Clindamycin and Benzoyl Peroxide

INDICATIONS AND USAGE Clindamycin and benzoyl peroxide topical gel, 1%/5% is indicated for the topical treatment of acne vulgaris.

DOSAGE AND ADMINISTRATION Clindamycin and benzoyl peroxide topical gel, 1%/5% should be applied twice daily, morning and evening, or as directed by a physician, to affected areas after the skin is gently washed, rinsed with warm water and patted dry.

WARNINGS 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 THE CONDITION. 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.

CONTRAINDICATIONS Clindamycin and benzoyl peroxide topical gel, 1%/5% is contraindicated in those individuals who have shown hypersensitivity to any of its components or to lincomycin. It is also contraindicated in those having a history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis.

ADVERSE REACTIONS During clinical trials, the most frequently reported adverse event in the clindamycin and benzoyl peroxide topical gel, 1%/5% treatment group was dry skin (12%). The Table below lists local adverse events reported by at least 1% of patients in the clindamycin and benzoyl peroxide topical gel, 1%/5% and vehicle groups. Local Adverse Events – all causalities in >/= 1% of patients Clindamycin and benzoyl peroxide topical gel, 1%/5% n=420 Vehicle n=168 Application site reaction 13 (3%) 1 (<1%) Dry skin 50 (12%) 10 (6%) Pruritus 8 (2%) 1 (<1%) Peeling 9 (2%) - Erythema 6 (1%) 1 (<1%) Sunburn 5 (1%) - The actual incidence of dry skin might have been greater were it not for the use of a moisturizer in these studies. Anaphylaxis, as well as allergic reactions leading to hospitalization, have been reported during post-marketing use of clindamycin/benzoyl peroxide products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

CLINICAL PHARMACOLOGY An in vitro percutaneous penetration study comparing clindamycin and benzoyl peroxide topical gel, 1%/5% and topical 1% clindamycin gel alone, demonstrated there was no statistical difference in penetration between the two drugs. Mean systemic bioavailability of topical clindamycin in clindamycin and benzoyl peroxide topical gel, 1%/5% is suggested to be less than 1%. Benzoyl peroxide has been shown to be absorbed by the skin where it is converted to benzoic acid. Less than 2% of the dose enters systemic circulation as benzoic acid. It is suggested that the lipophilic nature of benzoyl peroxide acts to concentrate the compound into the lipid-rich sebaceous follicle. Pharmacokinetics: The pharmacokinetics (plasma and urine) of clindamycin from clindamycin and benzoyl peroxide topical gel, 1%/5% was studied in male and female patients (n=13) with acne vulgaris. Clindamycin and benzoyl peroxide topical gel, 1%/5% (~2g) was applied topically to the face and back twice daily for four and a half (4.5) days. Quantifiable (>LOQ=1ng/mL) clindamycin plasma concentrations were obtained in six of thirteen subjects (46.2%) on Day 1 and twelve of thirteen subjects (92.3%) on Day 5. Peak plasma concentrations (C max ) of clindamycin ranged from 1.47 ng/mL to 2.77 ng/mL on Day 1 and 1.43 ng/mL to 7.18 ng/mL on Day 5. The AUC (0-12h) ranged from 2.74 ng.h/mL to 12.86 ng.h/mL on Day 1 and 11.4 ng.h/mL to 69.7 ng.h/mL on Day 5. The amount of clindamycin excreted in the urine during the 12 hour dosing interval increased from a mean (SD) of 5745 (3130) ng on Day 1 to 12069 (7660) ng on Day 5. The mean % (SD) of the administered dose that was excreted in the urine ranged from 0.03% (0.02) to 0.08% (0.04). A comparison of the single (Day 1) and multiple (Day 5) dose plasma and urinary concentrations of clindamycin indicates that there is accumulation of clindamycin following multiple dosing of clindamycin and benzoyl peroxide topical gel, 1%/5%. The degree of accumulation calculated from the plasma and urinary excretion data was ~2-fold. Microbiology: The clindamycin and benzoyl peroxide components individually have been shown to have in vitro activity against Propionibacterium acnes an organism which has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical trials with this product.