Ketoconazole

KETOCONAZOLE- ketoconazole tablet
Apotex Corp

Ketoconazoletablet30tablets

WARNING

When used orally, ketoconazole has been associated with hepatic toxicity, including some fatalities. Patients receiving this drug should be informed by the physician of the risk and should be closely monitored. See WARNINGS and PRECAUTIONS sections.

Coadministration of terfenadine with Ketoconazole Tablets is contraindicated. Rare cases of serious cardiovascular adverse events, including death, ventricular tachycardia and tordades de pointes have been observed in patients taking Ketoconazole Tablets concomitantly with terfenadine, due to increased terfenadine concentrations induced by Ketoconazole Tablets. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS 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 CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections.

Coadministration of cisapride with ketoconazole is contraindicated. Serious cardiovascular adverse events including ventricular tachycardia, ventricular fibrillation and torsades de pointes have occurred in patients taking ketoconazole concomitantly with cisapride. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections.

DESCRIPTION

Ketoconazole is a synthetic broad-spectrum antifungal agent available in scored white to off-white tablets. Each tablet, for oral administration contains 200 mg ketoconazole. In addition, each tablet also contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and methylcellulose. Ketoconazole is cis-1- acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxyl]phenyl] piperazine and has the following structural formula:

Structure

Ketoconazole is a white to almost white, odorless powder, soluble in acids, with a molecular weight of 531.44.

CLINICAL PHARMACOLOGY

Mean peak plasma levels of approximately 3.5 µg/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. Following absorption from the gastrointestinal tract, 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, of which 2 to 4% is unchanged drug. 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.

Ketoconazole Indications and Usage

Ketoconazole Tablets are indicated for the treatment of the following systemic fungal infections: candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. 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. (See BOX WARNING, WARNINGS, and PRECAUTIONS sections.)

Concomitant administration of Ketoconazole Tablets with cisapride is contraindicated. (See BOX WARNING, WARNINGS, and PRECAUTIONS sections.)

Concomitant administration of Ketoconazole Tablets with oral triazolam is contraindicated. (See PRECAUTIONS section.)

Ketoconazole is contraindicated in patients who have shown hypersensitivity to the drug.

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, 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 Tablet 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 Tablet treatment. Several cases of hepatitis have been reported in pediatric patients.

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 Tablets 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 treatment with Ketoconazole Tablets. 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 BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS sections.)

Concomitant administration of Ketoconazole Tablets with cisapride is contraindicated because it has resulted in markedly elevated cisapride plasma concentrations and prolonged QT interval, and has rarely been associated with ventricular arrhythmias and torsades de pointes. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS sections.)

In European clinical trials 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 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 mechanism responsible for this phenomenon is obscure. Limited studies in dogs failed to demonstrate such an effect on the metacarpals and ribs.

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