Clindesse

6 ADVERSE REACTIONS Most common adverse reactions reported in ≥2% of patients and at a higher rate in the Clindesse group than in the placebo group are vaginosis fungal (14%), headache (7%), back pain (5%), constipation (2%), and urinary tract infection (2%) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Adverse Event Clindesse N=85 n (%) Placebo N=85 n (%) Vaginosis fungal NOS* 12 (14) 7 (8) Headache NOS 6 (7) 2 (2) Back Pain 4 (5) 1 (1) Constipation 2 (2) 0 (0) Urinary tract infection NOS 2 (2) 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 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 ( 12.1 )] . 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

4 CONTRAINDICATIONS • History of hypersensitivity to clindamycin or other lincosamides ( 4.1 ) • History of regional enteritis, ulcerative colitis, or a history of Clostridioides difficile- associated diarrhea ( 4.2 , 5.1 ) 4.1 Hypersensitivity Do not administer Clindesse 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 [see Adverse Reactions ( 6.2 )] . 4.2 History of Bowel Disease Do not administer Clindesse to patients with regional enteritis, ulcerative colitis, or a history of Clostridioides difficile -associated diarrhea.

11 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 C 18 H 34 CIN 2 O 8 PS. 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. Structural Formula

2 DOSAGE AND ADMINISTRATION The recommended dose is the complete contents of a single pre-filled applicator containing 5 g of Clindesse cream administered once intravaginally at any time of the day. Not for ophthalmic, dermal, or oral use. • For intravaginal use only • A single applicator of cream administered once intravaginally at any time of the day ( 2 ) • Not for ophthalmic, dermal, or oral use

1 INDICATIONS AND USAGE Clindesse is a lincosamide antibacterial indicated for the treatment of bacterial vaginosis in non-pregnant women ( 1.1 ) 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.

10 OVERDOSAGE Vaginally applied clindamycin phosphate vaginal cream 2% could be absorbed in sufficient amounts to produce systemic effects [see Warnings and Precautions (5.1) and Adverse Reactions ( 6.2 )] .

7 DRUG INTERACTIONS No formal drug interaction studies have been conducted for Clindesse. Neuromuscular blocking agents: Enhanced action of neuromuscular blocking agents can occur; use with caution ( 7.1 ) 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.

12 CLINICAL PHARMACOLOGY 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) AUC 0-inf and C max estimates were 175 (38.6 to 541) ng/mL•hr and 6.6 (0.8 to 39) ng/mL, respectively. The mean C max 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 )] .

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) AUC 0-inf and C max estimates were 175 (38.6 to 541) ng/mL•hr and 6.6 (0.8 to 39) ng/mL, respectively. The mean C max 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.

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3 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. One single-dose, pre-filled disposable applicator delivers approximately 5 g of cream containing approximately 100 mg of clindamycin ( 3 )

Clindesse clindamycin phosphate CLINDAMYCIN PHOSPHATE CLINDAMYCIN EDETATE DISODIUM GLYCERYL ISOSTEARATE LECITHIN, SOYBEAN METHYLPARABEN MICROCRYSTALLINE WAX MINERAL OIL POLYGLYCERYL-3 OLEATE PROPYLPARABEN SILICON DIOXIDE SORBITOL WATER

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.

13 NONCLINICAL TOXICOLOGY 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.

NDA050793

Clindesse

clindamycin phosphate

45802-042

HUMAN PRESCRIPTION DRUG

VAGINAL

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 )] .

Package/Label Display Panel - Carton Clindesse® (clindamycin phosphate) Vaginal Cream, 2% NDC 45802-042-01 Rx Only This applicator delivers approximately 5 g of vaginal cream containing approximately 100 mg of clindamycin. One complete course of therapy in a convenient, prefilled, and disposable applicator. NET WT 5.8 g The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation. carton serialization-template.jpg

17 PATIENT COUNSELING INFORMATION 17.1 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. 17.2 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. 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 )] . 17.3 Fungal Vaginal Infections Inform the patient that vaginal fungal infections can occur following use of Clindesse and may require treatment with an antifungal drug [see Adverse Reactions ( 6.1 )] . 17.4 Accidental Exposure to the Eye Inform the patient that Clindesse 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. Manufactured by Padagis ® Yeruham, Israel Patents at www.padagis.com/patents Cleocin is a registered trademark of Pharmacia & Upjohn Company. 2S000 RC PH5

14 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 % Cure Placebo N=66 % Cure Treatment Difference † (%) [97.5% Confidence Interval] 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] 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 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 % Cure Clindamycin Vaginal Cream (7 doses) N=211 % Cure Treatment Difference † (%) [95% Confidence Interval] 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] † 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) 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 % Cure Clindamycin Vaginal Cream (7 doses) N=125 % Cure Treatment Difference † (%) [95% Confidence Interval] 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] † 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

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.

8.3 Nursing Mothers Caution should be exercised when Clindesse 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.

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.

8.1 Pregnancy Pregnancy Category B Clindesse should be used during pregnancy only if clearly needed. There are no adequate and well-controlled studies of Clindesse 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 should be used during pregnancy only if clearly needed.

8 USE IN SPECIFIC POPULATIONS Nursing Mothers: Caution should be exercised when administered to a nursing woman ( 8.3 ) 8.1 Pregnancy Pregnancy Category B Clindesse should be used during pregnancy only if clearly needed. There are no adequate and well-controlled studies of Clindesse 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 should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers Caution should be exercised when Clindesse 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. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Clindesse (clindamycin phosphate) Vaginal Cream, 2%, is available in cartons containing one single-dose, pre-filled disposable applicator (NDC 45802-042-01). Each applicator delivers approximately 5 g of vaginal cream containing approximately 100 mg of clindamycin. Store at 20°-25°C (68°-77°F). [See USP Controlled Room Temperature.] Avoid heat above 30°C (86°F).