MYRBETRIQ

MYRBETRIQ (mirabegron extended-release tablets) for oral use and MYRBETRIQ Granules (mirabegron for extended-release oral suspension) are beta-3 adrenergic agonists. The chemical name of mirabegron is 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide having an empirical formula of C 21 H 24 N 4 O 2 S and a molecular weight of 396.51. The structural formula of mirabegron is: Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide. Each MYRBETRIQ (mirabegron extended-release tablets) for oral use contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: butylated hydroxytoluene, hydroxypropyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, polyethylene oxide, red ferric oxide (25 mg tablet only), and yellow ferric oxide. Each bottle of MYRBETRIQ Granules (mirabegron for extended-release oral suspension) contains approximately 8.3 g of granules, which contain 830 mg of mirabegron, and the following inactive ingredients: acesulfame potassium, diluted hydrochloric acid, ethylparaben, hypromellose, magnesium stearate, mannitol, methylparaben, silicon dioxide, simethicone, sodium polystyrene sulfonate, and xanthan gum. After reconstituted with 100 mL water, the suspension contains 8 mg/mL of mirabegron. Mirabegron structural formula

MYRBETRIQ is a 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, either alone or in combination with the muscarinic antagonist solifenacin succinate. ( 1.1 ) • Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older and weighing 35 kg or more. ( 1.2 ) MYRBETRIQ Granules is a beta-3 adrenergic agonist indicated for the treatment of NDO in pediatric patients aged 3 years and older. ( 1.2 ) 1.1 Adult Overactive Bladder (OAB) MYRBETRIQ Monotherapy MYRBETRIQ ® is indicated for the treatment of OAB in adult patients with symptoms of urge urinary incontinence, urgency, and urinary frequency. MYRBETRIQ Combination Therapy with Solifenacin Succinate MYRBETRIQ, in combination with the muscarinic antagonist solifenacin succinate, is indicated for the treatment of OAB in adult patients with symptoms of urge urinary incontinence, urgency, and urinary frequency. 1.2 Pediatric Neurogenic Detrusor Overactivity (NDO) MYRBETRIQ Granules MYRBETRIQ ® Granules is indicated for the treatment of NDO in pediatric patients aged 3 years and older. MYRBETRIQ MYRBETRIQ is indicated for the treatment of NDO in pediatric patients aged 3 years and older and weighing 35 kg or more.

DOSAGE AND A DM INISTRATION • MYRBETRIQ and MYRBETRIQ Granules are two different products and they are not substitutable on a milligram-per-milligram basis. Select the recommended product (MYRBETRIQ or MYRBETRIQ Granules) based on the indication and patient’s weight. Do not combine MYRBETRIQ and MYRBETRIQ Granules to achieve the total dose. A recommended dosage for MYRBETRIQ Granules for adults has not been determined. ( 2.1 ) OAB in Adults • The recommended starting dose of MYRBETRIQ is 25 mg orally once daily, either alone or in combination with solifenacin succinate 5 mg orally once daily. ( 2.2 ) • After 4 to 8 weeks, the MYRBETRIQ dose may be increased to 50 mg orally once daily. ( 2.2 ) NDO in Pediatric Patients 3 Years and Older • Pediatric Patients weighing less than 35 kg: Use MYRBETRIQ Granules: The recommended starting dose of MYRBETRIQ Granules is weight-based and administered as an extended-release oral suspension once daily. After 4 to 8 weeks, increase to the lowest effective dose without exceeding the maximum recommended dose. ( 2.3 ) • Pediatric Patients weighing 35 kg or more: Use MYRBETRIQ or MYRBETRIQ Granules: o The recommended starting dosage of MYRBETRIQ is 25 mg orally once daily. After 4 to 8 weeks, the MYRBETRIQ dose may be increased to 50 mg orally once daily. ( 2.3 ) o The recommended