Ketoconazole

KETOCONAZOLE- ketoconazole tablet
Aidarex Pharmaceuticals LLC

Rx only

WARNING

Ketoconazole tablets USP, 200 mg should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks.

Hepatotoxicity

Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation has occurred with the use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Patients receiving this drug should be informed by the physician of the risk and should be closely monitored. See WARNINGS section.

QT Prolongation and Drug Interactions Leading to QT Prolongation

Co-administration of the following drugs with ketoconazole is contraindicated: dofetilide, quinidine, pimozide, cisapride. Ketoconazole can cause elevated plasma concentrations of these drugs and may prolong QT intervals, sometimes resulting in life-threatening ventricular dysrhythmias such as torsades de pointes. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions sections.

DESCRIPTION

Ketoconazole tablets USP is a synthetic broad-spectrum antifungal agent available in scored white tablets, each containing 200 mg ketoconazole base for oral administration. Inactive ingredients are colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Ketoconazole is cis-1-acetyl-4-[4-[[2-(2,4dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxyl]phenyl] piperazine and has the following structural formula:

Chemical Structure
(click image for full-size original)

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

CLINICAL PHARMACOLOGY

Pharmacokinetics

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 Odealkylation 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 cerebrospinal fluid. Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption.

Electrocardiogram

Pre-clinical electrophysiological studies have shown that ketoconazole inhibits the rapidly activating component of the cardiac delayed rectifier potassium current, prolongs the action potential duration, and may prolong the QTc interval. Data from some clinical PK/PD studies and drug interaction studies suggest that oral dosing with ketoconazole at 200 mg twice daily for 3 to 7 days can result in an increase of the QTc interval: a mean maximum increase of about 6 to 12 msec was seen at ketoconazole peak plasma concentrations about 1 to 4 hours after ketoconazole administration.

MICROBIOLOGY

Mechanism of Action

Ketoconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane.

Activity In Vitro & In Vivo

Ketoconazole tablets USP, 200 mg are active against clinical infections with Blastomyces dermatitidis , Coccidioides immitis , Histoplasma capsulatum , Paracoccidioides brasiliensis.

INDICATIONS AND USAGE

Ketoconazole tablets USP, 200 mg should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks.

Ketoconazole tablets USP, 200 mg are indicated for the treatment of the following systemic fungal infections in patients who have failed or who are intolerant to other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Ketoconazole tablets USP, 200 mg should not be used for fungal meningitis because it penetrates poorly into the cerebrospinal fluid.

CONTRAINDICATIONS

Drug Interactions

Coadministration of a number of CYP3A4 substrates is contraindicated with ketoconazole tablets. Coadministration with ketoconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both therapeutic and adverse effects. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia. See WARNINGS section, and PRECAUTIONS: Drug Interactions section for specific examples.

Liver Disease

The use of ketoconazole tablets is contraindicated in patients with acute or chronic liver disease.

Hypersensitivity

Ketoconazole tablets USP, 200 mg is contraindicated in patients who have shown hypersensitivity to the drug.

WARNINGS

Ketoconazole tablets USP, 200 mg should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks.

Hepatotoxicity

Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation, has occurred with the use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity was reported both by patients receiving high doses for short treatment durations and by patients receiving low doses for long durations.

The hepatic injury has usually, but not always, been reversible upon discontinuation of ketoconazole tablets treatment. Cases of hepatitis have been reported in children.

At baseline, obtain laboratory tests (such as SGGT, alkaline phosphatase, ALT, AST, total bilirubin (TBL), Prothrombin Time (PT), International Normalization Ratio (INR), and testing for viral hepatitides). Patients should be advised against alcohol consumption while on treatment. If possible, use of other potentially hepatotoxic drugs should be avoided in patients receiving ketoconazole tablets.

Prompt recognition of liver injury is essential. During the course of treatment, serum ALT should be monitored weekly for the duration of treatment. If ALT values increase to a level above the upper limit of normal or 30 percent above baseline, or if the patient develops symptoms, ketoconazole treatment should be interrupted and a full set of liver tests should be obtained. Liver tests should be repeated to ensure normalization of values. Hepatotoxicity has been reported with restarting oral ketoconazole (rechallenge). If it is decided to restart oral ketoconazole, monitor the patient frequently to detect any recurring liver injury from the drug.

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