Myrbetriq Drug Information

    Generic name: MIRABEGRON

    beta3-Adrenergic Agonist [EPC]

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    Uses of Myrbetriq

    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.

    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 & Administration of Myrbetriq

    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. • Do not combine MYRBETRIQ and MYRBETRIQ Granules to achieve the total dose. • A recommended dosage for MYRBETRIQ Granules for adults has not been determined.

    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.

    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. Refer to the Prescribing Information for solifenacin succinate for additional information.

    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, 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. 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) Pediatric Patients weighing 35 kg or more: Use MYRBETRIQ or MYRBETRIQ Granules The recommended starting dosage of MYRBETRIQ is 25 mg orally once daily.

    The recommended starting dosage of MYRBETRIQ Granules is 6 mL (48 mg) orally once daily.

    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.

    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. After reconstitution with 100 mL water, the suspension contains 8 mg/mL of mirabegron.

    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. Take with food.

    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. Take with food to reduce potential exposure-related risks.

    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.

    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 RangeStarting DoseMaximum Volume
    11 kg to less than 22 kg3 mL (24 mg)6 mL (48 mg)
    22 kg to less than 35 kg4 mL (32 mg)8 mL (64 mg)
    Greater than or equal to 35 kgRefer to information in next section
    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) formulaStarting DoseMaximum Dose
    eGFR 30 to 89 mL/min/1.73 m 225 mg50 mg
    eGFR 15 to 29 mL/min/1.73 m 225 mg25 mg
    eGFR < 15 mL/min/1.73 m 2 or requiring dialysisNot recommended
    Table 3: MYRBETRIQ Recommended Dosage in Adult Patients with Hepatic Impairment (Administered Orally Once Daily)
    Hepatic Impairment ClassificationStarting DoseMaximum Dose
    Child-Pugh Class A (Mild hepatic impairment)25 mg50 mg
    Child-Pugh Class B (Moderate hepatic impairment)25 mg25 mg
    Child-Pugh Class C (Severe hepatic impairment)Not Recommended
    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 RangeStarting DoseMaximum Dose
    eGFR 30 to 89 mL/min/1.73 m 211 kg to less than 22 kg3 mL (24 mg)6 mL (48 mg)
    22 kg to less than 35 kg4 mL (32 mg)8 mL (64 mg)
    eGFR 15 to 29 mL/min/1.73 m 211 kg to less than 22 kg3 mL (24 mg)3 mL (24 mg)
    22 kg to less than 35 kg4 mL (32 mg)4 mL (32 mg)
    eGFR < 15 mL/min/1.73 m 2 or undergoing dialysisUse is Not Recommended
    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 ClassificationBody Weight RangeStarting DoseMaximum Dose
    Child-Pugh Class A (Mild hepatic impairment)11 kg to less than 22 kg3 mL (24 mg)6 mL (48 mg)
    22 kg to less than 35 kg4 mL (32 mg)8 mL (64 mg)
    Child-Pugh Class B (Moderate hepatic impairment)11 kg to less than 22 kg3 mL (24 mg)3 mL (24 mg)
    22 kg to less than 35 kg4 mL (32 mg)4 mL (32 mg)
    Child-Pugh Class C (Severe hepatic impairment)Use is Not Recommended
    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 DoseMaximum Dose
    eGFR 30 to 89 mL/min/1.73 m 26 mL (48 mg)10 mL (80 mg)
    eGFR 15 to 29 mL/min/1.73 m 26 mL (48 mg)6 mL (48 mg)
    eGFR < 15 mL/min/1.73 m 2 or undergoing dialysisUse is Not Recommended
    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 ClassificationStarting DoseMaximum 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

    Side Effects of Myrbetriq

    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. Study 1 also included an active control. 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. 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. 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 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 Eye disorders: glaucoma 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. 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 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 ( %). 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. 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. Studies 5 and 6 also included a placebo control.

    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 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. 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. 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).

    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 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). 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 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.

