Grisoral

Grisoral-PEG® (Grisoraleofulvin ultramicrosize) is indicated for the treatment of the following ringworm infections; tinea corporis (ringworm of the body), tinea pedis (athlete's foot), tinea cruris (ringworm of the groin and thigh), tinea barbae (barber's itch), tinea capitis (ringworm of the scalp), and tinea unguium (onychomycosis, ringworm of the nails), when caused by one or more of the following genera of fungi: Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, Trichophyton interdigitalis,Trichophyton verrucosum, Trichophyton megnini, Trichophyton gallinae, Trichophyton crateriform, Trichophyton sulphureum, Trichophyton schoenleini, Microsporum audouini, Microsporum canis, Microsporum gypseum and Epidermophyton floccosum. NOTE: Prior to therapy, the type of fungi responsible for the infection should be identified. The use of the drug is not justified in minor or trivial infections which will respond to topical agents alone. Grisoraleofulvin is not effective in the following: bacterial infections, candidiasis (moniliasis), histoplasmosis, actinomycosis, sporotrichosis, chromoblastomycosis, coccidioidomycosis, North American blastomycosis, cryptococcosis (torulosis), tinea versicolor and nocardiosis.

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 credits 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. Grisoraleofulvin will not eradicate the bacterial or monilial infection. Grisoral-PEG® tablets 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 Grisoraleofulvin 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 Grisoraleofulvin 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.

Two cases of conjoined twins have been reported since 1977 in patients taking Grisoraleofulvin during the first trimester of pregnancy. Grisoraleofulvin should not be prescribed to pregnant patients. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

This drug is contraindicated in patients with porphyria or hepatocellular failure and in individuals with a history of hypersensitivity to Grisoraleofulvin.

WARNINGS

Prophylactic Usage

Safety and efficacy of Grisoraleofulvin 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 Grisoraleofulvin use. These reactions may be serious and may result in hospitalization or death. If severe skin reactions occur, Grisoraleofulvin should be discontinued (see ADVERSE REACTIONS section).

Hepatotoxicity

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

PRECAUTIONS

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 Grisoraleofulvin is derived from species of Penicillium, the possibility of cross sensitivity with penicillin exists; however, known penicillin-sensitive patients have been treated without difficulty. Since a photosensitivity reaction is occasionally associated with Grisoraleofulvin therapy, patients should be warned to avoid exposure to intense natural or artificial sunlight. Lupus erythematosus or lupus-like syndromes have been reported in patients receiving Grisoraleofulvin. Grisoraleofulvin decreases the activity of warfarin-type anticoagulants so that patients receiving these drugs concomitantly may require dosage adjustment of the anticoagulant during and after Grisoraleofulvin therapy. Barbiturates usually depress Grisoraleofulvin activity and concomitant administration may require a dosage adjustment of the antifungal agent. There have been reports in the literature of possible interactions between Grisoraleofulvin and oral contraceptives. The effect of alcohol may be potentiated by Grisoraleofulvin, producing such effects as tachycardia and flush.

There have been post-marketing reports of severe skin and hepatic adverse events associated with Grisoraleofulvin use (see WARNINGS section).

When adverse reactions occur, they are most commonly of the hypersensitivity type such as skin rashes, urticaria, erythema multiforme-like drug reactions, and rarely, angioneurotic edema, and may necessitate withdrawal of therapy and appropriate countermeasures. Paresthesia of the hands and feet have been reported after extended therapy. 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 and leukopenia have been reported rarely. Administration of the drug should be discontinued if granulocytopenia occurs. When rare, serious reactions occur with Grisoraleofulvin, they are usually associated with high dosages, long periods of therapy, or both.

To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

No information provided.

Following oral administration, Grisoraleofulvin 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 Grisoraleofulvin is approximately one and one-half times that of the conventional microsize Grisoraleofulvin. This factor permits the oral intake of two-thirds as much ultramicrocrystalline Grisoraleofulvin 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.

In a bioequivalence study conducted in healthy volunteers (N=24) in the fasted state, 250 mg ultramicrocrystalline Grisoraleofulvin tablets were compared with 250 mg ultramicrocrystalline Grisoraleofulvin tablets that were physically altered (crushed) and administered with applesauce. The 250 mg ultramicrocrystalline Grisoraleofulvin tablets were found to be bioequivalent to the physically altered (crushed) 250 mg ultramicro-crystalline Grisoraleofulvin tablets (See Table 1).

Table 1: Mean (± SD) of the Pharmacokinetic Parameters for Grisoraleofulvin administered in applesauce as a Single Dose of Grisoral-PEG® 250-mg Tablets Uncrushed and Crushed to fasted Healthy Volunteers (N=24)