blets. these drugs should be used with caution when coadministered with ketoconazole tablets: ketoconazole tablets should be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity. acid neutralizing medicines (e.g. aluminum hydroxide) should be administered at least 1 hour before or 2 hours after the intake of ketoconazole tablets. upon coadministration, the antifungal activity should be monitored and the ketoconazole tablets dose increased as deemed necessary. coadministration of ketoconazole tablets with potent enzyme inducers of cyp3a4 may decrease the bioavailability of ketoconazole to such an extent that efficacy may be reduced. examples include: antibacterials: isoniazid, rifabutin (see also under ' drugs that may have their plasma concentrations increased '), rifampicin. anticonvulsants: carbamazepine (see also under ' drugs that may have their plasma concentrations increased '), phenytoin. antivirals: efavirenz, nevirapine. therefore, administration of potent enzyme inducers of cyp3a4 with ketoconazole tablets is not recommended. the use of these drugs should be avoided from 2 weeks before and during treatment with ketoconazole tablets, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy. upon coadministration, the antifungal activity should be monitored and the ketoconazole tablets dose increased as deemed necessary. drugs that may increase ketoconazole plasma concentrations potent inhibitors of cyp3a4 (e.g. antivirals such as ritonavir, ritonavir-boosted darunavir and ritonavir-boosted fosamprenavir) may increase the bioavailability of ketoconazole. these drugs should be used with caution when coadministered with ketoconazole tablets. patients who must take ketoconazole tablets concomitantly with potent inhibitors of cyp3a4 should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of ketoconazole, and the ketoconazole tablets dose should be decreased as deemed necessary. when appropriate, ketoconazole plasma concentrations should be measured. drugs that may have their plasma concentrations increased by ketoconazole ketoconazole can inhibit the metabolism of drugs metabolized by cyp3a4 and can inhibit the drug transport by p-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with ketoconazole. these elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. cyp3a4-metabolized drugs known to prolong the qt interval may be contraindicated with ketoconazole tablets, since the combination may lead to ventricular tachyarrhythmias, including occurrences of torsade de pointes, a potentially fatal arrhythmia. examples of drugs that may have their plasma concentrations increased by ketoconazole presented by drug class with advice regarding coadministration with ketoconazole tablets: drug class contraindicated not recommended use with caution comments under no circumstances should the drug be coadministered with ketoconazole tablets, and up to one week after discontinuation of treatment with ketoconazole. the use of the drug should be avoided during and up to one week after discontinuation of treatment with ketoconazole tablets, unless the benefits outweigh the potentially increased risks of side effects. if coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage should be reduced or interrupted as deemed necessary. when appropriate, plasma concentrations should be measured. the label of the coadministered drug should be consulted for information on dose adjustment and adverse effects. careful monitoring is recommended when the drug is coadministered with ketoconazole tablets. upon coadministration, patients should be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage should be reduced as deemed necessary. when appropriate, plasma concentrations should be measured. the label of the coadministered drug should be consulted for information on dose adjustment and adverse effects. alpha blockers tamsulosin analgesics methadone alfentanil, buprenorphine iv and sublingual, fentanyl, oxycodone, sufentanil methadone: the potential increase in plasma concentrations of methadone when coadministered with ketoconazole tablets may increase the risk of serious cardiovascular events including qt prolongation and torsade de pointes, or respiratory or cns depression. [see contraindications .] fentanyl: the potential increase in plasma concentrations of fentanyl when coadministered with ketoconazole tablets may increase the risk of potentially fatal respiratory depression. sufentanil: no human pharmacokinetic data of an interaction with ketoconazole are available. in vitro data suggest that sufentanil is metabolized by cyp3a4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with ketoconazole tablets. antiarrhythmics disopyramide, dofetilide, dronedarone, quinidine digoxin disopyramide, dofetilide, dronedarone, quinidine: the potential increase in plasma concentrations of these drugs when coadministered