Clindamycin Phosphate and Benzoyl Peroxide

1 INDICATIONS AND USAGE Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% is a combination of clindamycin phosphate (a lincosamide antibacterial) and benzoyl peroxide indicated for the topical treatment of inflammatory acne vulgaris. ( 1.1 ) Limitation of Use: Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% has not been demonstrated to have any additional benefit when compared with benzoyl peroxide alone in the same vehicle when used for the treatment of non-inflammatory acne. ( 1.2 ) 1.1 Indication Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% is indicated for the topical treatment of inflammatory acne vulgaris in patients 12 years and older. 1.2 Limitations of Use Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% has not been demonstrated to have any additional benefit when compared with benzoyl peroxide alone in the same vehicle when used for the treatment of non-inflammatory acne.

2 DOSAGE AND ADMINISTRATION Before applying Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/2.5%, wash your face gently with a mild soap, rinse with warm water, and pat your skin dry. Apply a pea-sized amount of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/2.5% to the face once daily. Avoid the eyes, mouth, mucous membranes, or areas of broken skin. Use of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/2.5% beyond 12 weeks has not been evaluated. Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents. Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/2.5% is not for oral, ophthalmic, or intravaginal use. • Apply a pea-sized amount of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/2.5% to the face once daily. (2) • Not for oral, ophthalmic, or intravaginal use. (2)

3 DOSAGE FORMS AND STRENGTHS Gel, 1.2%/5% Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% is a white to slightly yellow, opaque gel. Each gram of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% contains 12 mg clindamycin phosphate (equivalent to 10 mg of clindamycin) and 50 mg benzoyl peroxide. Gel, 1.2%/5%: Each gram of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% contains 12 mg clindamycin phosphate (equivalent to 10 mg of clindamycin) and 50 mg benzoyl peroxide. ( 3 )

4 CONTRAINDICATIONS Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% is contraindicated in: • Patients who have demonstrated hypersensitivity (e.g., anaphylaxis) to clindamycin, benzoyl peroxide, any components of the formulation, or lincomycin. ( 4 ) • Patients with a history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis (including pseudomembranous colitis). ( 4 ) 4.1 Hypersensitivity Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% is contraindicated in those individuals who have shown hypersensitivity to clindamycin, benzoyl peroxide, any components of the formulation, or lincomycin. Anaphylaxis, as well as allergic reactions leading to hospitalization, has been reported in postmarketing use with clindamycin phosphate and benzoyl peroxide gel, 1.2%/5% [ see Adverse Reactions ( 6.2 ) ]. 4.2 Colitis/Enteritis Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% is contraindicated in those individuals with a history of regional enteritis, ulcerative colitis, pseudomembranous colitis, or antibiotic-associated colitis [ see Warnings and Precautions ( 5.1 ) ].

6 ADVERSE REACTIONS The following adverse reaction is described in more detail in the Warnings and Precautions section of the label: Colitis [see Warnings and Precautions ( 5.1 )]. The most common local adverse reactions (≥5%) are erythema, peeling, dryness and burning. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. During clinical trials, 397 subjects used Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% once daily for 11 weeks for the treatment of moderate to moderately severe facial acne vulgaris. All subjects were graded for facial local skin reactions (erythema, peeling, burning, and dryness) on the following scale: 0 = absent, 1 = mild, 2 = moderate, and 3 = severe. The percentage of subjects that had symptoms present before treatment (at baseline) and during treatment is presented in Table 1. Table 1. Local Skin Reactions with Use of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% Combined Results from Five Trials (n = 397) % of Subjects Using Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% with Symptom Present Before Treatment (Baseline) During Treatment Symptom Mild Moderate Severe Mild Moderate Severe Erythema 28% 3% 0 26% 5% 0 Peeling 6% <1% 0 17% 2% 0 Burning 3% <1% 0 5% <1% 0 Dryness 6% <1% 0 15% 1% 0 (Percentages derived by number of subjects receiving Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% with symptom score/number of enrolled subjects receiving Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5%. 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. Anaphylaxis, as well as allergic reactions leading to hospitalization, has been reported in postmarketing use with Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5%. Urticaria, application site reactions, including discoloration have been reported.

