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TRIALISTMD · Drug Intelligence Platform
NDA 217347 — 2024
Anticholinergic · Dermatology · Primary Axillary Hyperhidrosis
Sofpironium
Sofdra™ · Botanix Pharmaceuticals
Sofpironium bromide is a new molecular entity and small molecule quaternary ammonium analogue of the anticholinergic glycopyrrolate. It reduces sweat production through selective, competitive inhibition of muscarinic receptor type 3 (M3) — the predominant receptor in axillary eccrine glands. Applied once daily at bedtime via a metered pump applicator, it was studied in adults and pediatric patients ≥9 years with primary axillary hyperhidrosis. NDA 217347 was submitted September 2022 and received a Complete Response in September 2023 due to human factors deficiencies; the clinical discipline recommended approval following a Class 2 resubmission reviewed in June 2024.
Drug Overview
NDA 217347
⚠ COMPLETE RESPONSE ISSUED — Human Factors deficiency (September 22, 2023): The Agency issued a Complete Response after the first review cycle because the HF validation study results demonstrated use errors, close calls, and use difficulties with critical tasks that could result in harm or compromised efficacy. The clinical discipline concluded that safety and efficacy had been acceptably demonstrated and identified no other CR issues. Following a Class 2 resubmission (December 20, 2023) with a redesigned user interface and a new HF validation study, the clinical discipline recommended approval in June 2024. The drug is approved for marketing in Japan as a 5% formulation.
Indication
Primary Axillary Hyperhidrosis
Adults and pediatric patients ≥9 years of age. First new topical prescription option since glycopyrronium tosylate cloth wipes (approved for ≥9 years).
Mechanism of Action
M3 Receptor Antagonist
Selective, competitive inhibitor of muscarinic receptor type 3 (M3) — the predominant receptor in axillary eccrine glands. Quaternary ammonium analogue of glycopyrrolate; designed for low systemic absorption.
Co-Primary Efficacy — Study 301
50.4% / 32.1%
≥2-point HDSM-Ax-7 improvement: 50.4% SB gel vs 32.1% vehicle; difference 18.3% (95% CI: 8.0, 28.7); p=0.0005
Co-Primary Efficacy — Study 302
63.3% / 47.1%
≥2-point HDSM-Ax-7 improvement: 63.3% SB gel vs 47.1% vehicle; difference 16.2% (95% CI: 5.4, 26.9); p=0.0040
Drug Class & Chemistry
| Property | Detail |
|---|---|
| Pharmacologic class | Anticholinergic; muscarinic receptor M3 antagonist; quaternary ammonium analogue of glycopyrrolate |
| Code name | BBI-4000 |
| Molecular type | New molecular entity (NME); small molecule |
| Formulation | Gel, 15%; clear to slightly translucent, colorless to pale yellow; metered pump container with applicator cap |
| Dosing device | Metered pump bottle with applicator cap over the dispenser and a covering cap; one pump actuation per underarm per day |
| Sponsor | Botanix Pharmaceuticals |
| Japan approval | Sofpironium bromide gel 5% approved for marketing in Japan (tradename not specified in review) |
Mechanism Detail
Mechanism of Action: Sofpironium bromide reduces sweat production by selective, competitive inhibition of muscarinic receptor type 3 (M3), which is the predominant receptor in the axillary eccrine glands that provide the watery secretions of hyperhidrosis. As a quaternary ammonium compound, it is designed to limit systemic absorption, reducing systemic anticholinergic side effects. Though variable, absorption of sofpironium bromide gel was generally low in clinical studies.
Source: NDA 217347 Multi-disciplinary Review, Ref ID 5249224; Class 2 Resubmission Review, Ref ID 5398431. Review date: June 14, 2024.
Baseline Characteristics — Pivotal Trials
BBI-4000-CL-301 & 302 (ITT)
Population: Intent-to-treat (ITT) population from two identically designed Phase 3 pivotal trials (Studies BBI-4000-CL-301 and BBI-4000-CL-302). Approximately 350 subjects per study; adults and pediatric patients ≥9 years of age with primary axillary hyperhidrosis. Randomized 1:1 to sofpironium bromide (SB) gel 15% or vehicle gel applied once daily at bedtime to each axilla for 42 days. Study 301 was conducted at 35 U.S. centers (35 randomized); Study 302 at 42 U.S. centers (33 randomized).
