Clindamycin Phosphate/Benzoyl Peroxide/Adapalene

CABTREO is indicated for the topical treatment of acne vulgaris in adult and pediatric patients 12 years of age and older. CABTREO is a combination of clindamycin phosphate (a lincosamide antibacterial), adapalene (a retinoid), and benzoyl peroxide indicated for the topical treatment of acne vulgaris in adult and pediatric patients 12 years of age and older. ( 1 )

Topical gel: 1.2% clindamycin phosphate, 0.15% adapalene, and 3.1% benzoyl peroxide as a white to off-white, opaque gel. CABTREO is supplied in 20-gram and 50-gram pumps. Topical gel: 1.2% clindamycin phosphate, 0.15% adapalene, and 3.1% benzoyl peroxide. CABTREO is supplied in 20-gram and 50-gram pumps. ( 3 )

CABTREO is contraindicated in patients with: Known hypersensitivity to clindamycin, adapalene, benzoyl peroxide, any other components of CABTREO, or lincomycin [ see Warnings and Precautions ( 5.1 )]. A history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis [ see Warnings and Precautions ( 5.2 )]. Known hypersensitivity to clindamycin, adapalene, benzoyl peroxide, any components of the formulation, or lincomycin. ( 4 ) History of regional enteritis, ulcerative colitis, or antibiotic-associated colitis. ( 4 )

Hypersensitivity : If a serious hypersensitivity reaction occurs, discontinue CABTREO immediately and initiate appropriate therapy. ( 5.1 ) Colitis : Clindamycin can cause severe colitis, which may result in death. Discontinue CABTREO if diarrhea occurs. ( 5.2 ) Photosensitivity : Avoid or minimize exposure to sunlight and sunlamps. Wear sunscreen and protective clothing when sun exposure cannot be avoided. ( 5.3 ) Skin Irritation and Allergic Contact Dermatitis : Erythema, scaling, dryness, stinging/burning, irritant and allergic contact dermatitis may occur with use of CABTREO and may necessitate discontinuation ( 5.4 )

5.1 Hypersensitivity Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, have been reported with use of clindamycin phosphate, benzoyl peroxide, and adapalene [see Adverse Reactions ( 6.2 )]. If a serious hypersensitivity reaction occurs, discontinue CABTREO immediately and initiate appropriate therapy.

5.2 Colitis Diarrhea, bloody diarrhea, and colitis have been reported with the use of topical and systemic clindamycin. Severe colitis has occurred with an onset of up to several weeks following cessation of therapy. Antiperistaltic agents such as opiates and diphenoxylate with atropine may prolong and/or worsen severe colitis. Severe colitis may result in death. Discontinue CABTREO if diarrhea occurs.

5.3 Photosensitivity CABTREO may increase sensitivity to ultraviolet light. Avoid or minimize sun exposure (including use of tanning beds, and sun lamps) following CABTREO application. Instruct patients to use sunscreen products and wear protective apparel (e.g., hat) when exposure to sun cannot be avoided.

5.4 Skin Irritation and Allergic Contact Dermatitis Stinging/burning/pain, erythema, dryness, irritation, exfoliation, and dermatitis have been reported with use of CABTREO. These application site adverse reactions occurred at a greater frequency in CABTREO-treated subjects than in vehicle-treated subjects. These adverse reactions are most likely to occur during the first four weeks of treatment [ see Adverse Reactions ( 6.1 )] . Irritant and allergic contact dermatitis have been reported with use of CABTREO. Weather extremes, such as wind or cold, may be irritating to patients under treatment with CABTREO. Depending upon the severity of these adverse reactions, instruct patients to use a moisturizer, reduce the frequency of the application of CABTREO, or discontinue use. Avoid applying CABTREO to areas of broken, eczematous, or sunburned skin. Avoid use of “waxing” as a depilatory method on skin treated with CABTREO. Avoid concomitant use of other potentially irritating topical products such as peeling, desquamating, or abrasive agents and products with high concentrations of alcohol, astringents, spices, or limes. Use of CABTREO with concomitant topical acne therapy has not been evaluated.

