1.1 Treatment of Bacterial Vaginosis

Clindesse is indicated for the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis) in non-pregnant women.

4.1 Hypersensitivity

Clindesse is contraindicated in individuals with a history of hypersensitivity to clindamycin or other lincosamides. Reported reactions to other formulations of clindamycin include rashes, urticaria, erythema multiforme, and anaphylactoid reactions [see Adverse Reactions (6.2)].

4.2 History of Bowel Disease

Clindesse is contraindicated in patients with regional enteritis, ulcerative colitis, or a history of Clostridioides difficile-associated diarrhea.

5.1 Clostridioides difficile-Associated Diarrhea (CDAD)

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated [see Adverse Reactions (6.2)].

5.2 Use with Condoms and Vaginal Contraceptive Diaphragms

This cream contains mineral oil that may weaken latex or rubber products such as condoms or vaginal contraceptive diaphragms. Therefore, the use of such barrier contraceptives is not recommended concurrently or for 5 days following treatment with Clindesse. During this time period, condoms may not be reliable for preventing pregnancy or for protecting against transmission of HIV and other sexually transmitted diseases [see Use in Specific Populations (8.3)].

6.1 Clinical Study Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Clindesse in 368 patients. Clindesse was studied in three clinical studies: placebo-controlled (n=85), active-controlled (n=263), and single-arm (n=20). The population was female, aged 18 to 78, who were diagnosed with bacterial vaginosis. Patient demographics in the trials were 51% Caucasian, 36% Black, 10% Hispanic, and 3% Asian, other or unknown. All patients received 100 mg clindamycin phosphate cream intravaginally in a single dose.

Of the 368 women treated with a single dose of Clindesse, 1.6% of the patients discontinued therapy due to adverse reactions. Adverse reactions occurred in 126 of 368 patients (34%) treated with Clindesse and in 32 of 85 patients (38%) treated with placebo.

Adverse reactions occurring in ≥2% of patients receiving Clindesse in the placebo-controlled clinical trial are shown in Table 1.

Table 1. Adverse Reactions Occurring in ≥2% of Clindesse-Treated Patients and at a Higher Rate than Placebo-Treated Patients

N = number of patients in intent-to-treat population

n (%) = number and percentage of patients with reported adverse reaction

NOS = not otherwise specified

 

*The use of clindamycin may result in the overgrowth of non-susceptible fungal organisms in the vagina and may require antifungal treatment

 

Other reactions reported by <1% of those women treated with Clindesse include:

 

Dermatologic: Pruritic rash

 

Gastrointestinal: Diarrhea, vomiting

 

General: Fatigue

 

Immune System: Hypersensitivity

 

Nervous System: Dizziness

 

Reproductive System: Dysfunctional uterine bleeding, dysmennorrhea, intermenstrual bleeding, pelvic pain, vaginal burning, vaginal irritation, vulvar erythema, vulvitis, vulvovaginal discomfort, vulvovaginal dryness, vulvovaginitis

6.2 Other Clindamycin Formulations

Clindesse affords minimal peak serum levels and systemic exposure (AUCs) of clindamycin compared to an oral or intravenous dose of clindamycin [see Clinical Pharmacology (12.3)]. Data from well-controlled trials directly comparing clindamycin administered orally to clindamycin administered vaginally are not available.

The following additional adverse reactions and altered laboratory tests have been reported with the oral or parenteral use of clindamycin:

Gastrointestinal: Abdominal pain, esophagitis, nausea, Clostridioides difficile-associated diarrhea [see Warnings and Precautions (5.1)].

Hematopoietic: Transient neutropenia (leukopenia), eosinophilia, agranulocytosis, and thrombocytopenia have been reported. No direct etiologic relationship to concurrent clindamycin therapy could be made in any of these reports.

Hypersensitivity Reactions: Maculopapular rash, vesiculobullous rash, and urticaria have been observed during drug therapy. Generalized mild to moderate morbilliform-like skin rashes are the most frequently reported of all adverse reactions. Cases of erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with clindamycin. A few cases of anaphylactoid reactions have been reported.

Liver: Jaundice and abnormalities in liver function tests have been observed during clindamycin therapy.

Musculoskeletal: Cases of polyarthritis have been reported.

Renal: Although no direct relationship of clindamycin to renal damage has been established, renal dysfunction as evidenced by azotemia, oliguria, and/or proteinuria has been observed in rare instances.

Immune System: Drug reaction with eosinophilia and systemic symptoms (DRESS) cases have been reported.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Clindesse. 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.

Dermatologic: Rash

Gastrointestinal: Hematochezia

Reproductive System: Vaginal erythema, vulvovaginal pruritis, vaginal discharge, vaginal swelling, vaginal bleeding, vaginal pain

7.1 Neuromuscular Blocking Agents

Orally or intravenously administered clindamycin has 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.

8.1 Pregnancy

Risk Summary

Clindesse has not been studied in pregnant women. The systemic exposure (based on AUC and Cmax) of Clindesse administered intravaginally is substantially lower than clindamycin administered intravenously [see Clinical Pharmacology (12.3)]; therefore, maternal use is not likely to result in significant fetal exposure to the drug. Available data from published observational studies and randomized controlled trials over decades of use with other clindamycin products during pregnancy have not identified an increased risk of major birth defects, miscarriage, or other adverse maternal and fetal outcomes.

In animal reproduction studies, no adverse developmental outcomes were observed in pregnant rats and mice administered oral doses of clindamycin at up to 600 mg/kg/day (58 and 29 times, respectively, the recommended human dose based on a body surface area comparison) (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Reproduction studies have been performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (58 and 29 times, respectively, the recommended human dose based on body surface area comparisons) and have revealed no evidence of harm to the fetus due to clindamycin.

8.2 Lactation

Risk Summary

The systemic exposure (based on AUC and Cmax) of Clindesse is substantially lower than intravenous administration of clindamycin [see Clinical Pharmacology (12.3)]; therefore, adverse effects on the breastfed infant are not expected from transfer of clindamycin into breastmilk. There are no data on the effect of clindamycin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Clindesse and any potential adverse effects on the breastfed infant from Clindesse or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

Clindesse contains mineral oil that may weaken latex or rubber products such as condoms or vaginal contraceptive diaphragms. Therefore, the use of such barrier contraceptives is not recommended concurrently or for 5 days following treatment with Clindesse. During this time period, condoms may not be reliable for preventing pregnancy or for protecting against transmission of HIV and other sexually transmitted diseases [see Warnings and Precautions (5.2)].

8.4 Pediatric Use

The safety and efficacy of Clindesse in the treatment of bacterial vaginosis in post-menarchal females have been established on the extrapolation of clinical trial data from adult women. The safety and efficacy of Clindesse in pre-menarchal females have not been established.

8.5 Geriatric Use

Clinical studies with Clindesse did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

12.1 Mechanism of Action

Clindamycin is an antibacterial drug [see Clinical Pharmacology, Microbiology (12.4)].

12.3 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.

12.4 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 (14)].

13.1 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.