e majority of the patients were caucasian (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%). 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: pruritus, rash, drug eruption, eczema gastrointestinal disorders: constipation

bserved 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. 8.2 lactation risk summary there are no data on the presence of vibegron in human milk, the effects of the drug on the breastfed infant, or the effects on milk production. when a single oral dose of radiolabeled vibegron was administered to postnatal nursing rats, radioactivity was observed in milk (see data ). when a drug is present in animal milk, it is likely that the drug will be present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for gemtesa and any potential adverse effects on the breastfed infant from gemtesa or from the underlying maternal condition. data animal data in a lactational transfer study, lactating rats were treated with a single oral dose of 10 mg/kg radiolabeled [ 3 h] vibegron on postpartum day 10. levels of radioactivity were determined in milk and plasma collected at 1, 4, 12, and 24 after dosing. the c max of total radioactivity in milk and plasma were observed at 9 and 2 hours after dosing, respectively, with a maximum milk-to-plasma concentration ratio of 2.2 observed at 12 hours after dosing. vibegron elimination from milk showed a similar trend as that from plasma. the radioactivity concentration in milk at 24 hours after administration was approximately 25% of the c max . 8.4 pediatric use the safety and effectiveness of gemtesa in pediatric patients have not been established. 8.5 geriatric use of 526 patients who received gemtesa in the clinical studies for oab with symptoms of urge urinary incontinence, urgency, and urinary frequency, 242 (46%) were 65 years of age or older, and 75 (14%) were 75 years of age or older [see clinical studies (14) ] . no overall differences in safety or effectiveness of gemtesa have been observed between patients 65 years of age and older and younger adult patients. 8.6 renal impairment no dosage adjustment for gemtesa is recommended for patients with mild, moderate, or severe renal impairment (egfr 15 to <90 ml/min/1.73 m 2 ). gemtesa has not been studied in patients with egfr <15 ml/min/1.73 m 2 (with or without hemodialysis) and is not recommended in these patients [see clinical pharmacology (12.3) ] . 8.7 hepatic impairment no dosage adjustment for gemtesa is recommended for patients with mild to moderate hepatic impairment (child-pugh a and b). gemtesa has not been studied in patients with severe hepatic impairment (child-pugh c) and is not recommended in this patient population [see clinical pharmacology (12.3) ] .

und 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.

recommended dose. 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.

on 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.

y in an in vitro human peripheral blood lymphocyte chromosomal aberration assay, and did not increase the frequency of micronucleated polychromatic erythrocytes in an in vivo rat bone marrow micronucleus assay. impairment of fertility in fertility/general reproductive toxicity studies conducted in rats, females were treated with daily oral doses of 0, 30, 100, 300, or 1000 mg/kg/day vibegron and males were treated with daily oral doses of 0, 10, 30, or 300 mg/kg/day vibegron. no effects on fertility were observed in female or male rats at doses up to 300 mg/kg/day, associated with systemic exposure (auc) at least 274-fold higher than in humans treated with the recommended daily dose of gemtesa. general toxicity, decreased fecundity, and decreased fertility were observed in female rats at 1000 mg/kg/day, associated with estimated systemic exposure 1867-fold higher than in humans treated with the recommended daily dose of gemtesa.

ipheral blood lymphocyte chromosomal aberration assay, and did not increase the frequency of micronucleated polychromatic erythrocytes in an in vivo rat bone marrow micronucleus assay. impairment of fertility in fertility/general reproductive toxicity studies conducted in rats, females were treated with daily oral doses of 0, 30, 100, 300, or 1000 mg/kg/day vibegron and males were treated with daily oral doses of 0, 10, 30, or 300 mg/kg/day vibegron. no effects on fertility were observed in female or male rats at doses up to 300 mg/kg/day, associated with systemic exposure (auc) at least 274-fold higher than in humans treated with the recommended daily dose of gemtesa. general toxicity, decreased fecundity, and decreased fertility were observed in female rats at 1000 mg/kg/day, associated with estimated systemic exposure 1867-fold higher than in humans treated with the recommended daily dose of gemtesa.

