Ketoconazole tablets should not be used for fungal meningitis because it penetrates poorly into the cerebral-spinal fluid.

Ketoconazole tablets are also indicated for the treatment of patients with severe recalcitrant cutaneous dermatophyte infections who have not responded to topical therapy or oral griseofulvin, or who are unable to take griseofulvin.

CONTRAINDICATIONS: 

Coadministration of terfenadine or astemizole with Ketoconazole tablets is contraindicated. Concomitant administration of Ketoconazole tablets with cisapride, with oral triazolam is contraindicated. Ketoconazole is contraindicated in patients who have shown hypersensitivity to the drug.

CLINICAL PHARMACOLOGY:

Mean peak plasma levels of approximately 3.5µg/mL are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal. Subsequent plasma elimination is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. Ketoconazole is converted into several inactive metabolites. The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation. About 13% of the dose is excreted in the urine, The major route of excretion is through the bile into the intestinal tract. In vitro, the plasma protein binding is about 99% mainly to the albumin fraction. Only a negligible proportion of Ketoconazole reaches the cerebral-spinal fluid. Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption.

Ketoconazole tablets are active against clinical infections with Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Phialophora spp. Ketoconazole tablets are also active against Trichophyton spp., Epidermophyton spp., and Microsporum spp. Ketoconazole is also active in vitro against a variety of fungi and yeast. In animal models, activity has been demonstrated against Candida spp., Blastomyces dermatitidis, Histoplasma capsulatum, Malassezia furfur, Coccidioides immitis, and Cryptococcus neoformans.

Mode of Action:   In vitro studies suggest that Ketoconazole impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes.  

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. The hepatic injury has usually, but not always, been reversible upon discontinuation of Ketoconazole tablet treatment.  In rare cases anaphylaxis has been reported after the first dose.

PRECAUTIONS:

General: Ketoconazole tablets have been demonstrated to lower serum testosterone. Ketoconazole tablets also decrease ACTH induced corticosteroid serum levels at similar high doses.

Ketoconazole tablets require acidity for dissolution. If concomitant antacids, anticholinergics, and H ₂ -blockers are needed, they should be given at least two hours after administration of Ketoconazole tablets.

Pregnancy: Pregnancy Category C

Nursing Mothers: Since Ketoconazole is probably excreted in the milk, mothers who are under treatment should not breast feed.

Pediatric Use: Ketoconazole tablets should not be used in pediatric patients unless the potential benefit outweighs the risks. 

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.

Ketoconazole tablets inhibit the metabolism of terfenadine, resulting in an increased plasma concentration of terfenadine.

Ketoconazole inhibits the metabolism of astemizole.

Ketoconazole potently inhibits the metabolism of cisapride resulting in a mean eight-fold increase in AUC of cisapride.

Ketoconazole tablets may alter the metabolism of cyclosporine, tacrolimus, and methylprednisolone, resulting in elevated plasma concentrations of the latter drugs.

Coadministration of Ketoconazole tablets with midazolam or triazolam has resulted in elevated plasma concentrations of the latter two drugs.

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.

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.

Concomitant administration of rifampin with Ketoconazole tablets reduces the blood levels of the latter. INH (isoniazid) is also reported to affect Ketoconazole concentrations adversely.

SIDE EFFECTS:

In rare cases, anaphylaxis has been reported after the first dose. 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. In contrast, the rare occurrences of hepatic dysfunction require special attention.

OVERDOSAGE:

In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed.

DOSAGE AND ADMINISTRATION:

Adults: The recommended starting dose of Ketoconazole tablets is a single daily administration of 200 mg (one tablet). In very serious infections or if clinical responsiveness is insufficient within the expected time, the dose may be increased to 400 mg (two tablets) once daily.

Children: In small numbers of children over 2 years of age, a single daily dose of 3.3 to 6.6 mg/kg has been used.

Treatment should be continued until tests indicate that active fungal infection has subsided. Inadequate periods of treatment may yield poor response and lead to early recurrence of clinical symptoms. Minimum treatment for candidiasis is one or two weeks. Patients with chronic mucocutaneous candidiasis usually require maintenance therapy. Minimum treatment for the other indicated systemic mycoses is six months.

Minimum treatment for recalcitrant dermatophyte infections is four weeks in cases involving glabrous skin. Palmar and plantar infections may respond more slowly. Apparent cures may subsequently recur after discontinuation of therapy in some cases. 

How Supplied: Each pack of Ruz-Ketoconazole 200 mg tablets contains 30 tablets in 3 blisters.

storage: Store at controlled room temperature below 30°C. Protect from light.  

Reference: PDR 2000, page 1450-1

                  USPDI for Professional Health Care, 2004, Page 314-23

                  Martindale 2005, Page 403-5