Vibegron

1 INDICATIONS AND USAGE GEMTESA is a beta-3 adrenergic agonist indicated for the treatment of: overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults. ( 1.1 ) overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adult males on pharmacological therapy for benign prostatic hyperplasia (BPH). ( 1.2 ) 1.1 Overactive Bladder in Adults GEMTESA ® is indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults. 1.2 Overactive Bladder in Adult Males with Benign Prostatic Hyperplasia (BPH) GEMTESA is indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adult males on pharmacological therapy for benign prostatic hyperplasia (BPH).

2 DOSAGE AND ADMINISTRATION The recommended dose is one 75 mg tablet orally once daily. ( 2.1 ) Swallow tablet whole with water. ( 2.1 ) Tablet may be crushed and mixed with applesauce. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of GEMTESA is one 75 mg tablet orally, once daily with or without food. Swallow GEMTESA tablets whole with a glass of water. In adults, GEMTESA tablets also may be crushed, mixed with a tablespoon (approximately 15 mL) of applesauce and taken immediately with a glass of water [see Clinical Pharmacology ( 12.3 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling: Urinary retention [see Warnings and Precautions ( 5.1 )] Most common adverse reactions (≥2%) reported with GEMTESA were headache, urinary tract infection, nasopharyngitis, diarrhea, nausea, and upper respiratory tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sumitomo Pharma America, Inc. at 1-833-876-8268 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. Overactive Bladder in Adults The safety of GEMTESA was evaluated in a 12-week, double-blind, placebo- and active-controlled study (Study 3003) in patients with OAB [see Clinical Studies ( 14.1 )] . A total of 545 patients received GEMTESA. The majority of the patients were White (78%) and female (85%) with a mean age of 60 years (range 18 to 93 years). Adverse reactions that were reported in Study 3003 at an incidence greater than placebo and in ≥2% of patients treated with GEMTESA are listed in Table 1 . Table 1: Adverse Reactions, Exceeding Placebo Rate, Reported in ≥2% of Patients Treated with GEMTESA 75 mg for up to 12 Weeks in Study 3003 GEMTESA 75 mg n (%) Placebo n (%) Number of Patients 545 540 Headache 22 (4.0) 13 (2.4) Nasopharyngitis 15 (2.8) 9 (1.7) Diarrhea 12 (2.2) 6 (1.1) Nausea 12 (2.2) 6 (1.1) Upper respiratory tract infection 11 (2.0) 4 (0.7) Other adverse reactions reported in <2% of patients treated with GEMTESA included: Gastrointestinal disorders: dry mouth, constipation Investigations: residual urine volume increased Renal and urinary disorders: urinary retention Vascular disorders: hot flush GEMTESA was also evaluated for long-term safety in an extension study (Study 3004) in 505 patients who completed the 12-week study (Study 3003). Of the 273 patients who received GEMTESA 75 mg once daily in the extension study, 181 patients were treated for a total of one year. Adverse reactions reported in ≥2% of patients treated with GEMTESA 75 mg for up to 52 weeks in the long-term extension study, and not already listed above, were urinary tract infection (6.6%) and bronchitis (2.9%). Overactive Bladder in Adult Males with BPH The safety of GEMTESA was evaluated in a 24-week double-blind, randomized, placebo-controlled study (Study 3005) in male patients with OAB on pharmacological therapy for BPH. A total of 553 patients received GEMTESA [see Clinical Studies ( 14.2 )] . Adverse reactions that were reported in Study 3005 at an incidence greater than placebo and in ≥2% of patients treated with GEMTESA are listed in Table 2 . Table 2: Adverse Reactions, Exceeding Placebo Rate, Reported in ≥2% of Patients Treated with GEMTESA 75 mg for up to 24 Weeks in Study 3005 GEMTESA 75 mg n (%) Placebo n (%) *Defined as an average systolic blood pressure (SBP) ≥140mmHg or diastolic BP (DBP) ≥90mmHg on 3 assessments at two consecutive visits, in non-hypertensive patients. *Defined as an average increase of SBP ≥20mmHg or DBP≥10mmHg on 3 assessments at two consecutive visits, or the initiation or increase in dose of antihypertensive medications at any visit, in hypertensive patients. Number of Patients 553 551 Hypertension* 50 (9.0) 46 (8.3) Urinary tract infection 14 (2.5) 12 (2.2) GEMTESA was also evaluated for long-term safety in a 28-week extension study (Study 3006) in 276 patients who completed the 24-week study (Study 3005). Of the 276 patients who received GEMTESA 75 mg once daily in the extension study, 124 patients were treated for a total of one year. There were no additional adverse reactions reported in Study 3006 that are not already included in Section 6.1 above. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of vibegron. 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. The following adverse events have been reported in association with vibegron use in worldwide postmarketing experience: Urologic disorders : urinary retention Skin and subcutaneous tissue disorders : angioedema of the face and larynx; hypersensitivity reactions, including urticaria, pruritus, rash and drug eruption; eczema Gastrointestinal disorders : constipation