The following adverse reactions are discussed in more detail in other sections of the labeling: Hypersensitivity [ see Warnings and Precautions ( 5.1 )] Colitis [see Warnings and Precautions ( 5.2 )] Skin Irritation and Allergic Contact Dermatitis [see Warnings and Precautions ( 5.4 )] The most common adverse reactions (occurring in >1% of the CABTREO group and greater than the vehicle group) were application site reactions, pain, erythema, dryness, irritation, exfoliation, and dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 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. In two multicenter, randomized, double-blind, vehicle-controlled clinical trials (Trial 1 and Trial 2), 363 adult and pediatric subjects 10 years of age and older with facial acne vulgaris were treated with CABTREO or vehicle topically once daily for 12 weeks [see Clinical Studies ( 14 )] . Adverse reactions reported by >1% of subjects treated with CABTREO and more frequently than subjects treated with vehicle are summarized in Table 1. These adverse reactions were mild (59%), moderate (36.4%), and severe (4.5%). Overall, 2.5% (6/242) of subjects discontinued CABTREO because of local skin reactions. Table 1: Adverse Reactions Reported by >1% of Subjects with Facial Acne Vulgaris Treated with CABTREO (and More Frequently than Vehicle) in Trials 1 and 2 Adverse Reactions N (%) CABTREO N=242 Vehicle N=121 Application site pain Application site pain also includes application site stinging and burning 33 (13.6) 1 (0.8) Application site erythema Application site erythema also includes erythema 11 (4.5) 0 Application site dryness Application site dryness also includes xerosis 10 (4.1) 1 (0.8) Application site irritation 5 (2.1) 0 Application site exfoliation 4 (1.7) 0 Application site dermatitis 3 (1.2) 0 Local tolerability evaluations were conducted at each study visit by assessment of erythema, scaling, itching, burning, and stinging. Table 2 presents the signs and symptoms of local facial tolerability during the 12 Week treatment period in subjects treated with CABTREO. Table 2: Facial Cutaneous Tolerability Assessment During 12-Week Treatment Period in Subjects with Acne Vulgaris Treated with CABTREO in Trials 1 and 2 Maximum During Treatment The denominators for calculating the percentages were the number of subjects with at least one post-baseline cutaneous tolerability assessment. Week 12 (End of Treatment) The denominators for calculating the percentages were the number of subjects with Week 12 assessment. Mild (%) Mod (%) Severe (%) Mild (%) Mod (%) Severe (%) CABTREO (N = 242) Erythema 34.2 19.7 2.1 22.4 6.5

0.5 Burning 29.6 10.7 3.0 4.2 1.4

0.9 Scaling 26.7 3.4 0 7.0 0.9 0 Itching 24.3 3.4 0.4 6.0 0.9 0 Stinging 20.5 5.1 2.6 2.3 0.9

0.5 Vehicle (N = 121) Erythema 22.5 21.7 1.7 25.5 5.5 0 Burning 2.5 0.8 0.8 0.9 0 0 Scaling 12.5 0 0 4.5 0 0 Itching 11.6 0.8 0 1.8 0 0 Stinging 3.3 0.8 0 1.8 0 0 Local tolerability scores for erythema, scaling, itching, burning, and stinging increased during the first two weeks of treatment and decreased thereafter.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of products containing clindamycin phosphate, adapalene, and benzoyl peroxide as the active ingredients. Because post-marketing adverse 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. Immune system disorders: anaphylaxis and allergic reactions including eyelid edema, throat tightness, swelling of the face, and eczema. [see Contraindications ( 4 )] . Local Adverse Reactions: sunburn, blister, pruritis, hyperpigmentation and hypopigmentation. Gastrointestinal Disorders: abdominal pain and gastrointestinal disturbances. Bacterial infections: gram negative folliculitis

Neuromuscular Blocking Agents Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Use CABTREO with caution in patients receiving such agents. Neuromuscular Blocking Agents: Use CABTREO with caution in patients receiving neuromuscular blocking agents. ( 7 )

