GRISEOFULVIN: 132 Adverse Event Reports & Safety Profile

DESCRIPTION Ultramicrosize Griseofulvin Tablets, USP contain ultramicrosize crystals of griseofulvin, an antibiotic derived from a species of Penicillium . Griseofulvin crystals are partly dissolved in polyethylene glycol 8000 and partly dispersed throughout the label matrix.

Each Ultramicrosize Griseofulvin

Tablet, USP contains 165 mg ultramicrosize griseofulvin, USP. The inactive ingredients for Ultramicrosize Griseofulvin Tablets, USP include: corn starch, lactose anhydrous, magnesium stearate, polyethylene glycol 8000, and sodium lauryl sulfate.

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Microbiology Griseofulvin is fungistatic with in vitro activity against various species of Microsporum, Epidermophyton , and Trichophyton . It has no effect on bacteria or on other genera of fungi.

Human Pharmacology

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. The efficiency of gastrointestinal absorption of ultramicrocrystalline griseofulvin is approximately one and one-half times that of the conventional microsize griseofulvin. This factor permits the oral intake of two-thirds as much ultramicrocrystalline griseofulvin as the microsize form. However, there is currently no evidence that this lower dose confers any significant clinical differences with regard to safety and/or efficacy.

INDICASTIONS 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.

DOSAGE AND ADMINISTRATION Accurate diagnosis of 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 athlete's foot, yeasts and bacteria may be involved as well as fungi. Griseofulvin will not eradicate the bacterial or monilial infection.

Ultramicrosize Griseofulvin

Tablets, USP may be swallowed whole or crushed and sprinkled onto 1 tablespoonful of applesauce and swallowed immediately without chewing. Adults: Daily administration of 375 mg (as a single dose or in divided doses) will give a satisfactory response in most patients with tinea corporis, tinea cruris, and tinea capitis. For those fungal infections more difficult to eradicate, such as tinea pedis and tinea unguium, a divided dose of 750 mg is recommended.

Pediatric

Use: Approximately 7.3 mg per kg of body weight per day of ultramicrosize griseofulvin is an effective dose for most pediatric patients. On this basis, the following dosage schedule is suggested: 16-27 kg: 125 mg to 187.5 mg daily. over 27 kg: 187.5 mg to 375 mg daily Children and infants 2 years of age and younger - dosage has not been established. Clinical experience with griseofulvin in children with tinea capitis indicates that a single daily dose is effective. Clinical relapse will occur if the medication is not continued until the infecting organism is eradicated.

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 1,000 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 1,000 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.

ADVERSE REACTIONS There have been post-marketing 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 Sigmapharm Laboratories, LLC, Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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).

Animal

Toxicology - Chronic feeding of griseofulvin, at levels ranging from 0.5%-2.5% of the diet resulted in the development of liver tumors in several strains of mice, particularly in males. Smaller particle sizes result 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 grisoefulvin at levels of 2.0%, 1.0% and 0.2% of the diet, and in female rats receiving the two higher dose levels. Although studies in other animal species have not yielded evidence of tumorigenicity, these studies were not of adequate design to form a basis for conclusion in this regard. In subacute toxicity studies, orally administered griseofulvin produced hepatocellular necrosis in mice, but this has not been seen in other species. Disturbances in porphyrin metabolism have been reported in griseofulvin-treated laboratory animals. Griseofulvin has been reported to have colchicine-like effect on mitosis and cocarcinogenicity with methylcholanthrene in cutaneous tumor induction in laboratory animals. Usage in Pregnancy - see CONTRAINDICATIONS section.

Animal Reproduction

Studies - It has been reported in the literature that griseofulvin was found to be embryotoxic and teratogenic on oral administration to pregnant rats. Pups with abnormalities have been reported in the litters of a few bitches treated with griseofulvin. Suppression of spermatogenesis has been reported to occur in rats, but investigation in man failed to confirm this.

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.

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.