Table 17 — Baseline Demographics (ITT)
| Characteristic | Study 301 SB Gel 15% N=173 | Study 301 Vehicle N=177 | Study 302 SB Gel 15% N=180 | Study 302 Vehicle N=171 |
|---|---|---|---|---|
| Age — Mean (SD), years | 32.9 (11.6) | 32.4 (10.9) | 32.1 (12.2) | 31.7 (11.1) |
| Age — Range | 11, 64 | 14, 71 | 10, 76 | 11, 69 |
| Age 9–11 years, n (%) | 1 (1%) | 0 (0%) | 2 (1%) | 2 (1%) |
| Age 12–17 years, n (%) | 14 (8%) | 12 (7%) | 13 (7%) | 8 (5%) |
| Age 18–64 years, n (%) | 158 (91%) | 163 (92%) | 161 (89%) | 158 (92%) |
| Age ≥65 years, n (%) | 0 (0%) | 2 (1%) | 4 (2%) | 3 (2%) |
| Female, n (%) | 98 (57%) | 99 (56%) | 92 (51%) | 103 (60%) |
| Male, n (%) | 75 (43%) | 78 (44%) | 88 (49%) | 68 (40%) |
| White, n (%) | 140 (81%) | 130 (73%) | 141 (78%) | 133 (78%) |
| Black or African American, n (%) | 31 (18%) | 43 (24%) | 32 (18%) | 34 (20%) |
| Asian, n (%) | 1 (1%) | 3 (2%) | 4 (2%) | 1 (1%) |
| American Indian or Alaska Native, n (%) | 0 (0%) | 0 (0%) | 2 (1%) | 1 (1%) |
| Unknown / not reported, n (%) | 1 (1%) | 1 (1%) | 1 (1%) | 2 (1%) |
| Hispanic or Latino, n (%) | 61 (35%) | 60 (34%) | 48 (27%) | 45 (26%) |
| Not Hispanic or Latino, n (%) | 111 (64%) | 117 (66%) | 132 (73%) | 124 (73%) |
| Not reported, n (%) | 1 (1%) | 0 (0%) | 0 (0%) | 2 (1%) |
Note: ITT population includes duplicate subject enrollments. Race reflects predominant race if multiple races selected. Source: CSR 301 (page 58) and CSR 302 (page 60); reproduced by statistical reviewer using adsl.xpt.
Table 18 — Baseline Disease Characteristics (ITT)
| Characteristic | Study 301 SB Gel 15% N=173 | Study 301 Vehicle N=177 | Study 302 SB Gel 15% N=180 | Study 302 Vehicle N=171 |
|---|---|---|---|---|
| HDSM-Ax-7 — Mean (SD) | 3.5 (0.3) | 3.5 (0.3) | 3.6 (0.3) | 3.6 (0.3) |
| HDSM-Ax-7 — Median | 3.4 | 3.6 | 3.6 | 3.6 |
| HDSM-Ax-7 — Range | 3.0, 4.0 | 2.9, 4.0 | 3.0, 4.0 | 3.0, 4.0 |
| GSP — Mean (SD), mg | 296.2 (257.1) | 298.5 (223.4) | 313.8 (283.7) | 308.4 (267.2) |
| GSP — Median, mg | 214.1 | 228.6 | 207.7 | 231.1 |
| GSP — Range, mg | 38.4, 1512.1 | 20.4, 1523.8 | 38.6, 1773.6 | 8.9, 2356.6 |
| Duration of Symptoms — Mean (SD), months | 179.3 (115.2) | 184.4 (116.9) | 202.6 (131.9) | 194.4 (117.3) |
| Duration of Symptoms — Median, months | 156.3 | 157.2 | 193.6 | 172.4 |
| Duration of Symptoms — Range, months | 6.5, 564.7 | 19.9, 588.6 | 9.1, 712.0 | 16.5, 495.4 |
HDSM-Ax-7 = Hyperhidrosis Disease Severity Measure-Axillary-7-item scale; Baseline/Day 1 (Visit 4) assessment. GSP = Gravimetric Sweat Production; baseline value is the median of observations on Visits 2, 3, and 4 (Visits 2 and 3 within 14 days prior to Baseline/Day 1). Source: Reviewer analysis using adhdsm.xpt, adgsp.xpt, and adsl.xpt.