with ketoconazole may increase the risk of serious cardiovascular events including qt prolongation. digoxin: 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. antibacterials rifabutin telithromycin rifabutin: see also under ' drugs that may decrease ketoconazole plasma concentrations '. telithromycin: a multiple-dose interaction study with ketoconazole showed that c max of telithromycin was increased by 51% and auc by 95%. anticoagulants and antiplatelet drugs rivaroxaban cilostazol, coumarins, dabigatran cilostazol: concomitant administration of single doses of cilostazol 100 mg and ketoconazole 400 mg approximately doubled cilostazol concentrations and altered (increase/decrease) the concentrations of the active metabolites of cilostazol. coumarins: ketoconazole may enhance the anticoagulant effect of coumarin-like drugs, thus the anticoagulant effect should be carefully titrated and monitored. dabigatran: in patients with moderate renal impairment (crcl 50 ml/min to ≤ 80 ml/min), consider reducing the dose of dabigatran to 75 mg twice daily when it is coadministered with ketoconazole. anticonvulsants carbamazepine carbamazepine: in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. in addition, the bioavailability of ketoconazole may be reduced by carbamazepine. antidiabetics repaglinide, saxagliptin antihelmintics and antiprotozoals praziquantel antimigraine drugs ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) eletriptan ergot alkaloids: the potential increase in plasma concentrations of ergot alkaloids when coadministered with ketoconazole tablets may increase the risk of ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. eletriptan: eletriptan should be used with caution with ketoconazole, and specifically, should not be used within at least 72 hours of treatment with ketoconazole. antineoplastics irinotecan dasatinib, lapatinib, nilotinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, paclitaxel, trimetrexate, vinca alkaloids irinotecan: the potential increase in plasma concentrations of irinotecan when coadministered with ketoconazole tablets may increase the risk of potentially fatal adverse events. docetaxel: in the presence of ketoconazole, the clearance of docetaxel in cancer patients was shown to decrease by 50%. antipsychotics, anxiolytics and hypnotics alprazolam, lurasidone, oral midazolam, pimozide, triazolam aripiprazole, buspirone, haloperidol, midazolam iv, quetiapine, ramelteon, risperidone alprazolam, midazolam, triazolam: coadministration of ketoconazole tablets with oral midazolam or triazolam, or alprazolam may cause several-fold increases in plasma concentrations of these drugs. this may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. pimozide: the potential increase in plasma concentrations of pimozide when coadministered with ketoconazole tablets may increase the risk of serious cardiovascular events including qt prolongation and torsade de pointes. aripiprazole: 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 ketoconazole is given concomitantly with aripiprazole, the aripiprazole dose should be reduced to one-half of the recommended dose. buspirone: ketoconazole is expected to inhibit buspirone metabolism and increase plasma concentrations of buspirone. if a patient has been titrated to a stable dosage on buspirone, a dose reduction of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. antivirals indinavir, maraviroc, saquinavir beta blockers nadolol calcium channel blockers felodipine, nisoldipine other dihydropyridines, verapamil calcium channel blockers can have a negative inotropic effect which may be additive to those of ketoconazole. the potential increase in plasma concentrations of calcium channel blockers when co-administered with ketoconazole tablets may increase the risk of edema and congestive heart failure. dihydropyridines: concomitant administration of ketoconazole tablets may cause several-fold increases in plasma concentrations of dihydropyridines. cardiovascular drugs, miscellaneous ranolazine aliskiren, bosentan ranolazine: the potential increase in plasma concentrations of ranolazine when coadministered with ketoconazole tablets may increase the risk of serious cardiovascular events including qt prolongation. bosentan: coadministration of bosentan 125 mg twice daily and ketoconazole, increased the plasma concentrations of bosentan by approximately 2-fold in normal volunteers. no dose adjustment of bosentan is necessary, but patients should be monitored for increased pharmacologic effects and adverse reactions of bosentan. diuretics eplerenone the potential increase in plasma concentrations of eplerenone when coadministered with ketoconazole tablets may increase the risk of hyperkalemia and hypotension. gastrointestinal drugs cisapride aprepitant cisapride: oral ketoconazole potently inhibits the metabolism of