 5 gram kilogram day Paclitaxel In one report L glutamine at a dose of 10 grams three times daily given 24 hours after receiving paclitaxel appeared to prevent the development of myalgia and arthralgia adverse reactions of paclitaxel Medroxyprogesterone Acetate L histidine was observed to enhance in tissue culture the effect of medroxyprogesterone acetate in reducing the number of human breast cancer cells that were in the S phase H1 and H2 Blockers Although not reported L histidine via its metabolism to histamine might decrease the efficacy of H1 and H2 blockers Concomitant use of calcium supplements and L lysine may increase calcium absorption Acetaminophen and methotrexate L methionine may decrease hepatic toxicity in those with acetaminophen overdosage or in those taking methotrexate Theoretically it may decrease hepatic toxicity in the case of other potential hepatotoxic drugs as well Gentamicin Methionine may protect against the ototoxic effects of gentamicin Non selective monoamine oxidase MAO inhibitors including phenelzine sulfate tranylcypromine sulfate and pargyline HC1 Concomitant use of L phenylalanine and non selective MAO inhibitors may cause hypertension Selegiline L phenylalanine and the selective MAO inhibitor selegiline may have synergistic antidepressant activity if used concomitantly Neuroleptic Drugs L phenylalanine may potentiate the tardive dyskinesia side reactions of neuroleptic drugs if used concomitantly with them Monoamine oxidase MAO inhibitors such as isocarboxazid e g Marplan phenelzine e g Nardil procarbazine e g Matulane selegiline e g Eldepryl and tranylcypromine e g Parnate Using these medicines with L tryptophan may increase the chance of side effects Non selective MAO inhibitors including tranylcypromine sulfate phenelzine sulfate and pargyline HC1 Concomitant use of L tyrosine and non selective MAO inhibitors may cause hypertension In one survey 2 3 of patients taking labetalol HCl in combination with tricyclic antidepressants experienced tremor as compared to 0 7 reported to occur with labetalol HCl alone The contribution of each of the treatments to this adverse reaction is unknown but the possibility of a drug interaction cannot be excluded Drugs possessing beta blocking properties can blunt the bronchodilator effect of beta receptor agonist drugs in patients with bronchospasm therefore doses greater than the normal antiasthmatic dose of beta agonist bronchodilator drugs may be required Cimetidine has been shown to increase the bioavailability of labetalol HCl Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol HCl special care should be used in establishing the dose required for blood pressure control in such patients Synergism has been shown between halothane anesthesia and intravenously administered labetalol HCl During controlled hypotensive anesthesia using labetalol HCl in association with halothane high concentrations 3 or above of halothane should not be used because the degree of hypotension will be increased and because of the possibility of a large reduction in cardiac output and an increase in central venous pressure The anesthesiologist should be informed when a patient is receiving labetalol HCl Labetalol HCl blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect If labetalol HCl is used with nitroglycerin in patients with angina pectoris additional antihypertensive effects may occur Care should be taken if labetalol is used concomitantly with calcium antagonists of the verapamil type Risk of Anaphylactic Reaction While taking beta blockers patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge either accidental diagnostic or therapeutic Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction Drug Laboratory Test Interactions The presence of labetalol metabolites in the urine may result in falsely elevated levels of urinary catecholamines metanephrine normetanephrine and vanillylmandelic acid when measured by fluorimetric or photometric methods In screening patients suspected of having a pheochromocytoma and being treated with labetalol HCl a specific method such as a high performance liquid chromatographic assay with solid phase extraction e g J Chromatogr 385 241 1987 should be employed in determining levels of catecholamines Labetalol HCl has also been reported to produce a false positive test for amphetamine when screening urine for the presence of drugs using the commercially available assay methods Toxi Lab A thin layer chromatographic assay and Emit d a u radioenzymatic assay When patients being treated with labetalol have a positive urine test for amphetamine using these techniques confirmation should be made by using more specific methods such as a gas chromatographic mass spectrometer technique Results of preliminary studies in humans and rats suggest that nonabsorbable antacids given concurrently with lactulose may inhibit the desired lactulose induced drop in colonic pH Therefore a possible lack of desired effect of treatment should be taken into consideration before such drugs are given concomitantly with lactulose Lamivudine is predominantly eliminated in the urine by active organic cationic secretion The possibility of interactions with other drugs administered concurrently should be considered particularly when their main route of elimination is active renal secretion via the organic cationic transport system e g trimethoprim No change in dose of either drug is recommended There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP SMX such as those used to treat Pneumocystis carinii pneumonia No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another Therefore use of lamivudine in combination with zalcitabine is not recommended Lansoprazole is metabolized through the cytochrome P450 system specifically through the CYP3A and CYP2C19 isozymes Studies have shown that lansoprazole does not have clinically significant interactions with other drugs metabolized by the cytochrome P450 system such as warfarin antipyrine indomethacin ibuprofen phenytoin propranolol prednisone diazepam clarithromycin or terfenadine in healthy subjects These compounds are metabolized through various cytochrome P450 isozymes including CYP1A2 CYP2C9 CYP2C19 CYP2D6 and CYP3A When lansoprazole was administered concomitantly with theophylline CYP1A2 CYP3A a minor increase 10 in the clearance of theophylline was seen Because the small magnitude and the direction of the effect on theophylline clearance this interaction is unlikely to be clinical concern Nonetheless individual patients may require additional titration of their theophylline dosage when lansoprazole is started or stopped to ensure clinically effective blood levels Lansoprazole has also been shown to have no clinically significant interaction with amoxicillin In a single dose crossover study examining lansoprazole 30 mg and omeprazole 20 mg each administered alone and concomitantly with sucralfate 1 gram absorption of the proton pump inhibitors was delayed and their bioavailability was reduced by 17 and 16 respectively when administered concomitantly with sucralfate Therefore proton pump inhibitors should be taken at least 30 minutes prior to sucralfate In clinical trials antacids were administered concomitantly with lansoprazole delayed release capsules this did not interfere with its effect Lansoprazole causes a profound and long lasting inhibition of gastric acid secretion therefore it is theoretically possible that lansoprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability e g ketoconazole ampicillin esters iron salts digoxin Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport Systems Lapatinib inhibits CYP3A4 and CYP2C8 in vitro at clinically relevant concentrations Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4 or CYP2C8 Lapatinib did not significantly inhibit the following enzymes in human liver microsomes CYP1A2 CYP2C9 CYP2C19 and CYP2D6 or UGT enzymes in vitro however the clinical significance is unknown Lapatinib inhibits human P glycoprotein If TYKERB is administered with drugs that are substrates of Pgp increased concentrations of the substrate drug are likely and caution should be exercised Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Lapatinib undergoes extensive metabolism by CYP3A4 and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes Ketoconazole In healthy subjects receiving ketoconazole a CYP3A4 inhibitor at 200 mg twice daily for 7 days systemic exposure AUC to lapatinib was increased to approximately 3 6 fold of control and half life increased to 1 7 fold of control Carbamazepine In healthy subjects receiving the CYP3A4 inducer carbamazepine at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days systemic exposure AUC to lapatinib was decreased approximately 72 Drugs that Inhibit Drug Transport Systems Lapatinib is a substrate of the efflux transporter P glycoprotein Pgp ABCB1 If TYKERB is administered with drugs that inhibit Pgp increased concentrations of lapatinib are likely and caution should be exercised Other Chemotherapy Agents In a separate study concomitant administration of lapatinib with capecitabine did not meaningfully alter the pharmacokinetics of either agent or the metabolites of capecitabine No formal drug interaction studies have been conducted In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with latanoprost If such drugs are used they should be administered with an interval of at least 5 minutes between applications Cholestyramine and Charcoal Administration of cholestyramine or activated charcoal in patients n 13 and volunteers n 96 resulted in a rapid and significant decrease in plasma M1 the active metabolite of leflunomide concentration Hepatotoxic Drugs Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic substances This is also to be considered when leflunomide treatment is followed by such drugs without a drug elimination procedure In a small n 30 combination study of ARAVA with methotrexate a 2 to 3 fold elevation in liver enzymes was seen in 5 of 30 patients All elevations resolved 2 with continuation of both drugs and 3 after discontinuation of leflunomide A 3 fold increase was seen in another 5 patients All of these also resolved 2 with continuation of both drugs and 3 after discontinuation of leflunomide Three patients met ACR criteria for liver biopsy 1 Roegnik Grade I 2 Roegnik Grade IIIa No pharmacokinetic interaction was identified NSAIDs In in vitro studies M1 was shown to cause increases ranging from 13 50 in the free fraction of diclofenac and ibuprofen at concentrations in the clinical range The clinical significance of this finding is unknown however there was extensive concomitant use of NSAIDs in clinical studies and no differential effect was observed Tolbutamide In in vitro studies M1 was shown to cause increases ranging from 13 50 in the free fraction of tolbutamide at concentrations in the clinical range The clinical significance of this finding is unknown Rifampin Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin M1 peak levels were increased 40 over those seen when ARAVA was given alone Because of the potential for ARAVA levels to continue to increase with multiple dosing caution should be used if patients are to be receiving both ARAVA and rifampin Warfarin Increased INR International Normalized Ratio when ARAVA and warfarin were co administered has been rarely reported Results from human in vitro metabolism studies and nonclinical studies show that REVLIMID lenalidomide is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450 based metabolic drug interactions in man Co administration of multiple doses of 10 mg of lenalidomide had no effect on the single dose pharmacokinetics of R and S warfarin Co administration of single 25 mg dose warfarin had no effect on the pharmacokinetics of total lenalidomide Expected changes in laboratory assessments of PT and INR were observed after warfarin administration but these changes were not affected by concomitant lenalidomide administration Concomitant treatment with thrombolytics eg rt PA or streptokinase may increase the risk of bleeding complications considerably enhance the effect of REFLUDAN on aPTT prolongation Concomitant treatment with coumarin derivatives vitamin K antagonists and drugs that affect platelet function may also increase the risk of bleeding Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of Femara with these drugs does not result in clinically significant drug interactions See CLINICAL PHARMACOLOGY Coadministration of Femara and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels by 38 on average There is no clinical experience to date on the use of Femara in combination with other anticancer agents Drug Laboratory Test Interactions None observed Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital phenytoin and primidone and increase the frequency of seizures in susceptible pediatric patients Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin enter the CSF primarily as 5 methyltetrahydro folate and in humans remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration However high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate Leucovorin may enhance the toxicity of 5 fluorouracil ERGAMISOL levamisole hydrochloride has been reported to produce ANTABUSE like side effects when given concomitantly with alcohol The physician is advised to monitor plasma levels of phenytoin and to decrease the dose if necessary Because of reports of prolongation of the prothrombin time beyond the therapeutic range in patients taking concurrent levamisole and warfarin sodium it is suggested that the prothrombin time be monitored carefully and the dose of warfarin sodium or other coumarin like drugs should be adjusted accordingly in patients taking both drugs in vitro data on metabolic interactions indicate that Keppra is unlikely to produce or be subject to pharmacokinetic interactions Levetiracetam and its major metabolite at concentrations well above cmax levels achieved within the therapeutic dose range are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms epoxide hydrolase or UDP glucuronidation enzymes In addition levetiracetam does not affect the in vitro glucuronidation of valproic acid Levetiracetam circulates largely unbound 10 bound to plasma proteins clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies phenytoin valproate oral contraceptive digoxin warfarin probenecid and through pharmacokinetic screening in the placebo controlled clinical studies in epilepsy patients Drug Drug Interactions Between Keppra And Other Antiepileptic Drugs AEDs Phenytoin Keppra 3000 mg daily had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy Pharmacokinetics of levetiracetam were also not affected by phenytoin Valproate Keppra 1500 mg twice daily did not alter the pharmacokinetics of valproate in healthy volunteers Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion There also was no effect on exposure to and the excretion of the primary metabolite ucb L057 Potential drug interactions between Keppra and other AEDs carbamazepine gabapentin lamotrigine phenobarbital phenytoin primidone and valproate were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo controlled clinical studies These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam Effect of AEDs in Pediatric Patients There was about a 22 increase of apparent total body clearance of levetiracetam when it was co administered with enzyme inducing AEDs Dose adjustment is not recommended Levetiracetam had no effect on plasma concentrations of carbamazepine valproate topiramate or lamotrigine Other Drug Interactions Oral Contraceptives Keppra 500 mg twice daily did not influence the pharmacokinetics of an oral contraceptive containing 0 03 mg ethinyl estradiol and 0 15 mg levonorgestrel or of the luteinizing hormone and progesterone levels indicating that impairment of contraceptive efficacy is unlikely Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam Digoxin Keppra 1000 mg twice daily did not influence the pharmacokinetics and pharmacodynamics ECG of digoxin given as a 0 25 mg dose every day Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam Warfarin Keppra 1000 mg twice daily did not influence the pharmacokinetics of R and S warfarin Prothrombin time was not affected by levetiracetam Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam Probenecid Probenecid a renal tubular secretion blocking agent administered at a dose of 500 mg four times a day did not change the pharmacokinetics of levetiracetam 1000 mg twice daily Cssmax of the metabolite ucb L057 was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same Renal clearance of ucb L057 in the presence of probenecid decreased 60 probably related to competitive inhibition of tubular secretion of ucb L057 The effect of Keppra on probenecid was not studied Although BETAGAN used alone has little or no effect on pupil size mydriasis resulting from concomitant therapy with BETAGAN and epinephrine may occur Close observation of the patient is recommended when a beta blocker is administered to patients receiving catecholamine depleting drugs such as reserpine because of possible additive effects and the production of hypotension and or marked bradycardia which may produce vertigo syncope or postural hypotension Patients receiving beta adrenergic blocking agents along with either oral or intravenous calcium antagonists should be monitored for possible atrioventricular conduction disturbances left ventricular failure and hypotension In patients with impaired cardiac function simultaneous use should be avoided altogether The concomitant use of beta adrenergic blocking agents with digitalis and calcium antagonists may have additive effects on prolonging atrioventricular conduction time Phenothiazine related compounds and beta adrenergic blocking agents may have additive hypotensite effects due to the inhibition of each other s metabolism Chirocaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide type local anesthetics since the toxic effects of these drugs could be additive In vitro studies indicate CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3 hydroxy levobupivacaine respectively Thus agents likely to be concomitantly administered with Chirocaine that are metabolized by this isoenzyme family may potentially interact with Chirocaine Although no clinical studies have been conducted it is likely that the metabolism of levobupivacaine may be affected by the known CYP3A4 inducers such as phenytoin phenobarbital rifampin CYP3A4 inhibitors azole antimycotics