Sofpironium Bromide

1 INDICATIONS AND USAGE SOFDRA is indicated for the treatment of primary axillary hyperhidrosis in adults and pediatric patients 9 years of age and older. SOFDRA is an anticholinergic indicated for the treatment of primary axillary hyperhidrosis in adults and pediatric patients 9 years of age and older ( 1 ).

2 DOSAGE AND ADMINISTRATION Do not shave armpits at least 8 hours before applying SOFDRA. Do not shower at least 30 minutes before applying SOFDRA. Apply SOFDRA to clean, dry skin once a day at bedtime. Apply a single pump actuation to the top of the supplied applicator. Spread the entire amount to cover 1 underarm. Apply a separate, single pump actuation to the top of the supplied applicator. Apply the entire amount to the second underarm. Allow to dry completely (5 minutes) before putting on clothing. Wash hands immediately with soap. For topical use only. Avoid fire, flame, and smoking during and immediately following application. Do not shower or wash underarms for at least 8 hours after application. Do not touch underarms after applying SOFDRA. Do not use more than once daily. Avoid transfer of SOFDRA to the periocular area [see Warnings and Precautions (5.3) ] . Do not apply SOFDRA to broken skin. Avoid using SOFDRA with occlusive dressings. Apply 1 pump of SOFDRA per underarm once a day at bedtime. For topical use only ( 2 ).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Urinary Retention [See Warnings and Precautions (5.1) ]. Most common adverse reactions (incidence ≥2%) are dry mouth, vision blurred, application site pain, application site erythema, mydriasis, application site dermatitis, application site pruritus, urinary retention, and application site irritation ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Botanix SB Inc. at 1-866-763-6337 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 practice. In two double-blind, vehicle controlled clinical trials (CARDIGAN 1 and CARDIGAN 2) of 700 subjects 10 to 76 years of age (353 subjects treated with SOFDRA and 347 subjects treated with vehicle), 44% of subjects were male, 79% were White, 21% were Black, and 1% were Asian. A total of 618 subjects completed at least 6 weeks of treatment, including 307 subjects treated with SOFDRA and 311 subjects treated with vehicle. Table 1 summarizes the most frequent adverse reactions (≥2%) in subjects with primary axillary hyperhidrosis treated with SOFDRA. Table 1: Adverse Reactions Occurring in ≥2% of Subjects with Primary Axillary Hyperhidrosis Treated with SOFDRA in Trials CARDIGAN 1 and 2 Adverse Reactions SOFDRA (N = 353) n (%) Vehicle (N = 347) n (%) Note: COVID-19 was observed in 8 (2%) SOFDRA and 2 (0.6%) vehicle subjects. Dry mouth 51 (14%) 2 (0.6%) Vision blurred 30 (9%) 1 (0.3%) Mydriasis 23 (7%) 0 Urinary retention 8 (2%) 0 Table 2 shows the local skin reactions reported ≥2%, which occurred more commonly in the SOFDRA group. Table 2: Local Skin Reactions Reported in ≥2% of Subjects with Primary Axillary Hyperhidrosis Treated with SOFDRA in Trials CARDIGAN 1 and 2 Local Skin Adverse Reactions SOFDRA (N = 353) n (%) Vehicle (N = 347) n (%) Pain 29 (8%) 6 (2%) Erythema 23 (7%) 1 (0.3%) Dermatitis 21 (6%) 1 (0.3%) Pruritus 16 (5%) 2 (0.6%) Irritation 8 (2%) 1 (0.3%) Exfoliation 7 (2%) 1 (0.3%) In an open-label, long-term safety trial (ARGYLE), 197 subjects were treated for 48 weeks with SOFDRA. Adverse reactions occurring at a frequency ≥2% were vision blurred (19%), dry mouth (17%), application site pruritus (15%), application site pain (15%), application site dermatitis (11%), application site erythema (8%), application site irritation (6%), mydriasis (5%), application site rash (4%), upper respiratory tract infection (4%), dry eye (4%), urinary retention (4%), application site exfoliation (3%), application site folliculitis (3%), hypertension (3%), application site dryness (2%), viral upper respiratory tract infection (2%), influenza (2%), and headache (2%).

12.3 Pharmacokinetics Absorption The pharmacokinetics of sofpironium were evaluated in adult patients with primary axillary hyperhidrosis following SOFDRA applied once daily to the underarms for 21 days. The mean ± standard deviation (SD) exposures of sofpironium in adults are presented in Table 3. There was no evidence of accumulation. Table 3: Mean (SD) Plasma Exposure of Sofpironium in Adults with Primary Axillary Hyperhidrosis Following SOFDRA Application on Day 1 PK Parameter Adult Patients C max (ng/mL) 2.71 (6.94) AUC 0-t (ng∙hr/mL) 45.1 (85.1) t max (hr) 5.34 (5.45) Distribution Plasma protein binding of sofpironium is around 34.8-37.8%. The major sofpironium metabolite (BBI-4010) had plasma protein binding around 2.3-3.7%. Elimination Metabolism Sofpironium is metabolized by nonenzymatic hydrolysis, CYP2D6 and CYP3A4 mediated-oxidative metabolism, and glycine conjugation. In plasma, sofpironium was the major component (38%) followed by the BBI-4010 (20%) metabolite. Excretion Urinary excretion of sofpironium and BBI-4010 were less than 0.5% of the applied dose. Specific Populations The pharmacokinetics of sofpironium were not evaluated in pregnant patients or patients with hepatic or renal impairment. Pediatric Subjects The mean ± SD exposures of sofpironium after a single dose in pediatric subjects 9 years to 16 years of age are presented in Table 4. After 24 weeks of dosing, trough concentrations of sofpironium were low and there was no evidence of accumulation. The exposure to major metabolite (BBI-4010) in pediatric subjects was similar to sofpironium exposure in adults. Table 4: Mean (SD) Plasma Exposure of Sofpironium in Pediatric Subjects Following Single Dose Administration of SOFDRA on Day 1 PK Parameter Pediatric Patients t max reported as median and range. C max (ng/mL) 1.30 (3.16) AUC 0-t (ng∙hr/mL) 14.6 (35.0) t max (hr) 4.0 (0.9, 23.1) Drug Interaction Studies No clinically significant differences in sofpironium pharmacokinetics were observed when used concomitantly with inhibitors of CYP3A4, OCT2, MATE1, or MATE2-K. In vivo Study In presence of 20 mg oral dose of paroxetine HCl (strong CYP2D6 inhibitor) C max and AUC 0-t of sofpironium increased by approximately twofold compared to when SOFDRA was administered alone. In vitro Studies Sofpironium is an inhibitor of CYP2D6, CYP3A4, OCT1, OCT2, and MATE1 in vitro. Sofpironium is not an inducer of CYP1A2, CYP2B6, or CYP3A4.