Griseofulvin (Page 2 of 3)

WARNINGS

Prophylactic Usage:
Safety and efficacy of griseofulvin for prophylaxis of fungal infections have not been established.

Serious Skin Reactions:
Severe skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis) and erythema multiforme have been reported with griseofulvin use. These reactions may be serious and may result in hospitalization or death. If severe skin reactions occur, griseofulvin should be discontinued (see ADVERSE REACTIONS section).

Hepatotoxicity:
Elevations in AST, ALT, bilirubin, and jaundice have been reported with griseofulvin use. These reactions may be serious and may result in hospitalization or death. Patients should be monitored for hepatic adverse events and discontinuation of griseofulvin considered if warranted (see ADVERSE REACTIONS section).

PRECAUTIONS

General:
Patients on prolonged therapy with any potent medication should be under close observation. Periodic monitoring of organ system function, including renal, hepatic and hematopoietic, should be done.

Since griseofulvin is derived from species of penicillin, the possibility of cross sensitivity with penicillin exists; however, known penicillin-sensitive patients have been treated without difficulty.

Lupus erythematosus, lupus-like syndromes or exacerbation of existing lupus erythematosus have been reported in patients receiving griseofulvin.

Since a photosensitivity reaction is occasionally associated with griseofulvin therapy, patients should be warned to avoid exposure to intense or prolonged natural or artificial sunlight.

Drug Interactions:

Griseofulvin has been reported in the literature to interfere with the metabolism of various compounds. Whether this is due to a P-450 mediated enzyme induction effects on sulfurtransferase and/or glucotransferase activity, or some other mechanism is unknown.

Griseofulvin decreases the activity of warfarin-type anticoagulants, so that patients receiving these drugs concomitantly may require dosage adjustment of the anticoagulant during and after griseofulvin therapy.

Griseofulvin may enhance the hepatic metabolism of estrogens, including the estrogen component of oral contraceptives, thereby reducing the effectiveness of contraception and causing menstrual irregularities. Therefore, an alternate or second form of birth control may be indicated during periods of concurrent use (see also CONTRAINDICATIONS).

Cyclosporine levels may be reduced when administered concomitantly with griseofulvin, resulting in a decrease in the pharmacologic effects of cyclosporine.

Serum salicylate concentrations may be decreased when griseofulvin is given concomitantly with salicylates.

Barbiturates usually depress griseofulvin activity by decreasing plasma levels and concomitant administration may require a dosage adjustment of the antifungal agent.

Nausea, vomiting, flushing, tachycardia, and severe hypotension have been reported following alcohol ingestion during griseofulvin therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

In subacute toxicity studies, orally administered griseofulvin produced hepatocellular necrosis in mice, but this has not been seen in other species. Chronic feeding of griseofulvin, at levels ranging from 0.5 to 2.5% of the diet, resulted in the development of liver tumors in several strains of mice, particularly in males. Smaller particle sizes resulted in an enhanced effect. Lower oral-dosage levels have not been tested. Subcutaneous administration of relatively small doses of griseofulvin once a week during the first three weeks of life has also been reported to induce hepatomata in mice. Thyroid tumors, mostly adenomas but some carcinomas, have been reported in male rats receiving griseofulvin at levels of 2.0%, 1.0%, and 0.2% of the diet, and in female rats receiving the two higher dose levels. Studies in other animal species were inadequate assessments of tumorigenicity.

Disturbances in porphyrin metabolism have been reported in griseofulvin-treated laboratory animals. Griseofulvin has been reported to have a colchicine-like effect on mitosis and was cocarcinogenic with methylcholanthrene in cutaneous tumor induction in laboratory animals. Griseofulvin interferes with chromosomal distribution during cell division, causing aneuploidy in plant and mammalian cells. These effects have been demonstrated in vitro at concentrations that may be achieved in the serum with the recommended therapeutic dosage.

Suppression of spermatogenesis has been reported to occur in rats and sperm abnormalities have been observed in griseofulvin treated mice, but these were not detected in man. Male patients should wait at least six months after completing griseofulvin therapy before fathering a child.

Pregnancy:

Teratogenic Effects: Pregnancy Category X: See CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions

Nursing Mothers:

It is not known if griseofulvin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for griseofulvin in animal studies (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:

Safety and effectiveness in pediatric patients 2 years of age and younger have not been established. Safety in pediatric patients older than 2 years of age at dosages greater than 10 mg/kg daily has not been established.

ADVERSE REACTIONS

There have been postmarketing reports of severe skin and hepatic adverse events associated with griseofulvin use (see WARNINGS section).

When adverse reactions occur, they are most commonly of the hypersensitivity type, such as skin rashes, urticaria, and rarely, angioneurotic edema, and erythema multiforme. These may necessitate withdrawal of therapy and appropriate countermeasures. Peripheral neuropathy and paresthesias of the hands and feet have been reported and may be related to treatment duration. Most patients treated with griseofulvin for less than six months experienced improvement or resolution of their neuropathy upon withdrawal of the griseofulvin. Other side effects reported occasionally are oral thrush, nausea, vomiting, epigastric distress, diarrhea, headache, fatigue, dizziness, insomnia, mental confusion and impairment of performance of routine activities.
Proteinuria, nephrosis (sometimes associated with existing systemic lupus erythematosus), leukopenia, coagulopathy, hepatitis, elevated liver enzymes, hyperbilirubinemia, and GI bleeding have been reported rarely. Administration of the drug should be discontinued if granulocytopenia occurs.

To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

OVERDOSAGE

There is limited experience on overdose with griseofulvin. In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures as required.

DOSAGE AND ADMINISTRATION

Accurate diagnosis of the infecting organism is essential. Identification should be made either by direct microscopic examination of a mounting of infected tissue in a solution of potassium hydroxide or by culture on an appropriate medium.

Medication must be continued until the infecting organism is completely eradicated as indicated by appropriate clinical or laboratory examination. Representative treatment periods are tinea capitis, 4 to 6 weeks; tinea corporis, 2 to 4 weeks; tinea pedis, 4 to 8 weeks; tinea unguium-depending on rate of growth-fingernails, at least 4 months; toenails, at least 6 months.

General measures in regard to hygiene should be observed to control sources of infection or reinfection. Concomitant use of appropriate topical agents is usually required, particularly in treatment of tinea pedis. In some forms of tinea pedis, yeasts and bacteria may be involved as well as dermatophytes. Griseofulvin will not eradicate these associated bacterial or yeast infections.

Adults: 0.5 g daily (125 mg four times a day, 250 mg twice a day, or 500 mg/day). Patients with less severe or 300 extensive infections may require less, whereas those with widespread lesions may require a starting dose of 0.75 g to 1.0 g/day. This may be reduced gradually to 0.5 g or less after a response has been noted. In all cases, the dosage should be individualized.

Pediatric patients (older than 2 years): A dosage of 10 mg/kg daily is usually adequate (pediatric patients from 30 to 50 lbs, 125 mg to 250 mg daily; pediatric patients over 50 lbs, 250 mg to 500 mg daily, in divided doses). Dosage should be individualized, as with adults. Clinical relapse will occur if the medication is not continued until the infecting organism is eradicated.

Safety is not established at higher doses than recommended.

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