Clindacin

6 ADVERSE REACTIONS The most common adverse reactions (>1%) are headache and application site reactions including burning, pruritus, and dryness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Medimetriks at 1-973-882-7512 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 clinical practice. A total of 439 subjects with mild to moderate acne vulgaris were treated once daily for 12 weeks with clindamycin phosphate foam. The incidence of adverse reactions occurring in ≥1% of the subjects in clinical trials comparing clindamycin phosphate foam and its vehicle is presented in Table 1. Table 1: Adverse Reactions Occurring in ≥ 1% of Subjects Adverse Reactions Number (%) of Subjects Clindamycin Phosphate Foam N = 439 Vehicle Foam N = 154 Headache 12 (3%) 1 (1%) Application site burning 27 (6%) 14 (9%) Application site pruritus 5 (1%) 5 (3%) Application site dryness 4 (1%) 5 (3%) Application site reaction, not otherwise specified 3 (1%) 4 (3%) In a contact sensitization study, none of the 203 subjects developed evidence of allergic contact sensitization to clindamycin phosphate foam. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of clindamycin phosphate foam: application site pain, application site erythema, diarrhea, urticaria, abdominal pain, hypersensitivity, rash, abdominal discomfort, nausea, seborrhea, application site rash, dizziness, pain of skin, colitis (including pseudomembranous colitis), and hemorrhagic diarrhea. 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. Abdominal pain and gastrointestinal disturbances, as well as gram-negative folliculitis, have also been reported in association with the use of topical formulations of clindamycin. Orally and parenterally administered clindamycin have been associated with severe colitis, which may end fatally.

4 CONTRAINDICATIONS Clindacin Foam is contraindicated in individuals with a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis (including pseudomembranous colitis). Clindacin Foam is contraindicated in individuals with a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis (including pseudomembranous colitis). ( 4 )

11 DESCRIPTION Clindacin Foam contains clindamycin (1%) as clindamycin phosphate. Clindamycin phosphate 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 -α-D- galacto -octopyranoside 2-(dihydrogen phosphate). The structural formula for clindamycin phosphate is represented below: Molecular Formula: C 18 H 34 CIN 2 O 8 PS Molecular Weight: 504.97 g/mol Clindacin Foam contains clindamycin (1%) as clindamycin phosphate, USP at a concentration equivalent to 10 mg clindamycin per gram in a thermolabile hydroethanolic foam vehicle consisting of cetyl alcohol, ethanol (58%), polysorbate 60, propylene glycol, purified water, and stearyl alcohol pressurized with a hydrocarbon (propane/butane) propellant. Chemical Structure

2 DOSAGE AND ADMINISTRATION Clindacin Foam is for topical use only, and not for oral, ophthalmic or intravaginal use. Apply Clindacin Foam once daily to affected areas after the skin is washed with mild soap and allowed to fully dry. Use enough to cover the entire affected area. If there has been no improvement after 6 to 8 weeks or if the condition becomes worse, treatment should be discontinued. The contents of Clindacin Foam are flammable; avoid fire, flame and/or smoking during and immediately following application. For topical use only; not for oral, ophthalmic, or intravaginal use. ( 2 ) Apply Clindacin Foam once daily to affected areas. ( 2 ) Flammable; avoid fire, flame and/or smoking during and immediately following application. ( 2 )

1 INDICATIONS AND USAGE Clindacin ® (clindamycin phosphate) Foam, 1% is indicated for topical application in the treatment of acne vulgaris in patients 12 years and older. Clindacin Foam is a lincosamide product indicated for acne vulgaris in patients 12 years and older. ( 1 )