7 DRUG INTERACTIONS • Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% should not be used in combination with erythromycin-containing products because of its clindamycin component. ( 7.1 ) 7.1 Erythromycin Avoid using Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% in combination with erythromycin-containing products due to its clindamycin component. In vitro studies have shown antagonism between erythromycin and clindamycin. The clinical significance of this in vitro antagonism is not known. 7.2 Concomitant Topical Medications Concomitant topical acne therapies should be used with caution since a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents. If irritancy or dermatitis occurs, reduce frequency of application or temporarily interrupt treatment and resume once the irritation subsides. Treatment should be discontinued if the irritation persists. 7.3 Neuromuscular Blocking Agents Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/5% should be used with caution in patients receiving such agents. 7.4 Topical Sulfone Products Use of topical benzoyl-peroxide-containing preparations with topical sulfone products may cause skin and facial hair to temporarily change color (yellow/orange).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/3.75% use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The limited published data on use of clindamycin in pregnant women with exposure during the first trimester are insufficient to inform a drug-associated risk of pregnancy-related adverse outcomes (see Data) . In limited published clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters has not been associated with an increased frequency of major birth defects. In animal reproduction studies, clindamycin did not cause malformations or embryo-fetal development toxicity in pregnant rats and mice when administered during the period of organogenesis at systemic doses up to 240 times the maximum recommended human dose (MRHD) of 2.5 g Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/3.75%, based on body surface area (BSA) comparisons (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and 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 Human Data In limited published trials in pregnant women administered clindamycin during the first trimester of pregnancy, there was no difference in the rate of major birth defects reported among in utero exposed infants compared to unexposed infants. These data cannot definitely establish or exclude any clindamycin-associated risk during pregnancy. Animal Data Animal reproductive/developmental toxicity studies have not been conducted with Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/3.75% or benzoyl peroxide. Developmental toxicity studies of clindamycin performed in pregnant rats and mice administered during the period of organogenesis at oral doses of up to 600 mg/kg/day (240 and 120 times the MRHD for clindamycin, respectively, based on BSA comparisons) or subcutaneous doses of up to 200 mg/kg/day (80 and 40 times the MRHD for clindamycin, respectively, based on BSA comparisons) revealed no malformations or embryo-fetal development toxicity. 8.2 Lactation Risk Summary There are no data on the presence of clindamycin or benzoyl peroxide in human milk, the effects on the breastfed child, or the effects on milk production following topical administration. However, clindamycin has been reported to be present in breast milk in small amounts following oral and parenteral administration. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/3.75% and any potential adverse effects on the breastfed child from Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/3.75% or from the underlying maternal condition. Clinical Considerations If used during lactation and Clindamycin Phosphate and Benzoyl Peroxide Gel, 1.2%/3.75% 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 and Benzoyl Peroxide Gel, 1.2%/3.75% in pediatric patients under the age of 12 years have not been evaluated. 8.5 Geriatric Use Clinical trials of clindamycin phosphate and benzoyl peroxide gel, 1.2%/3.75% did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action Clindamycin Clindamycin is a lincosamide antibacterial [see Clinical Pharmacology ( 12.4 )]. Benzoyl Peroxide Benzoyl peroxide is an oxidizing agent with bacteriocidal and keratolytic effects, but the precise mechanism of action is unknown.

11 DESCRIPTION Clindamycin phosphate and benzoyl peroxide gel, 1.2%/5% is a fixed combination product with two active ingredients in a white to off white gel formulation. Clindamycin phosphate, USP 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. Clindamycin phosphate, USP is C 18 H 34 ClN 2 O 8 PS and is a white or almost white, hygroscopic crystalline powder and soluble in water, practically insoluble in dichloromethane, chloroform, benzene and ether. The structural formula for clindamycin phosphate is represented below: Clindamycin phosphate has a molecular weight of 504.96 and its chemical name is methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl- trans -4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L- threo - D-D- galacto -octopyranoside 2-(dihydrogen phosphate). Benzoyl peroxide, USP is C 14 H 10 O 4 . It has the following structural formula: Hydrous benzoyl peroxide, USP has a molecular weight of 242.23. It is white or almost white amorphous or granular powder and practically insoluble in water, slightly soluble in alcohol, soluble in acetone, in chloroform, in dichloromethane and in ether with separation of water Each gram of clindamycin phosphate and benzoyl peroxide gel contains 10 mg (1%) clindamycin, as clindamycin phosphate, and 50 mg (5%) benzoyl peroxide in a base consisting of carbomer homopolymer (type C), dimethicone, disodium lauryl sulfosuccinate, edetate disodium, glycerin, methylparaben, poloxamer 182, purified water, silicon dioxide, and sodium hydroxide. Image Image

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Clindamycin Phosphate and Benzoyl Peroxide Gel 1.2%/3.75% is a white to off-white smooth gel supplied as a 50 g pump (NDC 51672-1403-4) 16.2 Dispensing Instructions for the Pharmacist Dispense clindamycin phosphate and benzoyl peroxide gel with a 10-week expiration date. Specify " Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not freeze." 16.3 Storage and Handling PHARMACIST: Prior to Dispensing: Store in a refrigerator, 2°C to 8°C (36°F to 46°F). PATIENT: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from freezing. Store pump upright. Keep out of the reach of children Keep container tightly closed.

16.1 How Supplied Clindamycin Phosphate and Benzoyl Peroxide Gel 1.2%/3.75% is a white to off-white smooth gel supplied as a 50 g pump (NDC 51672-1403-4)