cisapride resulting in a mean eight-fold increase in auc of cisapride, which can lead to serious cardiovascular events including qt prolongation. immunosuppressants everolimus, rapamycin (also known as sirolimus), temsirolimus budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, tacrolimus rapamycin (sirolimus): ketoconazole tablets 200 mg daily for 10 days increased the c max and auc of a single 5 mg dose of sirolimus by 4.3-fold and 10.9-fold, respectively in 23 healthy subjects. fluticasone: coadministration of fluticasone propionate and ketoconazole is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. lipid regulating drugs lovastatin, simvastatin atorvastatin the potential increase in plasma concentrations of atorvastatin, lovastatin and simvastatin when coadministered with ketoconazole tablets may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. respiratory drugs salmeterol urological drugs fesoterodine, sildenafil, solifenacin, tadalafil, tolterodine, vardenafil vardenafil: a single dose of 5 mg of vardenafil should not be exceeded when coadministered with ketoconazole. other colchicine, in subjects with renal or hepatic impairment; tolvaptan colchicine alcohol, cinacalcet colchicine: the potential increase in plasma concentrations of colchicine when coadministered with ketoconazole tablets may increase the risk of potentially fatal adverse events. tolvaptan: ketoconazole 200 mg administered with tolvaptan increased tolvaptan exposure by 5-fold. larger doses would be expected to produce larger increases in tolvaptan exposure. there is not adequate experience to define the dose adjustment that would be needed to allow safe use of tolvaptan with strong cyp3a inhibitors such as ketoconazole. alcohol: exceptional cases have been reported of a disulfiram-like reaction to alcohol, characterized by flushing, rash, peripheral edema, nausea and headache. all symptoms completely resolved within a few hours.

t baseline, obtain laboratory tests (such as sggt, alkaline phosphatase, alt, ast, total bilirubin (tbl), prothrombin time (pt), international normalization ratio (inr), and testing for viral hepatitides). patients should be advised against alcohol consumption while on treatment. if possible, use of other potentially hepatotoxic drugs should be avoided in patients receiving ketoconazole tablets. prompt recognition of liver injury is essential. during the course of treatment, serum alt should be monitored weekly for the duration of treatment. if alt values increase to a level above the upper limit of normal or 30 percent above baseline, or if the patient develops symptoms, ketoconazole treatment should be interrupted and a full set of liver tests should be obtained. liver tests should be repeated to ensure normalization of values. hepatotoxicity has been reported with restarting oral ketoconazole (rechallenge). if it is decided to restart oral ketoconazole, monitor the patient frequently to detect any recurring liver injury from the drug. qt prolongation and drug interactions leading to qt prolongation ketoconazole can prolong the qt interval. co-administration of the following drugs with ketoconazole is contraindicated: dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, ranolazine. ketoconazole can cause elevated plasma concentrations of these drugs which may prolong the qt interval, sometimes resulting in life-threatening ventricular dysrhythmias such as torsades de pointes. adrenal insufficiency ketoconazole tablets decrease adrenal corticosteroid secretion at doses of 400 mg and higher. this effect is not shared with other azoles. the recommended dose of 200 mg to 400 mg daily should not be exceeded. adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.). adverse reactions associated with unapproved uses ketoconazole has been used in high doses for the treatment of advanced prostate cancer and for cushing's syndrome when other treatment options have failed. the safety and effectiveness of ketoconazole have not been established in these settings and the use of ketoconazole for these indications is not approved by fda. in a clinical trial involving 350 patients with metastatic prostatic cancer, eleven deaths were reported within two weeks of starting treatment with high doses of ketoconazole tablets (1200 mg/day). it is not possible to ascertain from the information available whether death was related to ketoconazole therapy or adrenal insufficiency in these patients with serious underlying disease. hepatoxicity, including fatal cases and cases requiring liver transplantation, have been reported in patients who received ketoconazole for treatment of onychomycosis, cutaneous dermatophyte infections, or candida infections. hypersensitivity anaphylaxis has been reported after the first dose. several cases of hypersensitivity reactions including urticaria have also been reported.