7 DRUG INTERACTIONS 7.1 Erythromycin Clindamycin phosphate foam should not be used in combination with topical or oral erythromycin-containing products due to possible antagonism to its clindamycin component. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known. 7.2 Neuromuscular Blocking Agents Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, clindamycin phosphate foam should be used with caution in patients receiving such agents.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Mechanism of action of clindamycin in acne vulgaris is unknown [see Microbiology (12.4) ] . 12.2 Pharmacodynamics Pharmacodynamics of clindamycin phosphate foam is unknown. 12.3 Pharmacokinetics In an open label, parallel group study in 24 subjects with acne vulgaris, 12 subjects (3 male and 9 female) applied 4 grams of clindamycin phosphate foam once-daily for five days, and 12 subjects (7 male and 5 female) applied 4 grams of a clindamycin gel, 1%, once daily for five days. On Day 5, the mean C max and AUC (0-12) were 23% and 9% lower, respectively, for clindamycin phosphate foam than for the clindamycin gel, 1%. Following multiple applications of clindamycin phosphate foam, less than 0.024% of the total dose was excreted unchanged in the urine over 12 hours on Day 5. 12.4 Microbiology No microbiology studies were conducted in the clinical trials with this product. Clindamycin binds to the 50S ribosomal subunits of susceptible bacteria and prevents elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing protein synthesis. Clindamycin has been shown to have in vitro activity against Propionibacterium acnes ( P. acnes ), an organism that has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical studies with clindamycin phosphate foam. P. acnes resistance to clindamycin has been documented. Inducible Clindamycin Resistance: The treatment of acne with antimicrobials is associated with the development of antimicrobial resistance in P. acnes as well as other bacteria (e.g. Staphylococcus aureus, Streptococcus pyogenes ). The use of clindamycin may result in developing inducible resistance in these organisms. This resistance is not detected by routine susceptibility testing. Cross Resistance: Resistance to clindamycin is often associated with resistance to erythromycin.

12.1 Mechanism of Action Mechanism of action of clindamycin in acne vulgaris is unknown [see Microbiology (12.4) ] .

12.2 Pharmacodynamics Pharmacodynamics of clindamycin phosphate foam is unknown.

12.3 Pharmacokinetics In an open label, parallel group study in 24 subjects with acne vulgaris, 12 subjects (3 male and 9 female) applied 4 grams of clindamycin phosphate foam once-daily for five days, and 12 subjects (7 male and 5 female) applied 4 grams of a clindamycin gel, 1%, once daily for five days. On Day 5, the mean C max and AUC (0-12) were 23% and 9% lower, respectively, for clindamycin phosphate foam than for the clindamycin gel, 1%. Following multiple applications of clindamycin phosphate foam, less than 0.024% of the total dose was excreted unchanged in the urine over 12 hours on Day 5.

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3 DOSAGE FORMS AND STRENGTHS Clindacin Foam is a white to off-white thermolabile foam. Clindacin Foam contains 10 mg of clindamycin as clindamycin phosphate, USP per gram. Foam containing 1% clindamycin as clindamycin phosphate. ( 3 )

Clindacin clindamycin phosphate clindamycin phosphate clindamycin alcohol polysorbate 60 propylene glycol water stearyl alcohol cetyl alcohol

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenicity of a 1.2% clindamycin phosphate gel similar to clindamycin phosphate foam was evaluated by daily topical administration to mice for two years. The topical doses used in this study were approximately 3 and 15 times higher than the MRHD of clindamycin phosphate from clindamycin phosphate foam, based on BSA comparison and assuming 100% absorption. No significant increase in tumors was noted in the treated animals. The genotoxic potential of clindamycin was evaluated in an in vitro Ames assay and in an in vivo rat micronucleus 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenicity of a 1.2% clindamycin phosphate gel similar to clindamycin phosphate foam was evaluated by daily topical administration to mice for two years. The topical doses used in this study were approximately 3 and 15 times higher than the MRHD of clindamycin phosphate from clindamycin phosphate foam, based on BSA comparison and assuming 100% absorption. No significant increase in tumors was noted in the treated animals. The genotoxic potential of clindamycin was evaluated in an in vitro Ames assay and in an in vivo rat micronucleus 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.