e g ketoconazole certain protease inhibitors e g ritanovir macrolide antibiotics e g erythromycin and calcium channel antagonists e g verapamil CYP1A2 inducers omeprazole and CYP1A2 inhibitors furafylline and clarithromycin Dosage adjustment may be warranted when levobupivacaine is concurrently administered with CYP3A4 inhibitors and CYP1A2 inhibitors as systemic levobupivacaine levels may rise resulting in toxicity Specific drug interaction studies have not been conducted with Levofloxacin However the systemic administration of some quinolones has been shown to elevate plasma concentrations of theophylline interfere with the metabolism of caffeine and enhance the effects of the oral anticoagulant warfarin and its derivatives and has been associated with transient elevations in serum creatinine in patients receiving systemic cyclosporine concomitantly Interactions with Other CNS Agents Concurrent use of Levo Dromoran with all central nervous system depressants eg alcohol sedatives hypnotics other opioids general anesthetics barbiturates tricyclic antidepressants phenothiazines tranquilizers skeletal muscle relaxants and antihistamines may result in additive central nervous system depressant effects Respiratory depression hypotension and profound sedation or coma may occur When such combined therapy is contemplated the dose of one or both agents should be reduced Although no interaction between MAO inhibitors and Levo Dromoran has been observed it is not recommended for use with MAO inhibitors Most cases of serious or fatal adverse events involving Levo Dromoran reported to the manufacturer or the FDA have involved either the administration of large initial doses or too frequent doses of the drug to nonopioid tolerant patients or the simultaneous administration of levorphanol with other drugs affecting respiration The initial dose of levorphanol should be reduced by approximately 50 or more when it is given to patients along with another drug affecting respiration Interactions with Mixed Agonist Antagonist Opioid Analgesics Agonist antagonist analgesics eg pentazocine nalbuphine butorphanol dezocine and buprenorphine should NOT be administered to a patient who has received or is receiving a course of therapy with a pure agonist opioid analgesic such as Levo Dromoran In opioid dependent patients mixed agonist antagonist analgesics may precipitate withdrawal symptoms No Important Interactions To Date Levosimendan does not have clinically important pharmacokinetic interactions with captopril beta blockers felodipine digoxin warfarin isosorbide mononitrate carvedilol ethanol or itraconazole The magnitude and relative importance of the effects noted below are likely to be patient specific and may vary by such factors as age gender race intercurrent illnesses dose of either agent additional concomitant medications and timing of drug administration Any agent that alters thyroid hormone synthesis secretion distribution effect on target tissues metabolism or elimination may alter the optimal therapeutic dose of levothyroxine sodium Levothyroxine Sodium Absorption The following agents may bind and decrease absorption of levothyroxine sodium from the gastrointestinal tract aluminum hydoxide cholestyramine resin colestipol hydrochloride ferrous sulfate sodium polystyrene sulfonate soybean flour e g infant formula sucralfate Binding to Serum Proteins The following agents may either inhibit levothyroxine sodium binding to serum proteins or alter the concentrations of serum binding proteins androgens and related anabolic hormones asparaginase clofibrate estrogens and estrogen containing compounds 5 fluorouracil furosemide glucocorticoids meclofenamic acid mefenamic acid methadone perphenazine phenylbutazone phenytoin salicylates tamoxifen Thyroid Physiology The following agents may alter thyroid hormone or TSH levels generally by effects on thyroid hormone synthesis secretion distribution metabolism hormone action or elimination or altered TSH secretion aminoglutethimide p aminosalicylic acid amiodarone androgens and related anabolic hormones complex anions thiocyanate perchlorate pertechnetate antithyroid drugs b adrenergic blocking agents carbamazepine chloral hydrate diazepam dopamine and dopamine agonists ethionamide glucocorticoids heparin hepatic enzyme inducers insulin iodinated cholestographic agents iodine containing compounds levodopa lovastatin lithium 6 mercaptopurine metoclopramide mitotane nitroprusside phenobarbital phenytoin resorcinol rifampin somatostatin analogs sulfonamides sulfonylureas thiazide diuretics Adrenocorticoids Metabolic clearance of adrenocorticoids is decreased in hypothyroid patients and increased in hyperthyroid patients and may therefore change with changing thyroid status Amiodarone Amiodarone therapy alone can cause hypothyroidism or hyperthyroidism Anticoagulants Oral The hypoprothrombinemic effect of anticoagulants may be potentiated apparently by increased catabloism of vitamin K dependent clotting factors Antidiabetic Agents Insulin Sulfonylureas Requirements for insulin or oral antidiabetic agents may be reduced in hypothyroid patients with diabetes mellitus and may subsequently increase with the initiation of thyroid hormone replacement therapy b Adrenergic Blocking Agents Actions of some of beta blocking agents may be impaired when hypothyroid patients become euthyroid Cytokines interferon interleukin Cytokines have been reported to induce both hyperthyroidism and hypothyroidism Digitalis Glycosides Therapeutic effects of digitalis glycosides may be reduced Serum digitalis levels may be decreased in hyperthyroidism or when a hypothyroid patient becomes euthyroid Ketamine Marked hypertension and tachycardia have been reported in association with concomitant administration of levothyroxine sodium and ketamine Maprotiline Risk of cardiac arrhythmias may increase Sodium Iodide 123I and 131I Sodium Pertechnetate Tc99m Uptake of radiolabeled ions may be decreased Somatrem Somatropin Excessive concurrent use of thyroid hormone may accelerate epiphyseal closure Untreated hypothyroidism may interfere with the growth response to somatrem or somatropin Theophylline Theophylline clearance may decrease in hypothyroid patients and return toward normal when a euthyroid state is achieved Tricyclic Antidepressants Concurrent use may increase the therapeutic and toxic effects of both drugs possibly due to increased catecholamine sensitivity Onset of action of tricyclics may be accelerated Sympathomimetic Agents Possible increased risk of coronary insufficiency in patients with coronary artery disease The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe prolonged hypertension Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine Concurrent use of these agents should generally be avoided In situations when concurrent therapy is necessary careful patient monitoring is essential Concurrent administration of vasopressor drugs for the treatment of hypotension related to obstetric blocks and ergot type oxytocic drugs may cause severe persistent hypertension or cerebrovascular accidents Lincomycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents Therefore it should be used in caution in patients receiving such agents Antagonism between lincomycin and erythromycin in vitro has been demonstrated Because of possible clinical significance the two drugs should not be administered concurrently Oils may enhance absorption Therefore simultaneous use of creams ointments or oils should be avoided Monoamine Oxidase Inhibition Linezolid is a reversible nonselective inhibitor of monoamine oxidase Therefore linezolid has the potential for interaction with adrenergic and serotonergic agents Adrenergic Agents Some individuals receiving ZYVOX may experience a reversible enhancement of the pressor response to indirect acting sympathomimetic agents vasopressor or dopaminergic agents Commonly used drugs such as phenylpropanolamine and pseudoephedrine have been specifically studied Initial doses of adrenergic agents such as dopamine or epinephrine should be reduced and titrated to achieve the desired response Serotonergic Agents Co administration of linezolid and serotonergic agents was not associated with serotonin syndrome in Phase 1 2 or 3 studies Spontaneous reports of serotonin syndrome associated with co administration of ZYVOX and serotonergic agents including antidepressants such as selective serotonin reuptake inhibitors SSRIs have been reported Patients who are treated with ZYVOX and concomitant serotonergic agents should be closely observed for signs and symptoms of serotonin syndrome e g cognitive dysfunction hyperpyrexia hyperreflexia incoordination If any signs or symptoms occur physicians should consider discontinuation of either one or both agents ZYVOX or concomitant serotonergic agents Drug Laboratory Test Interactions There are no reported drug laboratory test interactions Oral Anticoagulants Thyroid hormones appear to increase catabolism of vitamin K dependent clotting factors If oral anticoagulants are also being given compensatory increases in clotting factor synthesis are impaired Patients stabilized on oral anticoagulants who are found to require thyroid replacement therapy should be watched very closely when thyroid is started If a patient is truly hypothyroid it is likely that a reduction in anticoagulant dosage will be required No special precautions appear to be necessary when oral anticoagulant therapy is begun in a patient already stabilized on maintenance thyroid replacement therapy Insulin or Oral Hypoglycemics Initiating thyroid replacement therapy may cause increases in insulin or oral hypoglycemic requirements The effects seen are poorly understood and depend upon a variety of factors such as dose and type of thyroid preparations and endocrine status of the patient Patients receiving insulin or oral hypoglycemics should be closely watched during initiation of thyroid replacement therapy Cholestyramine Cholestyramine binds both T4 and T3 in the intestine thus impairing absorption of these thyroid hormones In vitro studies indicate that the binding is not easily removed Therefore 4 to 5 hours should elapse between administration of cholestyramine and thyroid hormones Estrogen Oral Contraceptives Estrogens tend to increase serum thyroxine binding globulin TBg In a patient with a nonfunctioning thyroid gland who is receiving thyroid replacement therapy free levothyroxine may be decreased when estrogens are started thus increasing thyroid requirements However if the patients thyroid gland has sufficient function the decreased free thyroxine will result in a compensatory increase in thyroxine output by the thyroid Therefore patients without a functioning thyroid gland who are on thyroid replacement therapy may need to increase their thyroid dose if estrogens or estrogen containing oral contraceptives are given Tricyclic Antidepressants Use of thyroid products with imipramine and other tricyclic antidepressants may increase receptor sensitivity and enhance antidepressant activity transient cardiac arrhythmias have been observed Thyroid hormone activity may also be enhanced Digitalis Thyroid preparations may potentiate the toxic effects of digitalis Thyroid hormonal replacement increases metabolic rate which requires an increase in digitalis dosage Ketamine When administered to patients on a thyroid preparation this parenteral anesthetic may cause hypertension and tachycardia Use with caution and be prepared to treat hypertension if necessary Vasopressors Thyroxine increases the adrenergic effect of catecholamines such as epinephrine and norepinephrine Therefore injection of these agents into patients receiving thyroid preparations increases the risk of precipitating coronary insufficiency especially in patients with coronary artery disease Careful observation is required Drug Laboratory Test Interactions The following drugs or moieties are known to interfere with laboratory tests performed in patients on thyroid hormone therapy androgens corticosteroids estrogens oral contraceptives containing estrogens iodine containing preparations and the numerous preparations containing salicylates Changes in TBg concentration should be taken into consideration in the interpretation of T4 and T3 values In such cases the unbound free hormone should be measured Pregnancy estrogens and estrogen containing oral contraceptives increase TBg concentrations TBg may also be increased during infectious hepatitis Decreases in TBg concentrations are observed in nephrosis acromegaly and after androgen or corticosteroid therapy Familial hyper or hypo thyroxine binding globulinemias have been described The incidence of TBg deficiency approximates 1 in 9000 The binding of thyroxine by thyroxine binding prealbumin TBPA is inhibited by salicylates Medicinal or dietary iodine interferes with all in vivo tests of radio iodine uptake producing low uptakes which may not be reflective of a true decrease in hormone synthesis The persistence of clinical and laboratory evidence of hypothyroidism in spite of adequate dosage replacement indicates either poor patient compliance poor absorption excessive fecal loss or inactivity of the preparation Intracellular resistance to thyroid hormone is quite rare Urinary acidifying agents These agents ammonium chloride sodium acid phosphate etc increase the concentration of the ionized species of the amphetamine molecule thereby increasing urinary excretion Both groups of agents lower blood levels and efficacy of amphetamines Adrenergic blockers Adrenergic blockers are inhibited by amphetamines Antidepressants tricyclic Amphetamines may enhance the activity of tricyclic antidepressants or sympathomimetic agents d amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d amphetamine in the brain cardiovascular effects can be potentiated MAO inhibitors MAOI antidepressants as well as a metabolite of furazolidone slow amphetamine metabolism This slowing potentiates amphetamines increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings this can cause headaches and other signs of hypertensive crisis A variety of toxic neurological effects and malignant hyperpyrexia can occur sometimes with fatal results Antihistamines Amphetamines may counteract the sedative effect of antihistamines Antihypertensives Amphetamines may antagonize the hypotensive effects of antihypertensives Chlorpromazine Chlorpromazine blocks dopamine and norepinephrine receptors thus inhibiting the central stimulant effects of amphetamines and can be used to treat amphetamine poisoning Ethosuximide Amphetamines may delay intestinal absorption of ethosuximide Haloperidol Haloperidol blocks dopamine receptors thus inhibiting the central stimulant effects of amphetamines Lithium carbonate The anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate Meperidine Amphetamines potentiate the analgesic effect of meperidine Methenamine therapy Urinary excretion of amphetamines is increased and efficacy is reduced by acidifying agents used in methenamine therapy Norepinephrine Amphetamines enhance the adrenergic effect of norepinephrine Phenobarbital Amphetamines may delay intestinal absorption of phenobarbital co administration of phenobarbital may produce a synergistic anticonvulsant action Phenytoin Amphetamines may delay intestinal absorption of phenytoin co administration of phenytoin may produce a synergistic anticonvulsant action Propoxyphene In cases of propoxyphene overdosage amphetamine CNS stimulation is potentiated and fatal convulsions can occur Veratrum alkaloids Amphetamines inhibit the hypotensive effect of veratrum alkaloids Drug Laboratory Test Interactions Amphetamines can cause a significant elevation in plasma corticosteroid levels This increase is greatest in the evening Amphetamines may interfere with urinary steroid determinations Hypotension Patients on Diuretic Therapy Patients on diuretics and especially those in whom diuretic therapy was recently instituted may occasionally experience an excessive reduction of blood pressure after initiation of therapy with PRINIVIL The possibility of hypotensive effects with PRINIVIL can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with PRINIVIL If it is necessary to continue the diuretic initiate therapy with PRINIVIL at a dose of 5 mg daily and provide close medical supervision after the initial dose until blood pressure has stabilized When a diuretic is added to the therapy of a patient receiving PRINIVIL an additional antihypertensive effect is usually observed Studies with ACE inhibitors in combination with diuretics indicate that the dose of the ACE inhibitor can be reduced when it is given with a diuretic Non steroidal Anti inflammatory Agents In some patients with compromised renal function who are being treated with non steroidal anti inflammatory drugs the co administration of lisinopril may result in a further deterioration of renal function These effects are usually reversible Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors including lisinopril This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of PRINIVIL alone were compared to PRINIVIL given concomitantly with indomethacin the use of indomethacin was associated with a reduced antihypertensive effect although the difference between the two regimens was not significant Other Agents PRINIVIL has been used concomitantly with nitrates and or digoxin without evidence of clinically significant adverse interactions This included post myocardial infarction patients who were receiving intravenous or transdermal nitroglycerin No clinically important pharmacokinetic interactions occurred when PRINIVIL was used concomitantly with propranolol or hydrochlorothiazide The presence of food in the stomach does not alter the bioavailability of PRINIVIL Agents Increasing Serum Potassium PRINIVIL attenuates potassium loss caused by thiazide type diuretics Use of PRINIVIL with potassium sparing diuretics e g spironolactone triamterene or amiloride potassium supplements or potassium containing salt substitutes may lead to significant increases in serum potassium Therefore if concomitant use of these agents is indicated because of demonstrated hypokalemia they should be used with caution and with frequent monitoring of serum potassium Potassium sparing agents should generally not be used in patients with heart failure who are receiving PRINIVIL Lithium Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium including ACE inhibitors Lithium toxicity was usually reversible upon