    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. Skin and subcutaneous tissue disorders: angioedema of the face, lips, tongue, and larynx, with or without respiratory symptoms; pruritus Renal and urinary disorders: urinary retention

    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 ReactionPlacebo (%)MYRBETRIQ 25 mg (%)MYRBETRIQ 50 mg (%)
    Number of Patients13804321375
    Hypertension Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring predominantly in subjects with baseline hypertension.7.611.37.5
    Nasopharyngitis2.53.53.9
    Urinary Tract Infection1.84.22.9
    Headache3.02.13.2
    Constipation1.41.61.6
    Upper Respiratory Tract Infection1.72.11.5
    Arthralgia1.11.61.3
    Diarrhea1.31.21.5
    Tachycardia0.61.61.2
    Abdominal Pain0.71.40.6
    Fatigue1.01.41.2
    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 ReactionMYRBETRIQ 50 mg (%)Active Control (%)
    Number of Patients812812
    Hypertension9.29.6
    Urinary Tract Infection5.96.4
    Headache4.12.5
    Nasopharyngitis3.93.1
    Back Pain2.81.6
    Constipation2.82.7
    Dry Mouth2.88.6
    Dizziness2.72.6
    Sinusitis2.71.5
    Influenza2.63.4
    Arthralgia2.12.0
    Cystitis2.12.3
    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 ReactionPlacebo (%)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 Patients51050050012889971706
    Dry Mouth2.23.83.66.59.37.2
    Urinary Tract Infections Includes any recorded treatment-emergent UTI.5.34.04.23.67.04.0
    Constipation1.21.22.82.44.23.9
    Tachycardia0.81.61.60.72.20.9
    Dyspepsia0.60.40.20.71.11.3
    Dizziness0.40.81.21.21.30.4
    Vision Blurred0.40.20.20.90.71.1
    Arthralgia0.80.80.80.80.51.1
    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 ReactionMYRBETRIQ 50 mg (%)Solifenacin Succinate 5 mg (%)MYRBETRIQ 50 mg + Solifenacin Succinate 5 mg (%)
    Number of Patients3053031206
    Urinary Tract Infections Includes any recorded treatment-emergent UTI.6.25.98.4
    Dry Mouth3.95.96.1
    Constipation1.02.33.3
    Headache1.61.72.9
    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 ReactionPercentage (%) of Patients Reporting Adverse Reactions N=86
    Number of Patients51 (59.3)
    Urinary Tract Infection Includes any recorded UTI while patient was on treatment with MYRBETRIQ/MYRBETRIQ Granules.24.4
    Nasopharyngitis5.8
    Constipation4.7
    Headache3.5
    Nausea2.3
    Gastroenteritis2.3
    Rhinitis2.3
    Cough2.3

    Warnings & Cautions for Myrbetriq

    Increases in Blood Pressure Increases in Blood Pressure in Adults MYRBETRIQ/MYRBETRIQ Granules can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. MYRBETRIQ/MYRBETRIQ Granules 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).

    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 MYRBETRIQ/MYRBETRIQ Granules can increase blood pressure in pediatric patients. Periodic blood pressure determinations are recommended.

    MYRBETRIQ/MYRBETRIQ Granules 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.

    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.

    Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with MYRBETRIQ/MYRBETRIQ Granules. 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 MYRBETRIQ/MYRBETRIQ Granules and provide appropriate therapy and/or measures necessary to ensure a patent airway.

    Patients Taking Drugs Metabolized by CYP2D6 Since MYRBETRIQ/MYRBETRIQ Granules is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates is increased when coadministered with MYRBETRIQ/MYRBETRIQ Granules. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6.

    Drug Interactions with Myrbetriq

    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. 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.

    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.

    Pregnancy Safety for Myrbetriq

    Pregnancy Risk Summary There are no studies with the use of MYRBETRIQ/MYRBETRIQ Granules in pregnant women or adolescents to inform a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes. Mirabegron administration to pregnant animals during organogenesis resulted in reversible skeletal variations (in rats) at 22-fold (via AUC) the maximum recommended human dose (MRHD) of 50 mg/day and decreased fetal body weights (in rabbits) at 14-fold the MRHD. At maternally-toxic exposures in rats (96-fold), decreased fetal weight and increased fetal mortality were observed and, in rabbits (36-fold), cardiac findings (fetal cardiomegaly and fetal dilated aortae) were observed.