Table 15 — Subject Disposition (Studies 301 and 302)
| Population / Disposition | Study 301 SB Gel 15% N=173 | Study 301 Vehicle N=177 | Study 302 SB Gel 15% N=180 | Study 302 Vehicle N=171 |
|---|---|---|---|---|
| ITT¹, n (%) | 173 (100%) | 177 (100%) | 180 (100%) | 171 (100%) |
| mITT², n (%) | 169 (98%) | 173 (98%) | 180 (100%) | 169 (99%) |
| Safety Population³, n (%) | 173 (100%) | 176 (99%) | 180 (100%) | 171 (100%) |
| Discontinued treatment, n (%) | 19 (11%) | 10 (6%) | 19 (11%) | 13 (8%) |
| Discontinued study, n (%) | 23 (13%) | 15 (8%) | 20 (11%) | 16 (9%) |
| — Adverse event | 5 (3%) | 0 (0%) | 9 (5%) | 0 (0%) |
| — Lost to follow-up | 10 (6%) | 8 (5%) | 4 (2%) | 8 (5%) |
| — Withdrawal by subject | 4 (2%) | 4 (2%) | 6 (3%) | 6 (4%) |
| — Protocol violation | 2 (1%) | 3 (2%) | 0 (0%) | 2 (1%) |
| — Pregnancy | 1 (1%) | 0 (0%) | 0 (0%) | 0 (0%) |
| — Physician decision | 0 (0%) | 0 (0%) | 1 (1%) | 0 (0%) |
| — Other | 1 (1%) | 0 (0%) | 0 (0%) | 0 (0%) |
¹ All randomized subjects (includes subjects with multiple randomizations). ² All subjects randomized only once. ³ Randomized and treated subjects (includes subjects with multiple randomizations). Note: All subjects who discontinued due to adverse events were on the SB gel arm. Four subjects were randomized multiple times across both studies and are excluded from mITT. Source: CSR 301 (page 52) and CSR 302 (page 54); reproduced by statistical reviewer using adsl.xpt.
Study Design Summary
| Parameter | Detail |
|---|---|
| Design | Multicenter, randomized, double-blind, vehicle-controlled, parallel-group Phase 3 pivotal efficacy and safety study |
| Randomization | 1:1 (SB gel 15%:vehicle); approximately 350 subjects per study |
| Treatment duration | 42 days (6 weeks); once-daily application at bedtime to each axilla; planned mean duration ~42 days |
| Key inclusion criteria | Age ≥9 years; primary axillary hyperhidrosis; HDSM-Ax-7 score 3–4 at screening and baseline; gravimetric sweat production ≥50 mg/axilla and ≥150 mg combined (both axillae) in 5 minutes; symptoms ≥6 months’ duration |
| Co-primary endpoints | (1) Proportion of subjects ≥12 years with ≥2-point improvement in HDSM-Ax-7 score from baseline to end of treatment (EOT); (2) Change from baseline to EOT in gravimetric sweat production (GSP; ranked analysis) |
| Sites | Study 301: 39 U.S. sites, 35 randomized subjects. Study 302: 42 U.S. sites, 33 randomized subjects |
| Trial identifiers | Study 301: BBI-4000-CL-301 (NCT03836287) | Study 302: BBI-4000-CL-302 (NCT03948646) |
| Pediatric note | Only 5 subjects aged 9 to <12 years enrolled across both studies; HDSM-Ax-7 Child Version used; results presented for ≥12 years (Adult Version) per FDA recommendation |
Source: NDA 217347 Multi-disciplinary Review, Ref ID 5249224, Tables 15, 17, and 18 (Section 8). ITT = all randomized subjects. HDSM-Ax-7 = Hyperhidrosis Disease Severity Measure-Axillary-7-item scale. GSP = Gravimetric Sweat Production.
Clinical Efficacy
Studies BBI-4000-CL-301 & 302
Trial Design: Two multicenter, randomized, double-blind, vehicle-controlled Phase 3 trials (BBI-4000-CL-301 and BBI-4000-CL-302; NCT03836287 and NCT03948646). Approximately 350 subjects ≥9 years per study, randomized 1:1 to SB gel 15% or vehicle QD at bedtime for 42 days. Co-primary endpoints: ≥2-point improvement in HDSM-Ax-7 score (≥12 years) and change from baseline in gravimetric sweat production (GSP) — both at end of treatment (EOT).
Total Subjects (Both Trials)
701
Study 301: N=350 (173 SB gel, 177 vehicle); Study 302: N=351 (180 SB gel, 171 vehicle); 1:1 randomization
Treatment Duration
42 Days
Once-daily application at bedtime; one pump actuation per axilla; planned mean duration 42 days
Mean Age at Baseline
~32 years
Mean age 32.1–32.9 years across arms; 91% aged 18–64; <1% aged 9–11; 7% aged 12–17
Mean GSP at Baseline
~300 mg
Mean gravimetric sweat production 296–314 mg across arms; median 207–231 mg; inclusion required ≥150 mg combined both axillae
Co-Primary Endpoint 1 — ≥2-Point HDSM-Ax-7 Improvement (≥12 years, ITT)
BBI-4000-CL-301 (Study 301) · NCT03836287 · N=173 SB Gel / N=177 Vehicle
Treatment difference: 18.3% (95% CI: 8.0, 28.7); p=0.0005. ITT; multiple imputation.