discontinuation of lithium and the ACE inhibitor It is recommended that serum lithium levels be monitored frequently if PRINIVIL is administered concomitantly with lithium Lofexidine may enhance the CNS depressive effects of alcohol barbiturates and other sedatives Lofexidine may enhance the effects of anti hypertensive drug therapy Concomitant use of tricyclic antidepressants may reduce the efficacy of lofexidine Theophylline In three pharmacokinetic studies including 46 normal healthy subjects theophylline clearance and concentration were not significantly altered by the addition of lomefloxacin In clinical studies where patients were on chronic theophylline therapy lomefloxacin had no measurable effect on the mean distribution of theophylline concentrations or the mean estimates of theophylline clearance Though individual theophylline levels fluctuated there were no clinically significant symptoms of drug inter action Antacids and sucralfate Sucralfate and antacids containing magnesium or aluminum as well as formulations containing divalent and trivalent cations such as Videx didanosine chewable buffered tablets or the pediatric powder for oral solution can form chelation complexes with lomefloxacin and interfere with its bioavailability Sucralfate administered 2 hours before lomefloxacin resulted in a slower absorption mean C max decreased by 30 and mean T max increased by 1 hour and a lesser extent of absorption mean AUC decreased by approximately 25 Magnesium and aluminum containing antacids administered concomitantly with lomefloxacin significantly decreased the bioavailability 48 of lomefloxacin Separating the doses of antacid and lomefloxacin minimizes this decrease in bioavailability therefore administration of these agents should precede lomefloxacin dosing by 4 hours or follow lomefloxacin dosing by at least 2 hours Caffeine Two hundred mg of caffeine equivalent to 1 to 3 cups of American coffee was administered to 16 normal healthy volunteers who had achieved steady state blood concentrations of lomefloxacin after being dosed at 400 mg qd This did not result in any statistically or clinically relevant changes in the pharmacokinetic parameters of either caffeine or its major metabolite paraxanthine No data are available on potential interactions in individuals who consume greater than 200 mg of caffeine per day or in those such as the geriatric population who are generally believed to be more susceptible to the development of drug induced CNS related adverse effects Other quinolones have demonstrated moderate to marked interference with the metabolism of caffeine resulting in a reduced clearance a prolongation of plasma half life and an increase in symptoms that accompany high levels of caffeine Cimetidine Cimetidine has been demonstrated to interfere with the elimination of other quinolones This interference has resulted in significant increases in half life and AUC The interaction between lomefloxacin and cimetidine has not been studied Cyclosporine Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with other members of the quinolone class Interaction between lomefloxacin and cyclosporine has not been studied Omeprazole No clinically significant changes in lomefloxacin pharmacokinetics AUC C max or T max were observed when a single dose of lomefloxacin 400 mg was given after multiple doses of omeprazole 20 mg qd in 13 healthy volunteers Changes in omeprazole pharmacokinetics were not studied Phenytoin No significant differences were observed in mean phenytoin AUC C max C min or T max although C max increased by 11 when extended phenytoin sodium capsules 100 mg tid were coadministered with lomefloxacin 400 mg qd for five days in 15 healthy males Lomefloxacin is unlikely to have a significant effect on phenytoin metabolism Probenecid Probenecid slows the renal elimination of lome floxacin An increase of 63 in the mean AUC and increases of 50 and 4 respectively in the mean T max and mean C max were noted in 1 study of 6 individuals Terfenadine No clinically significant changes occurred in heart rate or corrected QT intervals or in terfenadine metabolite or lomefloxacin pharmacokinetics during concurrent administration of lomefloxacin and terfenadine at steady state in 28 healthy males Warfarin Quinolones may enhance the effects of the oral anticoagulant warfarin or its derivatives When these products are administered concomitantly prothrombin or other suitable coagulation tests should be monitored closely However no clinically or statistically significant differences in prothrombin time ratio or warfarin enantiomer pharmacokinetics were observed in a small study of 7 healthy males who received both warfarin and lomefloxacin under steady state conditions There was no evidence in clinical trials of drug interactions with concurrent medications Probenecid As with other b lactam antibiotics renal excretion of loracarbef is inhibited by probenecid and resulted in an approximate 80 increase in the AUC for loracarbef Loratadine 10 mg once daily has been coadministered with therapeutic doses of erythromycin cimetidine and ketoconazole in controlled clinical pharmacology studies in adult volunteers Although increased plasma concentrations AUC 0 24 hrs of loratadine and or descarboethoxyloratadine were observed following coadministration of loratadine with each of these drugs in normal volunteers n 24 in each study there were no clinically relevant changes in the safety profile of loratadine as assessed by electrocardiographic parameters clinical laboratory tests vital signs and adverse events There were no significant effects on QTc intervals and no reports of sedation or syncope No effects on plasma concentrations of cimetidine or ketoconazole were observed Plasma concentrations AUC 0 24 hrs of erythromycin decreased 15 with coadministration of loratadine relative to that observed with erythromycin alone The clinical relevance of this difference is unknown These above findings are summarized in TABLE 1 TABLE 1 Effects on Plasma Concentrations AUC 0 24 hrs of Loratadine and Descarboethoxyloratadine After 10 Days of Coadministration Loratadine 10 mg in Normal Volunteers Loratadine Descarboethoxyloratadine Erythromycin 500 mg q8h 40 46 Cimetidine 300 mg qid 103 6 Ketoconazole 200 mg q12h 307 73 There does not appear to be an increase in adverse events in subjects who received oral contraceptives and loratadine Tablets The benzodiazepines including lorazepam produce CNS depressant effects when administered with such medications as barbiturates or alcohol Injection Lorazepam injection like other injectable benzodiazepines produces depression of the central nervous system when administered with ethyl alcohol phenothiazines barbiturates MAO inhibitors and other antidepressants When scopolamine is used concomitantly with injectable lorazepam an increased incidence of sedation hallucinations and irrational behavior has been observed No significant drug drug pharmacokinetic interactions have been found in interaction studies with hydrochlorothiazide digoxin warfarin cimetidine and phenobarbital Rifampin an inducer of drug metabolism decreased the concentrations of losartan and its active metabolite In humans two inhibitors of P450 3A4 have been studied Ketoconazole did not affect the conversion of losartan to the active metabolite after intravenous administration of losartan and erythromycin had no clinically significant effect after oral administration Fluconazole an inhibitor of P450 2C9 decreased active metabolite concentration and increased losartan concentration The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined Subjects who do not metabolize losartan to active metabolite have been shown to have a specific rare defect in cytochrome P450 2C9 These data suggest that the conversion of losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4 As with other drugs that block angiotensin II or its effects concomitant use of potassium sparing diuretics e g spironolactone triamterene amiloride potassium supplements or salt substitutes containing potassium may lead to increases in serum potassium As with other antihypertensive agents the antihypertensive effect of losartan may be blunted by the non steroidal anti inflammatory drug indomethacin CYP3A4 Interactions Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4 Potent inhibitors of CYP3A4 below increase the risk of myopathy by reducing the elimination of lovastatin Pharmacokinetics Itraconazole Ketoconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Cyclosporine Large quantities of grapefruit juice 1 quart daily Interactions with lipid lowering drugs that can cause myopathy when given alone The risk of myopathy is also increased by the following lipid lowering drugs that are not potent CYP3A4 inhibitors but which can cause myopathy when given alone See WARNINGS Myopathy Rhabdomyolysis Gemfibrozil Other fibrates Niacin nicotinic acid 1 g day Other drug interactions Danazol The risk of myopathy rhabdomyolysis is increased by concomitant administration of danazol particularly with higher doses of lovastatin see WARNINGS Myopathy Rhabdomyolysis Amiodarone or Verapamil The risk of myopathy rhabdomyolysis is increased when either amiodarone or verapamil is used concomitantly with a closely related member of the HMG CoA reductase inhibitor class see WARNINGS Myopathy Rhabdomyolysis Coumarin Anticoagulants In a small clinical trial in which lovastatin was administered to warfarin treated patients no effect on prothrombin time was detected However another HMG CoA reductase inhibitor has been found to produce a less than two second increase in prothrombin time in healthy volunteers receiving low doses of warfarin Also bleeding and or increased prothrombin time have been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin It is recommended that in patients taking anticoagulants prothrombin time be determined before starting lovastatin and frequently enough during early therapy to insure that no significant alteration of prothrombin time occurs Once a stable prothrombin time has been documented prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants If the dose of lovastatin is changed the same procedure should be repeated Lovastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants Propranolol In normal volunteers there was no clinically significant pharmacokinetic or pharmacodynamic interaction with concomitant administration of single doses of lovastatin and propranolol Digoxin In patients with hypercholesterolemia concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations Oral Hypoglycemic Agents In pharmacokinetic studies of MEVACOR in hypercholesterolemic noninsulin dependent diabetic patients there was no drug interaction with glipizide or with chlorpropamide There have been rare reports of significant respiratory depression stupor and or hypotension with the concomitant use of loxapine and lorazepam The risk of using loxapine in combination with CNS active drugs has not been systematically evaluated Therefore caution is advised if the concomitant administration of loxapine and CNS active drugs is required The absorption of lymecycline may be affected by the simultaneous administration of indigestion remedies iron or zinc supplements Oral contraceptives may be less effective while you are taking lymecycline Warfarin Meclofenamate sodium enhances the effect of warfarin Therefore when meclofenamate sodium is given to a patient receiving warfarin the dosage of warfarin should be reduced to prevent excessive prolongation of the prothrombin time Aspirin Concurrent administration of aspirin may lower meclofenamate sodium plasma levels possibly by competing for protein binding sites The urinary excretion of meclofenamate sodium is unaffected by aspirin indicating no change in meclofenamate sodium absorption Meclofenamate sodium does not affect serum salicylate levels Greater fecal blood loss results from concomitant administration of both drugs than from either drug alone Propoxyphene The concurrent administration of propoxyphene hydrochloride does not affect the bioavailability of meclofenamate sodium Antacids Concomitant administration of aluminum and magnesium hydroxides does not interfere with absorption of meclofenamate sodium Aspirin As with other NSAIDs concomitant administration of Ponstel and aspirin is not generally recommended because of the potential of increased adverse effects Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices This may indicate that they could enhance the toxicity of methotrexate Caution should be used when NSAIDs are administered concomitantly with methotrexate ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors Furosemide Clinical studies as well as post marketing observations have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients This response has been attributed to inhibition of renal prostaglandin synthesis During concomitant therapy of Ponstel with furosemide the patient should be observed closely for signs of renal failure as well as to assure diuretic efficacy Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance The mean minimum lithium concentration increased 15 and the renal clearance was decreased by approximately 20 These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID Thus when NSAIDs and lithium are administered concurrently subjects should be observed carefully for signs of lithium toxicity Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone Antacids In a single dose study n 6 ingestion of an antacid containing 1 7 gram of magnesium hydroxide with 500 mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125 and 36 respectively A number of compounds are inhibitors of CYP2C9 including fluconazole lovastatin and trimethoprim Drug interaction studies of mefenamic acid and these compounds have not been conducted The possibility of altered safety and efficacy should be considered when Ponstel is used concomitantly with these drugs Drug drug interactions with Mefloquine have not been explored in detail There is one report of cardiopulmonary arrest with full recovery in a patient who was taking a beta blocker propranolol The effects of Mefloquineuine on the compromised cardiovascular system have not been evaluated The benefits of Mefloquine therapy should be weighed against the possibility of adverse effects in patients with cardiac disease Because of the danger of a potentially fatal prolongation of the QTc interval halofantrine must not be given simultaneously with or subsequent to Mefloquine Concomitant administration of Mefloquine and other related compounds eg quinine quinidine and chloroquine may produce electrocardiographic abnormalities and increase the risk of convulsions If these drugs are to be used in the initial treatment of severe malaria Mefloquine administration should be delayed at least 12 hours after the last dose There is evidence that the use of halofantrine after Mefloquineuine causes a significant lengthening of the QTc interval Clinically significant QTc prolongation has not been found with Mefloquineuine alone This appears to be the only clinically relevant interaction of this kind with Mefloquine although theoretically coadministration of other drugs known to alter cardiac conduction eg anti arrhythmic or beta adrenergic blocking agents calcium channel blockers antihistamines or H1 blocking agents tricyclic antidepressants and phenothiazines might also contribute to a prolongation of the QTc interval There are no data that conclusively establish whether the concomitant administration of Mefloquineuine and the above listed agents has an effect on cardiac function In patients taking an anticonvulsant eg valproic acid carbamazepine phenobarbital or phenytoin the concomitant use of Mefloquine may reduce seizure control by lowering the plasma levels of the anticonvulsant Therefore patients concurrently taking antiseizure medication and Mefloquine should have the blood level of their antiseizure medication monitored and the dosage adjusted appropriately When Mefloquine is taken concurrently with oral live typhoid vaccines attenuation of immunization cannot be excluded Vaccinations with attenuated live bacteria should therefore be completed at least 3 days before the first dose of Mefloquine No other drug interactions are known Nevertheless the effects of Mefloquine on travelers receiving comedication particularly diabetics or patients using anticoagulants should be checked before departure In clinical trials the concomitant administration of sulfadoxine and pyrimethamine did not alter the adverse reaction profile Broad Spectrum Antibiotics Broad spectrum antibiotics may sterilize the bowel and decrease the vitamin K contribution to the body by the intestinal microflora Cephalosporins Cephalosporins containing side chains of N methylthiotetrazole cefmenoxime cefoperazone cefotetan cefamandole latamoxef or methylthiadiazole cefazolin can cause vitamin K deficiency and hypoprothrombinemia These cephalosporins are inhibitors of hepatic vitamin K epoxide reductase Cholestyramine Concomitant intake of cholestyramine and vitamin K may reduce the absorption of vitamin K Colestipol Concomitant intake of colestipol and vitamin K may reduce the absorption of vitamin K Mineral Oil Concomitant intake of mineral oil and vitamin K may reduce the absorption of vitamin K Orlistat Orlistat may decrease the absorption of vitamin K Salicylates Salicylates in large doses may inhibit vitamin K epoxide reductase resulting in vitamin K deficiency Warfarin Vitamin K can antagonize the effect of warfarin Nabilone should be administered with caution to patients who are taking other psychoactive drugs or CNS depressants including alcohol barbiturates and narcotic analgesics or to those with a history of psychiatric disorder including manic depressive illness and schizophrenia Nabilone has been shown to have an additive CNS depressant effect when given with either diazepam secobarbitone sodium alcohol or codeine In vitro studies have shown that because of its affinity for protein 6MNA may displace other protein bound drugs from their binding site Caution should be exercised when administering nabumetone with warfarin since interactions have been seen with other NSAIDs Concomitant administration of an aluminum containing antacid had no significant effect in the bioavailability of 6MNA When administered with food or milk there is more rapid absorption however the total amount of 6MNA in the plasma is unchanged When administered concurrently the following drugs