starting dosage of MYRBETRIQ Granules, administered as an extended-release oral suspension, is 6 mL (48 mg) orally once daily. After 4 to 8 weeks, increase to a maximum dosage of MYRBETRIQ Granules 10 mL (80 mg) orally once daily ( 2.3 ) Adult or Pediatric Patients with Renal or Hepatic Impairment : Refer to the full prescribing information for recommended dosage. ( 2.4 , 2.5 ) Preparation for MYRBETRIQ Granules : Refer to the full prescribing information. ( 2.6 ) Administration • MYRBETRIQ: o Adult patients: Swallow MYRBETRIQ whole with water. Do not chew, divide, or crush. Take with or without food. ( 2.7 ) o Pediatric patients: Swallow MYRBETRIQ whole with water. Do not chew, divide, or crush. Take with food. ( 2.7 ) • MYRBETRIQ Granules: o Pediatric patients: Take MYRBETRIQ Granules prepared as an extended-release oral suspension. Take with food. ( 2.7 ) 2.1 Important Dosage Information MYRBETRIQ and MYRBETRIQ Granules are two different products and they are not substitutable on a milligram-per-milligram basis: • Select the recommended product (MYRBETRIQ or MYRBETRIQ Granules) based on the indication and patient’s weight [see Indications and Usage ( 1 ) and Dosage and Administration ( 2.2 , 2.3 , 2.4 , 2.5 )]. • Do not combine MYRBETRIQ and MYRBETRIQ Granules to achieve the total dose. • A recommended dosage for MYRBETRIQ Granules for adults has not been determined. 2.2 Recommended Dosage for Adult Patients with OAB MYRBETRIQ Monotherapy The recommended starting dosage of MYRBETRIQ is 25 mg orally once daily. If needed, increase to the maximum dosage of MYRBETRIQ 50 mg orally once daily after 4 to 8 weeks. For administration instructions, see Dosage and Administration ( 2.7 ) . MYRBETRIQ Combination Therapy with Solifenacin Succinate The recommended starting dosage for combination treatment is MYRBETRIQ 25 mg orally once daily and solifenacin succinate 5 mg orally once daily. If needed, increase to the maximum dosage of MYRBETRIQ 50 mg orally once daily after 4 to 8 weeks. Refer to the Prescribing Information for solifenacin succinate for additional information. For administration instructions, see Dosage and Administration ( 2.7 ) . 2.3 Recommended Dosage for Pediatric Patients Aged 3 Years and Older with NDO For pediatric patients 3 years of age and older, select the appropriate product (MYRBETRIQ or MYRBETRIQ Granules) based on the patient’s weight. Pediat ric Patients weighing less than 35 kg: Use MYRBETRIQ Granules The recommended starting and maximum doses of MYRBETRIQ Granules, administered as extended-release oral suspension once daily [see Dosage and Administration ( 2.6 )] , are shown in Table 1 . The recommended dosages are determine d based on patient weight. Evaluate patients periodically for potential dosage adjustment. For administration instruc tions, see Dosage and Administration ( 2.7 ) . Table 1: MYRBETRIQ Granules Recommended Dosage for Pediatric Patients Aged 3 Years and Older Weighing Less Than 35 kg as an Extended-Release Oral Suspension (Administered Orally Once Daily) Body Weight Range Starting Dose Maximum Volume 11 kg to less than 22 kg 3 mL (24 mg) 6 mL (48 mg) 22 kg to less than 35 kg 4 mL (32 mg) 8 mL (64 mg) Greater than or equal to 35 kg Refer to information in next section Pediatric Patients weighing 35 kg or more: Use MYRBETRIQ or MYRBETRIQ Granules The recommended starting dosage of MYRBETRIQ is 25 mg orally once daily. If needed, increase to a maximum dosage of MYRBETRIQ 50 mg orally once daily after 4 to 8 weeks. For administration instructions , see Dosage and Administration ( 2.7 ). The recommended starting dosage of MYRBETRIQ Granules is 6 mL (48 mg) orally once daily. If needed, increase to a maximum dosage of MYRBETRIQ Granules 10 mL (80 mg) orally once daily after 4 to 8 weeks. For administration instructions, see Dosage and Administration ( 2.7 ). 