BBI-4000-CL-302 (Study 302) · NCT03948646 · N=180 SB Gel / N=171 Vehicle
Treatment difference: 16.2% (95% CI: 5.4, 26.9); p=0.0040. ITT; multiple imputation.
Co-Primary Endpoint 2 — Change from Baseline in Gravimetric Sweat Production (ITT)
GSP Ranked Analysis — Study 301
Difference in Ranks [LS Means (SE)]: −14.9 (6.8) vs +14.8 (6.7); p=0.0019. 25th–75th percentile SB: −200.5, −52.4 mg; Vehicle: −227.5, −28.5 mg.
GSP Ranked Analysis — Study 302
Difference in Ranks [LS Means (SE)]: −9.9 (7.1) vs +11.8 (7.5); p=0.0296. 25th–75th percentile SB: −260.1, −75.0 mg; Vehicle: −230.0, −59.5 mg.
Co-Primary Efficacy Summary Table
| Endpoint | Study 301 SB Gel N=173 | Study 301 Vehicle N=177 | Study 302 SB Gel N=180 | Study 302 Vehicle N=171 |
|---|---|---|---|---|
| ≥2-pt HDSM-Ax-7 improvement (≥12 yrs) | 50.4% | 32.1% | 63.3% | 47.1% |
| Treatment difference (95% CI) | 18.3% (8.0, 28.7) | 16.2% (5.4, 26.9) | ||
| p-value (HDSM-Ax-7) | 0.0005 | 0.0040 | ||
| Median change in GSP (mg) | −127.8 | −100.3 | −142.6 | −134.2 |
| p-value (GSP ranked analysis) | 0.0019 | 0.0296 | ||
Source: NDA 217347 Multi-disciplinary Review, Ref ID 5249224, Table 1 and Tables 22–29. ITT population; multiple imputation. GSP ranked analysis per protocol (non-normality confirmed). HDSM-Ax-7 = Hyperhidrosis Disease Severity Measure-Axillary-7-item scale; GSP = Gravimetric Sweat Production.
Safety & Adverse Drug Reactions
Studies 301, 302, & 303
Boxed Warning: None. Sofpironium bromide has no FDA-required Boxed Warning.
Safety Database: Phase 3 safety population: 173 (Study 301) and 180 (Study 302) subjects treated with SB gel 15%. Long-term safety from Study BBI-4000-CL-303 (open-label extension, 48 weeks, N=300). Overall, adverse events were reversible and mild to moderate in severity. ECG changes and cardiac adverse events were not considered clinically significant.
Key Safety Considerations
Anticholinergic Side Effects
Main safety considerations are anticholinergic effects including dilated pupils, blurry vision, dry eye, dry mouth, constipation, and urinary hesitation. These reflect M3 receptor inhibition extending beyond the intended axillary eccrine target.
Local Skin Reactions (>1%, SB Gel > Vehicle)
Application site pain, redness, dermatitis, and itching were the most common local skin reactions reported >1% and more frequently in the SB gel arm vs vehicle. See Table 42 in medical review.
Discontinuations Due to AEs
Study 301: 5 (3%) SB gel subjects vs 0 vehicle discontinued due to AEs. Study 302: 9 (5%) SB gel vs 0 vehicle discontinued due to AEs. All AE-related discontinuations were in the SB gel arm.
Cardiac / ECG
ECG changes and cardiac adverse events observed were not considered clinically significant by the review team. Pulse rate changes summarized in medical review Table 41.
Warnings & Precautions
- Anticholinergic effects — dilated pupils, blurry vision, dry eye, dry mouth, constipation, urinary hesitation. Monitor patients, particularly those with conditions predisposing to urinary retention.
- Local skin reactions — application site pain, redness, dermatitis, pruritus reported >1% more frequently with SB gel than vehicle. Discontinue if severe local reactions occur.
- Human Factors — original HF validation study identified critical use errors with metered pump applicator. Revised user interface and IFU implemented following Complete Response; new HF validation study submitted April 2024.