may interact with beta adrenergic receptor blocking agents Anesthetics general exaggeration of the hypotension induced by general anesthetics Antidiabetic drugs oral agents and insulin hypoglycemia or hyperglycemia adjust dosage of antidiabetic drug accordingly Catecholamine depleting drugs e g reserpine additive effect monitor closely for evidence of hypotension and or excessive bradycardia e g vertigo syncope postural hypotension Response to Treatment for Anaphylactic Reaction While taking beta blockers patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge either accidental diagnostic or therapeutic Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction No pharmacokinetic based drug drug interaction studies have been conducted with SYNAREL However because nafarelin acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P 450 enzymes and the drug is only about 80 bound to plasma proteins at 4 C drug interactions would not be expected to occur Tetracycline a bacteriostatic antibiotic may antagonize the bactericidal effect of penicillin and concurrent use of these drugs should be avoided No specific information available Elevated plasma levels of theophylline have been reported with concomitant quinolone use There have been reports of theophylline related side effects in patients on concomitant therapy with quinolones and theophylline Therefore monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required Quinolones have been shown to interfere with the metabolism of caffeine This may lead to reduced clearance of caffeine and the prolongation of its plasma half life Quinolones including nalidixic acid may enhance the effects of the oral anticoagulant warfarin or its derivatives When these products are administered concomitantly prothrombin time or other suitable coagulation test should be closely monitored Nitrofurantoin interferes with the therapeutic action of nalidixic acid Antacids containing magnesium aluminum or calcium sucralfate or divalent or trivalent cations such as iron multivitamins containing zinc and Videx Didanosine chewable buffered tablets or the pediatric powder for oral solution may substantially interfere with the absorption of quinolones resulting in systemic levels considerably lower than desired These agents should not be taken within the two hour period before or within the two hour period after nalidixic acid administration Elevated serum levels of cyclosporine have been reported with the concomitant use of some quinolones and cyclosporine Therefore cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly Studies to evaluate possible interactions between REVIA and drugs other than opiates have not been performed Consequently caution is advised if the concomitant administration of REVIA and other drugs is required The safety and efficacy of concomitant use of REVIA and disulfiram is unknown and the concomitant use of two potentially hepatotoxic medications is not ordinarily recommended unless the probable benefits outweigh the known risks Lethargy and somnolence have been reported following doses of REVIA and thioridazine Patients taking REVIA may not benefit from opioid containing medicines such as cough and cold preparations antidiarrheal preparations and opioid analgesics In an emergency situation when opioid analgesia must be administered to a patient receiving REVIA the amount of opioid required may be greater than usual and the resulting respiratory depression may be deeper and more prolonged The use of NSAIDs in patients who are receiving ACE inhibitors may potentiate renal disease states In vitro studies have shown that naproxen anion because of its affinity for protein may displace from their binding sites other drugs which are also albumin bound Theoretically the naproxen anion itself could likewise be displaced Short term controlled studies failed to show that taking the drug significantly affects prothrombin times when administered to individuals on coumarin type anticoagulants Caution is advised nonetheless since interactions have been seen with other nonsteroidal agents of this class Similarly patients receiving the drug and a hydantoin sulfonamide or sulfonylurea should be observed for signs of toxicity to these drugs Concomitant administration of naproxen and aspirin is not recommended because naproxen is displaced from its binding sites during the concomitant administration of aspirin resulting in lower plasma concentrations and peak plasma levels The natriuretic effect of furosemide has been reported to be inhibited by some drugs of this class Inhibition of renal lithium clearance leading to increases in plasma lithium concentrations has also been reported Naproxen and other NSAIDs can reduce the antihypertensive effect of propranolol and other beta blockers Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half life significantly Caution should be used if naproxen is administered concomitantly with methotrexate Naproxen naproxen sodium and other NSAIDs have been reported to reduce the tubular secretion of methotrexate in an animal model possibly increasing the toxicity of methotrexate Drug Laboratory Test Interactions Naproxen may decrease platelet aggregation and prolong bleeding time This effect should be kept in mind when bleeding times are determined The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and or its metabolites with m dinitrobenzene used in this assay Although 17 hydroxy corticosteroid measurements Porter Silber test do not appear to be artifactually altered it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter Silber test is to be used Naproxen may interfere with some urinary assays of 5 hydroxy indoleacetic acid 5HIAA Ergot containing drugs have been reported to cause prolonged vasospastic reactions Because there is a theoretical basis that these effects may be additive use of ergotamine containing or ergot type medications like dihydroergotamine or methysergide and naratriptan within 24 hours is contraindicated The administration of naratriptan with other 5 HT1 agonists has not been evaluated in migraine patients Because their vasospastic effects may be additive coadministration of naratriptan and other 5 HT1 agonists within 24 hours of each other is not recommended Selective serotonin reuptake inhibitors SSRIs e g fluoxetine fluvoxamine paroxetine sertraline have been reported rarely to cause weakness hyperreflexia and incoordination when coadministered with 5 HTv agonists If concomitant treatment with naratriptan and an SSRI is clinically warranted appropriate observation of the patient is advised Drug Laboratory Test Interactions AMERGE Tablets are not known to interfere with commonly employed clinical laboratory tests After multiple dosing interferon beta 1a AVONEX 30 mcg IM once weekly reduced TYSABRI clearance by approximately 30 The similarity of the TYSABRI associated adverse event profile between Study 1 without co administered AVONEX and Study 2 with co administered AVONEX indicates that this alteration in clearance does not necessitate reduction of the TYSABRI dose to maintain safety General Results of studies in multiple sclerosis patients taking TYSABRI and concomitant interferon beta 1a AVONEX 30 mcg IM once weekly or glatiramer acetate were inconclusive with regard to the need for dose adjustment of the beta interferon or glatiramer acetate In vitro drug metabolism studies indicate that Starlix is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 70 and to a lesser extent CYP3A4 30 Starlix is a potential inhibitor of the CYP2C9 isoenzyme in vivo as indicated by its ability to inhibit the in vitro metabolism of tolbutamide Inhibition of CYP3A4 metabolic reactions was not detected in in vitro experiments Glyburide In a randomized multiple dose crossover study patients with Type 2 diabetes were administered 120 mg Starlix three times a day before meals for 1 day in combination with glyburide 10 mg daily There were no clinically relevant alterations in the pharmacokinetics of either agent Metformin When Starlix 120 mg three times daily before meals was administered in combination with metformin 500 mg three times daily to patients with Type 2 diabetes there were no clinically relevant changes in the pharmacokinetics of either agent Digoxin When Starlix 120 mg before meals was administered in combination with a single 1 mg dose of digoxin to healthy volunteers there were no clinically relevant changes in the pharmacokinetics of either agent Warfarin When healthy subjects were administered Starlix 120 mg three times daily before meals for four days in combination with a single dose of warfarin 30 mg on day 2 there were no alterations in the pharmacokinetics of either agent Prothrombin time was not affected Diclofenac Administration of morning and lunch doses of Starlix 120 mg in combination with a single 75 mg dose of diclofenac in healthy volunteers resulted in no significant changes to the pharmacokinetics of either agent Nateglinide is highly bound to plasma proteins 98 mainly albumin In vitro displacement studies with highly protein bound drugs such as furosemide propranolol captopril nicardipine pravastatin glyburide warfarin phenytoin acetylsalicylic acid tolbutamide and metformin showed no influence on the extent of nateglinide protein binding Similarly nateglinide had no influence on the serum protein binding of propranolol glyburide nicardipine warfarin phenytoin acetylsalicylic acid and tolbutamide in vitro However prudent evaluation of individual cases is warranted in the clinical setting Certain drugs including nonsteroidal anti inflammatory agents NSAIDs salicylates monoamine oxidase inhibitors and non selective beta adrenergic blocking agents may potentiate the hypoglycemic action of Starlix and other oral antidiabetic drugs Certain drugs including thiazides corticosteroids thyroid products and sympathomimetics may reduce the hypoglycemic action of Starlix and other oral antidiabetic drugs When these drugs are administered to or withdrawn from patients receiving Starlix the patient should be observed closely for changes in glycemic control In clinical studies Tilade has been co administered with other anti asthma medications including inhaled and oral bronchodilators and inhaled corticosteroids with no evidence of increased frequency of adverse events or laboratory abnormalities No formal drug drug interaction studies however have been conducted Nelfinavir is an inhibitor of CYP3A cytochrome P450 3A Coadministration of VIRACEPT and drugs primarily metabolized by CYP3A e g dihydropyridine calcium channel blockers may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects Nelfinavir is metabolized in proof by C P A Coadministration of VIRACEPT and drugs that induce CYP3A may decrease nelfinavir plasma concentrations and reduce its therapeutic effect Coadministration of VIRACEPT and drugs that inhibit CYP3A may increase nelfinavir plasma concentrations Based on known metabolic profiles clinically significant drug interactions are not expected between VIRACEPT and dapsone trimethoprim sulfamethoxazole clarithromycin erythromycin itraconazole or fluconazole Drugs That Should Not Be Coadministered With VIRACEPT Antiarrhythmics amiodarone quinidine Antihistamines astemizole terfenadine Antimigraine ergot derivatives Antimycobacterial agents rifampin Benzodiazepines midazolam triazolam GI motility agents cisapride Drugs Which Require a Dose Reduction When Coadminstered With VIRACEPT Antimycobacterial agents rifabutin This table is not all inclusive VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly Antihistamines Terfenadine Administration of terfenadine with VIRACEPT resulted in the appearance of unchanged terfenadine in plasma therefore VIRACEPT should not be administered concurrently with terfenadine because of the potential for serious and or life threatening cardiac arrhythmias Because a similar interaction is likely VIRACEPT should also not be administered concurrently with astemizole Anti HIV Protease Inhibitors Indinavir Coadministration of indinavir with VIRACEPT resulted in an 83 increase in nelfinavir plasma AUC and a 51 increase in indinavir plasma A C Currently there are no safety and efficacy data available from the use of this combination Ritonavir Coadministration of ritonavir with VIRACEPT resulted in a 152 increase in nelfinavir plasma AUC and very little change in ritonavir plasma A C Currently there are no safety and efficacy data available from the use of this combination Saquinavir Coadministration of saquinavir using an experimental soft gelatin capsule formulation of saquinavir 1200mg with VIRACEPT resulted in an 18 increase in nelfinavir plasma AUC and a 4 fold increase in saquinavir plasma A C If used in combination with saquinavir hard gelatin capsules at the recommended dose of 600 mg tid no dose adjustments are needed Currently there are no safety and efficacy data available from the use of this combination Antifungal Agents Ketoconazole Coadministration of ketoconazole with VIRACEPT resulted in a 35 increase in nelfinavir plasma A C This change was not considered clinically significant and no dose adjustment is needed when ketoconazole and VIRACEPT are coadministered Anti HIV Reverse Transcriptase Inhibitors Didanosine It is recommended that didanosine be administered on an empty stomach therefore nelfinavir should be administered with food one hour after or more than two hours before didanosine A dose adjustment is not needed when zidovudine is administered with VIRACEPT Little or no change in the pharmacokinetics of either drug was observed when VIRACEPT was coadministered with lamivudine or stavudine Antimycobacterial Agents Rifabutin Coadministration of rifabutin and VIRACEPT resulted in a 32 decrease in nelfinavir plasma AUC and a 207 increase in rifabutin plasma A C It is recommended that the dose of rifabutin be reduced to one half the usual dose when administered with VIRACEPT Rifampin Coadministration of rifampin and VIRACEPT resulted in an 82 decrease in nelfinavir plasma A C VIRACEPT and rifampin should not be coadministered Oral Contraceptives Ethinyl Estradiol and Norethindrone Coadministration of VIRACEPT with OVCON 35 resulted in a 47 decrease in ethinyl estradiol and an 18 decrease in norethindrone plasma concentrations Alternate or additional contraceptive measures should be used during therapy with VIRACEPT Caution should be taken in concurrent or serial use of other neurotoxic and or nephrotoxic drugs because of possible enhancement of the nephrotoxicity and or ototoxicity of neomycin Caution should also be taken in concurrent or serial use of other aminoglycosides and polymyxins because they may enhance neomycin s nephrotoxicity and or ototoxicity and potentiate neomycin sulfate neuromuscular blocking effects Oral neomycin inhibits the gastrointestinal absorption of penicillin V oral vitamin B 12 methotrexate and 5 fluorouracil The gastrointestinal absorption of digoxin also appears to be inhibited Therefore digoxin serum levels should be monitored Oral neomycin sulfate may enhance the effect of coumarin in anticoagulants by decreasing vitamin K availability Certain antibiotics especially neomycin streptomycin and kanamycin have a mild but definite nondepolarizing blocking action which may accentuate neuromuscular block These antibiotics should be used in the myasthenic patient only where definitely indicated and then careful adjustment should be made of adjunctive anticholinesterase dosage Local and some general anesthetics antiarrhythmic agents and other drugs that interfere with neuromuscular transmission should be used cautiously if at all in patients with myasthenia gravis the dose of Prostigmin may have to be increased accordingly No trials specifically examining potential drug interactions with Natrecor were conducted although many concomitant drugs were used in clinical trials No drug interactions were detected except for an increase in symptomatic hypotension in patients receiving oral ACE inhibitors The co administration of Natrecor with IV vasodilators such as nitroglycerin nitroprusside milrinone or IV ACE inhibitors has not been evaluated these drugs were not co administered with Natrecor in clinical trials Netilmicin should not be administered concomitantly with potent loop diuretics such as furosemide and ethacrynic acid as the potential for ototoxicity is enhanced by the combination Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes 3A4 and 2B6 Nevirapine is known to be an inducer of these enzymes As a result drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when coadministered with nevirapine The specific pharmacokinetic changes that occur with co administration of nevirapine and other drugs are listed in CLINICAL PHARMACOLOGY Table 1 Clinical comments about possible dosage modifications based on these pharmacokinetic changes are listed in Table 3 The data inTables 1 and 3 are based on the results of drug interaction studies conducted in HIV 1 seropositive subjects unless otherwise indicated In addition to established drug interactions there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system These potential drug interactions are listed in Table 4 Although specific drug interaction studies in HIV 1 seropositive subjects have not been conducted for the classes of drugs listed in Table 4 additional clinical monitoring may be warranted when co administering these drugs The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex As a result when giving these drugs concomitantly plasma warfarin levels may change with the potential for increases in coagulation time When warfarin is co administered with nevirapine anticoagulation levels should be monitored frequently Table 3 Established Drug Interactions Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment Clarithromycin Clarithromycin 14OH clarithromycin Clarithromycin exposure was significantly decreased by nevirapine however 14 OH metabolite concentrations were increased Because clarithromycin active metabolite has reduced activity against Mycobacteriumavium intracellulare complex overallactivity against this pathogen may bealtered Alternatives to clarithromycin such as azithromycin should be considered Efavirenz Efavirenz Appropriate doses for this combination are not established Ethinyl estradiol and Norethindrone Ethinyl estradiol Norethindrone Oral contraceptives and other hormonalmethods of birth control should not be usedas the sole method of contraception inwomen taking nevirapine since nevirapinemay lower the plasma levels of