ANDA090785

Clindacin

clindamycin phosphate

43538-179

HUMAN PRESCRIPTION DRUG

TOPICAL

12.4 Microbiology No microbiology studies were conducted in the clinical trials with this product. Clindamycin binds to the 50S ribosomal subunits of susceptible bacteria and prevents elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing protein synthesis. Clindamycin has been shown to have in vitro activity against Propionibacterium acnes ( P. acnes ), an organism that has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical studies with clindamycin phosphate foam. P. acnes resistance to clindamycin has been documented. Inducible Clindamycin Resistance: The treatment of acne with antimicrobials is associated with the development of antimicrobial resistance in P. acnes as well as other bacteria (e.g. Staphylococcus aureus, Streptococcus pyogenes ). The use of clindamycin may result in developing inducible resistance in these organisms. This resistance is not detected by routine susceptibility testing. Cross Resistance: Resistance to clindamycin is often associated with resistance to erythromycin.

PRINCIPAL DISPLAY PANEL - 100 g Can Carton NDC 43538-179-10 Rx Only Clindacin ® (Clindamycin Phosphate) Foam, 1% MEDIMETRIKS PHARMACEUTICALS, INC. 100 g PRINCIPAL DISPLAY PANEL - 100 g Can Carton

Manufactured for: MEDIMETRIKS PHARMACEUTICALS, INC. 383 Route 46 West • Fairfield, NJ 07004-2402 US • www.medimetriks.com Manufactured by Padagis, Yeruham, Israel Iss: 4/22 IP053 4T500 EK J1

17 PATIENT COUNSELING INFORMATION See FDA-Approved patient labeling (Patient Information) . 17.1 Instructions for Use Patients should be advised to wash their skin with mild soap and allow it to dry before applying Clindacin Foam. Patients should use enough Clindacin Foam to cover the face and to apply once daily. Patients should dispense Clindacin Foam directly into the cap or onto a cool surface. Patients should wash their hands after applying Clindacin Foam. 17.2 Skin Irritation Clindacin Foam may cause irritation such as erythema, scaling, itching, burning, or stinging. Patients should be advised to discontinue use if excessive irritancy or dermatitis occur. 17.3 Colitis In the event a patient treated with Clindacin Foam experiences severe diarrhea or gastrointestinal discomfort, Clindacin Foam should be discontinued and a physician should be contacted.

Instructions for Use Clindacin ® (klin-da-sin) (clindamycin phosphate) (klin-da-MYE-sin fos-fate) Foam, 1% Important Information: Clindacin Foam is for use on the skin only. Do not use Clindacin Foam in your eyes, mouth or vagina. Step 1: Remove the clear cap from the Clindacin Foam can. Step 2: Hold the can upright and firmly press the nozzle to dispense Clindacin Foam into the clear cap. Dispense enough Clindacin Foam to cover the entire affected area. If the can seems warm or the foam seems runny, run the can under cold water. Step 3: Pick up small amounts of Clindacin Foam with your fingertips and gently rub the foam into the affected area until the foam disappears. Step 4: Wash your hands after applying Clindacin Foam. Throw away any of the unused medicine that you dispensed out of the can. How should I store Clindacin Foam? Store Clindacin Foam at room temperature between 68°F to 77°F (20°C to 25°C). Keep Clindacin Foam away from heat. Never throw the can into a fire, even if the can is empty. Do not store Clindacin Foam at temperatures above 120°F (49°C). Do not break through (puncture) the Clindacin Foam can. Keep Clindacin Foam and all medicines out of the reach of children. The Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Manufactured for: MEDIMETRIKS PHARMACEUTICALS, INC. 383 Route 46 West • Fairfield, NJ 07004-2402 US • www.medimetriks.com Manufactured by Padagis, Yeruham, Israel Iss: 04/22 IP053 4T500 EK J1 Image Image Image Image Image

