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Clindesse (Clindamycin Phosphate Vaginal) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Clindamycin phosphate, a lincosamide, 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. 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-(alpha)-D-galacto-octopyranoside 2-(dihydrogen phosphate). It has a molecular weight of 504.96, and the molecular formula is C18H34CIN2O8PS. The structural formula is represented below:

Clindesse is a semi-solid, white cream, which contains clindamycin phosphate, USP, at a concentration equivalent to 20 mg clindamycin base per gram. The cream also contains edetate disodium, glycerol monoisostearate, lecithin, methylparaben, microcrystalline wax, mineral oil, polyglyceryl-3-oleate, propylparaben, purified water, silicon dioxide and sorbitol solution.

Clindesse does not comply with the pH test of the USP monograph for clindamycin phosphate vaginal cream.

CLINICAL PHARMACOLOGY

Mechanism of Action

Clindamycin is an antibacterial drug [see Clinical Pharmacology, Microbiology ]

Pharmacokinetics

Following a single intravaginal application of Clindesse cream to 20 healthy women, the mean (range) AUC0-inf and Cmax estimates were 175 (38.6 to 541) ng/mL• hr and 6.6 (0.8 to 39) ng/mL, respectively. The mean Cmax of clindamycin for Clindesse was approximately 0.3%, 0.1%, and 7.6% of that observed after the administration of a 150 mg Cleocin oral capsule (2.5 mcg/mL), a 600 mg Cleocin intravenous injection (10.9 mcg/mL), and a single dose of 100 mg of Cleocin Vaginal Cream (86.5 ng/mL), respectively. The peak serum concentration of clindamycin was attained approximately 20 hours post dosing for Clindesse.

Microbiology

Mechanism of Action

Clindamycin inhibits bacterial protein synthesis at the level of the bacterial ribosome. The antibiotic binds preferentially to the 50S ribosomal subunit and affects the process of peptide chain initiation. Although clindamycin phosphate is inactive in vitro, in vivo hydrolysis converts this compound to the antibacterially active clindamycin.

Activity In Vitro

Clindamycin is an antibacterial agent active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis:
Bacteroides spp.
Gardnerella vaginalis
Mobiluncus spp.
Mycoplasma hominis
Peptostreptococcus spp.

Standard methodology for the susceptibility testing of the potential bacterial vaginosis pathogens has not been defined. Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis [see Clinical Studies].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential. Genotoxicity tests performed included a rat micronucleus test and an Ames test. Both tests were negative. Fertility studies in rats treated orally with up to 300 mg/kg/day (29 times the recommended human dose based on body surface area comparisons) revealed no effects on fertility or mating ability.

CLINICAL STUDIES

Two clinical studies were conducted to evaluate the efficacy of Clindesse for the treatment of bacterial vaginosis. A clinical diagnosis of bacterial vaginosis was defined by the presence of a homogeneous vaginal discharge that (a) has a pH of greater than 4.5, (b) emits a "fishy" amine odor when mixed with a 10% KOH solution, and (c) contains clue cells on microscopic examination. Gram’s stain results consistent with a diagnosis of bacterial vaginosis include (a) markedly reduced or absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype, and (c) absent or few white blood cells.

In a randomized, double-blind, placebo-controlled, clinical study involving 144 non-pregnant female patients aged 18 to 64 with a baseline Nugent score ≥4, Clindesse demonstrated statistically significantly higher cure rates over placebo as measured by therapeutic cure, clinical cure, and Nugent score cure (Table 2) assessed at 21-30 days after administration of the drug. Therapeutic cure was a composite endpoint which required both clinical cure and Nugent score cure. Clinical cure required normal vaginal discharge, vaginal pH <4.7, <20% clue cells on wet mount preparation, and negative "whiff" test (detection of amine odor on addition of 10% KOH solution to sample of the vaginal discharge). A Nugent score of 0-3 was considered a Nugent score cure. The Nugent scoring is based on microscopic examination of the Gram’s stained vaginal smears for quantification of specific bacterial morphotypes. Cure rates were consistently higher for Clindesse compared to placebo for the following demographic subsets: age, race, height, weight, sexual behavior, and recalcitrant infection status.