patic function abnormal skin and subcutaneous tissues disorders: erythema multiforme, rash, dermatitis, erythema, urticaria, pruritus, alopecia, xeroderma musculoskeletal and connective tissue disorders: myalgia reproductive system and breast disorders: menstrual disorder general disorders and administration site conditions: asthenia, fatigue, hot flush, malaise, edema peripheral, pyrexia, chills investigations: platelet count decreased. post-marketing experience the following adverse reactions have been identified during postapproval use of ketoconazole tablets. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. the following adverse reactions were reported during post-marketing experience: blood and lymphatic system disorders: thrombocytopenia immune system disorders: allergic conditions including anaphylactic shock, anaphylactic reaction, angioneurotic edema endocrine disorders: adrenocortical insufficiency nervous system disorders: reversible intracranial pressure increased (e.g. papilloedema, fontanelle bulging in infants) hepatobiliary disorders: serious hepatotoxicity including hepatitis cholestatic, biopsy-confirmed hepatic necrosis, cirrhosis, hepatic failure including cases resulting in transplantation or death skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis, photosensitivity musculoskeletal and connective tissue disorders: arthralgia reproductive system and breast disorders: erectile dysfunction; with doses higher than the recommended therapeutic dose of 200 or 400mg daily, azoospermia.

blets. these drugs should be used with caution when coadministered with ketoconazole tablets: ketoconazole tablets should be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity. acid neutralizing medicines (e.g. aluminum hydroxide) should be administered at least 1 hour before or 2 hours after the intake of ketoconazole tablets. upon coadministration, the antifungal activity should be monitored and the ketoconazole tablets dose increased as deemed necessary. coadministration of ketoconazole tablets with potent enzyme inducers of cyp3a4 may decrease the bioavailability of ketoconazole to such an extent that efficacy may be reduced. examples include: antibacterials: isoniazid, rifabutin (see also under ' drugs that may have their plasma concentrations increased '), rifampicin. anticonvulsants: carbamazepine (see also under ' drugs that may have their plasma concentrations increased '), phenytoin. antivirals: efavirenz, nevirapine. therefore, administration of potent enzyme inducers of cyp3a4 with ketoconazole tablets is not recommended. the use of these drugs should be avoided from 2 weeks before and during treatment with ketoconazole tablets, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy. upon coadministration, the antifungal activity should be monitored and the ketoconazole tablets dose increased as deemed necessary. drugs that may increase ketoconazole plasma concentrations potent inhibitors of cyp3a4 (e.g. antivirals such as ritonavir, ritonavir-boosted darunavir and ritonavir-boosted fosamprenavir) may increase the bioavailability of ketoconazole. these drugs should be used with caution when coadministered with ketoconazole tablets. patients who must take ketoconazole tablets concomitantly with potent inhibitors of cyp3a4 should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of ketoconazole, and the ketoconazole tablets dose should be decreased as deemed necessary. when appropriate, ketoconazole plasma concentrations should be measured. drugs that may have their plasma concentrations increased by ketoconazole ketoconazole can inhibit the metabolism of drugs metabolized by cyp3a4 and can inhibit the drug transport by p-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with ketoconazole. these elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. cyp3a4-metabolized drugs known to prolong the qt interval may be contraindicated with ketoconazole tablets, since the combination may lead to ventricular tachyarrhythmias, including occurrences of torsade de pointes, a potentially fatal arrhythmia. examples of drugs that may have their plasma concentrations increased by ketoconazole presented by drug class with advice regarding coadministration with ketoconazole tablets: drug class contraindicated not recommended use with caution comments under no circumstances should the drug be coadministered with ketoconazole tablets, and up to one