Adverse Reactions ≥2% — CARDIGAN 1 & 2 Combined
§6.1Source: Two double-blind, vehicle-controlled trials (CARDIGAN 1 / Study 301 and CARDIGAN 2 / Study 302); N=353 sofpironium, N=347 vehicle. 44% male, 79% White, 21% Black, 1% Asian. 618 subjects completed ≥6 weeks of treatment.
| Adverse Reaction | Sofpironium (N=353) | Vehicle (N=347) |
|---|---|---|
| Dry mouth | 51 (14%) | 2 (0.6%) |
| Vision blurred | 30 (9%) | 1 (0.3%) |
| Mydriasis | 23 (7%) | 0 |
| Urinary retention | 8 (2%) | 0 |
Source: FDA PI NDA 217347 (Ref ID 5399984), §6.1 Table 1. COVID-19 occurred in 8 (2%) sofpironium and 2 (0.6%) vehicle subjects.
Local Skin Reactions ≥2% — CARDIGAN 1 & 2 Combined
§6.1| Application Site Reaction | Sofpironium (N=353) | Vehicle (N=347) |
|---|---|---|
| Application site pain | 29 (8%) | 6 (2%) |
| Application site erythema | 23 (7%) | 1 (0.3%) |
| Application site dermatitis | 21 (6%) | 1 (0.3%) |
| Application site pruritus | 16 (5%) | 2 (0.6%) |
| Application site irritation | 8 (2%) | 1 (0.3%) |
| Application site exfoliation | 7 (2%) | 1 (0.3%) |
Source: FDA PI NDA 217347 (Ref ID 5399984), §6.1 Table 2.
Long-Term Safety — ARGYLE (48-Week Open-Label)
§6.1ARGYLE Trial: Open-label, long-term safety trial; N=197 subjects treated with sofpironium for 48 weeks. Adverse reactions occurring at frequency ≥2% listed below.
| Adverse Reaction | Sofpironium (N=197) — 48 weeks |
|---|---|
| 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% |
| Headache | 2% |
Source: FDA PI NDA 217347 (Ref ID 5399984), §6.1 ARGYLE long-term safety data.
Use in Specific Populations
Pediatric Use (≥9 years)
Proposed and studied in patients ≥9 years of age. Only 5 subjects aged 9–11 enrolled across both pivotal trials; HDSM-Ax-7 Child Version used for this age group. Primary efficacy analysis uses ≥12-year-old data (Adult Version) per FDA recommendation. Long-term pediatric safety from Study 303.
Pregnancy
One subject in Study 301 on SB gel arm discontinued due to pregnancy. Reproductive and developmental toxicity studies conducted; see nonclinical review. Adequate data in humans not available.
Geriatric Use
<2% of subjects were ≥65 years across both trials; limited data in elderly. No specific dose adjustment stated. Anticholinergic effects may be more pronounced in elderly patients.
Japan Postmarketing Data
Sofpironium bromide gel 5% is approved in Japan. Pharmacovigilance report submitted with resubmission; adverse events occurring during the reporting period were consistent with the currently approved labeling.
Source: NDA 217347 Multi-disciplinary Review, Ref ID 5249224; Class 2 Resubmission Review, Ref ID 5398431. Safety population = randomized and treated subjects.
Dosing & Contraindications
Standard Dosing
- Apply sofpironium bromide gel 15% once daily at bedtime
- One pump actuation per underarm (axilla)
- Applied using the pump cap applicator onto each axilla
- Wash hands with soap and water immediately after use
- Applied topically; not for oral, ophthalmic, or other routes
Special Populations
- Pediatric (≥9 years): Proposed indication; studied at same dose as adults (one pump per axilla QD)
- Pediatric (<9 years): Not studied; not approved
- Geriatric: No specific dose adjustment stated; limited trial data in ≥65 years
- Renal/Hepatic impairment: Not reported in medical review — systemic exposure low with topical application
- Pregnancy/Lactation: Insufficient human data; use only if benefit justifies risk
Contraindications
- Medical conditions that can be exacerbated by anticholinergic effects of sofpironium bromide
- Glaucoma
- Paralytic ileus
- Unstable cardiovascular status in acute hemorrhage
- Severe ulcerative colitis; toxic megacolon complicating ulcerative colitis
- Myasthenia gravis
- Sjögren’s syndrome
Device / Application Instructions
- Metered pump container with applicator cap over dispenser and covering cap
- Applicator cap labeled with intended use/purpose (per revised IFU post-CR)
- IFU revised to reduce complexity and improve salience of key steps
- “Wash hands with soap and water immediately after use” placed on principal display panel of carton and container labeling
- Revised to address tilting/spilling use error identified in first HF validation study
Source: FDA PI NDA 217347 (Ref ID 5399984), Sections 1–5; NDA 217347 Medical Review, Ref ID 5249224; Class 2 Resubmission Review, Ref ID 5398431.