Table 2. Efficacy of Clindesse for Treatment of Bacterial Vaginosis in a Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study
Outcome

Clindesse

N=78

Placebo

N=66

Treatment Difference (%)

[97.5% Confidence Interval]

  % Cure % Cure  
N = number of patients in treatment group (modified intent-to-treat population defined as all subjects randomized who received at least one dose of study medication, and who had a baseline Nugent score of at least 4)
†Treatment difference = Clindesse minus placebo cure rates
Therapeutic Cure 29.5 3.0 26.5 [14.0, 39.0]
Clinical Cure 41.0 19.7 21.3 [4.7, 38.0]
Nugent Score Cure 44.9 6.1 38.8 [24.6, 53.1]

In a second controlled clinical study involving 432 patients aged 18 to 78 with a baseline Nugent score of ≥4, 221 women self-administered a single dose of Clindesse, and 211 women self-administered a single daily dose of a formulation of clindamycin vaginal cream for 7 days. A single dose of Clindesse was shown to be similar to 7 daily doses of the clindamycin vaginal cream for treatment of bacterial vaginosis as measured by therapeutic cure, clinical cure or Nugent score cure assessed at 21-30 days after administration of the drug in the modified intent-to-treat population (Table 3) and for the per protocol population (Table 4). The study endpoints were identical to those described above for the placebo-controlled study. Statistical analyses did not reveal any significant differences when controlling for the following demographic variables: age, race, height, weight, sexual behavior, and recalcitrant infection status.

The cure rates reported in the clinical studies with Clindesse were based on resolution of 4 out of 4 Amsel criteria and a Nugent score of <4, while the criteria for cure in previous clinical studies with the clindamycin vaginal cream were based solely on resolution of 2 out of 4 Amsel criteria, resulting in higher reported rates of cure for bacterial vaginosis.

Table 3. Efficacy of Clindesse in Treatment of Bacterial Vaginosis in a Randomized, Investigator-Blind, Active-Controlled Comparative Study – Modified-Intent-to-Treat
Outcome

Clindesse

Single Dose

N=221

Clindamycin Vaginal Cream
(7 doses)

N=211

Treatment Difference (%)

[95% Confidence Interval]

  % Cure % Cure  
†Treatment difference = Clindesse minus clindamycin vaginal cream cure rates
N = number of patients in treatment group (modified intent-to-treat population defined as all subjects randomized who received at least one dose of study medication, and who had a baseline Nugent score of at least 4)
Therapeutic Cure 33.0 37.0 -3.9 [-12.9, 5.1]
Clinical Cure 53.4 54.0 -0.6 [-10.0, 8.8]
Nugent Score Cure 45.7 49.3 -3.6 [-13.1, 5.8]
Table 4. Efficacy of Clindesse in Treatment of Bacterial Vaginosis in a Randomized, Investigator-Blind, Active-Controlled Comparative Study – Per Protocol
Outcome

Clindesse

Single Dose

N=126

Clindamycin Vaginal Cream
(7 doses)

N=125

Treatment Difference (%) [95% Confidence Interval]
  % Cure % Cure  
† Treatment difference = Clindesse minus clindamycin vaginal cream cure rates
N = number of patients in treatment group (per protocol population defined as all subjects included in the modified intent-to-treat population who completed the study without significant protocol violation)
Four subjects (2 from each treatment group) did not have complete Nugent scores and were not included in the Nugent Score cure analysis
Therapeutic Cure 42.1 45.6 -3.5 [-15.8, 8.7]
Clinical Cure 64.3 63.2 1.1 [-10.8, 13.0]
Nugent Score Cure 56.5 57.7 -1.3 [-13.6, 11.1]

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