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NIZORAL® Tablets should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks.
Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation, has occurred with the use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity was reported both by patients receiving high doses for short treatment durations and by patients receiving low doses for long durations.
At 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 NIZORAL® 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, and cisapride. 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.
NIZORAL® 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 - 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.
Co-administration of NIZORAL® 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 NIZORAL® Tablets with oral triazolam, oral midazolam, or alprazolam is contraindicated. (See CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONS sections.)
Co-administration of CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin, and lovastatin is contraindicated with NIZORAL® Tablets. (See CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONS sections.)
NIZORAL® Tablets have been demonstrated to lower serum testosterone. Once therapy with NIZORAL® Tablets has been discontinued, serum testosterone levels return to baseline values. Testosterone levels are impaired with doses of 800 mg per day and abolished by 1600 mg per day. Clinical manifestations of decreased testosterone concentrations may include gynecomastia, impotence and oligospermia.
Information for Patients
Patients should be instructed to report any signs and symptoms which may suggest liver dysfunction so that appropriate biochemical testing can be done. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, abdominal pain, jaundice, dark urine or pale stools (see WARNINGS section).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Ketoconazole did not show any signs of mutagenic potential when evaluated using the dominant lethal mutation test or the Ames Salmonella microsomal activator assay. Ketoconazole was not carcinogenic in an 18-month, oral study in Swiss albino mice or a 24-month oral carcinogenicity study in Wistar rats at dose levels of 5, 20 and 80 mg/kg/day. The high dose in these studies was approximately 1x (mouse) or 2x (rat) the clinical dose in humans based on a mg/m² comparison.
Pregnancy Category C: Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when given in the diet at 80 mg/kg/day (2 times the maximum recommended human dose, based on body surface area comparisons). However, these effects may be related to maternal toxicity, evidence of which also was seen at this and higher dose levels.
There are no adequate and well controlled studies in pregnant women. NIZORAL® Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Ketoconazole has also been found to be embryotoxic in the rat when given in the diet at doses higher than 80 mg/kg during the first trimester of gestation.
In addition, dystocia (difficult labor) was noted in rats administered oral ketoconazole during the third trimester of gestation. This occurred when ketoconazole was administered at doses higher than 10 mg/kg (about one fourth the maximum human dose, based on body surface area comparison).
Ketoconazole has been shown to be excreted in the milk. Mothers who are under treatment with NIZORAL® Tablets should not breast feed.
NIZORAL® Tablets have not been systematically studied in children of any age, and essentially no information is available on children under 2 years. NIZORAL® Tablets should not be used in pediatric patients unless the potential benefit outweighs the risks.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 8/2/2013
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