U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  53

ADVERSE REACTIONS

­ Most common adverse reactions (=2%) reported with GEMTESA were headache, urinary tract infection, nasopharyngitis, diarrhea, nausea, and upper respiratory tract infection.

CONTRAINDICATIONS

­ Do not use if prior hypersensitivity reaction to vibegron or any components of the product.

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 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Urinary Retention-                                                                                                                      Inform patients that GEMTESA has been associated with urinary retention. Inform patients that the risk of urinary retention may be increased in patients taking muscarinic antagonist medications for the treatment of OAB. Instruct patients to contact their healthcare provider if they experience symptoms consistent with urinary retention while taking GEMTESA 

Administration Instructions-                                                                                                  Advise patients that GEMTESA tablets can be swallowed whole with a glass of water or may be crushed, mixed with a tablespoon of applesauce and taken immediately with a glass of water [see Dosage and Administration

 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.

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                                        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.

2. Pharmacodynamics -                                                                                                       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.

3. Pharmacokinetics -                                                                                                        Mean vibegron Cmax 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 (Rac) was 1.7 for Cmax and 2.4 for AUC0-24hr.

Absorption-                                                                                                                           Median vibegron Tmax 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 m2 ), moderate (eGFR 30 to <60 mL/min/1.73 m2 ), and severe (eGFR 15 to <30 mL/min/1.73 m2 ) renal impairment, or moderate (Child-Pugh B) hepatic impairment.

Drug Interaction Studies-                                                                                                 Clinical Studies Digoxin:                                                                                                   Concomitant administration of vibegron increased digoxin Cmax 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.

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. Reference ID: 4721695

USE IN SPECIFIC POPULATIONS

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.

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.

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.

3.Pediatric Use-                                                                                                                          The safety and effectiveness of GEMTESA in pediatric patients have not been established.  

4. 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 

No overall differences in safety or effectiveness of GEMTESA have been observed between patients 65 years of age and older and younger adult patients.

5. 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 m2 ). GEMTESA has not been studied in patients with eGFR <15 mL/min/1.73 m2 (with or without hemodialysis) and is not recommended in these patients.

6. 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 be studied in patients with severe hepatic impairment (Child-Pugh C) and is not recommended in this patient population 

 OVERDOSAGE-                                                                                                                            There is no experience with inadvertent GEMTESA overdosage. In case of suspected overdose, treatment should be symptomatic and supportive.