Name of the medicinal product

Clindesse

Qualitative and quantitative composition

Dosage Forms And Strengths

Clindesse is an intravaginal cream containing clindamycin phosphate 2%. Each pre-filled, single-dose applicator delivers approximately 5 g of cream containing approximately 100 mg of clindamycin.

Storage And Handling

Clindesse (clindamycin phosphate) Vaginal Cream, 2%, is available in cartons containing one single-dose, pre-filled disposable applicator (NDC 64011-124-08). Each applicator delivers approximately 5 g of vaginal cream containing approximately 100 mg of clindamycin.

Store at 20°-25°C (68°-77°F). Avoid heat above 30°C (86°F).

Manufactured by KV Pharmaceutical™ Co. for Ther-Rx™ Corporation. St. Louis, MO 63044. Revised: 12/2010

Therapeutic indications

Treatment of Bacterial Vaginosis

Clindesse (clindamycin phosphate) 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.

Dosage (Posology) and method of administration

The recommended dose is the complete contents of a single pre-filled applicator containing 5 g of Clindesse (clindamycin phosphate) cream administered once intravaginally at any time of the day.

Not for ophthalmic, dermal, or oral use.

Contraindications

Hypersensitivity

Do not administer Clindesse (clindamycin phosphate) to 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.

History of Bowel Disease

Do not administer Clindesse (clindamycin phosphate) to patients with regional enteritis, ulcerative colitis, or a history of Clostridium difficile-associated diarrhea.

Special warnings and precautions for use

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Clostridium difficile-Associated Diarrhea (CDAD)

Clostridium 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.

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 (clindamycin phosphate). During this time period, condoms may not be reliable for preventing pregnancy or for protecting against transmission of HIV and other sexually transmitted diseases.

Patient Counseling Information

Vaginal Intercourse and Use with Vaginal Products

Instruct the patient not to engage in vaginal intercourse, or use other vaginal products (such as tampons or douches) during treatment with this product.

Use with Condoms and Vaginal Contraceptive Diaphragms

Advise the patient that this cream contains mineral oil that may weaken latex or rubber products such as condoms or vaginal contraceptive diaphragms. Therefore, do not use barrier contraceptives concurrently or for 5 days following treatment with Clindesse (clindamycin phosphate). During this time period, condoms may not be reliable for preventing pregnancy or for protecting against transmission of HIV and other sexually transmitted diseases.

Fungal Vaginal Infections

Inform the patient that vaginal fungal infections can occur following use of Clindesse (clindamycin phosphate) and may require treatment with an antifungal drug.

Accidental Exposure to the Eye

Inform the patient that Clindesse (clindamycin phosphate) contains ingredients which cause burning and irritation of the eye. In the event of accidental contact with the eye, rinse the eye with copious amounts of cool tap water and consult a physician.

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.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Clindesse (clindamycin phosphate) should be used during pregnancy only if clearly needed. There are no adequate and well-controlled studies of Clindesse (clindamycin phosphate) in pregnant women.

Another intravaginal formulation containing 2% clindamycin phosphate has been studied in pregnant women during the second trimester. In women treated for seven days, abnormal labor was reported in 1.1% of patients who received that clindamycin vaginal cream formulation compared with 0.5% of patients who received placebo.

Reproduction studies have been performed in rats and mice using oral and parenteral 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.

Because animal reproduction studies are not always predictive of human response, Clindesse (clindamycin phosphate) should be used during pregnancy only if clearly needed.

Nursing Mothers

Caution should be exercised when Clindesse (clindamycin phosphate) is administered to a nursing woman. It is not known if clindamycin is excreted in human milk following the use of vaginally administered clindamycin. Clindamycin has been detected in human milk after oral or parenteral administration.

Because of the potential for serious adverse reactions in nursing infants, a decision to continue or discontinue nursing should take into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of Clindesse (clindamycin phosphate) 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 (clindamycin phosphate) in pre-menarchal females have not been established.

Geriatric Use

Clinical studies with Clindesse (clindamycin phosphate) 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.

Interaction with other medicinal products and other forms of interaction

SIDE EFFECTS

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

Adverse reactions occurring in ≥ 1% of patients receiving Clindesse (clindamycin phosphate) in the three clinical studies are shown in Table 1.

Table 1: Adverse Reactions Occurring in ≥ 1% of Clindesse (clindamycin phosphate) -Treated Patients and at a Higher Rate than Placebo-Treated Patients

Adverse Event	Clindesse (clindamycin phosphate) N=368 n (%)	Placebo N=85 n (%)
Vaginosis fungal NOS*	52 (14)	7 (8)
Headache NOS	10 (3)	2 (2)
Back pain	6 (2)	1 (1)
Constipation	4 (1)	0 (0)
Urinary tract infection NOS	4 (1)	0 (0)
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 (clindamycin phosphate) 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

Other Clindamycin Formulations

Clindesse (clindamycin phosphate) affords minimal peak serum levels and systemic exposure (AUCs) of clindamycin compared to an oral or intravenous dose of clindamycin. 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, Clostridium difficile-associated diarrhea

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.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Clindesse (clindamycin phosphate). 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

DRUG INTERACTIONS

No formal drug interaction studies have been conducted for Clindesse (clindamycin phosphate).

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.

Fertility, pregnancy and lactation

Pregnancy Category B

Clindesse (clindamycin phosphate) should be used during pregnancy only if clearly needed. There are no adequate and well-controlled studies of Clindesse (clindamycin phosphate) in pregnant women.

Another intravaginal formulation containing 2% clindamycin phosphate has been studied in pregnant women during the second trimester. In women treated for seven days, abnormal labor was reported in 1.1% of patients who received that clindamycin vaginal cream formulation compared with 0.5% of patients who received placebo.

Reproduction studies have been performed in rats and mice using oral and parenteral 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.

Because animal reproduction studies are not always predictive of human response, Clindesse (clindamycin phosphate) should be used during pregnancy only if clearly needed.

Undesirable effects

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

Adverse reactions occurring in ≥ 1% of patients receiving Clindesse (clindamycin phosphate) in the three clinical studies are shown in Table 1.

Table 1: Adverse Reactions Occurring in ≥ 1% of Clindesse (clindamycin phosphate) -Treated Patients and at a Higher Rate than Placebo-Treated Patients

Adverse Event	Clindesse (clindamycin phosphate) N=368 n (%)	Placebo N=85 n (%)
Vaginosis fungal NOS*	52 (14)	7 (8)
Headache NOS	10 (3)	2 (2)
Back pain	6 (2)	1 (1)
Constipation	4 (1)	0 (0)
Urinary tract infection NOS	4 (1)	0 (0)
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