CLINDAMYCIN PHOSPHATE AND BENZOYL PEROXIDE
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Mylan Pharmaceuticals Inc.
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DESCRIPTION
Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% contains clindamycin phosphate, (7(S)-chloro-7-deoxylincomycin-2-phosphate). Clindamycin phosphate is a water soluble ester of the semi-synthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent antibiotic lincomycin.
Chemically, clindamycin phosphate is (C18H34ClN2O8PS). The structural formula for clindamycin is represented below:
Clindamycin phosphate has a molecular weight of 504.97 and its chemical name is Methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans- 4-propyl-L-2-pyrrolidinecarboxamido) - 1-thio-L- threo-alpha-D- galacto-octopyranoside 2-(dihydrogen phosphate).
Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% also contains benzoyl peroxide, for topical use.
Chemically, benzoyl peroxide is (C14H10O4). It has the following structural formula:
Benzoyl peroxide has a molecular weight of 242.23.
Each gram of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% contains, as dispensed, 10 mg (1%) clindamycin as phosphate and 50 mg (5%) benzoyl peroxide in a base of carbomer, propylene glycol, potassium hydroxide, and purified water.
CLINICAL PHARMACOLOGY
An in vitro percutaneous penetration study comparing ClindamycinPhosphate and Benzoyl Peroxide 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 ClindamycinPhosphate and Benzoyl Peroxide 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.
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.
CLINICAL STUDIES
In two adequate and well controlled clinical studies of 758 patients, 214 used Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5%, 210 used benzoyl peroxide, 168 used clindamycin, and 166 used vehicle. Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% applied twice daily for 10 weeks was significantly more effective than vehicle in the treatment of moderate to moderately severe facial acne vulgaris. Patients were evaluated and acne lesions counted at each clinical visit; weeks 2, 4, 6, 8 and 10. The primary efficacy measures were the lesion counts and the investigator’s global assessment evaluated at week 10. Patients were instructed to wash the face with a mild soap, using only the hands. Fifteen minutes after the face was thoroughly dry, application was made to the entire face. Non-medicated make-up could be applied at one hour after the Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% application. If a moisturizer was required, the patients were provided a moisturizer to be used as needed. Patients were instructed to avoid sun exposure. Percent reductions in lesion counts after treatment for 10 weeks in these two studies are shown below:
| Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% n = 120 | Benzoyl peroxide n = 120 | Clindamycin n = 120 | Vehicle n = 120 |
| Mean percent reduction in inflammatory lesion counts | |||
| 46% | 32% | 16% | +3% |
| Mean percent reduction in non-inflammatory lesion counts | |||
| 22% | 22% | 9% | +1% |
| Mean percent reduction in total lesion counts | |||
| 36% | 28% | 15% | 0.2% |
| Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% n = 95 | Benzoyl peroxide n = 95 | Clindamycin n = 49 | Vehicle n = 48 |
| Mean percent reduction in inflammatory lesion counts | |||
| 63% | 53% | 45% | 42% |
| Mean percent reduction in non-inflammatory lesion counts | |||
| 54% | 50% | 39% | 36% |
| Mean percent reduction in total lesion counts | |||
| 58% | 52% | 42% | 39% |
The Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% group showed greater overall improvement than the benzoyl peroxide, clindamycin and vehicle groups as rated by the investigator.
INDICATIONS AND USAGE
Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% is indicated for the topical treatment of acne vulgaris.
CONTRAINDICATIONS
Clindamycin Phosphate and Benzoyl Peroxide 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.