thesemedications An alternative or additional method of contraception is recommended Fluconazole Nevirapine Because of the risk of increased exposure tonevirapine caution should be used inconcomitant administration and patients should be monitored closely for nevirapine associated adverse events Indinavir Indinavir Appropriate doses for this combination arenot established but an increase in thedosage of indinavir may be required Ketoconazole Ketoconazole Nevirapine and ketoconazole should not beadministered concomitantly becausedecreases in ketoconazole plasmaconcentrations may reduce the efficacy of the drug Lopinavir Ritonavir Lopinavir A dose increase of lopinavir ritonavir to 533 133 mg twice daily with food isrecommended in combination with nevirapine Methadone Methadonea Methadone levels may be decreased increased dosages may be required to prevent symptoms of opiate withdrawal Methadone maintained patients beginning nevirapine therapy should be monitored forevidence of withdrawal and methadone dose should be adjusted accordingly Nelfinavir Nelfinavir M8 The appropriate dose for nelfinavir incombination with nevirapine with respectto safety and efficacy has not been established Rifabutin Rifabutin Rifabutin and its metabolite concentrationswere moderately increased Due to highintersubject variability however somepatients may experience large increases inrifabutin exposure and may be at higher riskfor rifabutin toxicity Therefore caution should be used in concomitant administration Rifampin Nevirapine Nevirapine and rifampin should not beadministered concomitantly becausedecreases in nevirapine plasmaconcentrations may reduce the efficacy ofthe drug Physicians needing to treatpatients co infected with tuberculosis andusing a nevirapine containing regimen mayuse rifabutin instead Saquinavir Saquinavir Appropriate doses for this combination arenot established but an increase in thedosage of saquinavir may be required aBased on reports of narcotic withdrawal syndrome in patients treated with nevirapine and methadone concurrently and evidence of decreased plasma concentrations of methadone Table 4 Potential Drug Interactions Use With Caution Dose Adjustment of Co administered Drug May Be Needed due to Possible Decrease in Clinical Effect Examples of Drugs in Which Plasma Concentrations May Be Decreased By Co administration With Nevirapine Drug Class Examples of Drugs Antiarrhythmics Amiodarone disopyramide lidocaine Anticonvulsants Carbamazepine clonazepam ethosuximide Antifungals Itraconazole Calcium channel blockers Diltiazem nifedipine verapamil Cancer chemotherapy Cyclophosphamide Ergot alkaloids Ergotamine Immunosuppressants Cyclosporin tacrolimus sirolimus Motility agents Cisapride Opiate agonists Fentanyl Examples of Drugs in Which Plasma Concentrations May Be Increased By Co administration With Nevirapine Antithrombotics Warfarin Potential effect on anticoagulation Monitoring of anticoagulation levels is recommended Fat redistribution Redistribution accumulation of body fat including central obesity dorsocervical fat enlargement buffalo hump peripheral wasting facial wasting breast enlargement and cushingoid appearance have been observed in patients receiving antiretroviral therapy The mechanism and long term consequences of these events are currently unknown A causal relationship has not been established Interactions for Vitamin B3 Niacin Antihypertensive Therapy Nicotinic acid may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension Aspirin Concomitant aspirin may decrease the metabolic clearance of nicotinic acid The clinical relevance of this finding is unclear Other Concomitant alcohol or hot drinks may increase the side effects of flushing and pruritus and should be avoided at the time of drug ingestion Beta Blockers In controlled clinical studies adrenergic beta receptor blockers have been frequently administered concomitantly with nicardipine HCl The combination is well tolerated Cimetidine Cimetidine increases nicardipine HCl plasma levels Patients receiving the two drugs concomitantly should be carefully monitored Digoxin Some calcium blockers may increase the concentration of digitalis preparations in the blood Nicardipine HCl usually does not alter the plasma levels of digoxin however serum digoxin levels should be evaluated after concomitant therapy with nicardipine HCl is initiated Maalox Coadministration of Maalox TC had no effect on nicardipine HCl absorption Even though such interactions were not seen during clinical studies with nicardipine HCl an increased volume of circulating fluids might be required if such an interaction were to occur Cyclosporine Concomitant administration of nicardipine and cyclosporine levels Plasma concentrations of cyclosporine should therefore be closely monitored and its dosage reduced accordingly in patients treated with nicardipine When therapeutic concentrations of furosemide propranolol dipyridamole warfarin quinidine or naproxen were added to human plasma in vitro the plasma protein binding of nicardipine HCl was not altered Physiological changes resulting from smoking cessation with or without nicotine replacement may alter the pharmacokinetics of certain concomitant medications such as tricyclic antidepressants and theophylline Doses of these and perhaps other medications may need to be adjusted in patients who successfully quit smoking Beta adrenergic Blocking Agents Experience in over 1400 patients in a non comparative clinical trial has shown that concomitant administration of nifedipine and beta blocking agents is usually well tolerated but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure severe hypotension or exacerbation of angina Long Acting Nitrates Nifedipine may be safely co administered with nitrates but there have been no controlled studies to evaluate the antianginal effectiveness of this combination Digitalis Immediate Release Capsules Since there have been isolated reports of patients with elevated digoxin levels and there is a possible interaction between digoxin and nifedipine it is recommended that digoxin levels be monitored when initiating adjusting and discontinuing nifedipine to avoid possible over or under digitalization Extended Release Tablets Administration of nifedipine with digoxin increased digoxin levels in 9 of 12 normal volunteers The average increase was 45 Another investigator found no increase in digoxin levels in 13 patients with coronary artery disease In an uncontrolled study of over 200 patients with congestive heart failure during which digoxin blood levels were not measured digitalis toxicity was not observed Since there have been isolated reports of patients with elevated digoxin levels it is recommended that digoxin levels be monitored when initiating adjusting and discontinuing nifedipine to avoid possible over or under digitalization Quinidine Immediate Release Capsules There have been rare reports of an interaction between quinidine and nifedipine with a decreased plasma level of quinidine Coumarin Anticoagulants There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered However the relationship to nifedipine therapy is uncertain Cimetidine A study in 6 healthy volunteers has shown a significant increase in peak nifedipine plasma levels 80 and area under the curve 74 after a 1 week course of cimetidine at 1000 mg per day and nifedipine at 40 mg per day Ranitidine produced smaller non significant increases The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P 450 the enzyme system probably responsible for the first pass metabolism of nifedipine If nifedipine therapy is initiated in a patient currently receiving cimetidine cautious titration is advised In vitro nilutamide has been shown to inhibit the activity of liver cytochrome P 450 isoenzymes and therefore may reduce the metabolism of compounds requiring these systems Consequently drugs with a low therapeutic margin such as vitamin K antagonists phenytoin and theophylline could have a delayed elimination and increases in their serum half life leading to a toxic level The dosage of these drugs or others with a similar metabolism may need to be modified if they are administered concomitantly with nilutamide For example when vitamin K antagonists are administered concomitantly with nilutamide prothrombin time should be carefully monitored and if necessary the dosage of vitamin K antagonists should be reduced It is possible that the cardiovascular action of other calcium channel blockers could be enhanced by the addition of Nimotop In Europe Nimotop was observed to occasionally intensify the effect of antihypertensive compounds taken concomitantly by patients suffering from hypertension this phenomenon was not observed in North American clinical trials A study in eight healthy volunteers has shown a 50 increase in mean peak nimodipine plasma concentrations and a 90 increase in mean area under the curve after a one week course of cimetidine at 1 000 mg day and nimodipine at 90 mg day This effect may be mediated by the known inhibition of hepatic cytochrome P 450 by cimetidine which could decrease first pass metabolism of nimodipine A 30 to 45 increase in AUC and Cmax of nisoldipine was observed with concomitant administration of cimetidine 400 mg twice daily Ranitidine 150 mg twice daily did not interact significantly with nisoldipine AUC was decreased by 15 20 No pharmacodynamic effects of either histamine H2 receptor antagonist were observed Coadministration of phenytoin with 40 mg SULAR tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels Coadministration of SULAR with phenytoin or any known CYP3A4 inducer should be avoided and alternative antihypertensive therapy should be considered Pharmacokinetic interactions between nisoldipine and beta blockers atenolol propranolol were variable and not significant Propranolol attenuated the heart rate increase following administration of immediate release nisoldipine The blood pressure effect of SULAR tended to be greater in patients on atenolol than in patients on no other antihypertensive therapy Quinidine at 648 mg bid decreased the bioavailability AUC of nisoldipine by 26 but not the peak concentration The immediate release but not the coat core formulation of nisoldipine increased plasma quinidine concentrations by about 20 This interaction was not accompanied by ECG changes and its clinical significance is not known No significant interactions were found between nisoldipine and warfarin or digoxin Tizoxanide is highly bound to plasma protein 99 9 Therefore caution should be used when administering nitazoxanide concurrently with other highly plasma protein bound drugs with narrow therapeutic indices as competition for binding sites may occur e g warfarin In vitro metabolism studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes Although no drug drug interaction studies have been conducted in vivo it is expected that no significant interaction would occur when nitazoxanide is co administered with drugs that either are metabolized by or inhibit cytochrome P450 enzymes No formal drug interaction studies have been performed and a clinically significant interaction with other medications used in the treatment of hypoxic respiratory failure cannot be excluded based on the available data INOmax has been administered with tolazoline dopamine dobutamine steroids surfactant and high frequency ventilation Although there are no study data to evaluate the possibility nitric oxide donor compounds including sodium nitroprusside and nitroglycerin may have an additive effect with INOmax on the risk of developing methemoglobinemia An association between prilocaine and an increased risk of methaemoglobinaemia particularly in infants has specifically been described in a literature case report This risk is present whether the drugs are administered as oral parenteral or topical formulations Antacids containing magnesium trisilicate when administered concomitantly with nitrofurantoin reduce both the rate and extent of absorption The mechanism for this interaction probably is adsorption of nitrofurantoin onto the surface of magnesium trisilicate Uricosuric drugs such as probenecid and sulfinpyrazone can inhibit renal tubular secretion of nitrofurantoin The resulting increase in nitrofurantoin serum levels may increase toxicity and the decreased urinary levels could lessen its efficacy as a urinary tract antibacterial Drug Laboratory Test Interactions As a result of the presence of nitrofurantoin a false positive reaction for glucose in the urine may occur This has been observed with Benedict s and Fehling s solutions but not with the glucose enzymatic test The vasodilating effects of nitroglycerin may be additive with those of other vasodilators Alcohol in particular has been found to exhibit additive effects of this variety Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination Dose adjustments of either class of agents may be necessary The hypotensive effect of sodium nitroprusside is augmented by that of most other hypotensive drugs including ganglionic blocking agents negative inotropic agents and inhaled anesthetics No interactions have been observed between nizatidine and theophylline chlordiazepoxide lorazepam lidocaine phenytoin and warfarin Nizatidine does not inhibit the cytochrome P 450 linked drug metabolizing enzyme system therefore drug interactions mediated by inhibition of hepatic metabolism are not expected to occur In patients given very high doses 3900 mg of aspirin daily increases in serum salicylate levels were seen when nizatidine 150 mg b i d was administered concurrently The effectiveness of progestin only pills is reduced by hepatic enzyme inducing drugs such as the anticonvulsants phenytoin carbamazepine and barbiturates and the antituberculosis drug rifampin No significant interaction has been found with broad spectrum antibiotics Elevated plasma levels of theophylline have been reported with concomitant quinolone use There have been reports of theophylline related side effects in patients on concomitant therapy with norfloxacin and theophylline Therefore monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin Therefore cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly Quinolones including norfloxacin may enhance the effects of oral anticoagulants including warfarin or its derivatives or similar agents When these products are administered concomitantly prothrombin time or other suitable coagulation tests should be closely monitored The concomitant administration of quinolones including norfloxacin with glyburide a sulfonylurea agent has on rare occasions resulted in severe hypoglycemia Therefore monitoring of blood glucose is recommended when these agents are co administered Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of Norfloxacin in the urinary tract Multivitamins or other products containing iron or zinc antacids or sucralfate should not be administered concomitantly with or within 2 hours of the administration of norfloxacin because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin Videx Didanosine chewable buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with or within 2 hours of the administration of norfloxacin because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin Some quinolones have also been shown to interfere with the metabolism of caffeine This may lead to reduced clearance of caffeine and a prolongation of its plasma half life Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin A similar association though less marked has been suggested with barbiturates phenylbutazone phenytoin sodium carbamazepine griseofulvin topiramate and possibly with ampicillin and tetracyclines 72 A possible interaction has been suggested with hormonal contraceptives and the herbal supplement St Johns Wort based on some reports of oral contraceptive users experiencing breakthrough bleeding shortly after starting St Johns Wort Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St Johns Wort Healthcare prescribers are advised to consult the package inserts of medication administered concomitantly with oral contraceptives Steady state serum concentrations of tricyclic antidepressants are reported to fluctuate significantly when cimetidine is either added or deleted from the drug regimen Serious anticholinergic symptoms severe dry mouth urinary retention blurred vision have been associated with elevations in the serum levels of tricyclic antidepressants when cimetidine is added to the drug regimen In addition higher than expected steady state serum concentrations of tricyclic antidepressants have been observed when therapy is initiated in patients already taking cimetidine In well controlled patients undergoing concurrent therapy with cimetidine a decrease in the steady state serum concentrations of tricyclic antidepressants may occur when cime tidine therapy is discontinued The therapeutic efficacy of tricyclic antidepressants may be compromised in these patients when cimetidine is discontinued Several of the tricyclic antidepressants have been cited in these reports There have been greater than 2 fold increases in previously stable plasma levels of other antidepressants including nortriptyline when fluoxetine hydrochloride has been administered in combination with these agents Fluoxetine and its active metabolite norfluoxe tine have long half lives 4 to 16 days for norfluoxetine that may affect strategies during conversion from one drug to the other Administration of reserpine during therapy with a tricyclic antidepressant has been shown to produce a stimulating effect in some depressed patients Close supervision and careful adjustment of the dosage are required when nortriptyline hydrochloride is used with other anticholinergic drugs or sympathomimetic drugs The patient should be informed that the response to alcohol may be exaggerated Drugs Metabolized by P450IID6 A subset 3 to 10 of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isoenzyme P450IID6 Such individuals are referred to as poor metabolizers of drugs such as debrisoquin dextromethorphan and the tricyclic antidepressants These individuals may have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses In addition certain drugs that are metabolized by this isoenzyme including many antidepressants tricyclic antidepressants selective serotonin reuptake inhibitors and others may inhibit the activity of this isoenzyme and thus may make normal metab olizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system leading to drug interactions Concomitant use of