week after discontinuation of treatment with ketoconazole. the use of the drug should be avoided during and up to one week after discontinuation of treatment with ketoconazole tablets, unless the benefits outweigh the potentially increased risks of side effects. if coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage should be reduced or interrupted as deemed necessary. when appropriate, plasma concentrations should be measured. the label of the coadministered drug should be consulted for information on dose adjustment and adverse effects. careful monitoring is recommended when the drug is coadministered with ketoconazole tablets. upon coadministration, patients should be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage should be reduced as deemed necessary. when appropriate, plasma concentrations should be measured. the label of the coadministered drug should be consulted for information on dose adjustment and adverse effects. alpha blockers tamsulosin analgesics methadone alfentanil, buprenorphine iv and sublingual, fentanyl, oxycodone, sufentanil methadone: the potential increase in plasma concentrations of methadone when coadministered with ketoconazole tablets may increase the risk of serious cardiovascular events including qt prolongation and torsade de pointes, or respiratory or cns depression. [see contraindications .] fentanyl: the potential increase in plasma concentrations of fentanyl when coadministered with ketoconazole tablets may increase the risk of potentially fatal respiratory depression. sufentanil: no human pharmacokinetic data of an interaction with ketoconazole are available. in vitro data suggest that sufentanil is metabolized by cyp3a4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with ketoconazole tablets. antiarrhythmics disopyramide, dofetilide, dronedarone, quinidine digoxin disopyramide, dofetilide, dronedarone, quinidine: the potential increase in plasma concentrations of these drugs when coadministered with ketoconazole may increase the risk of serious cardiovascular events including qt prolongation. digoxin: 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. antibacterials rifabutin telithromycin rifabutin: see also under ' drugs that may decrease ketoconazole plasma concentrations '. telithromycin: a multiple-dose interaction study with ketoconazole showed that c max of telithromycin was increased by 51% and auc by 95%. anticoagulants and antiplatelet drugs rivaroxaban cilostazol, coumarins, dabigatran cilostazol: concomitant administration of single doses of cilostazol 100 mg and ketoconazole 400 mg approximately doubled cilostazol concentrations and altered (increase/decrease) the concentrations of the active metabolites of cilostazol. coumarins: ketoconazole may enhance the anticoagulant effect of coumarin-like drugs, thus the anticoagulant effect should be carefully titrated and monitored. dabigatran: in patients with moderate renal impairment (crcl 50 ml/min to ≤ 80 ml/min), consider reducing the dose of dabigatran to 75 mg twice daily when it is coadministered with ketoconazole. anticonvulsants carbamazepine carbamazepine: in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. in addition, the bioavailability of ketoconazole may be reduced by carbamazepine. antidiabetics repaglinide, saxagliptin antihelmintics and antiprotozoals praziquantel antimigraine drugs ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) eletriptan ergot alkaloids: the potential increase in plasma concentrations of ergot alkaloids when coadministered with ketoconazole tablets may increase the risk of ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. eletriptan: eletriptan should be used with caution with ketoconazole, and specifically, should not be used within at least 72 hours of treatment with ketoconazole. antineoplastics irinotecan dasatinib, lapatinib, nilotinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, paclitaxel, trimetrexate, vinca alkaloids irinotecan: the potential increase in plasma concentrations of irinotecan when coadministered with ketoconazole tablets may increase the risk of potentially fatal adverse events. docetaxel: in the presence of ketoconazole, the clearance of docetaxel in cancer patients was shown to decrease by 50%. antipsychotics, anxiolytics and hypnotics alprazolam, lurasidone, oral midazolam, pimozide, triazolam aripiprazole, buspirone, haloperidol, midazolam