Ketoconazole (Page 2 of 3)

PRECAUTIONS

General

Ketoconazole Tablets have been demonstrated to lower serum testosterone. Once therapy with Ketoconazole 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. Ketoconazole Tablets also decrease ACTH induced corticosteroid serum levels at similar high doses. The recommended dose of 200 mg – 400 mg daily should be followed closely.

In four subjects with drug-induced achlorhydria, a marked reduction in ketoconazole absorption was observed. Ketoconazole Tablets require acidity for dissolution. If concomitant antacids, anticholinergics, and H2 -blockers are needed, they should be given at least two hours after administration of Ketoconazole Tablets. In cases of achlorhydria, the patients should be instructed to dissolve each tablet in 4 mL aqueous solution of 0.2 N HCl. For ingesting the resulting mixture, they should use a drinking straw so as to avoid contact with the teeth. This administration should be followed with a cup of tap water.

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.Signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine or pale stools (see WARNINGS section).

Drug Interactions

Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system. Coadministration of 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 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 Ketoconazole Tablets.

Coadministration of 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 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The dominant lethal mutation test in male and female mice revealed that single oral doses of ketoconazole as high as 80 mg/kg produced no mutation in any stage of germ cell development. The Ames Salmonella microsomal activator assay was also negative. A long term feeding study in Swiss Albino mice and in Wistar rats showed no evidence of oncogenic activity.

Pregnancy

Teratogenic effects

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 (10 times the maximum recommended human dose). 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. Ketoconazole Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

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 (higher than 1.25 times the maximum human dose).

It is likely that both the malformations and the embryotoxicity resulting from the administration of oral ketoconazole during gestation are a reflection of the particular sensitivity of the female rat to this drug. For example, the oral LD50 of ketoconazole given by gavage to the female rat is 166 mg/kg whereas in the male rat the oral LD50 is 287 mg/kg.

Nursing Mothers

Since ketoconazole is probably excreted in the milk, mothers who are under treatment should not breast feed.

Pediatric Use

Ketoconazole Tablets have not been systematically studied in pediatric patients of any age, and essentially no information is available on pediatric patients under 2 years. Ketoconazole Tablets should not be used in pediatric patients unless the potential benefit outweighs the risks.

Adverse Reactions to Ketoconazole

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 Ketoconazole Tablets. In contrast, the rare occurrences of hepatic dysfunction require special attention (see WARNINGS section).

In worldwide postmarketing experience with 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 Ketoconazole Tablets is uncertain.

Neuropsychiatric disturbances, including suicidal tendencies and severe depression, have occurred rarely in patients using 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 cisapride can result in prolongation of the QT interval and has rarely been associated with ventricular arrhythmias. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections.)

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