tricyclic antidepressants with other drugs metabolized by cytochrome P450IID6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug Therefore co administration of tricyclic antidepressants with other drugs that are metabolized by this isoenzyme including other antidepressants phenothiazines carbamazepine and Type 1C antiarrhythmics eg propafenone flecainide and encainide or that inhibit this enzyme eg quinidine should be approached with caution Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4 5 with potentially important effects on plasma concentrations of other drugs In addition several AED s that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs Results demonstrate that oxcarbazepine and its pharmacologically active 10 monohydroxy metabolite MHD have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated CYP1A2 CYP2A6 CYP2C9 CYP2D6 CYP2E1 CYP4A9 and CYP4A11 with the exception of CYP2C19 and CYP3A4 5 Although inhibition of CYP 3A4 5 by OXC and MHD did occur at high concentrations it is not likely to be of clinical significance The inhibition of CYP 2C19 by OXC and MHD however is clinically relevant In vitro the UDP glucuronyl transferase level was increased indicating induction of this enzyme Increases of 22 with MHD and 47 with oxcarbazepine were observed As MHD the predominant plasma substrate is only a weak inducer of UDP glucuronyl transferase it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP glucuronyl transferase e g valproic acid lamotrigine In addition oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family CYP3A4 and CYP3A5 responsible for the metabolism of dihydropyridine calcium antagonists and oral contraceptives resulting in a lower plasma concentration of these drugs As binding of MHD to plasma proteins is low 40 clinically significant interactions with other drugs through competition for protein binding sites are unlikely Antiepileptic drugs Potential interactions between Trileptal and other AEDs were assessed in clinical studies The effect of these interactions on mean AUCs and Cmin are summarized in Table 2 Table 2 Summary of AED interactions with Trileptal AED Co administered Dose of AED mg day Trileptal dose mg day Influence of Trileptal on AED Concentration Mean change 90 Confidence Interval Influence of AED On MHD Concentration Mean change 90 Confidence Interval Carbamazepine 400 2000 900 nc1 40 decrease CI 17 decrease 57 decrease Phenobarbital 100 150 600 1800 14 increase CI 2 increase 24 increase 25 decrease CI 12 decrease 51 decrease Phenytoin 250 500 600 1800 nc1 2 30 decrease CI 3 decrease 48 decrease 1200 2400 up to 40 increase3 CI 12 increase 60 increase Valproic acid 400 2800 600 1800 nc1 18 decrease CI 13 decrease 40 decrease 1 nc denotes a mean change of less than 10 2 Pediatrics 3 Mean increase in adults at high Trileptal doses In vivo the plasma levels of phenytoin increased by up to 40 when Trileptal was given at doses above 1200 mg day Therefore when using doses of Trileptal greater than 1200 mg day during adjunctive therapy a decrease in the dose of phenytoin may be required The increase of phenobarbital level however is small 15 when given with Trileptal Strong inducers of cytochrome P450 enzymes i e carbamazepine phenytoin and phenobarbital have been shown to decrease the plasma levels of MHD 29 40 No autoinduction has been observed with Trileptal Hormonal contraceptives Co administration of Trileptal with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components ethinylestradiol EE and levonorgestrel LNG The mean AUC values of EE were decreased by 48 90 CI 22 65 in one study and 52 90 CI 38 52 in another study 1 2 The mean AUC values of LNG were decreased by 32 90 CI 20 45 in one study and 52 90 CI 42 52 in another study Therefore concurrent use of Trileptal with hormonal contraceptives may render these contraceptives less effective Studies with other oral or implant contraceptives have not been conducted Calcium Antagonists After repeated co administration of Trileptal the AUC of felodipine was lowered by 28 90 CI 20 33 Verapamil produced a decrease of 20 90 CI 18 27 of the plasma levels of MHD Other drug interactions Cimetidine erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD Results with warfarin wshow no evidence of interaction with either single or repeated doses of Trileptal In a Phase I trial using escalating doses of TAXOL 110 200 mg m2 and cisplatin 50 or 75 mg m2 given as sequential infusions myelosuppression was more profound when TAXOL was given after cisplatin than with the alternate sequence ie TAXOL before cisplatin Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33 when TAXOL was administered following cisplatin The metabolism of TAXOL is catalyzed by cytochrome P450 isoen zymes CYP2C8 and CYP3A4 In the absence of formal clinical drug interaction studies caution should be exercised when administering TAXOL concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4 Potential interactions between TAXOL a substrate of CYP3A4 and protease inhibitors ritonavir saquinavir indinavir and nelfinavir which are substrates and or inhibitors of CYP3A4 have not been evaluated in clinical trials Reports in the literature suggest that plasma levels of doxorubicin and its active metabolite doxorubicinol may be increased when paclitaxel and doxorubicin are used in combination Hematology TAXOL therapy should not be administered to patients with baseline neutrophil counts of less than 1 500 cells mm3 In order to monitor the occurrence of myelotoxicity it is recommended that frequent peripheral blood cell counts be performed on all patients receiving TAXOL Patients should not be re treated with subsequent cycles of TAXOL until neutrophils recover to a level 1500 cells mm3 and platelets recover to a level 100 000 cells mm3 In the case of severe neutropenia 500 cells mm3 for seven days or more during a course of TAXOL therapy a 20 reduction in dose for subsequent courses of therapy is recommended For patients with advanced HIV disease and poor risk AIDS related Kaposi s sarcoma TAXOL at the recommended dose for this disease can be initiated and repeated if the neutrophil count is at least 1000 cells mm3 Hypersensitivity Reactions Patients with a history of severe hypersensitivity reactions to products containing Cremophor EL eg cyclosporin for injection concentrate and teniposide for injection concentrate should not be treated with TAXOL In order to avoid the occurrence of severe hypersensitivity reactions all patients treated with TAXOL should be premedicated with corticosteroids such as dexamethasone diphen hydramine and H2 antagonists such as cimetidine or ranitidine Minor symptoms such as flushing skin reactions dyspnea hypotension or tachycardia do not require interruption of therapy However severe reactions such as hypotension requiring treatment dyspnea requiring bronchodilators angioedema or generalized urticaria require immediate discontinuation of TAXOL and aggressive symptomatic therapy Patients who have developed severe hypersensitivity reactions should not be rechallenged with TAXOL Cardiovascular Hypotension bradycardia and hypertension have been observed during administration of TAXOL but generally do not require treatment Occasionally TAXOL infusions must be interrupted or discontinued because of initial or recurrent hypertension Frequent vital sign monitoring particularly during the first hour of TAXOL infusion is recommended Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities Nervous System Although the occurrence of peripheral neuropathy is frequent the development of severe symptomatology is unusual and requires a dose reduction of 20 for all subsequentcourses of TAXOL TAXOL contains dehydrated alcohol USP 396 mg mL consideration should be given to possible CNS and other effects of alcohol Hepatic There is limited evidence that the myelotoxicity of TAXOL may be exacerbated in patients with serum total bilirubin 2 times ULN Extreme caution should be exercised when administering TAXOL to such patients with dose reduction as recommended in DOSAGE AND ADMINISTRATION Table 17 InjectionSite Reaction Injection site reactions including reactions secondary to extravasation were usually mild and consisted of erythema tenderness skin discoloration or swelling at the injection site These reactions have been observed more frequently with the 24 hour infusion than with the 3 hour infusion Recurrence of skin reactions at a site of previous extravasation following administration of TAXOL at a different site ie recall has been reported rarely Rare reports of more severe events such as phlebitis cellulitis induration skin exfoliation necrosis and fibrosis have been received as part of the continuing surveillance of TAXOL safety In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days A specific treatment for extravasation reactions is unknown at this time Given the possibility of extravasation it is advisable to closely monitor the infusion site for possible infiltration during drug administration Treatment with PEGASYS once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25 increase in theophylline AUC Theophylline serum levels should be monitored and appropriate dose adjustments considered for patients given both theophylline and PEGASYS There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9 CYP 2C19 CYP 2D6 or CYP 3A4 In patients with chronic hepatitis C treated with PEGASYS in combination with COPEGUS PEGASYS treatment did not affect ribavirin distribution or clearance Nucleoside Analogues Didanosine Co administration of COPEGUS and didanosine is not recommended Reports of fatal hepatic failure as well as peripheral neuropathy pancreatitis and symptomatic hyperlactatemia lactic acidosis have been reported in clinical trials Stavudine and Zidovudine Ribavirin can antagonize the in vitro antiviral activity of stavudine and zidovudine against HIV Therefore concomitant use of ribavirin with either of these drugs should be avoided Carcinogenesis Mutagenesis Impairment of Fertility Carcinogenesis PEGASYS has not been tested for its carcinogenic potential Mutagenesis PEGASYS did not cause DNA damage when tested in the Ames bacterial mutagenicity assay and in the in vitro chromosomal aberration assay in human lymphocytes either in the presence or absence of metabolic activation Use With Ribavirin Ribavirin is genotoxic and mutagenic The carcinogenic potential of ribavirin has not been fully determined In a p53 mouse carcinogenicity study at doses up to the maximum tolerated dose of 100 mg kg day ribavirin was not oncogenic However on a body surface area basis this dose was 0 5 times maximum recommended human 24 hour dose of ribavirin A study in rats to assess the carcinogenic potential of ribavirin is ongoing Mutagenesis Impairment of Fertility PEGASYS may impair fertility in women Prolonged menstrual cycles and or amenorrhea were observed in female cynomolgus monkeys given sc injections of 600 m g kg dose 7200 m g m2 dose of PEGASYS every other day for one month at approximately 180 times the recommended weekly human dose for a 60 kg person based on body surface area Menstrual cycle irregularities were accompanied by both a decrease and delay in the peak 17b estradiol and progesterone levels following administration of PEGASYS to female monkeys A return to normal menstrual rhythm followed cessation of treatment Every other day dosing with 100m g kg 1200m g m2 PEGASYS equivalent to approximately 30 times the recommended human dose had no effects on cycle duration or reproductive hormone status The effects of PEGASYS on male fertility have not been studied However no adverse effects on fertility were observed in male Rhesus monkeys treated with non pegylated interferon alfa 2a for 5 months at doses up to 25 x 106 IU kg day Pregnancy Pregnancy Category C PEGASYS has not been studied for its teratogenic effect Non pegylated interferon alfa 2a treatment of pregnant Rhesus monkeys at approximately 20 to 500 times the human weekly dose resulted in a statistically significant increase in abortions No teratogenic effects were seen in the offspring delivered at term PEGASYS should be assumed to have abortifacient potential There are no adequate and well controlled studies of PEGASYS in pregnant women PEGASYS is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus PEGASYS is recommended for use in women of childbearing potential only when they are using effective contraception during therapy Pregnancy Category X Use With Ribavirin see CONTRAINDICATIONS Significant teratogenic and or embryocidal effects have been demonstrated in all animal species exposed to ribavirin COPEGUS therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment cessation such cases should be reported to the COPEGUS Pregnancy Registry at 1 800 526 6367 Nursing Mothers It is not known whether peginterferon or ribavirin or its components are excreted in human milk The effect of orally ingested peginterferon or ribavirin from breast milk on the nursing infant has not been evaluated Because of the potential for adverse reactions from the drugs in nursing infants a decision must be made whether to discontinue nursing or discontinue PEGASYS and COPEGUS treatment Pediatric Use The safety and effectiveness of PEGASYS alone or in combination with COPEGUS in patients below the age of 18 years have not been established PEGASYS contains benzyl alcohol Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in neonates and infants which are sometimes fatal Geriatric Use Younger patients have higher virologic response rates than older patients Clinical studies of PEGASYS alone or in combination with COPEGUS did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects Adverse reactions related to alpha interferons such as CNS cardiac and systemic eg flu like effects may be more severe in the elderly and caution should be exercised in the use of PEGASYS in this population PEGASYS and COPEGUS are excreted by the kidney and the risk of toxic reactions to this therapy may be greater in patients with impaired renal function Because elderly patients are more likely to have decreased renal function care should be taken in dose selection and it may be useful to monitor renal function PEGASYS should be used with caution in patients with creatinine clearance 50 mL min and COPEGUS should not be administered to patients with creatinine clearance 50 mL min Aminoglycosides The mixing of piperacillin with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside Vecuronium When used in the perioperative period piperacillin has been implicated in the prolongation of the neuromuscular blockade of vecuronium Caution is indicated when piperacillin is used perioperatively In one controlled clinical study the ureidopenicillins including piperacillin were reported to prolong the action of vecuronium Due to their similar mechanism of action it is expected that the neuromuscular blockade produced by any of the non depolarizing muscle relaxants could be prolonged in the presence of piperacillin Probenecid The oral combination of probenecid before intramuscular injection of PIPRACIL produces an increase in piperacillin peak serum level of about 30 Anticoagulants Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin oral anticoagulants or other drugs that may affect the blood coagulation system or the thrombocyte function Methotrexate Piperacillin sodium may reduce the excretion of methotrexate Therefore serum levels of methotrexate should be monitored in patients to avoid drug toxicity Drug Laboratory Test Interactions As with other penicillins the administration of PIPRACIL may result in a false positive reaction for glucose in the urine using a copper reduction method It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used There have been reports of positive test results using the Bio Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin tazobactam injection who were subsequently found to be free of Aspergillus infection Cross reactions with non Aspergillus polysaccharides and polyfuranoses with the Bio Rad Laboratories Platelia Aspergillus EIA test have been reported Therefore positive test results in patients receiving piperacillin should be interpreted cautiously and confirmed by other diagnostic methods Phenothiazines Taking piperazine and a phenothiazine together may increase the risk of convulsions seizures Pyrantel e g Antiminth Taking piperazine and pyrantel together may decrease the effects of piperazine ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of Angiotensin Converting Enzyme ACE inhibitors In patients with mild to moderate hypertension administration of 25 mg daily of VIOXX with the ACE inhibitor benazepril 10 to 40 mg for 4 weeks was associated with an average increase in mean arterial pressure of about 3 mm Hg compared to ACE inhibitor alone This interaction should be given consideration in patients taking VIOXX concomitantly with ACE inhibitors Aspirin Concomitant administration of low dose aspirin with VIOXX may result in an increased rate of GI ulceration or other complications compared to use of VIOXX alone In a 12 week endoscopy study conducted in OA patients there was no difference in the cumulative incidence of endoscopic gastroduodenal ulcers in patients taking low dose 81 mg enteric coated aspirin plus VIOXX 25 mg daily as compared to those taking ibuprofen 2400 mg daily alone Patients taking low dose aspirin plus ibuprofen were not studied At steady state VIOXX 50 mg once daily had no effect on the anti platelet activity of low dose 81 mg once daily aspirin as assessed by ex vivo platelet aggregation and serum TXB2 generation in clotting blood Because of its lack of platelet effects VIOXX is not a substitute for aspirin for cardiovascular prophylaxis Therefore in patients taking VIOXX antiplatelet therapies should not be discontinued and should be considered in patients with an indication for cardiovascular prophylaxis Prospective long term studies on concomitant administration of VIOXX and aspirin have not been conducted Cimetidine Co administration with high doses of cimetidine 800 mg twice daily increased the Cmax of rofecoxib by 21 the AUC0 120hr by 23 and the t1 2 by 15 These small changes are not clinically significant and no dose adjustment is necessary Digoxin Rofecoxib 75 mg once daily for 11 days does not alter the plasma concentration profile or renal elimination of digoxin after a single 0 5 mg oral dose Furosemide Clinical studies as well as post marketing observations have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients