GEMTESA - vibegron_tablet, film coated

Vibegron is a selective human beta-3 adrenergic receptor agonist. Activation of the beta-3 adrenergic receptor increases bladder capacity by relaxing the detrusor smooth muscle during bladder filling. Vibegron's exposure-response relationship and the time course of pharmacodynamic response are not fully characterized. Blood Pressure In a 4-week, randomized, placebo-controlled, ambulatory blood pressure study in OAB patients (n=200), daily treatment with GEMTESA 75 mg was not associated with clinically significant changes in blood pressure. Subjects enrolled in this study had a mean age of 59 years and 75% were female. Thirty-five percent of subjects had pre-existing hypertension at baseline and 29% of all subjects were taking at least 1 concomitant antihypertensive medication. Cardiac Electrophysiology GEMTESA does not prolong the QT interval to any clinically relevant extent at a single dose 5. 3 times the approved recommended dose. Mean vibegron C max ac max 0-24hr Absorption Median vibegron T max 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. 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. 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 2 2 2 Drug Interaction Studies Clinical Studies Digoxin max Other Drugs: In Vitro Studies Cytochrome P450 (CYP) Enzymes: Transporter Systems:.

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 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 GEMTESA registered.

The recommended dose is one 75 mg tablet orally once daily. 1 Swallow tablet whole with water. 1 Tablet may be crushed and mixed with applesauce. 1 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.

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. 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. gov/medwatch. 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 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. 4) Nasopharyngitis 15 (2. 7) Diarrhea 12 (2. 1) Nausea 12 (2. 1) Upper respiratory tract infection 11 (2. 7) Other adverse reactions reported in <2% of patients treated with GEMTESA included: Gastrointestinal disorders: Investigations: Renal and urinary disorders: Vascular disorders: 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. 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 12 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. 3) Urinary tract infection 14 (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. 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 Skin and subcutaneous tissue disorders Gastrointestinal disorders.

[see Warnings and Precautions ( 5. 2 Do not use if prior hypersensitivity reaction to vibegron or any components of the product.

Pediatric use 8. 4 End-stage Renal Disease with or without Hemodialysis 8. 6 Severe Hepatic Impairment 8. 7 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. 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. 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 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 max max The safety and effectiveness of GEMTESA in pediatric patients have not been established. 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. 1 Of the total number of GEMTESA-treated patients in clinical studies for OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency in adult males on pharmacological therapy for benign prostatic hyperplasia (BPH), 347 (63%) were 65 years of age and older, while 100 (18%) were 75 years of age and older [see Clinical Studies ( 14. 2 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 2 [see Clinical Pharmacology ( 12. 3 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.

Concomitant use of GEMTESA increases digoxin maximal concentrations (C max [see Clinical Pharmacology ( 12. 3 Digoxin 7.