iv, quetiapine, ramelteon, risperidone alprazolam, midazolam, triazolam: coadministration of ketoconazole tablets with oral midazolam or triazolam, or alprazolam may cause several-fold increases in plasma concentrations of these drugs. this may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. pimozide: the potential increase in plasma concentrations of pimozide when coadministered with ketoconazole tablets may increase the risk of serious cardiovascular events including qt prolongation and torsade de pointes. aripiprazole: 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 ketoconazole is given concomitantly with aripiprazole, the aripiprazole dose should be reduced to one-half of the recommended dose. buspirone: ketoconazole is expected to inhibit buspirone metabolism and increase plasma concentrations of buspirone. if a patient has been titrated to a stable dosage on buspirone, a dose reduction of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. antivirals indinavir, maraviroc, saquinavir beta blockers nadolol calcium channel blockers felodipine, nisoldipine other dihydropyridines, verapamil calcium channel blockers can have a negative inotropic effect which may be additive to those of ketoconazole. the potential increase in plasma concentrations of calcium channel blockers when co-administered with ketoconazole tablets may increase the risk of edema and congestive heart failure. dihydropyridines: concomitant administration of ketoconazole tablets may cause several-fold increases in plasma concentrations of dihydropyridines. cardiovascular drugs, miscellaneous ranolazine aliskiren, bosentan ranolazine: the potential increase in plasma concentrations of ranolazine when coadministered with ketoconazole tablets may increase the risk of serious cardiovascular events including qt prolongation. bosentan: coadministration of bosentan 125 mg twice daily and ketoconazole, increased the plasma concentrations of bosentan by approximately 2-fold in normal volunteers. no dose adjustment of bosentan is necessary, but patients should be monitored for increased pharmacologic effects and adverse reactions of bosentan. diuretics eplerenone the potential increase in plasma concentrations of eplerenone when coadministered with ketoconazole tablets may increase the risk of hyperkalemia and hypotension. gastrointestinal drugs cisapride aprepitant cisapride: oral ketoconazole potently inhibits the metabolism of cisapride resulting in a mean eight-fold increase in auc of cisapride, which can lead to serious cardiovascular events including qt prolongation. immunosuppressants everolimus, rapamycin (also known as sirolimus), temsirolimus budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, tacrolimus rapamycin (sirolimus): ketoconazole tablets 200 mg daily for 10 days increased the c max and auc of a single 5 mg dose of sirolimus by 4.3-fold and 10.9-fold, respectively in 23 healthy subjects. fluticasone: coadministration of fluticasone propionate and ketoconazole is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. lipid regulating drugs lovastatin, simvastatin atorvastatin the potential increase in plasma concentrations of atorvastatin, lovastatin and simvastatin when coadministered with ketoconazole tablets may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. respiratory drugs salmeterol urological drugs fesoterodine, sildenafil, solifenacin, tadalafil, tolterodine, vardenafil vardenafil: a single dose of 5 mg of vardenafil should not be exceeded when coadministered with ketoconazole. other colchicine, in subjects with renal or hepatic impairment; tolvaptan colchicine alcohol, cinacalcet colchicine: the potential increase in plasma concentrations of colchicine when coadministered with ketoconazole tablets may increase the risk of potentially fatal adverse events. tolvaptan: ketoconazole 200 mg administered with tolvaptan increased tolvaptan exposure by 5-fold. larger doses would be expected to produce larger increases in tolvaptan exposure. there is not adequate experience to define the dose adjustment that would be needed to allow safe use of tolvaptan with strong cyp3a inhibitors such as ketoconazole. alcohol: exceptional cases have been reported of a disulfiram-like reaction to alcohol, characterized by flushing, rash, peripheral edema, nausea and headache. all symptoms completely resolved within a few hours.

m human dose, based on body surface area comparison).