2.4 Recommended Dosage in Adult Patients with Renal or Hepatic Impairment Dosage in Adults with Renal Impairment The recommended dosage of MYRBETRIQ (administered orally once daily) in adult patients with renal impairment is described in Table 2 [see Use in Specific Populations ( 8.6 )]. For administration instructions, see Dosage and Administration ( 2.7 ). Table 2: MYRBETRIQ Recommended Dosage in Adult Patients with Renal Impairment (Administered Orally Once Daily) Estimated GFR Estimated GFR using the modification of diet in renal disease (MDRD) formula Starting Dose Maximum Dose eGFR 30 to 89 mL/min/1.73 m 2 25 mg 50 mg eGFR 15 to 29 mL/min/1.73 m 2 25 mg 25 mg eGFR < 15 mL/min/1.73 m 2 or requiring dialysis Not recommended Dosage in Adults with Hepatic Impairment The recommended dosage of MYRBETRIQ (administered orally once daily) in adult patients with hepatic impairment is described in Table 3 [see Use in Specific Populations ( 8.7 )]. For administration instructions, see Dosage and Administration ( 2.7 ). Table 3: MYRBETRIQ Recommended Dosage in Adult Patients with Hepatic Impairment (Administered Orally Once Daily) Hepatic Impairment Classification Starting Dose Maximum Dose Child-Pugh Class A (Mild hepatic impairment) 25 mg 50 mg Child-Pugh Class B (Moderate hepatic impairment) 25 mg 25 mg Child-Pugh Class C (Severe hepatic impairment) Not Recommended 2.5 Recommended Dosage in Pediatric Patients with Renal or Hepatic Impairment For pediatric patients 3 years of age and older, select the appropriate product (MYRBETRIQ or MYRBETRIQ Granules) based on the patient’s weight. Pediatric Patients Weighing Less Than 35 kg with Renal or Hepatic Impairment: Use MYRBETRIQ Granules Dosage in Pediatric Patients with Renal Impairment The recommended dosage of MYRBETRIQ Granules in pediatric patients with renal impairment (administered orally once daily) is described in Table 4 [see Use in Specific Populations ( 8.6 )]. For administration instructions, see Dosage and Administration ( 2.7 ). Table 4: MYRBETRIQ Granules Recommended Dosage in Pediatric Patients Aged 3 Years and Older Weighing Less Than 35 kg with Renal Impairment (Administered Orally Once Daily) Estimated GFR Estimate GFR using a validated eGFR estimating equation for the pediatric age range of the approved indication. Body Weight Range Starting Dose Maximum Dose eGFR 30 to 89 mL/min/1.73 m 2 11 kg to less than 22 kg 3 mL (24 mg) 6 mL (48 mg) 22 kg to less than 35 kg 4 mL (32 mg) 8 mL (64 mg) eGFR 15 to 29 mL/min/1.73 m 2 11 kg to less than 22 kg 3 mL (24 mg) 3 mL (24 mg) 22 kg to less than 35 kg 4 mL (32 mg) 4 mL (32 mg) eGFR < 15 mL/min/1.73 m 2 or undergoing dialysis Use is Not Recommended Dosage in Pediatric Patients with Hepatic Impairment The recommended dosage of MYRBETRIQ Granules in pediatric patients with hepatic impairment (administered orally once daily) is described in Table 5 [see Use in Specific Populations ( 8.7 )] . For administration instructions, see Dosage and Administration ( 2.7 ). Table 5: MYRBETRIQ Granules Recommended Dosage in Pediatric Patients Aged 3 Years and Older Weighing Less Than 35 kg with Hepatic Impairment (Administered Orally Once Daily) Hepatic Impairment Classification Body Weight Range Starting Dose Maximum Dose Child-Pugh Class A (Mild hepatic impairment) 11 kg to less than 22 kg 3 mL (24 mg) 6 mL (48 mg) 22 kg to less than 35 kg 4 mL (32 mg) 8 mL (64 mg) Child-Pugh Class B (Moderate hepatic impairment) 11 kg to less than 22 kg 3 mL (24 mg) 3 mL (24 mg) 22 kg to less than 35 kg 4 mL (32 mg) 4 mL (32 mg) Child-Pugh Class C (Severe hepatic impairment) Use is Not Recommended Pediatric Patients weighing 35 kg or more with renal or