= 65 years. Table 4 Table 4: Mean Baseline and Change from Baseline at Week 12 for Micturition Frequency, "Need to Urinate Immediately" (Urgency Episodes), UUI Episodes and Volume Voided per Micturition Parameter GEMTESA 75 mg (N = 538) Placebo (N = 542) * Least squares mean adjusted for study visit, baseline value, geographical region, interaction of visit by treatment, and stratification factors as randomized (baseline average micturitions per day**, alpha blocker use with or without 5-ARI, baseline urinary incontinence**), geographical region, study visit, and study visit by treatment interaction term. ** Baseline average micturitions per day stratification factor is not included in the model where the continuous value of baseline average micturitions per day is present; baseline urinary incontinence is not included in the model for UUI; *** Only subjects with baseline incontinence have UUI analyzed. Average Daily Number of Micturitions Baseline mean 11. 96 Change from Baseline * -2. 30 Difference from Placebo -0. 74 95% Confidence Interval -1. 46 Average Daily Number of “Need to Urinate Immediately” (Urgency) Episodes Baseline mean 9. 00 Change from Baseline * -2. 93 Difference from Placebo -0. 95 95% Confidence Interval -1. 54 Average Daily Number of UUI Episodes N *** 146 151 Baseline mean 3. 23 Change from Baseline * -2. 39 Difference from Placebo -0. 80 95% Confidence Interval -1. 27 Average Volume Voided (mL) per Micturition Baseline mean 166. 43 Change from Baseline * 25. 56 Difference from Placebo 15. 07 95% Confidence Interval 9. 02 Figure 3 Figure 4 Figure 3: Mean (SE) Change from Baseline in the Average Daily Number of Micturitions in Male Patients with BPH on Pharmacological Therapy Figure 4: Mean (SE) Change from Baseline in the Average Daily Number of Urgency Episodes in Male Patients with BPH on Pharmacological Therapy Figure 3 Figure 4.">OVERDOSAGE
There is no experience with inadvertent GEMTESA overdosage. In case of suspected overdose, treatment should be symptomatic and supportive.
NONCLINICAL TOXICOLOGY
Carcinogenesis No carcinogenicity was observed in long-term studies conducted in mice and rats treated with daily oral doses of vibegron for approximately 2 years. In the mouse carcinogenicity study, CD-1 mice were treated with daily oral doses of vibegron up to 90 mg/kg/day in males and up to 150 mg/kg/day in females, corresponding to estimated systemic exposures (AUC) 21- and 55-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. In the rat carcinogenicity study, Sprague Dawley rats were treated with daily oral doses of vibegron up to 30 mg/kg/day in males and up to 180 mg/kg/day in females, corresponding to systemic exposures (AUC) 18- and 117-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. Mutagenesis Vibegron was not mutagenic in in vitro in vitro in vivo 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.
CLINICAL STUDIES
The efficacy of GEMTESA was evaluated in a 12-week, double-blind, randomized, placebo-controlled, and active-controlled trial (Study 3003, NCT03492281) in patients with OAB (urge urinary incontinence, urgency, and urinary frequency). Patients were randomized 5:5:4 to receive either GEMTESA 75 mg, placebo, or active control orally, once daily for 12 weeks. For study entry, patients had to have symptoms of OAB for at least 3 months with an average of 8 or more micturitions per day and at least 1 urge urinary incontinence (UUI) per day, or an average of 8 or more micturitions per day and an average of at least 3 urgency episodes per day. Urge urinary incontinence was defined as leakage of urine of any amount because the patient felt an urge or need to urinate immediately. The study population included OAB medication-naïve patients as well as patients who had received prior therapy with OAB medications. The co-primary endpoints were change from baseline in average daily 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 White (78%) and female (85%) with a mean age of 60 (range 18 to 93) years. Table 3 Table 3: 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 Placebo * Least squares mean adjusted for treatment, baseline, sex, geographical region, study visit, and study visit by treatment interaction term. Average Daily Number of Micturitions Baseline mean (n) 11. 8 (520) Change from Baseline * -1. 3 (475) Difference from Placebo -0. 5 95% Confidence Interval -0. 2 p-value <0. 001 Average Daily Number of UUI Episodes Baseline mean (n) 3. 5 (405) Change from Baseline * -2. 4 (372) Difference from Placebo -0. 6 95% Confidence Interval -0. 3 p-value <0. 0001 Average Daily Number of “Need to Urinate Immediately” (Urgency) Episodes Baseline mean (n) 8. 1 (520) Change from Baseline * -2. 0 (475) Difference from Placebo -0. 7 95% Confidence Interval -1. 2 p-value 0. 002 Average Volume Voided (mL) per Micturition Baseline mean (n) 155 (524) 148 (514) Change from Baseline * 23 (490) 2 (478) Difference from Placebo 21 95% Confidence Interval 14, 28 p-value <0. 0001 Figure 1 Figure 2 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 The safety, tolerability, and efficacy of GEMTESA was evaluated in a multinational 24-week, double-blind, randomized, placebo-controlled trial (Study 3005, NCT03902080) in male patients at least 45 years of age with OAB on pharmacological therapy (i. , treatment with an alpha blocker, with or without a 5-alpha reductase inhibitor) for BPH. A total of 1105 patients were randomized 1:1 to receive either GEMTESA 75 mg or placebo once daily for 24 weeks. For study entry, patients had symptoms of OAB (an average of 8 or more micturitions per day, 3 or more urgency episodes per day with or without incontinence, and 2 or more nocturia episodes per night) while taking pharmacological therapy for at least 2 months for the treatment of lower urinary tract symptoms due to BPH. Randomization was stratified based on the baseline average number of micturition episodes per day, alpha blocker use with or without 5 alpha reductase inhibitor use, and urinary incontinence. The co-primary endpoints were change from baseline in the average daily number of micturitions and the average daily number of “need to urinate immediately” (urgency) episodes at week 12. Additional endpoints included change from baseline in the average daily number of urge urinary incontinence (UUI) episodes and the average volume voided per micturition. A total of 1104 patients received at least one daily dose of placebo (n=551) or GEMTESA 75 mg (n=553). The majority of patients were White (87%) and enrolled in the U. The mean age was 67 years (range 45 to 97) and at least 63% were >= 65 years. Table 4 Table 4: Mean Baseline and Change from Baseline at Week 12 for Micturition Frequency, "Need to Urinate Immediately" (Urgency Episodes), UUI Episodes and Volume Voided per Micturition Parameter GEMTESA 75 mg (N = 538) Placebo (N = 542) * Least squares mean adjusted for study visit, baseline value, geographical region, interaction of visit by treatment, and stratification factors as randomized (baseline average micturitions per day**, alpha blocker use with or without 5-ARI, baseline urinary incontinence**), geographical region, study visit, and study visit by treatment interaction term. ** Baseline average micturitions per day stratification factor is not included in the model where the continuous value of baseline average micturitions per day is present; baseline urinary incontinence is not included in the model for UUI; *** Only subjects with baseline incontinence have UUI analyzed. Average Daily Number of Micturitions Baseline mean 11. 96 Change from Baseline * -2. 30 Difference from Placebo -0. 74 95% Confidence Interval -1. 46 Average Daily Number of “Need to Urinate Immediately” (Urgency) Episodes Baseline mean 9. 00 Change from Baseline * -2. 93 Difference from Placebo -0. 95 95% Confidence Interval -1. 54 Average Daily Number of UUI Episodes N *** 146 151 Baseline mean 3. 23 Change from Baseline * -2. 39 Difference from Placebo -0. 80 95% Confidence Interval -1. 27 Average Volume Voided (mL) per Micturition Baseline mean 166. 43 Change from Baseline * 25. 56 Difference from Placebo 15. 07 95% Confidence Interval 9. 02 Figure 3 Figure 4 Figure 3: Mean (SE) Change from Baseline in the Average Daily Number of Micturitions in Male Patients with BPH on Pharmacological Therapy Figure 4: Mean (SE) Change from Baseline in the Average Daily Number of Urgency Episodes in Male Patients with BPH on Pharmacological Therapy Figure 3 Figure 4.

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GEMTESA - vibegron_tablet, film coated Product manual source documgent