Warnings & Precautions — Dosing Relevant
§5- Urinary Retention (§5.1): Use with caution in patients with documented history of urinary retention, prostatic hypertrophy, or bladder-neck obstruction. Discontinue immediately if signs/symptoms develop (difficulty passing urine, distended bladder).
- Control of Body Temperature (§5.2): Anticholinergic-mediated reduction in sweating can cause heat illness (hyperpyrexia, heat stroke) in high ambient temperatures. Avoid use if patient is not sweating in hot environments.
- Operating Machinery / Automobile (§5.3): Transient blurred vision may occur. If blurred vision develops, discontinue use and avoid driving or operating machinery until resolved.
Drug Interactions
§7| Interacting Drug/Class | Effect | Recommendation |
|---|---|---|
| Other anticholinergics (§7.1) | Additive anticholinergic adverse effects (e.g., dry mouth, blurred vision, urinary retention, decreased sweating) | Avoid coadministration |
| Strong CYP2D6 inhibitors (§7.2) — e.g., paroxetine 20 mg oral | Paroxetine increased sofpironium Cmax and AUC₀‑t approximately 2-fold in vivo | Avoid coadministration |
| CYP3A4 inhibitors, OCT2 inhibitors, MATE1/MATE2-K inhibitors | No clinically significant differences in sofpironium PK observed in drug interaction studies | No dose adjustment required |
Source: FDA PI NDA 217347 (Ref ID 5399984), §7.1–7.2, §12.3 Drug Interaction Studies.
Administration Instructions
§2| Parameter | Recommendation |
|---|---|
| Dose | 1 pump actuation per underarm (axilla) once daily at bedtime; total 2 pump actuations per day |
| Application surface | Clean, dry, intact skin of the underarm area only; do not apply to broken skin |
| Pre-application | Do not shave armpits ≥8 hours before use; do not shower ≥30 minutes before use |
| Post-application | Allow to dry completely (~5 minutes) before putting on clothing; do not shower or wash underarms for ≥8 hours after application |
| Hand hygiene | Wash hands immediately with soap and water after each application — residual gel on hands can cause blurred vision if eyes are touched |
| Occlusion | Avoid occlusive dressings; do not touch underarms after applying |
| Flammability | Avoid fire, flame, and smoking during and immediately following application (gel contains 77.2% v/v dehydrated alcohol) |
| Periocular area | Avoid transfer of gel to periocular area |
| Frequency | Do not use more than once daily |
Source: FDA PI NDA 217347 (Ref ID 5399984), §2 Dosage and Administration.
Labeling
NDA 217347| Item | Detail |
|---|---|
| Product name | Sofdra™ (sofpironium) topical gel, 12.45% |
| INN / active moiety | Sofpironium (as sofpironium bromide) |
| Dosage form & strength | Topical gel; 12.45% w/w sofpironium (equivalent to 15% sofpironium bromide); clear to translucent, colorless to pale yellow viscous gel |
| Container / delivery device | 50 mL airless bottle with multi-dose metered pump and applicator cap; one pump actuation delivers 0.67 mL (72 mg sofpironium / 87 mg sofpironium bromide); 60 pump actuations per bottle |
| Inactive ingredients | Citric acid; 77.2% v/v dehydrated alcohol; hexylene glycol; hydroxypropyl cellulose; isopropyl myristate |
| NDC | 83723-010-50 |
| Storage | Store upright at 20°C–25°C (68°F–77°F); excursions permitted 15°C–30°C (59°F–86°F) [USP Controlled Room Temperature]. Flammable — keep away from heat or flame. |
| Applicant / manufacturer | Botanix SB Inc., Wayne, PA 19087 |
| Initial U.S. approval | 2024 |
| PI revision date | 06/2024 |
| PI Reference ID | 5399984 |
Clinical Pharmacology
§12Mechanism of Action (§12.1): Sofpironium bromide is a competitive inhibitor of acetylcholine receptors located on peripheral tissues including sweat glands. It indirectly reduces the rate of sweating by preventing stimulation of these receptors. As a quaternary ammonium compound designed for low systemic absorption, its anticholinergic effects are principally local.
Pharmacodynamics (§12.2): Pharmacodynamics of Sofdra are not fully characterised. At 3× the exposure associated with the maximum approved recommended dose, sofpironium does not prolong the QTc interval to any clinically relevant extent.
