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warnings and cautions
5 WARNINGS AND PRECAUTIONS Increases in Blood Pressure: Can increase blood pressure in adult or pediatric patients. Periodically monitor blood pressure, especially in hypertensive patients. Mirabegron is 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 can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Mirabegron is 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, MYRBETRIQ was 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, MYRBETRIQ, taken as monotherapy or in combination with solifenacin succinate 5 mg, 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 MYRBETRIQ. Increases in Blood Pressure in Pediatric Patients 3 Years and Older Mirabegron 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 is not recommended for use in pediatric patients with severe uncontrolled hypertension, defined as a systolic and/or diastolic blood pressure above the 99th percentile plus 5 mm Hg for age, sex, and stature using appropriate reference values [see Adverse Reactions ( 6.1 )]. 5.2 Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Muscarinic Antagonist Medications for OAB In patients taking MYRBETRIQ, 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, MYRBETRIQ should still be administered with caution to patients with clinically significant BOO. For example, monitor these patients for signs and symptoms of urinary retention. MYRBETRIQ should also be administered with caution to patients taking muscarinic antagonist medications for the treatment of OAB, including solifenacin succinate [see Clinical Pharmacology ( 12.2 )]. 5.3 Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with mirabegron. 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 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 is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates is increased when coadministered with mirabegron. 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 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 in pediatric patients with NDO (≥ 3%) were UTI, nasopharyngitis, constipation, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 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 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 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 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 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 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 )]