hepatic impairment: Use MYRBETRIQ or MYRBETRIQ Granules Dosage in Pediatric Patients with Renal Impairment The recommended dosage of MYRBETRIQ in pediatric patients with renal impairment weighing 35 kg or more (administered orally once daily) is described in Table 2 (above). Note that the dosage is the same as for adult patients with renal impairment [see Dosage and Administration ( 2.4 ) and Use in Specific Populations ( 8.6 )] . For administration instructions, see Dosage and Administration ( 2.7 ). The recommended dosage of MYRBETRIQ Granules in pediatric patients with renal impairment weighing 35 kg or more (administered orally once daily) is described in Table 6 [see Use in Specific Populations ( 8.6 )] . For administration instructions, see Dosage and Administration ( 2.7 ). Table 6: MYRBETRIQ Granules Recommended Dosage in Pediatric Patients Aged 3 Years and Older with Renal Impairment Weighing 35 kg or More (Administered Orally Once Daily) Estimated GFR Estimate GFR using a validated eGFR estimating equation for the pediatric age range of the approved indication. Starting Dose Maximum Dose eGFR 30 to 89 mL/min/1.73 m 2 6 mL (48 mg) 10 mL (80 mg) eGFR 15 to 29 mL/min/1.73 m 2 6 mL (48 mg) 6 mL (48 mg) eGFR < 15 mL/min/1.73 m 2 or undergoing dialysis Use is Not Recommended Dosage in Pediatric Patients with Hepatic Impairment The recommended dosage of MYRBETRIQ in pediatric patients with hepatic impairment weighing 35 kg or more (administered orally once daily) is described in Table 3 (above). Note that the dosage is the same as for adult patients with hepatic impairment [see Dosage and Administration ( 2.4 ) and Use in Specific Populations ( 8.6 )] . For administration instructions, see Dosage and Administration ( 2.7 ). The recommended dosage of MYRBETRIQ Granules in pediatric patients with hepatic impairment weighing 35 kg or more (administered orally once daily) is described in Table 7 [see Use in Specific Populations ( 8.7 )]. For administration instructions, see Dosage and Administration ( 2.7 ). Table 7: MYRBETRIQ Granules Recommended Dosage in Pediatric Patients Aged 3 Years and Older with Hepatic Impairment Weighing 35 kg or More (Administered Orally Once Daily) Hepatic Impairment Classification Starting Dose Maximum Dose Child-Pugh Class A (Mild hepatic impairment) 6 mL (48 mg) 10 mL (80 mg) Child-Pugh Class B (Moderate hepatic impairment) 6 mL (48 mg) 6 mL (48 mg) Child-Pugh Class C (Severe hepatic impairment) Use is Not Recommended 2.6 Preparation and Storage Instructions for MYRBETRIQ Granules The required dose for MYRBETRIQ Granules (mirabegron for extended-release oral suspension) is calculated based on the weight of the patient. Prepare oral suspension at the time of dispensing. Keep the bottle in the pouch up until the time of reconstitution. • Discard the pouch and desiccant prior to reconstitution. Do not dispense. • Tap the closed bottle several times to loosen the granules. • Measure 100 mL of water, add the total amount to the bottle, and immediately shake vigorously for 1 minute, then let it stand for 10 to 30 minutes. Shake vigorously again for 1 minute. • If granules have not dispersed, shake vigorously for another 1 minute. • Record the 28-day expiration date on the container and carton based on the reconstitution date. • Give the patient an appropriate dosing device. • Store the reconstituted suspension at 20°C to 25°C (68°F to 77°F) for up to 28 days. • Discard the unused portion after 28 days [see How Supplied/Storage and Handling ( 16.2 )] . After reconstitution with 100 mL water, the suspension contains 8 mg/mL of mirabegron. 