8.1 Pregnancy Risk Summary Available data with CABTREO use in pregnant women are insufficient to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with CABTREO. Clindamycin In published clinical trials and observational studies with pregnant women, oral or IV administration of clindamycin has not been associated with an increased frequency of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, clindamycin phosphate did not cause malformations or embryofetal development toxicity in pregnant rats and mice when administered during the period of organogenesis at systemic doses up to 192 times the maximum recommended human dose (MRHD) of 2.5 g CABTREO, based on a body surface area (mg/m 2 ) comparison. Adapalene Available data from clinical trials with adapalene topical gel use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of adapalene to pregnant rats and rabbits during organogenesis at doses 64 and 128 times, respectively, the MRHD resulted in fetal skeletal and visceral malformations ( see Data) . Benzoyl peroxide The systemic exposure of topical benzoyl peroxide is unknown. Based on published literature, benzoyl peroxide is rapidly metabolized to benzoic acid (an endogenous substance), which is eliminated in the urine. Hence, maternal use is not expected to result in fetal exposure of the drug. 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, 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 Animal Data Animal reproductive/developmental toxicity studies have not been conducted with CABTREO. Clindamycin phosphate administration during the period of organogenesis in pregnant rats and mice at oral doses up to 600 mg/kg/day (192 and 96 times the MRHD, respectively, based on a mg/m 2 comparison) or subcutaneous doses up to 200 mg/kg/day (64 and 32 times the MRHD, respectively, based on a mg/m 2 comparison) did not cause fetal malformations or fetotoxicity. No malformations were observed in rats treated with oral adapalene doses of 0.15 to 5.0 mg/kg/day (up to 13 times the MRHD based on a mg/m 2 comparison). However, malformations were observed in rats and rabbits when treated with oral doses of ≥ 25 mg/kg/day adapalene (64 and 128 times the MRHD, respectively, based on a mg/m 2 comparison). Findings included cleft palate, microphthalmia, encephalocele, and skeletal abnormalities in rats and umbilical hernia, exophthalmos, and kidney and skeletal abnormalities in rabbits. Dermal adapalene embryofetal development studies in rats and rabbits at doses up to 6.0 mg/kg/day adapalene (up to 15 and 30 times the MRHD, respectively, based on a mg/m 2 comparison) exhibited no fetotoxicity and only minimal increases in skeletal variations (supernumerary ribs in both species and delayed ossification in rabbits).

8.2 Lactation Risk Summary The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CABTREO and any potential adverse effects on the breastfed child from CABTREO or from the underlying maternal condition. Clindamycin There are no data on the presence of clindamycin 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 human milk in small amounts following oral and parenteral administration. Adapalene There are no data on the presence of topical adapalene gel or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies, adapalene is present in rat milk with oral administration of the drug. When a drug is present in animal milk, it is likely that the drug will be present in human milk. It is possible that topical administration of large amounts of adapalene could result in sufficient systemic absorption to produce detectable quantities in human milk ( see Clinical Considerations). Benzoyl peroxide There are no data on the presence of topical benzoyl peroxide in human milk, its effects on the breastfed infant, or its effects on milk production. The systemic exposure of benzoyl peroxide is unknown. Based on the published literature, benzoyl peroxide is rapidly metabolized to benzoic acid (an endogenous substance), which is eliminated in the urine. Any amount of benzoyl peroxide excreted into human milk by a nursing mother would be expected to be rapidly metabolized by tissue and stomach esterases. Clinical Considerations To minimize potential exposure to the breastfed infant via breastmilk, use CABTREO on the smallest area of skin and for the shortest duration possible while breastfeeding. To avoid direct infant exposure, advise patients who are breastfeeding not to apply CABTREO directly to the nipple and areola. If applied to the patient’s chest, care should be taken to avoid infant exposure via direct contact with the infant skin.

8.4 Pediatric Use The safety and effectiveness of CABTREO for the topical treatment of acne vulgaris have been established in pediatric patients 12 years of age and older. Use of CABTREO for this indication is supported by data from two randomized, double-blind, vehicle-controlled trials [ see Clinical Studies ( 14 )]. The safety and effectiveness of CABTREO have not been established in pediatric patients younger than 12 years of age.

8.5 Geriatric Use Clinical studies of CABTREO did not include any subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

Clindamycin: Clindamycin is a lincosamide antibacterial [see Microbiology ( 12.4 )] . Adapalene: Adapalene binds to specific retinoic acid nuclear receptors but does not bind to cytosolic receptor protein. Biochemical and pharmacological profile studies have demonstrated that adapalene is a modulator of cellular differentiation, keratinization and inflammatory processes. However, the significance of these findings with regard to the mechanism of action of adapalene for the treatment of acne is unknown. Benzoyl Peroxide: Benzoyl peroxide is an oxidizing agent with bactericidal and keratolytic effects but the precise mechanism of action is unknown.