    The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects or miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data No embryo-fetal lethality or morphological fetal developmental abnormalities were produced in pregnant rats following daily oral administration of mirabegron during the period of organogenesis (Days 7 to 17 of gestation) at mg/kg, doses which were associated with systemic exposures (AUC) and 96-fold the MRHD.

    Skeletal variations (wavy ribs, delayed ossification) were observed in fetuses at doses 22-fold the systemic exposure at the MRHD and were reversible during development. Exposures 96-fold the MRHD were maternally-toxic (mortality, decreased body weight gain) and associated with fetal growth reduction. At 10 mg/kg/day (14-fold the MRHD) and higher, fetal body weights were reduced.

    At 30 mg/kg/day, maternal toxicity (increased heart rate, mortality, reduced body weight gain, reduced food consumption) occurred, and fetal deaths, fetal cardiomegaly and fetal dilated aortae were observed at systemic exposure levels (AUC) 36-fold the MRHD. Decreased maternal body weight was observed along with decreased pup survival in the first few days after birth (92.7% survival) compared to the control group (98.8% survival), at 100 mg/kg/day (22-fold the MRHD). Pup body weight gain was reduced until postnatal day 7 but not further affected throughout the remainder of the lactation period.

    In utero and lactational exposure did not affect developmental milestones, behavior, or fertility of offspring. No effects were observed at 30 mg/kg/day.

    Pediatric Use of Myrbetriq

    • Pediatric Use The safety and effectiveness have been established only for the following pediatric indications:
    • MYRBETRIQ: Treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 3 years of age and older and weighing 35 kg or more.
    • MYRBETRIQ Granules: Treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 3 years of age and older. The safety and effectiveness of MYRBETRIQ/MYRBETRIQ Granules in pediatric patients aged 3 years and older have been established for the treatment of neurogenic detrusor overactivity (NDO) and the information on this use is discussed throughout the labeling. Use of MYRBETRIQ/MYRBETRIQ Granules for this indication is supported by evidence from a 52-week, open-label, baseline-controlled, multicenter, dose titration trial in pediatric patients 3 years of age and older with NDO (Study 9). Results showed an improvement from baseline in maximum cystometric (bladder) capacity (MCC) with MYRBETRIQ/MYRBETRIQ Granules use. The most commonly reported adverse reactions in Study 9 (≥ 3%) were UTI, nasopharyngitis, constipation, and headache. Increased mean systolic and diastolic blood pressures with use of MYRBETRIQ/MYRBETRIQ Granules occurred in patients less than 12 years of age with larger increases in patients younger than 8 years of age. Take MYRBETRIQ/MYRBETRIQ Granules with food to reduce potential exposure-related risks, such as increased heart rate, as predicted by modeling of vital signs data in Study 9.

    Contraindications for Myrbetriq

    MYRBETRIQ/MYRBETRIQ Granules is contraindicated in patients with known hypersensitivity reactions to mirabegron or any inactive ingredients of the tablet or oral suspension. Hypersensitivity to mirabegron or any inactive ingredients.

    Overdosage Information for Myrbetriq

    Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdosage should be symptomatic and supportive.

    In the event of overdosage, pulse rate, blood pressure and ECG monitoring is recommended.

    Clinical Studies of Myrbetriq

    MYRBETRIQ Monotherapy for Adult OAB MYRBETRIQ was evaluated in three, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Studies 1, 2, and 3). Entry criteria required that patients had symptoms of overactive bladder for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urgency with or without incontinence over a 3-day period. The population included both naïve patients who had not received prior muscarinic antagonist pharmacotherapy for overactive bladder (48%) and those who had received prior muscarinic antagonist pharmacotherapy for OAB (52%).

    In Study 1 (NCT00689104), patients were randomized to placebo, MYRBETRIQ 50 mg, MYRBETRIQ 100 mg, or an active control once daily. In Study 2 (NCT00662909), patients were randomized to placebo, MYRBETRIQ 50 mg or MYRBETRIQ 100 mg once daily. In Study 3 (NCT00912964), patients were randomized to placebo, MYRBETRIQ 25 mg or MYRBETRIQ 50 mg once daily.