12.3 Pharmacokinetics Mean vibegron C max and AUC increased in a greater than dose-proportional manner up to 600 mg (8 times the approved recommended dosage). Steady state concentrations are achieved within 7 days of once daily dosing. The mean accumulation ratio (R ac ) was 1.7 for C max and 2.4 for AUC 0-24hr . Absorption Median vibegron T max is approximately 1 to 3 hours. Oral administration of a 75 mg vibegron tablet crushed and mixed with 15 mL of applesauce resulted in no clinically relevant changes in vibegron pharmacokinetics when compared to administration of an intact 75 mg vibegron tablet. Effect of Food No clinically significant differences in vibegron pharmacokinetics were observed following administration of a high-fat meal (53% fat, 869 calories [32.1 g protein, 70.2 g carbohydrate, and 51.1 g fat]). Distribution The mean apparent volume of distribution is 6304 liters. Human plasma protein binding of vibegron is approximately 50%. The average blood-to-plasma concentration ratio is 0.9. Elimination Vibegron has an effective half-life of 30.8 hours across all populations. Metabolism Metabolism plays a minor role in the elimination of vibegron. CYP3A4 is the predominant enzyme responsible for in vitro metabolism. Excretion Following a radiolabeled dose, approximately 59% of the dose (54% as unchanged) was recovered in feces and 20% (19% as unchanged) in urine. Specific Populations No clinically significant differences in the pharmacokinetics of vibegron were observed based on age (18 to 93 years), sex, race/ethnicity (Japanese vs. non-Japanese), mild (eGFR 60 to <90 mL/min/1.73 m 2 ), moderate (eGFR 30 to <60 mL/min/1.73 m 2 ), and severe (eGFR 15 to <30 mL/min/1.73 m 2 ) renal impairment, or moderate (Child-Pugh B) hepatic impairment. The effect of more severe renal impairment (eGFR <15 mL/min/1.73 m 2 ) with or without hemodialysis or severe (Child-Pugh C) hepatic impairment on vibegron pharmacokinetics was not studied. Drug Interaction Studies Clinical Studies Digoxin : Concomitant administration of vibegron increased digoxin C max and AUC by 21% and 11%, respectively. Other Drugs: No clinically significant differences in vibegron pharmacokinetics were observed when used concomitantly with ketoconazole (P-gp and strong CYP3A4 inhibitor), diltiazem (P-gp and moderate CYP3A4 inhibitor), rifampin (strong CYP3A4 inducer), or tolterodine. No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with vibegron: tolterodine, tolterodine 5-hydroxy metabolite, metoprolol, combined oral contraceptive (ethinyl estradiol, levonorgestrel), or warfarin. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Vibegron is a CYP3A4 substrate. Vibegron did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Vibegron did not induce CYP1A2, CYP2B6, or CYP3A4. Transporter Systems: Vibegron is a P-gp substrate. Vibegron did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K at clinically relevant concentrations.