itor, the bioavailability of a single 200 mg dose of ketoconazole under fasted conditions was decreased to 17% of the bioavailability of ketoconazole administered alone. when ketoconazole was administered with non-diet cola after pretreatment with omeprazole, the bioavailability was 65% of that after administration of ketoconazole alone. distribution in vitro , the plasma protein binding is about 99% mainly to the albumin fraction. ketoconazole is widely distributed into tissues; however, only a negligible proportion reaches the cerebrospinal fluid. metabolism following absorption from the gastrointestinal tract, ketoconazole tablets are converted into several inactive metabolites. in vitro studies have shown that cyp3a4 is the major enzyme involved in the metabolism of ketoconazole. the major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, by hepatic microsomal enzymes. in addition, oxidative o-dealkylation and aromatic hydroxylation does occur. ketoconazole has not been demonstrated to induce its own metabolism. elimination elimination from plasma is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. approximately 13% of the dose is excreted in the urine, of which 2 to 4% is unchanged drug. the major route of excretion is through the bile into the intestinal tract with about 57% being excreted in the feces. special populations patients with hepatic or renal impairment in patients with hepatic or renal impairment, the overall pharmacokinetics of ketoconazole was not significantly different when compared with healthy subjects. pediatric patients limited pharmacokinetic data are available on the use of ketoconazole tablets in the pediatric population. measurable ketoconazole plasma concentrations have been observed in pre-term infants (single or daily doses of 3 to 10 mg/kg) and in pediatric patients 5 months of age and older (daily doses of 3 to 13 mg/kg) when the drug was administered as a suspension, tablet or crushed tablet. limited data suggest that absorption may be greater when the drug is administered as a suspension compared to a crushed tablet. conditions that raise gastric ph may lower or prevent absorption (see section precautions: drug interactions ). maximum plasma concentrations occurred 1 to 2 hours after dosing and were in the same general range as those seen in adults who received a 200 to 400 mg dose. electrocardiogram pre-clinical electrophysiological studies have shown that ketoconazole inhibits the rapidly activating component of the cardiac delayed rectifier potassium current, prolongs the action potential duration, and may prolong the qt c interval. data from some clinical pk/pd studies and drug interaction studies suggest that oral dosing with ketoconazole at 200 mg twice daily for 3 to 7 days can result in an increase of the qt c interval: a mean maximum increase of about 6 to 12 msec was seen at ketoconazole peak plasma concentrations about 1 to 4 hours after ketoconazole administration. microbiology mechanism of action ketoconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome p-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. this results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. activity in vitro & in vivo ketoconazole tablets usp, 200 mg are active against clinical infections with blastomyces dermatitidis , coccidioides immitis , histoplasma capsulatum , paracoccidioides brasiliensis .

ity of a single 200 mg dose of ketoconazole under fasted conditions was decreased to 17% of the bioavailability of ketoconazole administered alone. when ketoconazole was administered with non-diet cola after pretreatment with omeprazole, the bioavailability was 65% of that after administration of ketoconazole alone. distribution in vitro , the plasma protein binding is about 99% mainly to the albumin fraction. ketoconazole is widely distributed into tissues; however, only a negligible proportion reaches the cerebrospinal fluid. metabolism following absorption from the gastrointestinal tract, ketoconazole tablets are converted into several inactive metabolites. in vitro studies have shown that cyp3a4 is the major enzyme involved in the metabolism of ketoconazole. the major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, by hepatic microsomal enzymes. in addition, oxidative o-dealkylation and aromatic hydroxylation does occur. ketoconazole has not been demonstrated to induce its own metabolism. elimination elimination from plasma is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. approximately 13% of the dose is excreted in the urine, of which 2 to 4% is unchanged drug. the major route of excretion is through the bile into the intestinal tract with about 57% being excreted in the feces. special populations patients with hepatic or renal impairment in patients with hepatic or renal impairment, the overall pharmacokinetics of ketoconazole was not significantly different when compared with healthy subjects. pediatric patients limited pharmacokinetic data are available on the use of ketoconazole tablets in the pediatric population. measurable ketoconazole plasma concentrations have been observed in pre-term infants (single or daily doses of 3 to 10 mg/kg) and in pediatric patients 5 months of age and older (daily doses of 3 to 13 mg/kg) when the drug was administered as a suspension, tablet or crushed tablet. limited data suggest that absorption may be greater when the drug is administered as a suspension compared to a crushed tablet. conditions that raise gastric ph may lower or prevent absorption (see section precautions: drug interactions ). maximum plasma concentrations occurred 1 to 2 hours after dosing and were in the same general range as those seen in adults who received a 200 to 400 mg dose.