1 INDICATIONS AND USAGE Mirabegron 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.

( 1.1 ) Neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older and weighing 35 kg or more.

( 1.2 ) 1.1 Adult Overactive Bladder (OAB) Mirabegron Monotherapy Mirabegron 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) Mirabegron Mirabegron is indicated for the treatment of NDO in pediatric patients aged 3 years and older and weighing 35 kg or more.

6 ADVERSE REACTIONS 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 mirabegron 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 mirabegron in pediatric patients with NDO (≥ 3%) were UTI, nasopharyngitis, constipation, and headache.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 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.

Mirabegron 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 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 mirabegron 25 mg, 1,375 received mirabegron 50 mg, and 929 received mirabegron 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 was also evaluated for safety in 1632 patients who received mirabegron 50 mg once daily (n=812 patients) or mirabegron 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 mirabegron in a previous 12-week study.

In Study 4, 1,385 patients received mirabegron continuously for at least 6 months, 1311 patients received mirabegron for at least 9 months, and 564 patients received mirabegron 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 mirabegron 25 mg or 50 mg once daily for up to 12 weeks.

The most commonly reported adverse reactions (greater than 2% of mirabegron 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 Mirabegron 25 mg or 50 mg Once Daily in Studies 1, 2, and 3 Adverse Reaction Placebo (%) Mirabegron 25 mg (%) Mirabegron 50 mg (%) Number of Patients 1380 432 1375 Hypertension 1 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 1.

Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring predominantly in subjects with baseline hypertension.

Other adverse reactions reported by less than 1% of patients treated with mirabegron 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 mirabegron 50 mg for up to 52 weeks in Study 4.

The most commonly reported adverse reactions (> 3% of mirabegron 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 Mirabegron 50 mg Once Daily in Study 4 Adverse Reaction Mirabegron 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 mirabegron 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 mirabegron 50 mg; and these markers subsequently returned to baseline while both patients continued mirabegron.

In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with mirabegron 50 mg, mirabegron 100 mg, and active control once daily, respectively.

Neoplasms reported by 2 patients treated with mirabegron 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 mirabegron 100 mg as well as an herbal medication (Kyufu Gold).

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) The safety of mirabegron 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 mirabegron 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 mirabegron 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 Mirabegron in Study 9 Adverse Reaction Percentage (%) of Patients Reporting Adverse Reactions N=86 Number of Patients 51 (59.3) Urinary Tract Infection 1 24.4 Nasopharyngitis 5.8 Constipation 4.7 Headache 3.5 Nausea 2.3 Gastroenteritis 2.3 Rhinitis 2.3 Cough 2.3 1.

Includes any recorded UTI while patient was on treatment with mirabegron.

Increased Blood Pressure in Pediatric Patients with NDO Treated with Mirabegron : 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 mirabegron at a dose equivalent of mirabegron extended-release tablets 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 95th percentile for age, sex, and stature during Study 9.

Stage 1 hypertension, defined as repeated blood pressure measurements at or above the 95th 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 mirabegron.

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) ]