Drug Information for KETOCONAZOLE TABLETS USP200 mg (Apotex Corp.): WARNINGS

  • Hepatotoxicity, primarily of the hepatocellular type, has been associated with the use of Ketoconazole Tablets, including rare fatalities. The reported incidence of hepatotoxicity has been about 1:10,000 exposed patients, but this probably represents some degree of under-reporting, as is the case for most reported adverse reactions to drugs. The median duration of Ketoconazole Tablet therapy in patients who developed symptomatic hepatotoxicity was about 28 days, although the range extended to as low as 3 days. The hepatic injury has usually, but not always, been reversible upon discontinuation of Ketoconazole Tablet treatment. Several cases of hepatitis have been reported in pediatric patients.

    Prompt recognition of liver injury is essential. Liver function tests (such as SGGT, alkaline phosphatase, SGPT, SGOT and bilirubin) should be measured before starting treatment and at frequent intervals during treatment. Patients receiving Ketoconazole Tablets concurrently with other potentially hepatotoxic drugs should be carefully monitored, particularly those patients requiring prolonged therapy or those who have had a history of liver disease.

    Most of the reported cases of hepatic toxicity have to date been in patients treated for onychomycosis. Of 180 patients worldwide developing idiosyncratic liver dysfunction during Ketoconazole Tablet therapy, 61.3% had onychomycosis and 16.8% had chronic recalcitrant dermatophytoses.

    Transient minor elevations in liver enzymes have occurred during treatment with Ketoconazole Tablets. The drug should be discontinued if these persist, if the abnormalities worsen, or if the abnormalities become accompanied by symptoms of possible liver injury.

    In rare cases anaphylaxis has been reported after the first dose. Several cases of hypersensitivity reactions including urticaria have also been reported.

    Coadministration of Ketoconazole Tablets and terfenadine has led to elevated plasma concentrations of terfenadine which may prolong QT intervals, sometimes resulting in life-threatening cardiac dysrhythmias. Cases of torsades de pointes and other serious ventricular dysrhythmias, in rare cases leading to fatality, have been reported among patients taking terfenadine concurrently with Ketoconazole Tablets. Coadministration of Ketoconazole Tablets and terfenadine is contraindicated.

    Coadministration of astemizole with Ketoconazole Tablets is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS sections.)

    Concomitant administration of Ketoconazole Tablets with cisapride is contraindicated because it has resulted in markedly elevated cisapride plasma concentrations and prolonged QT interval, and has rarely been associated with ventricular arrhythmias and torsades de pointes. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS sections.)

    In European clinical trials 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 in these patients with serious underlying disease. However, high doses of Ketoconazole Tablets are known to suppress adrenal corticosteroid secretion.

    In female rats treated three to six months with ketoconazole at dose levels of 80 mg/kg and higher, increased fragility of long bones, in some cases leading to fracture, was seen. The maximum "no-effect" dose level in these studies was 20 mg/kg (2.5 times the maximum recommended human dose). The mechanism responsible for this phenomenon is obscure. Limited studies in dogs failed to demonstrate such an effect on the metacarpals and ribs.

  • Drug Information Provided by National Library of Medicine (NLM).