2.7 Administration Instructions Administration instructions for MYRBETRIQ and MYRBETRIQ Granules differ based on the patient population. MYRBETRIQ Adult patients: Swallow MYRBETRIQ whole with water. Do not chew, divide, or crush. Take with or without food. Pediatric patients: Swallow MYRBETRIQ whole with water. Do not chew, divide, or crush. Take with food [see Use in Specific Populations ( 8.4 )] . MYRBETRIQ Granules Adult patients: A recommended dosage for MYRBETRIQ Granules for adults has not been determined. Pediatric patients: Take MYRBETRIQ Granules prepared as an extended-release oral suspension [see Dosage and Administration ( 2.6 )] . Take with food to reduce potential exposure-related risks [see Use in Specific Populations ( 8.4 )] . 2.8 Missed Dose Instruct patients to take any missed doses as soon as they remember, unless more than 12 hours have passed since the missed dose. If more than 12 hours have passed, the missed dose can be skipped, and the next dose should be taken at the usual time.

MYRBETRIQ/MYRBETRIQ Granules is contraindicated in patients with known hypersensitivity reactions to mirabegron or any inactive ingredients of the tablet or oral suspension [see Adverse Reactions ( 6.1 , 6.2 )] . Hypersensitivity to mirabegron or any inactive ingredients. ( 4 )

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 )] • Most commonly reported adverse reactions with MYRBETRIQ monotherapy in adult patients with OAB (> 2% and > placebo) were hypertension, nasopharyngitis, urinary tract infection, and headache. ( 6.1 ) • Most commonly reported adverse reactions with MYRBETRIQ, in combination with solifenacin succinate in adult patients with OAB (> 2% and > placebo and > comparator), were dry mouth, urinary tract infection, constipation, and tachycardia. ( 6.1 ) • Most commonly reported adverse reactions with MYRBETRIQ/MYRBETRIQ Granules in pediatric patients with NDO (≥ 3%) were UTI, nasopharyngitis, constipation, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 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 clinical practice. MYRBETRIQ 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), MYRBETRIQ was 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 MYRBETRIQ 25 mg, 1375 received MYRBETRIQ 50 mg, and 929 received MYRBETRIQ 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). MYRBETRIQ was also evaluated for safety in 1632 patients who received MYRBETRIQ 50 mg once daily (n=812 patients) or MYRBETRIQ 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 received MYRBETRIQ in a previous 12-week study. In Study 4, 1385 patients received MYRBETRIQ continuously for at least 6 months, 1311 patients received MYRBETRIQ for at least 9 months, and 564 patients received MYRBETRIQ for at least 1 year. The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2, and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness, and tachycardia. Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo. Table 8 lists the adverse reactions, derived from all adverse events, that were reported in Studies 1, 2, and 3 at an incidence greater than placebo and in 1% or more of patients treated with MYRBETRIQ 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of MYRBETRIQ patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection, and headache. Table 8: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Placebo Rate and Reported in ≥ 1% of OAB Patients Treated with MYRBETRIQ 25 mg or 50 mg Once Daily in Studies 1, 2, and 3 Adverse Reaction Placebo (%) MYRBETRIQ 25 mg (%) MYRBETRIQ 50 mg (%) Number of Patients 1380 432 1375 Hypertension Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring predominantly in subjects with baseline hypertension. 