Griseofulvin

GRISEOFULVIN- griseofulvin tablet
Sandoz Inc

DESCRIPTION

Griseofulvin tablets, USP (microsize) contains griseofulvin microsize for oral administration. The active ingredient, griseofulvin, is a fungistatic antibiotic, derived from a species of Penicillium. The chemical name of griseofulvin is 7-chloro-2’,4,6-trimethoxy-6’β-methylspiro[benzofuran-2(3H),1’-[2]cyclohexane]-3-4’-dione. Its structural formula is:

Griseofulvin occurs as a white to creamy white, bitter tasting powder which is very slightly soluble in water and sparingly soluble in alcohol. Griseofulvin microsize contains particles of approximately 2 to 4 µm in diameter.

Griseofulvin tablets, USP (microsize) are available as follows:

250 mg, white to off-white round, flat, beveled edge, scored tablets engraved with ‘I27’ on one side and score on the other.

500 mg, white to off-white round, flat, beveled edge, scored tablets engraved with ‘I26’ on one side and score on the other.

Each tablet contains 250 mg or 500 mg of griseofulvin microsize, and also contains calcium stearate, colloidal silicon dioxide, corn starch, crospovidone, dibasic calcium phosphate, and sodium starch glycolate.

CLINICAL PHARMACOLOGY

Griseofulvin absorption from the gastrointestinal tract varies considerably among individuals, mainly because of insolubility of the drug in aqueous media of the upper GI tract. Drug absorption has been estimated to range between 27 and 72%. After an oral dose, griseofulvin is primarily absorbed from the duodenum with some absorption occurring from the jejunum and ileum. The peak serum level in fasting adults given 0.5 g of griseofulvin microsize occurs at about four hours and ranges between 0.5 to 2 mcg/mL. The serum level may be increased by giving the drug with a meal with a high fat content. In one study in pediatric patients 19 months to 11 years of age, 10 mg/kg of griseofulvin microsize given with milk resulted in mean peak serum concentrations approximately four-fold greater than the same griseofulvin dose given alone (1.29 mcg/mL versus 0.34 mcg/mL, respectively). Also, the area under the curve value was ten-fold larger when 10 mg/kg griseofulvin and milk were administered simultaneously as compared to the same dosage given to fasting patients. In addition, griseofulvin administered with milk resulted in more consistently detected serum levels across subjects.

Following oral administration, griseofulvin is deposited in the keratin precursor cells and has a greater affinity for diseased tissue. The drug is tightly bound to the new keratin which becomes highly resistant to fungal invasions. When the drug is discontinued, griseofulvin concentrations in the skin decline less rapidly than those in plasma. Griseofulvin is metabolized by the liver to 6-desmethylgriseofulvin and its glucuronide conjugate.

Griseofulvin has a variable elimination half-life in plasma (9 to 24 hours). Approximately 30% of a single oral dose of griseofulvin is excreted in the urine within 24 hours and about 50% of the dose is excreted in the urine within 5 days, mostly in the form of metabolites. Unchanged griseofulvin in the urine accounts for less than 1% of the administered dose. In addition, approximately one-third of a single dose of griseofulvin is excreted in feces within 5 days. Griseofulvin is also excreted in perspiration.

Microbiology

Mechanism of Action

The mechanism of griseofulvin consists of binding microtubular proteins, which are required for mitosis.

Activity In Vivo

Griseofulvin may be active against most strains of the following dermatophytes as described in the INDICATIONS AND USAGE section:

Epidermophyton floccosum, Microsporum audouinii, Microsporum canis, Microsporum gypseum, Trichophyton crateriformis, Trichophyton gallinae, Trichophyton interdigitalis, Trichophyton megnini, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton sulphureum, Trichophyton schoenleini, Trichophyton tonsurans and Trichophyton verrucosum.

It has no effect on bacteria or on other genera of fungi.

Activity In Vitro

In vitro , griseofulvin has been shown to have activity against many dermatophytes, but the clinical significance is unknown.

Drug Resistance

Although there have been reports of dermatophyte resistance to griseofulvin, the clinical significance is unknown.

INDICATIONS AND USAGE

Griseofulvin tablets, USP are indicated for the treatment of dermatophyte infections of the skin not adequately treated by topical therapy, hair and nails, namely:

Tinea corporis

Tinea pedis

Tinea cruris

Tinea barbae

Tinea capitis

Tinea unguium when caused by one or more of the following species of fungi:

Epidermophyton floccosum

Microsporum audouinii

Microsporum canis

Microsporum gypseum

Trichophyton crateriform

Trichophyton gallinae

Trichophyton interdigitalis

Trichophyton megnini

Trichophyton mentagrophytes

Trichophyton rubrum

Trichophyton schoenleini

Trichophyton sulphureum

Trichophyton tonsurans

Trichophyton verrucosum

Note: Prior to therapy, a dermatophyte should be identified as responsible for the infection.

Prior to initiating treatment, appropriate specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis.

Griseofulvin tablets, USP are not effective in the following:

Bacterial infections

Candidiasis (Moniliasis)

Histoplasmosis

Actinomycosis

Sporotrichosis

Chromoblastomycosis

Coccidioidomycosis

North American Blastomycosis

Cryptococcosis (Torulosis)

Tinea versicolor

Nocardiosis

The use of this drug is not justified in minor or trivial dermatophyte infections which will respond to topical agents alone.

CONTRAINDICATIONS

Griseofulvin is contraindicated in patients with porphyria or hepatocellular failure, and in individuals with a history of hypersensitivity to griseofulvin.

Griseofulvin may cause fetal harm when administered to a pregnant woman. Two published cases of conjoined twins have been reported in patients taking griseofulvin during the first trimester of pregnancy, therefore, griseofulvin is contraindicated in women who are or may become pregnant during treatment. Women taking estrogen-containing oral contraceptives may be at increased risk of becoming pregnant while on griseofulvin (see also PRECAUTIONS, Drug Interactions). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Although no direct causal relationship has been established, spontaneous abortion has been reported rarely coincident with the use of griseofulvin.

Note: The Maximum Recommend Human Dose (MRHD) was set at 500 mg/day for the multiple of human exposure calculations performed in this label. If higher doses than 500 mg/day were used clinically, then the multiple of human exposure would be correspondingly reduced for that dose. For example, if a 1000 mg/day dose was administered to an individual, then the multiple of human exposure would be reduced by a factor of 2.

Griseofulvin has been shown to be embryotoxic and teratogenic in pregnant rats when given at a daily oral dose of 250 mg/kg/day [4X the Maximum Recommended Human Dose (MRHD) based on Body Surface Area (BSA)]. Griseofulvin also has been shown to be embryotoxic and teratogenic in pregnant cats treated weekly with griseofulvin at doses of 500 to 1000 mg/week. There are reports of teratogenicity in a Golden Retriever when doses of 750 mg/day [1.2X the MRHD based on BSA] were administered for four weeks prior to and throughout the pregnancy, and in a study in which beagles were administered 35 mg/kg/day [1.9X the MRHD based on BSA] for intervals from one week up to the entire gestation period. Teratogenicity was also seen in mice when griseofulvin was administered in doses equivalent to 5g/kg/day [40X the MRHD based on BSA] for 2 consecutive days at various stages of the pregnancy.