WARNINGS
ORALLY AND PARENTERALLY ADMINISTERED CLINDAMYCIN HAS BEENASSOCIATED WITH SEVERE COLITIS WHICH MAY RESULT IN PATIENTDEATH. USE OF THE TOPICAL FORMULATION OF CLINDAMYCIN RESULTSIN ABSORPTION OF THE ANTIBIOTIC FROM THE SKIN SURFACE. DIARRHEA,BLOODY DIARRHEA, AND COLITIS (INCLUDING PSEUDOMEMBRANOUSCOLITIS) HAVE BEEN REPORTED WITH THE USE OF TOPICAL ANDSYSTEMIC CLINDAMYCIN. STUDIES INDICATE A TOXIN(S) PRODUCED BYCLOSTRIDIA IS ONE PRIMARY CAUSE OF ANTIBIOTIC- ASSOCIATED COLITIS.THE COLITIS IS USUALLY CHARACTERIZED BY SEVERE PERSISTENTDIARRHEA AND SEVERE ABDOMINAL CRAMPS AND MAY BE ASSOCIATEDWITH THE PASSAGE OF BLOOD AND MUCUS. ENDOSCOPIC EXAMINATION MAY REVEAL PSEUDOMEMBRANOUS COLITIS. STOOL CULTUREFOR Clostridium Difficile AND STOOL ASSAY FOR C. difficile TOXIN MAYBE HELPFUL DIAGNOSTICALLY. WHEN SIGNIFICANT DIARRHEA OCCURS,THE DRUG SHOULD BE DISCONTINUED. LARGE BOWEL ENDOSCOPYSHOULD BE CONSIDERED TO ESTABLISH A DEFINITIVE DIAGNOSIS INCASES OF SEVERE DIARRHEA. ANTIPERISTALTIC AGENTS SUCH AS OPIATESAND DIPHENOXYLATE WITH ATROPINE MAY PROLONG AND/ORWORSEN THE CONDITION. DIARRHEA, COLITIS, AND PSEUDOMEMBRANOUSCOLITIS HAVE BEEN OBSERVED TO BEGIN UP TO SEVERAL WEEKSFOLLOWING CESSATION OF ORAL AND PARENTERAL THERAPY WITHCLINDAMYCIN.
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.
PRECAUTIONS
General
For dermatological use only; not for ophthalmic use. Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents.
The use of antibiotic agents may be associated with the overgrowth of nonsusceptible organisms including fungi. If this occurs, discontinue use of this medication and take appropriate measures.
Avoid contact with eyes and mucous membranes.
Clindamycin and erythromycin containing products should not be used in combination. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known.
Information for Patients
Patients using Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% should receive the following information and instructions:
- Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% is to be used as directed by the physician. It is for external use only. Avoid contact with eyes, and inside the nose, mouth, and all mucous membranes, as this product may be irritating.
- This medication should not be used for any disorder other than that for which it was prescribed.
- Patients should not use any other topical acne preparation unless otherwise directed by physician.
- Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using Clindamycin Phospate and Benzoyl Peroxide Gel, 1%/5%. To minimize exposure to sunlight, a wide-brimmed hat or other protective clothing should be worn, and a sunscreen with SPF 15 rating or higher should be used.
- Patients who develop allergic symptoms such as severe swelling or shortness of breath should discontinue Clindamycin Phosphate and Benzoly PeroxideGel, 1%/5% and contact their physician immediately. In addition, patients should report any signs of local adverse reactions to their physician.
- Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% may bleach hair or colored fabric.
- Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% can be stored at room temperature up to 25°C (77°F) for 3 months. Do not freeze. Discard any unused product after 3 months.
- Before applying Clindamycin Phosphate and Benzoyl Peroxide Gel,1%/5% to affected areas wash the skin gently, then rinse with warm water and pat dry.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Benzoyl peroxide has been shown to be a tumor promoter and progression agent in a number of animal studies. The clinical significance of this is unknown. Benzoyl peroxide in acetone at doses of 5 and 10 mg administered twice per week induced skin tumors in transgenic Tg.AC mice in a study using 20 weeks of topical treatment.
In a 52 week dermal photocarcinogenicity study in hairless mice, the median time to onset of skin tumor formation was decreased and the number of tumors per mouse increased following chronic concurrent topical administration of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% with exposure to ultraviolet radiation (40 weeks of treatment followed by 12 weeks of observation).
Genotoxicity studies were not conducted with Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5%. Clindamycin phosphate was not genotoxic in Salmonella typhimurium or in a rat micronucleus test. Clindamycin phosphate sulfoxide, an oxidative degradation product of clindamycin phosphate and benzoyl peroxide, was not clastogenic in a mouse micronucleus test. Benzoyl peroxide has been found to cause DNA strand breaks in a variety of mammalian cell types, to be mutagenic in S. typhimurium tests by some but not all investigators, and to cause sister chromatid exchanges in Chinese hamster ovary cells. Studies have not been performed with Clindamycin Phosphateand Benzoyl Peroxide Gel, 1%/5% or benzoyl peroxide to evaluate the effect on fertility. Fertility studies in rats treated orally with up to 300 mg/kg/day of clindamycin (approximately 120 times the amount of clindamycin in the highest recommended adult human dose of 2.5 grams Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5%, based on mg/m2) revealed no effects on fertility or mating ability.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Animal reproductive/developmental toxicity studies have not been conducted with Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% or benzoyl peroxide. Developmental toxicity studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (240 and 120 times amount of clindamycin in the highest recommended adult human dose based on mg/m2, respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (100 and 50 times the amount of clindamycin in the highest recommended adult human dose based on mg/m2, respectively) revealed no evidence of teratogenicity.