7.6 11.3 7.5 Nasopharyngitis 2.5 3.5 3.9 Urinary Tract Infection 1.8 4.2 2.9 Headache 3.0 2.1 3.2 Constipation 1.4 1.6 1.6 Upper Respiratory Tract Infection 1.7 2.1 1.5 Arthralgia 1.1 1.6 1.3 Diarrhea 1.3 1.2 1.5 Tachycardia 0.6 1.6 1.2 Abdominal Pain 0.7 1.4 0.6 Fatigue 1.0 1.4 1.2 Other adverse reactions reported by less than 1% of patients treated with MYRBETRIQ in Studies 1, 2, or 3 included: Cardiac disorders : palpitations, blood pressure increased [see Clinical Pharmacology ( 12.2 )] Eye disorders : glaucoma [see Clinical Pharmacology ( 12.2 )] Gastrointestinal disorders : dyspepsia, gastritis, abdominal distension Infections and Infestations : sinusitis, rhinitis Investigations : GGT increased, AST increased, ALT increased, LDH increased Renal and urinary disorders : nephrolithiasis, bladder pain Reproductive system and breast disorders : vulvovaginal pruritus, vaginal infection Skin and subcutaneous tissue disorders : urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema Table 9 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with MYRBETRIQ 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (> 3% of MYRBETRIQ patients) were hypertension, urinary tract infection, headache, and nasopharyngitis. Table 9: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Reported in > 2% of OAB Patients Treated with MYRBETRIQ 50 mg Once Daily in Study 4 Adverse Reaction MYRBETRIQ 50 mg (%) Active Control (%) Number of Patients 812 812 Hypertension 9.2 9.6 Urinary Tract Infection 5.9 6.4 Headache 4.1 2.5 Nasopharyngitis 3.9 3.1 Back Pain 2.8 1.6 Constipation 2.8 2.7 Dry Mouth 2.8 8.6 Dizziness 2.7 2.6 Sinusitis 2.7 1.5 Influenza 2.6 3.4 Arthralgia 2.1 2.0 Cystitis 2.1 2.3 In Study 4, in patients treated with MYRBETRIQ 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking MYRBETRIQ 50 mg; and these markers subsequently returned to baseline while both patients continued MYRBETRIQ. In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with MYRBETRIQ 50 mg, MYRBETRIQ 100 mg, and active control once daily, respectively. Neoplasms reported by 2 patients treated with MYRBETRIQ 100 mg included breast cancer, lung neoplasm malignant, and prostate cancer. A causal relationship between mirabegron and these reported neoplasms has not been established. In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST, and bilirubin in a patient taking MYRBETRIQ 100 mg as well as an herbal medication (Kyufu Gold). MYRBETRIQ Combination Therapy with Solifenacin Succinate for Adult OAB In three, 12-week, double-blind, randomized, active-controlled safety and efficacy studies in patients with OAB (Studies 5, 6, and 7), combination treatment of MYRBETRIQ and solifenacin succinate was evaluated for safety in 6818 patients [see Clinical Studies ( 14.2 )] . Studies 5 and 6 also included a placebo control. For the combined Studies 5, 6, and 7, 997 patients received combination treatment with MYRBETRIQ 25 mg and solifenacin succinate 5 mg, and 1706 patients received combination treatment with MYRBETRIQ 50 mg and solifenacin succinate 5 mg. In these studies, the majority of the patients were Caucasian (88%) and female (77%) with a mean age of 57 years (range 18 to 89 years). MYRBETRIQ 50 mg and solifenacin succinate 5 mg coadministration was also evaluated for safety in 1814 patients in a 52-week, double-blind, randomized, active-controlled study in patients with OAB (Study 8) [see Clinical Studies ( 14.2 )] . In Studies 5, 6, and 7, the most commonly reported adverse reactions (greater than 2% of patients treated with combination therapy of MYRBETRIQ and solifenacin succinate 5 mg, and greater than placebo and/or MYRBETRIQ or solifenacin succinate comparator at the same dose as in the combination treatment) were dry mouth, urinary tract infection, constipation, and tachycardia. The most frequent adverse reactions (≥ 0.2%) leading to discontinuation in the coadministration trials were dry mouth and urinary retention. Table 10 lists the adverse