This response has been attributed to inhibition of renal prostaglandin synthesis Ketoconazole Ketoconazole 400 mg daily did not have any clinically important effect on the pharmacokinetics of rofecoxib Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance In post marketing experience there have been reports of increases in plasma lithium levels Thus when VIOXX and lithium are administered concurrently subjects should be observed carefully for signs of lithium toxicity Methotrexate VIOXX 12 5 25 and 50 mg each dose administered once daily for 7 days had no effect on the plasma concentration of methotrexate as measured by AUC0 24hr in patients receiving single weekly methotrexate doses of 7 5 to 20 mg for rheumatoid arthritis At higher than recommended doses VIOXX 75 mg administered once daily for 10 days increased plasma concentrations by 23 as measured by AUC0 24hr in patients receiving methotrexate 7 5 to 15 mg week for rheumatoid arthritis At 24 hours postdose a similar proportion of patients treated with methotrexate alone 94 and subsequently treated with methotrexate co administered with 75 mg of rofecoxib 88 had methotrexate plasma concentrations below the measurable limit 5 ng mL Standard monitoring of methotrexate related toxicity should be continued if VIOXX and methotrexate are administered concomitantly Oral Contraceptives Rofecoxib did not have any clinically important effect on the pharmacokinetics of ethinyl estradiol and norethindrone Prednisone prednisolone Rofecoxib did not have any clinically important effect on the pharmacokinetics of prednisolone or prednisone Rifampin Co administration of VIOXX with rifampin 600 mg daily a potent inducer of hepatic metabolism produced an approximate 50 decrease in rofecoxib plasma concentrations Therefore a starting daily dose of 25 mg of VIOXX should be considered for the treatment of osteoarthritis when VIOXX is co administered with potent inducers of hepatic metabolism Theophylline VIOXX 12 5 25 and 50 mg administered once daily for 7 days increased plasma theophylline concentrations AUC 0 by 38 to 60 in healthy subjects administered a single 300 mg dose of theophylline Adequate monitoring of theophylline plasma concentrations should be considered when therapy with VIOXX is initiated or changed in patients receiving theophylline These data suggest that rofecoxib may produce a modest inhibition of cytochrome P450 CYP 1A2 Therefore there is a potential for an interaction with other drugs that are metabolized by CYP 1A2 e g amitriptyline tacrine and zileuton Warfarin Anticoagulant activity should be monitored particularly in the first few days after initiating or changing VIOXX therapy in patients receiving warfarin or similar agents since these patients are at an increased risk of bleeding complications In single and multiple dose studies in healthy subjects receiving both warfarin and rofecoxib prothrombin time measured as INR was increased by approximately 8 to 11 In post marketing experience bleeding events have been reported predominantly in the elderly in association with increases in prothrombin time in patients receiving VIOXX concurrently with warfarin DRUG INTERACTIONS Several drug interaction studies have been completed with both INVIRASE and FORTOVASE Observations from drug interaction studies with FORTOVASE may not be predictive for INVIRASE Because ritonavir is coadministered prescribers should also refer to the prescribing information for ritonavir regarding drug interactions associated with this agent The metabolism of saquinavir is mediated by cytochrome P450 with the specific isoenzyme CYP3A4 responsible for 90 of the hepatic metabolism Additionally saquinavir is a substrate for P Glycoprotein Pgp Therefore drugs that affect CYP3A4 and or Pgp may modify the pharmacokinetics of saquinavir Similarly saquinavir might also modify the pharmacokinetics of other drugs that are substrates for CYP3A4 or Pgp Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed CONTRAINDICATIONS Additional drugs that are not recommended for coadministration with INVIRASE and ritonavir are included below These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy With some agents the metabolism may be induced resulting in decreased concentrations Drugs That Should Not Be Coadministered With INVIRASE Ritonavir Drug Class Drug Name Clinical Comment Antiarrhythmics Amiodarone bepridil flecainide propafenone quinidine CONTRAINDICATED due to potential for serious and or life threatening reactions Antihistamines astemizole terfenadine CONTRAINDICATED due to potential for serious and or life threatening cardiac arrhythmias Ergot Derivatives Dihydroergotamine ergonovine ergotamine methylergonovine CONTRAINDICATED due to potential for serious and life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues Antimycobacterial Agents rifampin CONTRAINDICATED since the coadministration of this product with saquinavir in an antiretroviral regimen reduces the plasma concentrations of saquinavir Garlic Capsules Garlic capsules should not be used while taking saquinavir FORTOVASE as the sole protease inhibitor due to the risk of decreased saquinavir plasma concentrations No data are available for the coadministration of INVIRASE ritonavir or FORTOVASE ritonavir and garlic capsules GI Motility Agent cisapride CONTRAINDICATED due to potential for serious and or life threatening reactions such as cardiac arrhythmias Herbal Products St John s wort hypericum perforatum WARNING coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors HMG CoA Reductase Inhibitors lovastatin simvastatin WARNING potential for serious reactions such as risk of myopathy including rhabdomyolysis Sedatives Hypnotics triazolam midazolam CONTRAINDICATED due to potential for serious and or life threatening reactions such as prolonged or increased sedation or respiratory depression No longer marketed in the US Drugs That Are Mainly Metabolized by CYP3A4 Although specific studies have not been performed coadministration with drugs that are mainly metabolized by CYP3A4 eg calcium channel blockers dapsone disopyramide quinine amiodarone quinidine warfarin tacrolimus cyclosporine ergot derivatives pimozide carbamazepine fentanyl alfentanyl alprazolam and triazolam may have elevated plasma concentrations when coadministered with saquinavir therefore these combinations should be used with caution Since INVIRASE is coadministered with ritonavir the ritonavir label should be reviewed for additional drugs that should not be coadministered Inducers of CYP3A4 Coadministration with compounds that are potent inducers of CYP3A4 eg phenobarbital phenytoin dexamethasone carbamazepine may result in decreased plasma levels of saquinavir Sulfacetamide preparations are incompatible with silver preparations Interations Sulfapyridine may interact with any of the following Acetaminophen e g Tylenol with long term high dose use or Amiodarone e g Cordarone or Anabolic steroids nandrolone e g Anabolin oxandrolone e g Anavar oxymetholone e g Anadrol stanozolol e g Winstrol or Androgens male hormones or Antithyroid agents medicine for overactive thyroid or Carbamazepine e g Tegretol or Carmustine e g BiCNU or Chloroquine e g Aralen or Dantrolene e g Dantrium or Daunorubicin e g Cerubidine or Disulfiram e g Antabuse or Divalproex e g Depakote or Estrogens female hormones or Etretinate e g Tegison or Gold salts medicine for arthritis or Hydroxychloroquine e g Plaquenil or Mercaptopurine e g Purinethol or Naltrexone e g Trexan with long term high dose use or Oral contraceptives birth control pills containing estrogen or Other anti infectives by mouth or by injection medicine for infection or Phenothiazines acetophenazine e g Tindal chlorpromazine e g Thorazine fluphenazine e g Prolixin mesoridazine e g Serentil perphenazine e g Trilafon prochlorperazine e g Compazine promazine e g Sparine promethazine e g Phenergan thioridazine e g Mellaril trifluoperazine e g Stelazine triflupromazine e g Vesprin trimeprazine e g Temaril or Plicamycin e g Mithracin or Valproic acid e g Depakene Use of sulfapyridine with these medicines may increase the chance of side effects affecting the liver Acetohydroxamic acid e g Lithostat or Dapsone or Furazolidone e g Furoxone or Nitrofurantoin e g Furadantin or Primaquine or Procainamide e g Pronestyl or Quinidine e g Quinidex or Quinine e g Quinamm or Sulfoxone e g Diasone or Vitamin K e g AquaMEPHYTON Synkayvite Use of sulfapyridine with these medicines may increase the chance of side effects affecting the blood Anticoagulants blood thinners or Ethotoin e g Peganone or Mephenytoin e g Mesantoin Use of sulfapyridine with these medicines may increase the chance of side effects of these medicines Antidiabetics oral diabetes medicine you take by mouth Use of oral antidiabetics with sulfapyridine may increase the chance of side effects affecting the blood and or the side effects or oral antidiabetics Methotrexate e g Mexate Use of methotrexate with sulfapyridine may increase the chance of side effects affecting the liver and or the side effects of methotrexate Methyldopa e g Aldomet Use of methyldopa with sulfapyridine may increase the chance of side effects affecting the liver and or the blood Phenytoin e g Dilantin Use of phenytoin with sulfapyridine may increase the chance of side effects affecting the liver and or the side effects of phenytoin In evaluating the potential for interactions among co administered antiepilepsy drugs AEDs whether or not an AED induces or does not induce metabolic enzymes is an important consideration Phenytoin phenobarbital and carbamazepine are ge nerally classified as enzyme inducers valproate and gabapentin are not GABITRIL is considered to be a non enzyme inducing AED The drug interaction data described in this section were obtained from studies involving either healthy subjects or patients with epilepsy Effects of GABITRIL on other Antiepilepsy Drugs AEDs Phenytoin Tiagabine had no effect on the steady state plasma concentrations of phenytoin in patients with epilepsy Carbamazepine Tiagabine had no effect on the steady state plasma concentrations of carbamazepine or its epoxide metabolite in patients with epilepsy Valproate Tiagabine causes a slight decrease about 10 in steady state valproate concentrations Phenobarbital or Primidone No formal pharmacokinetic studies have been performed examining the addition of tiagabine to regimens containing phenobarbital or primidone The addition of tiagabine in a limited number of patients in three well controlled studies caused no systematic changes in phenobarbital or primidone concentrations when compared to placebo Effects of other Antiepilepsy Drugs AEDs on GABITRIL Carbamazepine Population pharmacokinetic analyses indicate that tiagabine clearance is 60 greater in patients taking carbamazepine with or without other enzyme inducing AEDs Phenytoin Population pharmacokinetic analyses indicate that tiagabine clearance is 60 greater in patients taking phenytoin with or without other enzyme inducing AEDs Phenobarbital Primidone Population pharmacokinetic analyses indicate that tiagabine clearance is 60 greater in patients taking phenobarbital primidone with or without other enzyme inducing AEDs Valproate The addition of tiagabine to patients taking valproate chronically had no effect on tiagabine pharmacokinetics but valproate significantly decreased tiagabine binding in vitro from 96 3 to 94 8 which resulted in an increase of approximately 40 in the free tiagabine concentration The clinical relevance of this in vitro finding is unknown Interaction of GABITRIL with Other Drugs Cimetidine Co administration of cimetidine 800 mg day to patients taking tiagabine chronically had no effect on tiagabine pharmacokinetics Theophylline A single 10 mg dose of tiagabine did not affect the pharmacokinetics of theophylline at steady state Warfarin No significant differences were observed in the steady state pharmacokinetics of R warfarin or S warfarin with the addition of tiagabine given as a single dose Prothrombin times were not affected by tiagabine Digoxin Concomitant administration of tiagabine did not affect the steady state pharmacokinetics of digoxin or the mean daily trough serum level of digoxin Ethanol or Triazolam No significant differences were observed in the pharmacokinetics of triazolam 0 125 mg and tiagabine 10 mg when given together as a single dose The pharmacokinetics of ethanol were not affected by multiple dose administration of tiagabine Tiagabine has shown no clinically important potentiation of the pharmacodynamic effects of triazo lam or alcohol Because of the possible additive effects of drugs that may depress the nervous system ethanol or triazolam should be used cautiously in combination with tiagabine Oral Contraceptives Multiple dose administration of tiagabine 8 mg day monotherapy did not alter the pharmacokinetics of oral contraceptives in healthy women of childbearing age Antipyrine Antipyrine pharmacokinetics were not significantly different before and after tiagabine multiple dose regimens This indicates that tiagabine does not cause induction or inhibition of the hepatic microsomal enzyme systems responsible for the metabolism of antipyrine Interaction of GABITRIL with Highly Protein Bound Drugs In vitro data showed that tiagabine is 96 bound to human plasma protein and therefore has the potential to interact with other highly protein bound compounds Such an interaction can potentially lead to higher free fractions of either tiagabine or the competing drug The drug interaction studies with valdecoxib were performed both with valdecoxib and a rapidly hydrolyzed intravenous prodrug form The results from trials using the intravenous prodrug are reported in this section as they relate to the role of valdecoxib in drug interactions General In humans valdecoxib metabolism is predominantly mediated via CYP 3A4 and 2C9 with glucuronidation being a further 20 route of metabolism In vitro studies indicate that valdecoxib is a moderate inhibitor of CYP 2C19 IC50 6 g mL or 19 M and 2C9 IC50 13 g mL or 41 M and a weak inhibitor of CYP 2D6 IC50 31 g mL or 100 M and 3A4 IC50 44 g mL or 141 M Aspirin Concomitant administration of aspirin with valdecoxib may result in an increased risk of GI ulceration and complications compared to valdecoxib alone Because of its lack of anti platelet effect valdecoxib is not a substitute for aspirin for cardiovascular prophylaxis In a parallel group drug interaction study comparing the intravenous prodrug form of valdecoxib at 40 mg BID n 10 vs placebo n 9 valdecoxib had no effect on in vitro aspirin mediated inhibition of arachidonate or collagen stimulated platelet aggregation Methotrexate Valdecoxib 10 mg BID did not show a significant effect on the plasma exposure or renal clearance of methotrexate ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors This interaction should be given consideration in patients taking BEXTRA concomitantly with ACE inhibitors Furosemide Clinical studies as well as post marketing observations have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients This response has been attributed to inhibition of renal prostaglandin synthesis Anticonvulsants Phenytoin Steady state plasma exposure AUC of valdecoxib 40 mg BID for 12 days was decreased by 27 when co administered with multiple doses 300 mg QD for 12 days of phenytoin a CYP 3A4 inducer Patients already stabilized on valdecoxib should be closely monitored for loss of symptom control with phenytoin coadministration Valdecoxib did not have a statistically significant effect on the pharmacokinetics of phenytoin a CYP 2C9 and CYP 2C19 substrate Drug interaction studies with other anticonvulsants have not been conducted Routine monitoring should be performed when therapy with BEXTRA is either initiated or discontinued in patients on anticonvulsant therapy Dextromethorphan Dextromethorphan is primarily metabolized by CYP 2D6 and to a lesser extent by 3A4 Coadministration with valdecoxib 40 mg BID for 7 days resulted in a significant increase in dextromethorphan plasma levels suggesting that at these doses valdecoxib is a weak inhibitor of 2D6 Even so dextromethorphan plasma concentrations in the presence of high doses of valdecoxib were almost 5 fold lower than those seen in CYP 2D6 poor metabolizers suggesting that dose adjustment is not necessary Lithium Valdecoxib 40 mg BID for 7 days produced significant decreases in lithium serum clearance 25 and renal clearance 30 with a 34 higher serum exposure compared to lithium alone Lithium serum concentrations should be monitored closely when initiating or changing therapy with BEXTRA in patients receiving lithium Lithium carbonate 450 mg BID for 7 days had no effect on valdecoxib pharmacokinetics Warfarin The effect of valdecoxib on the anticoagulant effect of warfarin 1 8 mg day was studied in healthy subjects by coadministration of BEXTRA 40 mg BID for 7 days Valdecoxib caused a statistically significant increase in plasma exposures of R warfarin and S warfarin 12 and 15 respectively and in the pharmacodynamic effects prothrombin time measured as INR of warfarin While mean INR values were only slightly increased with coadministration of valdecoxib the day to day variability in individual INR values was increased Anticoagulant therapy should be monitored particularly during the first few weeks after initiating therapy with BEXTRA in patients receiving warfarin or similar agents Fluconazole and Ketoconazole Ketoconazole and fluconazole are predominantly CYP 3A4 and 2C9 inhibitors respectively Concomitant single dose administration of valdecoxib 20 mg with multiple doses of ketoconazole and fluconazole produced a significant increase in exposure of valdecoxib Plasma exposure AUC to valdecoxib was increased 62 when coadministered with fluconazole and 38 when coadministered with ketoconazole Glyburide Glyburide is a CYP 2C9 substrate Coadministration of valdecoxib 10 mg BID for 7 days with glyburide 5 mg QD or 10 mg BID did not affect the pharmacokinetics exposure of glyburide Coadministration of valdecoxib 40 mg BID day 1 and 40 mg QD days 2 7 with glyburide 5 mg QD did not affect either the pharmacokinetics exposure or the pharmacodynamics blood glucose and insulin levels of glyburide Coadministration of valdecoxib 40 mg BID day 1 and 40 mg QD days 2 7 with glyburide 10 mg glyburide BID resulted in 21 increase in glyburide AUC0 12 and a 16 increase in glyburide Cmax leading to a 16 decrease in glucose AUC0 24 Insulin parameters were