Tablets

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 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 treatment. Several cases of hepatitis have been reported in children.

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 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 ketoconazole treatment. 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 BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS.)

In European clinical trials involving 350 patients with metastatic prostatic cancer, eleven deaths were reported within two weeks of starting treatment with high dose of ketoconazole (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 mechanisms responsible for this phenomenon is obscure. Limited studies in dogs failed to demonstrated such an effect on the metacarpals and ribs.

General

Shampoo: If a reaction suggesting sensitivity or chemical irritation should occur, use of the medication should be discontinued.

Tablets: Ketoconazole tablets have been demonstrated to lower serum testosterone. Once therapy with ketoconazole 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 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.

Carcinogenesis, Mutagenesis, and 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 produce 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 rate 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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Shampoo: Ketoconazole is not detected in plasma after chronic shampooing.

Tablets: 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

Shampoo: Ketoconazole is not detected in plasma after chronic shampooing. Nevertheless, caution should be exercised when ketoconazole 2% shampoo is administered to a nursing woman.

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

Pediatric Use

Shampoo: Safety and effectiveness in children have not been established.

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

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