reactions, derived from all adverse events that were reported in Studies 5, 6, and 7 in 1% or more of patients treated with MYRBETRIQ 25 mg or 50 mg coadministered with solifenacin succinate 5 mg and at an incidence greater than placebo and mirabegron or solifenacin succinate comparator at the same dose as in the combination treatment when administered once daily for up to 12 weeks. Table 10: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Placebo and Comparator (at same dose level) Rate and Reported in ≥ 1% of OAB Patients Treated with Combination Therapy in Studies 5, 6, and 7 Adverse reactions occurring in patients treated with coadministration of MYRBETRIQ and solifenacin succinate in Study 7, that included a 4-week initial treatment period with MYRBETRIQ 25 mg + Solifenacin Succinate 5 mg, are included in the MYRBETRIQ 50 mg + Solifenacin Succinate 5 mg group. Adverse Reaction Placebo (%) MYRBETRIQ 25 mg (%) MYRBETRIQ 50 mg (%) Solifenacin Succinate 5 mg (%) MYRBETRIQ 25 mg + Solifenacin Succinate 5 mg (%) MYRBETRIQ 50 mg + Solifenacin Succinate 5 mg (%) Number of Patients 510 500 500 1288 997 1706 Dry Mouth 2.2 3.8 3.6 6.5 9.3 7.2 Urinary Tract Infections Includes any recorded treatment-emergent UTI. 5.3 4.0 4.2 3.6 7.0 4.0 Constipation 1.2 1.2 2.8 2.4 4.2 3.9 Tachycardia 0.8 1.6 1.6 0.7 2.2 0.9 Dyspepsia 0.6 0.4 0.2 0.7 1.1 1.3 Dizziness 0.4 0.8 1.2 1.2 1.3 0.4 Vision Blurred 0.4 0.2 0.2 0.9 0.7 1.1 Arthralgia 0.8 0.8 0.8 0.8 0.5 1.1 In Study 8, the most common adverse reactions (more than 2% of patients treated with coadministration of MYRBETRIQ and solifenacin succinate and exceeding comparator rate) were UTI, dry mouth, constipation, and headache. The most frequent adverse reactions leading to discontinuation in the trial were constipation (0.2%), urinary retention (0.2%), urinary hesitation (0.2%), and vision blurred (0.2%). In Study 8, serious adverse events of neoplasm were reported by 0.7%, 0.3%, and 0% of patients who received coadministration of MYRBETRIQ 50 mg and solifenacin succinate 5 mg, MYRBETRIQ 50 mg monotherapy, and solifenacin succinate 5 mg monotherapy, respectively. Neoplasms reported by more than 1 patient who received coadministration with MYRBETRIQ 50 mg and solifenacin succinate 5 mg included basal cell carcinoma (n=3), breast cancer (n=2), melanoma (n=2), and squamous cell carcinoma (n=2). A causal relationship between the coadministration of mirabegron and solifenacin succinate and these reported neoplasms has not been established. Table 11 lists the adverse reactions, derived from all adverse events that were reported at an incidence greater than comparator and in 2% or more of patients treated with MYRBETRIQ 50 mg coadministered with solifenacin succinate 5 mg once daily for up to 52 weeks in Study 8. Table 11: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Comparator Rate and Reported in ≥ 2% of OAB Patients Treated with Combination Therapy in Study 8 Adverse Reaction MYRBETRIQ 50 mg (%) Solifenacin Succinate 5 mg (%) MYRBETRIQ 50 mg + Solifenacin Succinate 5 mg (%) Number of Patients 305 303 1206 Urinary Tract Infections Includes any recorded treatment-emergent UTI. 6.2 5.9 8.4 Dry Mouth 3.9 5.9 6.1 Constipation 1.0 2.3 3.3 Headache 1.6 1.7 2.9 MYRBETRIQ/MYRBETRIQ Granules for Pediatric Neurogenic Detrusor Overactivity (NDO) The safety of MYRBETRIQ/MYRBETRIQ Granules was evaluated in a 52-week, open-label, baseline-controlled, multicenter, dose titration study (Study 9) [see Clinical Studies ( 14.3 )] . The study included 86 pediatric patients 3 to 17 years of age with neurogenic detrusor overactivity (NDO); 55% were female, 72% were White. Treatment was initiated at the weight-based starting recommended dose and was increased to a dose equivalent of MYRBETRIQ 50 mg