ily number of micturitions and average daily number of uui episodes at week 12. additional endpoints included change from baseline in average daily number of "need to urinate immediately" (urgency) episodes and average volume voided per micturition. a total of 1,515 patients received at least one daily dose of placebo (n=540), gemtesa 75 mg (n=545), or an active control treatment (n=430). the majority of patients were caucasian (78%) and female (85%) with a mean age of 60 (range 18 to 93) years. table 2 shows changes from baseline at week 12 for average daily number of micturitions, average daily number of uui episodes, average daily number of "need to urinate immediately" (urgency) episodes, and average volume voided per micturition. table 2: mean baseline and change from baseline at week 12 for micturition frequency, urge urinary incontinence episodes, "need to urinate immediately" (urgency) episodes, and volume voided per micturition parameter gemtesa 75 mg placebo average daily number of micturitions baseline mean (n) 11.3 (526) 11.8 (520) change from baseline least squares mean adjusted for treatment, baseline, sex, geographical region, study visit, and study visit by treatment interaction term. (n) -1.8 (492) -1.3 (475) difference from placebo -0.5 95% confidence interval -0.8, -0.2 p-value <0.001 average daily number of uui episodes baseline mean (n) 3.4 (403) 3.5 (405) change from baseline (n) -2.0 (383) -1.4 (372) difference from placebo -0.6 95% confidence interval -0.9, -0.3 p-value <0.0001 average daily number of "need to urinate immediately" (urgency) episodes baseline mean (n) 8.1 (526) 8.1 (520) change from baseline (n) -2.7 (492) -2.0 (475) difference from placebo -0.7 95% confidence interval -1.1, -0.2 p-value 0.002 average volume voided (ml) per micturition baseline mean (n) 155 (524) 148 (514) change from baseline (n) 23 (490) 2 (478) difference from placebo 21 95% confidence interval 14, 28 p-value <0.0001 figures 1 and 2 show the mean change from baseline over time in average daily number of micturitions and mean change from baseline over time in average daily number of uui episodes, respectively. figure 1: mean (se) change from baseline in the average daily number of micturitions figure 2: mean (se) change from baseline in the average daily number of uui episodes in patients with at least 1 average daily uui episode at baseline figure 1 figure 2

t known if gemtesa will harm your unborn baby. talk to your doctor if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. it is not known if gemtesa passes into your breast milk. talk to your doctor about the best way to feed your baby if you take gemtesa. tell your doctor about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. know the medicines you take. keep a list of them to show your doctor and pharmacist when you get a new medicine. how should i take gemtesa? take gemtesa exactly as your doctor tells you to take it. take 1 gemtesa tablet, by mouth, 1 time a day with or without food. swallow gemtesa tablets whole with a glass of water. you may also crush gemtesa tablets, mix with 1 tablespoon (about 15 ml) of applesauce, and take right away with a glass of water. what are the possible side effects of gemtesa? gemtesa may cause serious side effects including: inability to empty your bladder (urinary retention). gemtesa may increase your chances of not being able to empty your bladder, especially if you have bladder outlet obstruction or take other medicines for treatment of overactive bladder. tell your doctor right away if you are unable to empty your bladder. the most common side effects of gemtesa include: urinary tract infection headache nasal congestion, sore throat or runny nose diarrhea nausea upper respiratory tract infection these are not all the possible side effects of gemtesa. for more information, ask your doctor or pharmacist. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store gemtesa? store gemtesa at room temperature between 68°f to 77°f (20°c to 25°c). safely throw away medicine that is no longer needed in your household trash. you may also dispose of the unused medicine through a take-back option, if available. see www.fda.gov/drugdisposal for more information. keep gemtesa and all medicines out of the reach of children. general information about the safe and effective use of gemtesa. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use gemtesa for a condition for which it was not prescribed. do not give gemtesa to other people, even if they have the same symptoms that you have. it may harm them. you can ask your doctor or pharmacist for information about gemtesa that is written for health professionals. what are the ingredients in gemtesa? active ingredient: vibegron inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, mannitol, and microcrystalline cellulose. the light green film coating contains fd&c blue no. 2 - aluminum lake, hypromellose, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. manufactured for and distributed by: urovant sciences, inc. irvine, ca 92617 gemtesa ® is a trademark of urovant sciences gmbh, registered in the u.s. and other countries. all other trademarks are the property of their respective owners. patented: see https://www.urovant.com/about/product-patents © 2020 urovant sciences gmbh. all rights reserved. for more information, go to www.gemtesa.com or call 1-833-876-8268.