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Basic Drug Info
Drug Name:Ketoconazole
Manufacturer:Mylan Pharmaceuticals Inc.
Other Info:Mylan Pharmaceuticals Inc.Morgantown, WV 26505REV SEPTEMBER 1999KTCZ:R1



Clinical Trials:


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.
Systemic mycosis --

Candidiasis -- Infection with a fungus of the genus CANDIDA. It is usually a superficial infection of the moist areas of the body and is generally caused by CANDIDA ALBICANS. (Dorland, 27th ed)

Chronic Mucocutaneous Candidiasis -- A clinical syndrome characterized by development, usually in infancy or childhood, of a chronic, often widespread candidiasis of skin, nails, and mucous membranes. It may be secondary to one of the immunodeficiency syndromes, inherited as an autosomal recessive trait, or associated with defects in cell-mediated immunity, endocrine disorders, dental stomatitis, or malignancy.

Oral candidiasis -- Infection of the mucous membranes of the mouth by a fungus of the genus CANDIDA. (Dorland, 27th ed)

Blastomycosis -- A fungal infection that may appear in two forms: 1, a primary lesion characterized by the formation of a small cutaneous nodule and small nodules along the lymphatics that may heal within several months; and 2, chronic granulomatous lesions characterized by thick crusts, warty growths, and unusual vascularity and infection in the middle or upper lobes of the lung.

Coccidioidomycosis -- Infection with a fungus of the genus COCCIDIOIDES, endemic to the SOUTHWESTERN UNITED STATES. It is sometimes called valley fever but should not be confused with RIFT VALLEY FEVER. Infection is caused by inhalation of airborne, fungal particles known as arthroconidia, a form of FUNGAL SPORES. A primary form is an acute, benign, self-limited respiratory infection. A secondary form is a virulent, severe, chronic, progressive granulomatous disease with systemic involvement. It can be detected by use of COCCIDIOIDIN.

Histoplasmosis -- Infection resulting from inhalation or ingestion of spores of the fungus of the genus HISTOPLASMA, species H. capsulatum. It is worldwide in distribution and particularly common in the midwestern United States. (From Dorland, 27th ed)

Chromoblastomycosis -- Scaly papule or warty growth, caused by five fungi, that spreads as a result of satellite lesions affecting the foot or leg. The extremity may become swollen and, at its distal portion, covered with various nodular, tumorous, verrucous lesions that resemble cauliflower. In rare instances, the disease may begin on the hand or wrist and involve the entire upper extremity. (Arnold, Odom, and James, Andrew's Diseases of the Skin, 8th ed, p362)

Paracoccidioidomycosis -- A mycosis affecting the skin, mucous membranes, lymph nodes, and internal organs. It is caused by Paracoccidioides brasiliensis. It is also called paracoccidioidal granuloma. Superficial resemblance of P. brasiliensis to Blastomyces brasiliensis (BLASTOMYCES) may cause misdiagnosis.

skin infection -- Skin diseases caused by bacteria, fungi, parasites, or viruses.

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.
Hypersensitivity -- Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen.

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 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 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.
Branded Drugs
The following US Branded drugs contain Ketoconazole


EXTINA -- STIEFEL LABORATORIES INC

KETOZOLE -- TARO PHARMACEUTICALS USA INC

NIZORAL -- JANSSEN PHARMACEUTICA PRODUCTS LP

XOLEGEL -- STIEFEL LABORATORIES INC

NIZORAL -- ORTHO MCNEIL JANSSEN PHARMACEUTICALS INC

NIZORAL A-D -- MCNEIL CONSUMER HEALTHCARE


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