daily dose in adults by Week 8. Subsequent to the dose titration period, patients continued their optimized dose for the duration of the 52-week study (mean exposure duration 303 days, range 1 to 390 days). The most commonly reported adverse reactions were UTI, nasopharyngitis, constipation, and headache. Table 12 lists the adverse reactions that were reported in 2% or more of patients treated with MYRBETRIQ/MYRBETRIQ Granules for oral suspension in Study 9. Table 12: Percentages of Patients with Adverse Reactions Reported in ≥ 2% of Patients 3 to 17 Years of Age with Neurogenic Detrusor Overactivity (NDO) Treated with MYRBETRIQ/MYRBETRIQ Granules in Study 9 Adverse Reaction Percentage (%) of Patients Reporting Adverse Reactions N=86 Number of Patients 51 (59.3) Urinary Tract Infection Includes any recorded UTI while patient was on treatment with MYRBETRIQ/MYRBETRIQ Granules. 24.4 Nasopharyngitis 5.8 Constipation 4.7 Headache 3.5 Nausea 2.3 Gastroenteritis 2.3 Rhinitis 2.3 Cough 2.3 Increased Blood Pressure in Pediatric Patients with NDO Treated with MYRBETRIQ/MYRBETRIQ Granules: Mean systolic and diastolic blood pressures increased in Study 9 by 4.3 mm Hg and 1.7 mm Hg, respectively, in patients less than 12 years of age on MYRBETRIQ/MYRBETRIQ Granules at a dose equivalent of MYRBETRIQ 50 mg daily dose in adults. The blood pressure increases were larger in patients less than 8 years of age with mean systolic and diastolic blood pressure increases of 5.9 mm Hg and 2.3 mm Hg, respectively. Ten (24%) patients less than 12 years of age who were normotensive at baseline had at least one blood pressure measured at or above the 95 th percentile for age, sex, and stature during Study 9. Stage 1 hypertension, defined as repeated blood pressure measurements at or above the 95 th percentile for age, sex, and stature, was sustained in six of these 10 patients (60%) at the end of the study. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MYRBETRIQ/MYRBETRIQ Granules. 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 events have been reported in association with mirabegron use in worldwide postmarketing experience: Cardiac disorders : atrial fibrillation Gastrointestinal disorders : nausea, constipation, diarrhea Nervous system disorders : dizziness, headache There have been postmarketing reports of confusion, hallucinations, insomnia, and anxiety in patients taking mirabegron. The majority of these patients had pre-existing medical conditions or concomitant medications that may cause confusion, hallucinations, insomnia, and anxiety. A causal relationship between mirabegron and these disorders has not been established. Skin and subcutaneous tissue disorders : angioedema of the face, lips, tongue, and larynx, with or without respiratory symptoms [see Warnings and Precautions ( 5.3 )] ; pruritus Renal and urinary disorders : urinary retention [see Warnings and Precautions ( 5.2 )]

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: • 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 with or without solifenacin succinate, use the lowest dose of digoxin; monitor serum digoxin concentrations to titrate digoxin dose to desired clinical effect. ( 7.2 , 12.3 ) 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 MYRBETRIQ/MYRBETRIQ Granules 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%). Concomitant administration of 0.25 mg digoxin with a combination of 5 mg solifenacin and 50 mg mirabegron increased digoxin AUC tau and C max by approximately 10% and 14%, respectively. For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect [see Clinical Pharmacology ( 12.3 )] . 7.3 Warfarin The mean C max of S - and R -warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated [see Clinical Pharmacology ( 12.3 )] .