GEMTESA

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 )] .

4 CONTRAINDICATIONS GEMTESA is contraindicated in patients with known hypersensitivity to vibegron or any components of GEMTESA. Hypersensitivity reactions, such as angioedema, have occurred [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.2 )] . Do not use if prior hypersensitivity reaction to vibegron or any components of the product. ( 4 )

5 WARNINGS AND PRECAUTIONS Urinary Retention : Monitor for urinary retention, especially in patients with bladder outlet obstruction and also in patients taking muscarinic antagonist medications for OAB, in whom the risk of urinary retention may be greater. If urinary retention develops, discontinue GEMTESA. ( 5.1 ) Angioedema : Angioedema of the face and/or larynx has been reported with GEMTESA. ( 5.2 ) 5.1 Urinary Retention Urinary retention has been reported in patients taking GEMTESA. The risk of urinary retention may be increased in patients with bladder outlet obstruction and also in patients taking muscarinic antagonist medications for the treatment of OAB. Monitor patients for signs and symptoms of urinary retention, particularly in patients with bladder outlet obstruction or patients taking muscarinic antagonist medications for the treatment of OAB. Discontinue GEMTESA in patients who develop urinary retention [see Adverse Reactions ( 6.1 )] . 5.2 Angioedema Angioedema of the face and/or larynx has been reported with GEMTESA. Angioedema has been reported to occur hours after the first dose or after multiple doses. Angioedema, associated with upper airway swelling, may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, immediately discontinue GEMTESA and provide appropriate therapy and/or measures necessary to ensure a patent airway. GEMTESA is contraindicated in patients with known hypersensitivity to vibegron or any component of GEMTESA [see Contraindications ( 4 ) and Adverse Reactions ( 6.2 )] .

7 DRUG INTERACTIONS Concomitant use of GEMTESA increases digoxin maximal concentrations (C max ) and systemic exposure as assessed by area under the concentration-time curve (AUC) [see Clinical Pharmacology ( 12.3 )] . Serum digoxin concentrations should be monitored before initiating and during therapy with GEMTESA and used for titration of the digoxin dose to obtain the desired clinical effect. Continue monitoring digoxin concentrations upon discontinuation of GEMTESA and adjust digoxin dose as needed. Digoxin : Measure serum digoxin concentrations before initiating GEMTESA. Monitor serum digoxin concentrations to titrate digoxin dose to desired clinical effect. ( 7 )

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

8.1 Pregnancy Risk Summary There are no available data on GEMTESA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, no effects on embryo-fetal development were observed following administration of vibegron during the period of organogenesis at exposures approximately 275-fold and 285-fold greater than clinical exposure at the recommended daily dose of GEMTESA, in rats and rabbits, respectively. Delayed fetal skeletal ossification was observed in rabbits at approximately 898-fold clinical exposure, in the presence of maternal toxicity. In rats treated with vibegron during pregnancy and lactation, no effects on offspring were observed at 89-fold clinical exposure. Developmental toxicity was observed in offspring at approximately 458-fold clinical exposure, in the presence of maternal toxicity. No effects on offspring were observed at 89-fold clinical exposure (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry some risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In an embryo-fetal developmental toxicity study, pregnant rats were treated with daily oral doses of 0, 30, 100, 300, or 1000 mg/kg/day vibegron during the period of organogenesis (Days 6 to 20 of gestation). These doses were associated with systemic exposures (AUC) 0-, 9-, 89-, 275-, and 1867-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. No embryo-fetal developmental toxicity was observed at doses up to 300 mg/kg/day. Treatment with the high dose of 1000 mg/kg/day was discontinued due to maternal toxicity. In an embryo-fetal developmental toxicity study, pregnant rabbits were treated with daily oral doses of 0, 30, 100, or 300 mg/kg/day vibegron during the period of organogenesis (Days 7 to 20 of gestation). These doses were associated with systemic exposures (AUC) 0-, 86-, 285-, and 898-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. No embryo-fetal developmental toxicity was observed at doses of vibegron up to 100 mg/kg/day. Maternal toxicity (decreased food consumption), reduced fetal body weight, and an increased incidence of delayed skeletal ossification, were observed at 300 mg/kg/day. In a pre- and post-natal developmental toxicity study, pregnant or lactating rats were treated with daily oral doses of 0, 30, 100, or 500 mg/kg/day vibegron from day 6 of gestation through day 20 of lactation. These doses were associated with estimated systemic exposures (AUC) 0-, 9-, 89-, and 458-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. No developmental toxicity was observed in F1 offspring at doses up to 100 mg/kg/day. Maternal toxicity was observed during lactation (decreased body weight gain) at doses ≥100 mg/kg/day and during gestation (decreased body weight gain and food consumption) at 500 mg/kg/day. Developmental toxicity was observed in F1 offspring (increased stillborn index, lethality, reduced viability and weaning indices, decreased body weight and body weight gains, low physical development differentiation indices, and effects on sensory function and reflexes) at 500 mg/kg/day.