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In rare cases, anaphylaxis has been reported after the first dose. Several cases of hypersensitivity reactions including urticaria have also been reported. However, the most frequent adverse reactions were nausea and/or vomiting in approximately 3%, abdominal pain in 1.2%, pruritus in 1.5%, and the following in less than 1% of the patients: headache, dizziness, somnolence, fever and chills, photophobia, diarrhea, gynecomastia, impotence, thrombocytopenia, leukopenia, hemolytic anemia, and bulging fontanelles. Oligospermia has been reported in investigational studies with the drug at dosages above those currently approved. Oligospermia has not been reported at dosages up to 400 mg daily, however sperm counts have been obtained infrequently in patients treated with these dosages. Most of these reactions were mild and transient and rarely required discontinuation of NIZORAL® (ketoconazole) Tablets. In contrast, the rare occurrences of hepatic dysfunction require special attention (see WARNINGS section).

In worldwide postmarketing experience with NIZORAL® (ketoconazole) Tablets there have been rare reports of alopecia, paresthesia, and signs of increased intracranial pressure including bulging fontanelles and papilledema. Hypertriglyceridemia has also been reported but a causal association with NIZORAL® (ketoconazole) Tablets is uncertain.

Neuropsychiatric disturbances, including suicidal tendencies and severe depression, have occurred rarely in patients using NIZORAL® (ketoconazole) Tablets.

Ventricular dysrhythmias (prolonged QT intervals) have occurred with the concomitant use of terfenadine with ketoconazole tablets. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS sections.) Data suggest that coadministration of ketoconazole tablets and cisaspride can result in prolongation of the QT interval and has rarely been associated with ventricular arrhythmias. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections.)

Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system. Coadministration of NIZORAL® (ketoconazole) 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® (ketoconazole) 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. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS sections.)

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. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS sections.)

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. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS sections.)

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® (ketoconazole) Tablets.

Coadministration of NIZORAL® (ketoconazole) 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® (ketoconazole) 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 QTc 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.

Last reviewed on RxList: 4/20/2009
This monograph has been modified to include the generic and brand name in many instances.