14 CLINICAL STUDIES In one multicenter, randomized, double-blind, vehicle-controlled clinical trial, subjects with mild to moderate acne vulgaris used clindamycin phosphate foam or the vehicle foam once daily for twelve weeks. Treatment response, defined as the proportion of subjects clear or almost clear, based on the Investigator Static Global Assessment (ISGA), and the mean percent reductions in lesion counts at the end of treatment in this study are shown in Table 2. Table 2: Efficacy Results at Week 12 Efficacy Parameters Clindamycin Phosphate Foam N = 386 Vehicle Foam N = 127 Treatment response (ISGA) 31% 18% P<0.05 Percent reduction in lesion counts Inflammatory Lesions 49% 35% Noninflammatory Lesions 38% 27% Total Lesions 43% 31%

8.5 Geriatric Use The clinical study with clindamycin phosphate foam did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently than younger subjects.

8.4 Pediatric Use Safety and effectiveness of clindamycin phosphate foam in children under the age of 12 have not been studied.

8.1 Pregnancy Risk Summary There are no available data on clindamycin phosphate foam use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Animal reproduction studies have not been conducted with clindamycin phosphate foam. No evidence of fetal harm or malformations was observed in pregnant rats and mice administered daily subcutaneous or oral doses of clindamycin salts during organogenesis at doses that produced exposures up to 84 and 42 times, respectively, the maximum recommended human dose (MRHD) of clindamycin phosphate foam based on body surface area (BSA) comparisons and assuming 100% absorption [see Data ] . 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 conducted in rats and mice using subcutaneous or oral doses of clindamycin phosphate, clindamycin hydrochloride or clindamycin palmitate hydrochloride administered daily during organogenesis at doses up to the equivalent of 432 mg/kg/day clindamycin phosphate. These studies produced no evidence of fetal harm or malformations in rats or mice at exposures 84 or 42 times, respectively, the MRHD of clindamycin phosphate (i.e., 5 milliliters of clindamycin phosphate foam) based on BSA comparison and assuming 100% absorption.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on clindamycin phosphate foam use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Animal reproduction studies have not been conducted with clindamycin phosphate foam. No evidence of fetal harm or malformations was observed in pregnant rats and mice administered daily subcutaneous or oral doses of clindamycin salts during organogenesis at doses that produced exposures up to 84 and 42 times, respectively, the maximum recommended human dose (MRHD) of clindamycin phosphate foam based on body surface area (BSA) comparisons and assuming 100% absorption [see Data ] . 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 conducted in rats and mice using subcutaneous or oral doses of clindamycin phosphate, clindamycin hydrochloride or clindamycin palmitate hydrochloride administered daily during organogenesis at doses up to the equivalent of 432 mg/kg/day clindamycin phosphate. These studies produced no evidence of fetal harm or malformations in rats or mice at exposures 84 or 42 times, respectively, the MRHD of clindamycin phosphate (i.e., 5 milliliters of clindamycin phosphate foam) based on BSA comparison and assuming 100% absorption. 8.2 Lactation Risk Summary There is no information on the presence of clindamycin in human milk, or the effects on the breast-fed child, or the effects on milk production following use of clindamycin phosphate foam. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for clindamycin phosphate foam and any potential adverse effects on the breast-fed child from clindamycin phosphate foam or from the underlying maternal condition. Clinical Considerations If used during lactation and clindamycin phosphate foam is applied to the chest, care should be taken to avoid accidental ingestion by the infant. 8.4 Pediatric Use Safety and effectiveness of clindamycin phosphate foam in children under the age of 12 have not been studied. 8.5 Geriatric Use The clinical study with clindamycin phosphate foam did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently than younger subjects.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Clindacin ® (clindamycin phosphate) Foam, 1% contains 10 mg of clindamycin as clindamycin phosphate, USP per gram. The white to off-white thermolabile foam is available as follows: 100 gram aerosol can - NDC 43538- 179 -10 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Flammable. Avoid fire, flame or smoking during and immediately following application. Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store at temperature above 120°F (49°C). Keep out of reach of children.

16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Flammable. Avoid fire, flame or smoking during and immediately following application. Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store at temperature above 120°F (49°C). Keep out of reach of children.