MIRABEGRON

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 extended-release tablets can increase blood pressure in pediatric patients. Blood pressure increases may be larger in children (3 to less than 12 years of age) than in adolescents (12 to less than 18 years of age). Periodic blood pressure determinations are recommended. Mirabegron extended-release tablets is not recommended for use in pediatric patients with severe uncontrolled hypertension, defined as a systolic and/or diastolic blood pressure above the 99 th percentile plus 5 mm Hg for age, sex, and stature using appropriate reference values. 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. 5.2 Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Muscarinic Antagonist Medications for OAB In patients taking mirabegron extended-release tablets, urinary retention has been reported to occur in patients with bladder outlet obstruction (BOO) and in patients taking muscarinic antagonist medications for the treatment of OAB. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients treated with mirabegron; however, mirabegron extended-release tablets should still be administered with caution to patients with clinically significant BOO. For example, monitor these patients for signs and symptoms of urinary retention. Mirabegron extended-release tablets should also be administered with caution to patients taking muscarinic antagonist medications for the treatment of OAB [see Clinical Pharmacology ( 12.2 )] . 5.3 Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with mirabegron extended-release tablets. In some cases, angioedema occurred after the first dose, however, cases have been reported to occur hours after the first dose or after multiple doses. Angioedema, associated with upper airway swelling, may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, promptly discontinue mirabegron extended-release tablets and provide appropriate therapy and/or measures necessary to ensure a patent airway [see Adverse Reactions ( 6.2 )] . 5.4 Patients Taking Drugs Metabolized by CYP2D6 Since mirabegron extended-release tablet is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates is increased when coadministered with mirabegron extended-release tablet. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6 [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] .

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 received mirabegron extended-release tablets in a previous 12-week study. In Study 4, 1385 patients received mirabegron extended-release tablets continuously for at least 6 months, 1311 patients received mirabegron extended-release tablets for at least 9 months, and 564 patients received mirabegron extended-release tablets 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 extended-release tablets 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of mirabegron extended-release tablets 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 Extended-Release Tablets, 25 mg or 50 mg Once Daily in Studies 1, 2, and 3 Adverse Reaction Placebo (%) Mirabegron Extended- Release Tablets 25 mg (%) Mirabegron Extended- Release Tablets 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 mirabegron extended-release tablets 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 extended-release tablets 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of mirabegron extended-release tablets 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 Extended-Release Tablets 50 mg Once Daily in Study 4 Adverse Reaction Mirabegron Extended-Release Tablets 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 extended-release tablets 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 extended-release tablets 50 mg; and these markers subsequently returned to baseline while both patients continued mirabegron extended-release tablets. In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with mirabegron extended-release tablets 50 mg, mirabegron extended-release tablets 100 mg, and active control once daily, respectively. Neoplasms reported by 2 patients treated with mirabegron extended-release tablets 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 extended-release tablets 100 mg as well as an herbal medication (Kyufu Gold). 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of mirabegron extended-release tablets. 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 )]

<table ID="ID45" width="100%" styleCode="Noautorules"><caption>Table 8: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Placebo Rate and Reported in &#x2265; 1% of OAB Patients Treated with Mirabegron Extended-Release Tablets, 25 mg or 50 mg Once Daily in Studies 1, 2, and 3</caption><col width="24%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td align="center" styleCode="Lrule Toprule Rrule"><content styleCode="bold">Adverse Reaction</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">(%)</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Mirabegron Extended-</content> <content styleCode="bold">Release Tablets 25 mg</content> <content styleCode="bold">(%)</content> </td><td align="center" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Mirabegron Extended-</content> <content styleCode="bold">Release Tablets 50 mg</content> <content styleCode="bold"> (%)</content> </td></tr><tr><td align="left" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">Number of Patients</content> </td><td align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">1380</content> </td><td align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">432</content> </td><td align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">1375</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Hypertension <content styleCode="italics"><footnote ID="ID450"> Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring predominantly in subjects with baseline hypertension. </footnote></content> </td><td align="center" styleCode=" Botrule Rrule" valign="top">7.6 </td><td align="center" styleCode=" Botrule Rrule" valign="top">11.3 </td><td align="center" styleCode=" Botrule Rrule" valign="top">7.5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nasopharyngitis </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3.5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3.9 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Urinary Tract Infection </td><td align="center" styleCode=" Botrule Rrule">1.8 </td><td align="center" styleCode=" Botrule Rrule">4.2 </td><td align="center" styleCode=" Botrule Rrule">2.9 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Headache </td><td align="center" styleCode=" Botrule Rrule" valign="top">3.0 </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3.2 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Constipation </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.6 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Upper Respiratory Tract Infection </td><td align="center" styleCode=" Botrule Rrule">1.7 </td><td align="center" styleCode=" Botrule Rrule">2.1 </td><td align="center" styleCode=" Botrule Rrule">1.5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Arthralgia </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.6 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.3 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Diarrhea </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.3 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Tachycardia </td><td align="center" styleCode=" Botrule Rrule" valign="top">0.6 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.6 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.2 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Abdominal Pain </td><td align="center" styleCode=" Botrule Rrule" valign="top">0.7 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">0.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Fatigue </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.0 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.2 </td></tr></tbody></table>

<table ID="ID47" width="100%" styleCode="Noautorules"><caption>Table 9: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Reported in &gt; 2% of OAB Patients Treated with Mirabegron Extended-Release Tablets <sup/>50 mg Once Daily in Study 4 </caption><col width="31%"/><col width="34%"/><col width="34%"/><tbody><tr><td align="center" styleCode="Lrule Toprule Botrule Rrule Toprule"><content styleCode="bold">Adverse Reaction</content> </td><td align="center" styleCode=" Toprule Botrule Rrule"><content styleCode="bold">Mirabegron Extended-Release Tablets 50 mg</content> <content styleCode="bold">(%)</content> </td><td align="center" styleCode=" Toprule Botrule Rrule"><content styleCode="bold">Active Control (%)</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule"><content styleCode="bold">Number of Patients</content> </td><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">812</content> </td><td align="center" styleCode=" Botrule Rrule"><content styleCode="bold">812</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Hypertension </td><td align="center" styleCode=" Botrule Rrule" valign="top">9.2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">9.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Urinary Tract Infection </td><td align="center" styleCode=" Botrule Rrule" valign="top">5.9 </td><td align="center" styleCode=" Botrule Rrule" valign="top">6.4 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Headache </td><td align="center" styleCode=" Botrule Rrule" valign="top">4.1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nasopharyngitis </td><td align="center" styleCode=" Botrule Rrule" valign="top">3.9 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3.1 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Back Pain </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.8 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Constipation </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.8 </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.7 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Dry Mouth </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.8 </td><td align="center" styleCode=" Botrule Rrule" valign="top">8.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Dizziness </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.7 </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Sinusitis </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.7 </td><td align="center" styleCode=" Botrule Rrule" valign="top">1.5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Influenza </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.6 </td><td align="center" styleCode=" Botrule Rrule" valign="top">3.4 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Arthralgia </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.0 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Cystitis </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.1 </td><td align="center" styleCode=" Botrule Rrule" valign="top">2.3 </td></tr></tbody></table>