Clindamycin Phosphate

CLINDAMYCIN PHOSPHATE- clindamycin phosphate gel
Oceanside Pharmaceuticals

DESCRIPTION

Clindamycin Phosphate Topical Gel, 1%, a topical antibiotic, contains clindamycin phosphate, USP, at a concentration equivalent to 10 mg clindamycin per gram in a gel vehicle consisting of carbomer 941, methylparaben, polyethylene glycol 400, propylene glycol, purified water, and sodium hydroxide. Chemically, clindamycin phosphate is a water-soluble ester of the semi-synthetic antibiotic produced by a 7 (S)-chlorosubstitution of the 7 (R)-hydroxyl group of the parent antibiotic, lincomycin, and has the structural formula represented below:

clindagel-01
(click image for full-size original)

The chemical name for clindamycin phosphate is methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans -4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo -α-D-galacto -octopyranoside 2-(dihydrogen phosphate).

CLINICAL PHARMACOLOGY

Pharmacokinetics: In an open-label, parallel group study of 24 patients with acne vulgaris, once-daily topical administration of approximately 3 to 12 grams/day of Clindamycin Phosphate Topical Gel for 5 days resulted in peak plasma clindamycin concentrations that were less than 5.5 ng/mL.

Following multiple applications of Clindamycin Phosphate Topical Gel less than 0.04% of the total dose was excreted in the urine.

Microbiology: Although clindamycin phosphate is inactive invitro, rapid invitro hydrolysis converts this compound to clindamycin, which has antibacterial activity. Clindamycin inhibits bacteria protein synthesis at the ribosomal level by binding to the 50S ribosomal subunit and affecting the process of peptide chain initiation. In vitro studies indicated that clindamycin inhibited all tested Propionibacterium acnes cultures at a minimum inhibitory concentration (MIC) of 0.4 mcg/mL. Cross-resistance has been demonstrated between clindamycin and erythromycin.

CLINICAL STUDIES

In one 12-week multicenter, randomized, evaluator-blind, vehicle-controlled, parallel comparison clinical trial in which patients used Clindamycin Phosphate Topical Gel, 1%, once daily or the vehicle gel once daily, in the treatment of acne vulgaris of mild to moderate severity, Clindamycin Phosphate Topical Gel applied once daily was more effective than the vehicle applied once daily. The mean percent reductions in lesion counts at the end of treatment in this study are shown in the following table:

Lesions Clindamycin Phosphate Topical Gel QD
N=162
Vehicle Gel QD
N=82
*
P<0.05

Inflammatory

51%

40%*

Noninflammatory

25%

12%*

Total

38%

27%*

There was a trend in the investigator’s global assessment of the results, which favored Clindamycin Phosphate Topical Gel QD over the vehicle QD.

In a contact sensitization study, four of the 200 subjects appeared to develop suggestive evidence of allergic contact sensitization to Clindamycin Phosphate Topical Gel. There was no signal for contact sensitization in the clinical trials under normal use conditions.

INDICATIONS AND USAGE

Clindamycin Phosphate Topical Gel is indicated for topical application in the treatment of acne vulgaris. In view of the potential for diarrhea, bloody diarrhea, and pseudomembranous colitis, the physician should consider whether other agents are more appropriate (see CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS).

CONTRAINDICATIONS

Clindamycin Phosphate Topical Gel 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.

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 .

PRECAUTIONS

General:

Clindamycin Phosphate Topical Gel should be prescribed with caution in atopic individuals.

Drug Interactions:

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 Clindamycin Phosphate Topical Gel was evaluated by daily application to mice for 2 years. The daily doses used in this study were approximately 3 and 15 times higher than the human dose of clindamycin phosphate from 5 mL of Clindamycin Phosphate Topical Gel, 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 Clindamycin Phosphate Topical Gel 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.

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