tan, eplerenone, lovastatin, simvastatin and colchicine. (see precautions: drug interactions .) enhanced sedation coadministration of ketoconazole tablets with oral midazolam, oral triazolam or alprazolam has resulted in elevated plasma concentrations of these drugs. this may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. concomitant administration of ketoconazole tablets with oral triazolam, oral midazolam or alprazolam is contraindicated. (see precautions: drug interactions .) myopathy coadministration of cyp3a4 metabolized hmg-coa reductase inhibitors such as simvastatin, and lovastatin is contraindicated with ketoconazole tablets. (see precautions: drug interactions .) ergotism concomitant administration of ergot alkaloids such as dihydroergotamine and ergotamine with ketoconazole tablets is contraindicated. (see precautions: drug interactions .) liver disease the use of ketoconazole tablets is contraindicated in patients with acute or chronic liver disease. hypersensitivity ketoconazole tablets usp, 200 mg is contraindicated in patients who have shown hypersensitivity to the drug.

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.

tan, eplerenone, lovastatin, simvastatin and colchicine. (see precautions: drug interactions .) enhanced sedation coadministration of ketoconazole tablets with oral midazolam, oral triazolam or alprazolam has resulted in elevated plasma concentrations of these drugs. this may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. concomitant administration of ketoconazole tablets with oral triazolam, oral midazolam or alprazolam is contraindicated. (see precautions: drug interactions .) myopathy coadministration of cyp3a4 metabolized hmg-coa reductase inhibitors such as simvastatin, and lovastatin is contraindicated with ketoconazole tablets. (see precautions: drug interactions .) ergotism concomitant administration of ergot alkaloids such as dihydroergotamine and ergotamine with ketoconazole tablets is contraindicated. (see precautions: drug interactions .) liver disease the use of ketoconazole tablets is contraindicated in patients with acute or chronic liver disease. hypersensitivity ketoconazole tablets usp, 200 mg is contraindicated in patients who have shown hypersensitivity to the drug.

or, 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.