Evoclin foam, 1%

Pharmacokinetics:   In an open label, parallel group study in 24 patients with acne vulgaris, 12 patients (3 male and 9 female) applied 4 grams of Evoclin Foam once-daily for five days, and 12 patients (7 male and 5 female) applied 4 grams of Clindagel (clindamycin phosphate) Topical Gel, 1%, once daily for five days. On Day 5, the mean C max and AUC(0-12) were 23% and 9% lower, respectively, for Evoclin Foam than for Clindagel .

Following multiple applications of Evoclin Foam less than 0.024% of the total dose was excreted unchanged in the urine over 12 hours on Day 5.

Microbiology:   The clindamycin component has been shown to have in vitro activity against Propionibacterium acnes , an organism which is associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical trials with this product. Cross-resistance between clindamycin and erythromycin has been demonstrated.

Evoclin is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin, a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis.

Orally and parenterally administered clindamycin has been associated with severe colitis, which may result in patient death. Use of the topical formulation of clindamycin results in absorption of the antibiotic from the skin surface. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin.

Studies indicate a toxin(s) produced by Clostridia is one primary cause of antibiotic-associated colitis. The colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may be associated with the passage of blood and mucus. Endoscopic examination may reveal pseudomembranous colitis. Stool culture for Clostridium difficile and stool assay for C. difficile toxin may be helpful diagnostically.

When significant diarrhea occurs, the drug should be discontinued. Large bowel endoscopy should be considered to establish a definitive diagnosis in cases of severe diarrhea. Antiperistaltic agents, such as opiates and diphenoxylate with atropine, may prolong and/or worsen thecondition.

Diarrhea, colitis, and pseudomembranous colitis have been observed to begin up to several weeks following cessation of oral and parenteral therapy with clindamycin.

Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficile colitis.

Avoid contact of Evoclin with eyes. If contact occurs, rinse eyes thoroughly with water.

Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenicity of a 1% clindamycin phosphate gel similar to Evoclin was evaluated by daily application to mice for two years. The daily doses used in this study were approximately 3 and 15 times higher than the human dose of clindamycin phosphate from 5 milliliters of Evoclin, assuming complete absorption and based on a body surface area comparison. No significant increase in tumors was noted in the treated animals.

A 1% clindamycin phosphate gel similar to Evoclin caused a statistically significant shortening of the median time to tumor onset in a study in hairless mice in which tumors were induced by exposure to simulated sunlight.

Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative.

Reproduction studies in rats using oral doses of clindamycin hydrochloride and clindamycin palmitate hydrochloride have revealed no evidence of impaired fertility.

Pregnancy: Teratogenic effects - Pregnancy Category B

Reproduction studies have been performed in rats and mice using subcutaneous and oral doses of clindamycin phosphate, clindamycin hydrochloride and clindamycin palmitate hydrochloride. These studies revealed no evidence of fetal harm. The highest dose used in the rat and mouse teratogenicity studies was equivalent to a clindamycin phosphate dose of 432 mg/kg. For a rat, this dose is 84 fold higher, and for a mouse 42 fold higher, than the anticipated human dose of clindamycin phosphate from Evoclin based on a mg/m 2 comparison. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers:   It is not known whether clindamycin is excreted in human milk following use of Evoclin. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, 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 of Evoclin in children under the age of 12 have not been studied.

Geriatric Use:   The clinical study with Evoclin did not include sufficient numbers of patients aged 65 and over to determine if they respond differently than younger patients.

The incidence of adverse events occurring in >/=1% of the patients in clinical studies comparing Evoclin and its vehicle is presented below:

In a contact sensitization study, none of the 203 subjects developed evidence of allergic contact sensitization to Evoclin.

Orally and parenterally administered clindamycin has been associated with severe colitis, which may end fatally.

Cases of diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported as adverse reactions in patients treated with oral and parenteral formulations of clindamycin and rarely with topical clindamycin (see WARNINGS ). Abdominal pain and gastrointestinal disturbances, as well as gram-negative folliculitis, have also been reported in association with the use of topical formulations of clindamycin.

Topically applied Evoclin may be absorbed in sufficient amounts to produce systemic effects (see WARNINGS ).