not affected Because changes in glucose concentrations with valdecoxib coadministration were within the normal variability and individual glucose concentrations were above or near 70 mg dL dose adjustment for glyburide 5 mg QD and 10 mg BID with valdecoxib coadministration up to 40 mg QD is not indicated Coadministration of glyburide with doses higher than 40 mg valdecoxib e g 40 mg BID have not been studied Omeprazole Omeprazole is a CYP 3A4 substrate and CYP 2C19 substrate and inhibitor Valdecoxib steady state plasma concentrations 40 mg BID were not affected significantly with multiple doses of omeprazole 40 mg QD Coadministration with valdecoxib increased exposure of omeprazole AUC by 46 Drugs whose absorption is sensitive to pH may be negatively impacted by concomitant administration of omeprazole and valdecoxib However because higher doses up to 360 mg QD of omeprazole are tolerated in Zollinger Ellison ZE patients no dose adjustment for omeprazole is recommended at current doses Coadministration of valdecoxib with doses higher than 40 mg QD omeprazole has not been studied Oral Contraceptives Valdecoxib 40 mg BID did not induce the metabolism of the combination oral contraceptive norethindrone ethinyl estradiol 1 mg 35 mcg combination Ortho Novum 1 35 Coadministration of valdecoxib and Ortho Novum 1 35 increased the exposure of norethindrone and ethinyl estradiol by 20 and 34 respectively Although there is little risk for loss of contraceptive efficacy the clinical significance of these increased exposures in terms of safety is not known These increased exposures of norethindrone and ethinyl estradiol should be taken into consideration when selecting an oral contraceptive for women taking valdecoxib Diazepam Diazepam Valium is a CYP 3A4 and CYP 2C19 substrate Plasma exposure of diazepam 10 mg BID was increased by 28 following administration of valdecoxib 40 mg BID for 12 days while plasma exposure of valdecoxib 40 mg BID was not substantially increased following administration of diazepam 10 mg BID for 12 days Although the magnitude of changes in diazepam plasma exposure when coadministered with valdecoxib were not sufficient to warrant dosage adjustments patients may experience enhanced sedative side effects caused by increased exposure of diazepam under this circumstance Patients should be cautioned against engaging in hazardous activities requiring complete mental alertness such as operating machinery or driving a motor vehicle Effect of other drugs on Vardenafil In vitro studies Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 CYP isoforms 3A4 5 and to a lesser degree by CYP2C9 Therefore inhibitors of these enzymes are expected to reduce vardenafil clearance In vivo studies Cytochrome P450 Inhibitors Cimetidine 400 mg b i d had no effect on vardenafil bioavailability AUC and maximum concentration Cmax of vardenafil when co administered with 20 mg Vardenafil in healthy volunteers Erythromycin 500 mg t i d produced a 4 fold increase in vardenafil AUC and a 3 fold increase in Cmax when co administered with Vardenafil 5 mg in healthy volunteers It is recommended not to exceed a single 5 mg dose of Vardenafil in a 24 hour period when used in combination with erythromycin Ketoconazole 200 mg once daily produced a 10 fold increase in vardenafil AUC and a 4 fold increase in Cmax when co administered with Vardenafil 5 mg in healthy volunteers A 5 mg Vardenafil dose should not be exceeded when used in combination with 200 mg once daily ketoconazole Since higher doses of ketoconazole 400 mg daily may result in higher increases in Cmax and AUC a single 2 5 mg dose of Vardenafil should not be exceeded in a 24 hour period when used in combination with ketoconazole 400 mg daily HIV Protease Inhibitors Indinavir 800 mg t i d co administered with Vardenafil 10 mg resulted in a 16 fold increase in vardenafil AUC a 7 fold increase in vardenafil Cmax and a 2 fold increase in vardenafil half life It is recommended not to exceed a single 2 5 mg Vardenafil dose in a 24 hour period when used in combination with indinavir Ritonavir 600 mg b i d co administered with Vardenafil 5 mg resulted in a 49 fold increase in vardenafil AUC and a 13 fold increase in vardenafil Cmax The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir a highly potent CYP3A4 inhibitor which also inhibits CYP2C9 Ritonavir significantly prolonged the half life of vardenafil to 26 hours Consequently it is recommended not to exceed a single 2 5 mg Vardenafil dose in a 72 hour period when used in combination with ritonavir Other Drug Interactions No pharmacokinetic interactions were observed between vardenafil and the following drugs glyburide warfarin digoxin Maalox and ranitidine In the warfarin study vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters Effects of Vardenafil on other drugs In vitro studies Vardenafil and its metabolites had no effect on CYP1A2 2A6 and 2E1 Ki 100uM Weak inhibitory effects toward other isoforms CYP2C8 2C9 2C19 2D6 3A4 were found but Ki values were in excess of plasma concentrations achieved following dosing The most potent inhibitory activity was observed for vardenafil metabolite M1 which had a Ki of 1 4 uM toward CYP3A4 which is about 20 times higher than the M1 Cmax values after an 80 mg Vardenafil dose In vivo studies Nitrates The blood pressure lowering effects of sublingual nitrates 0 4 mg taken 1 and 4 hours after vardenafil and increases in heart rate when taken at 1 4 and 8 hours were potentiated by a 20 mg dose of Vardenafil in healthy middle aged subjects These effects were not observed when Vardenafil 20 mg was taken 24 hours before the NTG Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated and concomitant use of Vardenafil and nitrates is contraindicated Nifedipine Vardenafil 20 mg when co administered with slow release nifedipine 30 mg or 60 mg once daily did not affect the relative bioavailability AUC or maximum concentration Cmax of nifedipine a drug that is metabolized via CYP3A4 Nifedipine did not alter the plasma levels of Vardenafil when taken in combination In these patients whose hypertension was controlled with nifedipine Vardenafil 20 mg produced mean additional supine systolic diastolic blood pressure reductions of 6 5 mm Hg compared to placebo Alpha blockers When Vardenafil 10 or 20 mg was given to healthy volunteers either simultaneously or 6 hours after a 10 mg dose of terazosin significant hypotension developed in a substantial number of subjects With simultaneous dosing of Vardenafil 10 mg and terazosin 10 mg 6 of 8 subjects experienced a standing systolic blood pressure of less than 85 mm Hg With simultaneous dosing of Vardenafil 20 mg and terazosin 10 mg 2 of 9 subjects experienced a standing systolic blood pressure of less than 85 mm Hg When Vardenafil dosing was separated from terazosin 10 mg by 6 hours 7 of 28 subjects who received 20 mg of Vardenafil experienced a decrease in standing systolic blood pressure below 85 mm Hg In a similar study with tamsulosin in healthy volunteers 1 of 24 subjects dosed with Vardenafil 20 mg and tamsulosin 0 4 mg separated by 6 hours experienced a standing systolic blood pressure below 85 mm Hg Two of 16 subjects dosed simultaneously with Vardenafil 10 mg and tamsulosin 0 4 mg experienced a standing systolic blood pressure below 85 mm Hg The administration of lower doses of Vardenafil with alpha blockers has not been completely evaluated to determine if they can be safely administered together Based on these data Vardenafil should not be used in patients on alpha blocker therapy Ritonavir and indinavir Upon concomitant administration of 5 mg of Vardenafil with 600 mg BID ritonavir the Cmax and AUC of ritonavir were reduced by approximately 20 Upon administration of 10 mg of Vardenafil with 800 mg TID indinavir the Cmax and AUC of indinavir were reduced by 40 and 30 respectively Alcohol Alcohol 0 5 g kg body weight approximately 40 mL of absolute alcohol in a 70 kg person and vardenafil plasma levels were not altered when dosed simultaneously Vardenafil 20 mg did not potentiate the hypotensive effects of alcohol during the 4 hour observation period in healthy volunteers when administered with alcohol 0 5 g kg body weight Aspirin Vardenafil 10 mg and 20 mg did not potentiate the increase in bleeding time caused by aspirin two 81 mg tablets Other interactions Vardenafil had no effect on the pharmacodynamics of glyburide glucose and insulin concentrations and warfarin prothrombin time or other pharmacodynamic parameters Zidovudine There is no significant pharmacokinetic interaction between ZDV and zalcitabine which has been confirmed clinically Zalcitabine also has no significant effect on the intracellular phosphorylation of ZDV as shown in vitro in peripheral blood mononuclear cells or in two other cell lines U937 and Molt 4 In the same study it was shown that didanosine and stavudine had no significant effect on the intracellular phosphorylation of zalcitabine in peripheral blood mononuclear cells Lamivudine In vitro studies in peripheral blood mononuclear cells U937 and Molt 4 cells revealed that lamivudine significantly inhibited zalcitabine phosphorylation in a dose dependent manner Effects were already seen with doses corresponding to relevant plasma levels in humans and the intracellular phosphorylation of zalcitabine to its three metabolites including the active zalcitabine triphosphate metabolite was significantly inhibited Zalcitabine inhibited lamivudine phosphorylation at high concentration ratios 10 and 100 however it is considered to be unlikely that this decrease of phosphorylated lamivudine concentration is of clinical significance as lamivudine is a more efficient substrate for deoxycytidine kinase than zalcitabine These in vitro studies suggest that concomitant administration of zalcitabine and lamivudine in humans may result in sub therapeutic concentrations of active phosphorylated zalcitabine which may lead to a decreased antiretroviral effect of zalcitabine It is unknown how the effect seen in these in vitro studies translates into clinical consequences Concomitant use of zalcitabine and lamivudine is not recommended Saquinavir The combination of HIVID saquinavir and ZDV has been studied as triple combination in adults Pharmacokinetic data suggest that absorption metabolism and elimination of each of these drugs are unchanged when they are used together Drugs Associated With Peripheral Neuropathy The concomitant use of HIVID with drugs that have the potential to cause peripheral neuropathy should be avoided where possible Drugs that have been associated with peripheral neuropathy include antiretroviral nucleoside analogues chloramphenicol cisplatin dapsone disulfiram ethionamide glutethimide gold hydralazine iodoquinol isoniazid metronidazole nitrofurantoin phenytoin ribavirin and vincristine Concomitant use of HIVID with didanosine is not recommended Intravenous Pentamidine Treatment with HIVID should be interrupted when the use of a drug that has the potential to cause pancreatitis is required Death due to fulminant pancreatitis possibly related to intravenous pentamidine and HIVID has been reported If intravenous pentamidine is required to treat Pneumocystis carinii pneumonia treatment with HIVID should be interrupted Amphotericin Foscarnet and Aminoglycosides Drugs such as amphotericin foscarnet and aminoglycosides may increase the risk of developing peripheral neuropathy or other HIVID associated adverse events by interfering with the renal clearance of zalcitabine thereby raising systemic exposure Patients who require the use of one of these drugs with HIVID should have frequent clinical and laboratory monitoring with dosage adjustment for any significant change in renal function Probenecid or Cimetidine Concomitant administration of probenecid or cimetidine decreases the elimination of zalcitabine most likely by inhibition of renal tubular secretion of zalcitabine Patients receiving these drugs in combination with zalcitabine should be monitored for signs of toxicity and the dose of zalcitabine reduced if warranted Magnesium Aluminum containing Antacid Products Absorption of zalcitabine is moderately reduced approximately 25 when coadministered with magnesium aluminum containing antacid products The clinical significance of this reduction is not known hence zalcitabine is not recommended to be ingested simultaneously with magnesium aluminum containing antacids Metoclopramide Bioavailability is mildly reduced approximately 10 when zalcitabine and metoclopramide are coadministered Doxorubicin Doxorubicin caused a decrease in zalcitabine phosphorylation 50 inhibition of total phosphate formation in U937 Molt 4 cells Although there may be decreased zalcitabine activity because of lessened active metabolite formation the clinical relevance of these in vitro results are not known As with all drugs the potential exists for interaction with other drugs by a variety of mechanisms CNS Active Drugs Ethanol Sonata 10 mg potentiated the CNS impairing effects of ethanol 0 75 g kg on balance testing and reaction time for 1 hour after ethanol administration and on the digit symbol substitution test DSST symbol copying test and the variability component of the divided attention test for 2 5 hours after ethanol administration The potentiation resulted from a CNS pharmacodynamic interaction zaleplon did not affect the pharmacokinetics of ethanol Imipramine Coadministration of single doses of Sonata 20 mg and imipramine 75 mg produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration The interaction was pharmacodynamic with no alteration of the pharmacokinetics of either drug Paroxetine Coadministration of a single dose of Sonata 20 mg and paroxetine 20 mg daily for 7 days did not produce any interaction on psychomotor performance Additionally paroxetine did not alter the pharmacokinetics of Sonata reflecting the absence of a role of CYP2D6 in zaleplon s metabolism Thioridazine Coadministration of single doses of Sonata 20 mg and thioridazine 50 mg produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration The interaction was pharmacodynamic with no alteration of the pharmacokinetics of either drug Venlafaxine Coadministration of a single dose of zaleplon 10 mg and multiple doses of venlafaxine ER extended release 150 mg did not result in any significant changes in the pharmacokinetics of either zaleplon or venlafaxine In addition there was no pharmacodynamic interaction as a result of coadministration of zaleplon and venlafaxine ER Promethazine Coadministration of a single dose of zaleplon and promethazine 10 and 25 mg respectively resulted in a 15 decrease in maximal plasma concentrations of zaleplon but no change in the area under the plasma concentration time curve However the pharmacodynamics of coadministration of zaleplon and promethazine have not been evaluated Caution should be exercised when these 2 agents are coadministered Drugs That Induce CYP3A4 Rifampin CYP3A4 is ordinarily a minor metabolizing enzyme of zaleplon Multiple dose administration of the potent CYP3A4 inducer rifampin 600 mg every 24 hours q24h for 14 days however reduced zaleplon Cmax and AUC by approximately 80 The coadministration of a potent CYP3A4 enzyme inducer although not posing a safety concern thus could lead to ineffectiveness of zaleplon An alternative non CYP3A4 substrate hypnotic agent may be considered in patients taking CYP3A4 inducers such as rifampin phenytoin carbamazepine and phenobarbital Drugs That Inhibit CYP3A4 CYP3A4 is a minor metabolic pathway for the elimination of zaleplon because the sum of desethylzaleplon formed via CYP3A4 in vitro and its metabolites 5 oxo desethylzaleplon and 5 oxo desethylzaleplon glucuronide account for only 9 of the urinary recovery of a zaleplon dose Coadministration of single oral doses of zaleplon with erythromycin 10 mg and 800 mg respectively a strong selective CYP3A4 inhibitor produced a 34 increase in zaleplons maximal plasma concentrations and a 20 increase in the area under the plasma concentration time curve The magnitude of interaction with multiple doses of erythromycin is unknown Other strong selective CYP3A4 inhibitors such as ketoconazole can also be expected to increase the exposure of zaleplon A routine dosage adjustment of zaleplon is not considered necessary Drugs That Inhibit Aldehyde Oxidase The aldehyde oxidase enzyme system is less well studied than the cytochrome P450 enzyme system Diphenhydramine Diphenhydramine is reported to be a weak inhibitor of aldehyde oxidase in rat liver but its inhibitory effects in human liver are not known There is no pharmacokinetic interaction between zaleplon and diphenhydramine following the administration of a single dose 10 mg and 50 mg respectively of each drug However because both of these compounds have CNS effects an additive pharmacodynamic effect is possible Drugs That Inhibit Both Aldehyde Oxidase and CYP3A4 Cimetidine Cimetidine inhibits both aldehyde oxidase in vitro and CYP3A4 in vitro and in vivo the primary and secondary enzymes respectively responsible for zaleplon metabolism Concomitant administration of Sonata 10 mg and cimetidine 800 mg produced an 85 increase in the mean Cmax and AUC of zaleplon An initial dose of 5 mg should be given to patients who are concomitantly being treated with cimetidine Drugs Highly Bound to Plasma Protein Zaleplon is not highly bound to plasma proteins fraction bound 60 15 therefore the disposition of zaleplon is not expected to be sensitive to alterations in protein binding In addition administration of Sonata to a patient taking another drug that is highly protein bound should not cause transient increase in free concentrations of the other drug Drugs with a Narrow Therapeutic Index Digoxin Sonata 10 mg did not affect the pharmacokinetic or pharmacodynamic profile of digoxin 0 375 mg q24h for 8 days Warfarin Multiple oral doses of Sonata 20 mg q24h for 13 days did not affect the pharmacokinetics of warfarin R or S enantiomers or the pharmacodynamics prothrombin time following a single 25 mg oral dose of warfarin Drugs That Alter Renal Excretion Ibuprofen Ibuprofen is known to affect renal function and consequently alter the renal excretion of other drugs There was no apparent pharmacokinetic interaction between zaleplon and ibuprofen following single dose administration 10 mg and 600 mg respectively of each drug This was expected because zaleplon is primarily metabolized and renal excretion of unchanged zaleplon accounts for less than 1 of the administered dose