Clindamycin Phosphate/Benzoyl Peroxide/Adapalene

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION Cleanse the affected area gently. After the skin is dry, apply a thin layer of CABTREO to the affected area once daily. Wash hands thoroughly after application of CABTREO. Avoid the eyes, mouth, paranasal creases, mucous membranes, and areas of broken, eczematous, or sunburned skin [ see Warnings and Precautions ( 5.3 )]. CABTREO is for topical use only. Not for oral, ophthalmic, or intravaginal use. Apply a thin layer of CABTREO to the affected areas once daily. ( 2 ) Avoid the eyes, mouth, paranasal creases, mucous membranes, and areas of broken, eczematous, or sunburned skin. ( 2 ) Not for oral, ophthalmic, or intravaginal use. ( 2 )

6 ADVERSE REACTIONS 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

12.3 Pharmacokinetics Systemic exposure following topical application of CABTREO was evaluated in 28 subjects in an open-label, randomized, pharmacokinetic study. Subjects aged 12 years and older with moderate to severe acne vulgaris applied 2.2 ± 0.4 (mean ± SD) grams of CABTREO to the entire face (excluding eyes and lips), neck, upper chest, upper back and shoulders once daily for 28 days. Clindamycin phosphate concentrations were measurable in the majority of samples following single and repeated topical administration of CABTREO (LOQ = 0.05 ng/mL). The mean C max and mean AUC [0-t] values for clindamycin phosphate were 2.44 ng/mL (range: 0.15 to 6.14 ng/mL) and 30.7 ng•h/mL (range: 1.04 to 87.4 ng•h/mL) on Days 28-29, respectively. Clindamycin (C max and AUC [0-t] ) accumulated up to approximately 3-fold between Days 1-2 and Days 28-29 following once daily application of CABTREO. Adapalene concentrations were measurable in the majority of samples following single and repeated topical administration of CABTREO (LOQ = 0.10 ng/mL). The mean C max and mean AUC (0-t) values for adapalene were 0.10 ng/mL (range: 0 to 0.27 ng/mL) and 2.40 ng•h/mL (range: 0.56 to 3.87 ng•h/mL) on Days 28-29, respectively. Adapalene (AUC [0-t] ) accumulated up to approximately 3-fold between Days 1-2 and Days 28-29 for CABTREO. Benzoyl peroxide is absorbed by the skin where it is converted to benzoic acid and eliminated in the urine. Drug Interaction Studies In Vitro Studies Erythromycin products: Concurrent use with erythromycin topical or oral products may reduce the efficacy of CABTREO. This finding is based upon the mechanistic understanding of these drugs and published in vitro antagonism between erythromycin and clindamycin. This finding was not confirmed by a dedicated clinical study. While the clinical significance of this finding is unknown, it still warrants consideration given the potential impact on the efficacy of CABTREO.