There are no well-controlled trials in pregnant women treated with ClindamycinPhosphate and Benzoyl Peroxide Gel, 1%/5%. It also is not known whether Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% can cause fetal harm when administered to a pregnant woman.
Nursing Women
It is not known whether Clindamycin Phosphate and Benzoyl Peroxide Gel,1%/5% is ex creted in human milk after topical application. 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 this product in pediatric patients below the age of 12 have not been established.
ADVERSE REACTIONS
During clinical trials, the most frequently reported adverse event in the Clindamycin Phosphate and Benzoyl Peroxide 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 Phosphate and Benzoyl Peroxide Gel, 1%/5% and vehicle groups.
| Clindamycin Phosphate and BenzoylPeroxide Gel, 1%/5% n = 420 | Vehicle n = 168 |
|
| Application Site Reaction | 13 (3%) | 1 (< 1%) |
| Dry Skin | 50 (12%) | 10 (6%) |
| Pruritis | 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.
DOSAGE AND ADMINISTRATION
Clindamycin Phosphate and Benzoyl Peroxide 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.
HOW SUPPLIED AND COMPOUNDING INSTRUCTIONS
| Size (Net Weight) | NDC # | Benzoyl Peroxide Gel | Clindamycin Phosphate Solution (in plastic bottle) |
| 50 grams | 0378-8688-54 | 40 grams | 10 grams |
Prior to dispensing, add the solution in the bottle to the gel and stir until homogenous in appearance (1 to 11⁄2 minutes). Clindamycin Phosphate andBenzoyl Peroxide Gel, 1%/5% can be stored at room temperature up to 25°C (77°F) for 3 months. Place a 3 month expiration date on the labeling immediately following mixing.
Store at room temperature up to 25°C (77°F) [See USP].
Do not freeze. Keep tightly closed. Keep out of the reach of children.
US Patents 5,733,886; 6,117,843
Distributed by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505
Manufactured by:
Contract Pharmaceuticals Ltd.
Buffalo, NY 14213
090068
REVISED JUNE 2009
DW-M-CLBZPX:R3
PRINCIPAL DISPLAY PANEL - 1%/5% GEL
NDC 0378-8688-54
CLINDAMYCIN PHOSPHATE and
BENZOYL PEROXIDE GEL, 1%*/5%
FOR TOPICAL USE ONLY
Rx only
One 50 gram Jar
(after admixing)
CLINDAMYCIN PHOSPHATE and
BENZOYL PEROXIDE GEL, 1%*/5%
Each gram of Clindamycin Phosphate and Benzoyl
Peroxide Gel, 1%*/5% as dispensed, contains 10 mg
(1%) *clindamycin as phosphate and 50 mg (5%)
benzoyl peroxide in a base of carbomer, propylene
glycol, potassium hydroxide, and purified water.
Usual Dosage: Apply twice daily, morning and eve-
ning, or as directed by physician, to affected areas
after the skin is gently washed, rinsed with warm
water an patted dry. See package insert for full
prescribing information. Use within 3 months after
mixing. Store at room temperature up to 25°C (77°F)
[see USP]. Do not freeze. Keep tightly closed.
Precautions: For external use only. Avoid contact
with eyes. Keep out of reach of children. May bleach
fabric or hair.
US Patents 5,733,886; 6,117,843
TO THE PHARMACIST:
Important: Prior to dispensing, add the solution in
the bottle to the gel and stir until homogenous in
appearance (1 to 1½ minutes). Clindamycin Phosphate
and Benzoyl Peroxide Gel, 1%/5% can be stored at room
temperature up to 25°C (77°F) for 3 months. Place a 3 month
expiration date on the labeling immediately following mixing.
Distributed by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505
Manufactured by:
Contract Pharmaceuticals Ltd.
Buffalo, NY 14213
DW-M-8688-2C:R3
| CLINDAMYCIN PHOSPHATE AND BENZOYL PEROXIDE
clindamycin phosphate and benzoyl peroxide kit |
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| ANDA | ANDA065443 | 12/11/2009 | |
| Labeler - Mylan Pharmaceuticals Inc. (059295980) |