Uroblock

1 INDICATIONS AND USAGE Mirabegron extended-release tablets are beta-3 adrenergic agonist indicated for the treatment of: Overactive bladder (OAB) in adult patients with symptoms of urge urinary incontinence, urgency, and urinary frequency. ( 1.1 ) 1.1 Adult Overactive Bladder (OAB) Mirabegron Extended-Release Tablets Monotherapy Mirabegron extended-release tablets are indicated for the treatment of OAB in adult patients with symptoms of urge urinary incontinence, urgency, and urinary frequency. Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

2 DOSAGE AND ADMINISTRATION Mirabegron extended-release tablets and mirabegron for extended-release oral suspension are two different products and they are not substitutable on a milligram-per-milligram basis. Select the recommended product (mirabegron extended-release tablets or mirabegron for extended-release oral suspension) based on the indication. OAB in Adults The recommended starting dose of mirabegron extended-release tablets is 25 mg orally once daily. ( 2.2 ) After 4 to 8 weeks, the mirabegron extended-release tablets dose may be increased to 50 mg orally once daily. ( 2.2 ) Adult Patients with Renal or Hepatic Impairment: Refer to the full prescribing information for recommended dosage. ( 2.4 ) Administration Mirabegron Extended-Release Tablets: Adult patients: Swallow mirabegron extended-release tablets whole with water. Do not chew, divide, or crush. Take with or without food. ( 2.7 ) 2.1 Important Dosage Information Mirabegron extended-release tablets and mirabegron for extended-release oral suspension are two different products and they are not substitutable on a milligram-per milligram basis: Select the recommended product (mirabegron extended-release tablets or mirabegron for extended-release oral suspension) based on the indication [see Indications and Usage ( 1 )] . 2.2 Recommended Dosage for Adult Patients with OAB Mirabegron Extended-Release Tablets Monotherapy The recommended starting dosage of mirabegron extended-release tablets is 25 mg orally once daily. If needed, increase to the maximum dosage of mirabegron extended-release tablets 50 mg orally once daily after 4 to 8 weeks. For administration instructions, see Dosage and Administration ( 2.7 ) . Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information 2.4 Recommended…

12.2 Pharmacodynamics Urodynamics The effects of mirabegron on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of mirabegron once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, mirabegron should be administered with caution to patients with clinically significant BOO [see Warnings and Precautions ( 5.2 )] . Cardiac Electrophysiology The effect of multiple doses of mirabegron 50 mg, 100 mg, and 200 mg (four times the maximum recommended dose) once daily on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg), four-treatment arm, parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg mirabegron dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4 to 5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec). For the mirabegron 100 mg and 200 mg dose groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4 to 5 hours post dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the mirabegron 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec). In this thorough QT study, mirabegron increased heart rate on ECG in a dose-dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups…

6 ADVERSE REACTIONS Most commonly reported adverse reactions with mirabegron monotherapy in adult patients with OAB (> 2% and > placebo) were hypertension, nasopharyngitis, urinary tract infection, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions are discussed in more detail in other sections of the labeling. Hypertension [see Warnings and Precautions ( 5.1 )] Urinary Retention [see Warnings and Precautions ( 5.2 )] Angioedema [see Warnings and Precautions ( 5.3 )] 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 clinical practice. Mirabegron Extended-Release Tablets Monotherapy for Adult OAB In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies in patients with OAB (Studies 1, 2, and 3), mirabegron extended-release tablets were evaluated for safety in 2736 patients [see Clinical Studies ( 14.1 )] . Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received mirabegron extended-release tablets 25 mg, 1375 received mirabegron extended-release tablets 50 mg, and 929 received mirabegron extended-release tablets 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 to 95 years). Mirabegron extended-release tablets were also evaluated for safety in 1632 patients who received mirabegron extended-release tablets 50 mg once daily (n=812 patients) or mirabegron extended-release tablets 100 mg (n=820 patients) in a 1-year, randomized, fixed-dose, double-blind, active-controlled, safety study in patients with OAB (Study 4). Of these patients, 731…

4 CONTRAINDICATIONS Hypersensitivity to mirabegron or any inactive ingredients. ( 4 ) Mirabegron extended-release tablets are contraindicated in patients with known hypersensitivity reactions to mirabegron or any inactive ingredients of the tablet [see Adverse Reactions ( 6.1 , 6.2 )] .

5 WARNINGS AND PRECAUTIONS Increases in Blood Pressure : Can increase blood pressure in adult patients. Periodically monitor blood pressure, especially in hypertensive patients. Mirabegron extended-release tablets are not recommended in patients with severe uncontrolled hypertension. ( 5.1 ) Urinary Retention in Patients With Bladder Outlet Obstruction and in Patients Taking Muscarinic Antagonist Drugs for Overactive Bladder : Administer with caution in these patients because of risk of urinary retention. ( 5.2 ) Angioedema : Angioedema of the face, lips, tongue, and/or larynx has been reported with mirabegron. ( 5.3 , 6.2 ) 5.1 Increases in Blood Pressure Increases in Blood Pressure in Adults Mirabegron extended-release tablets can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Mirabegron extended-release tablets are not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg) [see Clinical Pharmacology ( 12.2 )]. In two, randomized, placebo-controlled, healthy adult volunteer studies, mirabegron extended-release tablets were associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo. In contrast, in adult OAB patients in clinical trials, mirabegron extended-release tablets, taken as monotherapy, the mean increase in systolic and diastolic blood pressure at the maximum recommended mirabegron dose of 50 mg was approximately 0.5 to 1 mm Hg greater than placebo. Worsening of pre-existing hypertension was reported infrequently in patients taking mirabegron extended-release tablets. Increases in Blood Pressure in Pediatric Patients 3 Years and Older Mirabegron…

7 DRUG INTERACTIONS Drugs Metabolized by CYP2D6 : Mirabegron is a CYP2D6 inhibitor and, when used concomitantly with drugs metabolized by CYP2D6, especially narrow therapeutic index drugs, appropriate monitoring and possible dose adjustment of those drugs may be necessary. ( 5.4 , 7.1 , 12.3 ) Digoxin : When initiating a combination of mirabegron and digoxin, use the lowest dose of digoxin; monitor serum digoxin concentrations to titrate digoxin dose to desired clinical effect. ( 7.2 , 12.3 ) Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. Drug interaction studies were conducted in adult patients to investigate the effect of coadministered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of coadministered drugs (e.g., ketoconazole, rifampin, solifenacin succinate, tamsulosin, and oral contraceptives) [see Clinical Pharmacology ( 12.3 )] . No dose adjustment is recommended when these drugs are coadministered with mirabegron. The following are drug interactions for which monitoring is recommended: 7.1 Drugs Metabolized by CYP2D6 Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme is increased when coadministered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when mirabegron extended-release tablet is coadministered with these drugs, especially with narrow therapeutic index CYP2D6 substrates [see Warnings and Precautions ( 5.4 ) and Clinical Pharmacology ( 12.3 )] . 7.2 Digoxin When given in combination, 100 mg mirabegron increased mean digoxin C max from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). For patients who are initiating a combination of mirabegron and digoxin, the…