Pharmacokinetics — Adults (§12.3)
Cmax (Adults)
2.71 ng/mL
Mean ± SD: 2.71 (6.94) ng/mL; Day 1, once-daily dosing to underarms
AUC₀‑t (Adults)
45.1 ng·h/mL
Mean ± SD: 45.1 (85.1) ng·h/mL; no evidence of accumulation over 21 days
tmax (Adults)
5.34 h
Mean ± SD: 5.34 (5.45) h after once-daily application
Protein Binding
34.8–37.8%
Sofpironium plasma protein binding. Major metabolite BBI-4010: 2.3–3.7%
Metabolism
CYP2D6 / 3A4
Nonenzymatic hydrolysis; CYP2D6 and CYP3A4 oxidative metabolism; glycine conjugation. Sofpironium 38%, BBI-4010 20% in plasma.
Urinary Excretion
<0.5%
Sofpironium and BBI-4010 urinary excretion each <0.5% of applied dose
Pharmacokinetics — Pediatric (§12.3)
Cmax (Pediatric)
1.30 ng/mL
Mean ± SD: 1.30 (3.16) ng/mL; single dose, ages 9–16 years
AUC₀‑t (Pediatric)
14.6 ng·h/mL
Mean ± SD: 14.6 (35.0) ng·h/mL; no evidence of accumulation at 24 weeks
tmax (Pediatric)
4.0 h
Median 4.0 h (range 0.9–23.1 h); BBI-4010 exposure similar to sofpironium exposure in adults
Source: FDA PI NDA 217347 (Ref ID 5399984), §12.1–12.3 Tables 3 and 4.
Labeling History & IFU Revisions
- Original IFU identified as having too much information, certain information lacking salience, and being folded (contributing to missed steps) — per first HF validation study.
- Revised IFU submitted December 20, 2023 as part of Class 2 resubmission (SDN 24); updated draft PI, IFU, carton and container labeling with proprietary name included.
- Statement “wash hands with soap and water immediately after use” added to principal display panel of carton and container labeling per CR requirement.
- Applicator labeled with intended use/purpose to address users not understanding what the applicator was or how to use it.
Adverse Event Reporting
| Contact | Detail |
|---|---|
| Reference IDs | 5249224 (original cycle multi-disciplinary review) / 5398431 (Class 2 resubmission review, June 14, 2024) |
| Reviewing division | Division of Dermatology and Dentistry (DDD), Office of Immunology and Inflammation (OII), CDER |
| Clinical reviewer | Roselyn E. Epps, M.D., FAAP, FAAD; Clinical Team Leader: David Kettl, M.D. |
Source: NDA 217347 Class 2 Resubmission Review, Ref ID 5398431; NDA 217347 Multi-disciplinary Review, Ref ID 5249224.
Regulatory History
NDA 217347 — Standard ReviewApplication Type
Original NDA
Standard Review. New Molecular Entity. NDA 217347Orig1s000. Pharmacologic class: anticholinergic (M3 antagonist).
Reviewing Division
DDD / OII
Division of Dermatology and Dentistry, Office of Immunology and Inflammation, CDER. Clinical reviewer: R. Epps, M.D.; Team Leader: D. Kettl, M.D.
Complete Response
Sep 22, 2023
CR issued for human factors deficiencies only. Clinical safety and efficacy acceptably demonstrated in first cycle. PDUFA goal date: September 23, 2023.
Clinical Discipline Recommendation
Approval
Clinical discipline recommended approval following Class 2 resubmission review completed June 14, 2024 (Ref ID 5398431).
Regulatory Timeline
PHASE 3 CONDUCT
Studies BBI-4000-CL-301 (NCT03836287) and BBI-4000-CL-302 (NCT03948646)
Two multicenter, randomized, double-blind, vehicle-controlled pivotal Phase 3 trials in ~350 subjects ≥9 years each. 1:1 randomization, SB gel 15% vs vehicle, once daily at bedtime for 42 days. Co-primary endpoints: HDSM-Ax-7 ≥2-point improvement and change in GSP at EOT.
SEPTEMBER 23, 2022
NDA 217347 Submitted and Received
Botanix SB submitted NDA 217347 for sofpironium bromide gel 15% for primary axillary hyperhidrosis in patients ≥9 years. Standard Review. PDUFA goal date: September 23, 2023.
SEPTEMBER 22, 2023
Complete Response Issued
Agency issued CR for NDA 217347 due solely to human factors (HF) study deficiencies — HF validation study demonstrated use errors and close calls with critical tasks. Clinical safety and efficacy were acceptably demonstrated; no other CR issues identified. Post-approval long-term safety routine pharmacovigilance considered adequate.
DECEMBER 20, 2023
Class 2 Resubmission (SDN 24)
Botanix submitted resubmission including: updated draft PI with proprietary name Sofdra; revised IFU; updated carton/container labeling; Japan pharmacovigilance safety update; HF validation study CSR.
APRIL 18, 2024
New HF Validation Study Results Submitted
Applicant submitted results from a new HF validation study addressing all CR requirements including redesigned applicator, revised IFU, and mitigations for tilting/spilling use error.
JUNE 14, 2024
Class 2 Resubmission Review Completed — Clinical Discipline Recommends Approval
Review completed by Roselyn E. Epps, M.D. and David Kettl, M.D. (DDD/OII). DMEPA concluded HF validation study results acceptable (May 20, 2024). CMC team recommended approval (June 11, 2024). OPDP and DMPP reviews completed. Clinical discipline recommended approval for sofpironium bromide gel 15% for primary axillary hyperhidrosis in patients ≥9 years. Reference ID: 5398431.
Key Review Issues
§7.4
Human Factors — Complete Response (Cycle 1)
The first HF validation study demonstrated use errors, close calls, and use difficulties with critical tasks that could result in harm or compromised efficacy (e.g., tilting/spilling the metered pump, not knowing what the applicator was). A Complete Response was issued September 22, 2023. The clinical discipline identified no other CR issues — safety and efficacy were acceptably demonstrated in the first review cycle.
Pediatric Age Threshold — HDSM-Ax Instrument Version
Only 5 subjects aged 9–11 years enrolled across both pivotal trials. FDA recommended the co-primary HDSM-Ax-7 endpoint analysis be restricted to subjects ≥12 years (Adult Version instrument). The Child Version was used for 9–11 year olds; results were supportive. The indication was ultimately approved for ≥9 years.
Gravimetric Sweat Production — Ranked Analysis
Due to non-normality of GSP data, a ranked ANCOVA was pre-specified and used for the co-primary GSP endpoint. Both studies met statistical significance (Study 301: p=0.0019; Study 302: p=0.0296). The statistical reviewer confirmed the ranked approach was appropriate.
Multiple Randomizations / Duplicate Enrollments
Four subjects were randomized multiple times across the two studies. The ITT population includes these duplicates; the modified ITT (mITT) excludes them. The primary efficacy analysis was pre-specified on the mITT population; results were robust to both analyses.
Postmarketing Requirements & Commitments
§7.5PMR/PMC: No postmarketing requirements or commitments specifically identified in the clinical review documents provided. Japan postmarketing pharmacovigilance data (sofpironium bromide gel 5%) were submitted with the Class 2 resubmission; events were consistent with approved labeling. Routine pharmacovigilance considered adequate by the review team.
| Domain | Detail |
|---|---|
| PMR/PMC identifier | Not reported in clinical review documents provided (Ref IDs 5249224, 5398431) |
| Postmarketing surveillance | Routine pharmacovigilance; Japan approval (sofpironium bromide 5% gel) provides additional postmarketing safety data |
| REMS | Not required |
Regulatory Submission Summary
| Aspect | Detail |
|---|---|
| Application number | NDA 217347 (Orig1s000) |
| Applicant | Botanix Pharmaceuticals |
| Submission / receipt date | September 23, 2022 |
| PDUFA goal date | September 23, 2023 |
| Review type | Standard Review; Original NDA; New Molecular Entity |
| Complete Response date | September 22, 2023 — HF deficiency only |
| Class 2 resubmission date | December 20, 2023 (SDN 24) |
| Pivotal trials | BBI-4000-CL-301 (NCT03836287) and BBI-4000-CL-302 (NCT03948646) |
| Co-primary endpoints met | Study 301: HDSM-Ax-7 50.4% vs 32.1% (p=0.0005); GSP ranked p=0.0019. Study 302: HDSM-Ax-7 63.3% vs 47.1% (p=0.0040); GSP ranked p=0.0296. All statistically significant. |
| Boxed Warning | None required |
| REMS | Not required |
| Priority Review / Breakthrough | Standard Review; no breakthrough or priority designation reported |
| Japan approval | Sofpironium bromide gel 5% approved in Japan; pharmacovigilance report submitted with resubmission — events consistent with approved labeling |
| Reference IDs | 5249224 (original cycle multi-disciplinary review) / 5398431 (Class 2 resubmission review, June 14, 2024) |
Source: NDA 217347 Class 2 Resubmission Review, Ref ID 5398431 (June 14, 2024); NDA 217347 Multi-disciplinary Review, Ref ID 5249224. Reviewed under Division of Dermatology and Dentistry (DDD), Office of Immunology and Inflammation (OII), CDER.