    The co-primary efficacy endpoints in all 3 trials were change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition. Efficacy of both 25 mg and 50 mg doses of MYRBETRIQ was maintained through the 12-week treatment period.

    Entry criteria required that patients had symptoms of OAB for at least 3 months duration, on average at least 8 micturitions and at least 1 urgency episode per day, and at least 3 episodes of incontinence, over a 7-day period. The population included both naïve patients who had not received prior pharmacotherapy for OAB (54%) and those who had received prior pharmacotherapy for OAB (46%). Results for the co-primary endpoints and mean volume voided per micturition for the overall patient population from Study 6 are shown in Table 14.

    Table 14: Mean Baseline and Change from Baseline at Week 12 Week 12 is the last observation on treatment. for Incontinence Episodes, Micturition Frequency, and Volume Voided per Micturition Overall Population with Overactive Bladder in Study 6 Figures 9 and 10 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours, and mean change from baseline over time in number of micturitions per 24 hours, in the overall patient population in Study 6. Figure 9: Mean Change from Baseline in Mean (± SE) Number of Incontinence Episodes per 24 Hours at Each Visit (FAS) – Study 6 Figure 10: Mean Change from Baseline in Mean (± SE) Number of Micturitions per 24 Hours at Each Visit (FAS) – Study 6 MYRBETRIQ as Add-on Therapy to Solifenacin Succinate MYRBETRIQ add-on therapy to solifenacin succinate was evaluated in one, 12-week, double-blind, randomized, active‑controlled, multicenter clinical trial in incontinent OAB patients who received solifenacin succinate for 4 weeks and required additional relief for their OAB symptoms (Study 7). Entry criteria required that patients had symptoms of OAB for at least 3 months duration (urge urinary incontinence, urgency, and urinary frequency), and at least 1 incontinence episode during a 3-day period after being treated with solifenacin succinate 5 mg for 4 weeks.

    After 4 weeks, all patients in the combination treatment arm had a dose increase from MYRBETRIQ 25 mg to MYRBETRIQ 50 mg. The primary efficacy endpoint in Study 7 (NCT01908829) was change from baseline to end of treatment (week 12) in mean number of incontinence episodes per 24 hours. Two important secondary endpoints were change from baseline to end of treatment in mean number of micturitions per 24 hours and change from baseline to end of treatment in mean volume voided per micturition.

    Results for the primary and additional endpoints from Study 7 are shown in Table 15. Table 15: Change from Baseline at Week 12 Week 12 is the last observation on treatment. for Incontinence Episodes, Micturition Frequency, and Volume Voided per Micturition in Patients with Overactive Bladder in Study 7 Long-term Coadministration of MYRBETRIQ with Solifenacin Succinate Long-term efficacy of coadministration of MYRBETRIQ 50 mg with solifenacin succinate 5 mg was evaluated in a 52-week, double-blind, randomized, active-controlled, parallel group, multicenter clinical trial in patients with OAB Study 8 (NCT02045862). The primary objective of this study was to evaluate the safety and tolerability of long-term combination treatment and the evaluation of efficacy was the secondary objective of the study.

    Entry criteria included patients who had completed Study 6 or Study 7 or new patients. Combination treatment with MYRBETRIQ and solifenacin succinate demonstrated statistically significant greater improvements from baseline compared to MYRBETRIQ 50 mg and solifenacin succinate 5 mg for both efficacy endpoints. Also, for the secondary efficacy variable of change from baseline to end of treatment in mean volume voided (MVV) per micturition, the increase in MVV was statistically significantly greater for combination treatment compared to the MYRBETRIQ 50 mg and solifenacin succinate 5 mg groups.

    Figure 9 Figure 10

    MYRBETRIQ/MYRBETRIQ Granules for Pediatric Neurogenic Detrusor Overactivity (NDO) The efficacy of MYRBETRIQ/MYRBETRIQ Granules was evaluated in Study 9 (NCT02751931), a 52-week, open-label, baseline-controlled, multicenter, dose titration study in pediatric patients 3 years of age and older for the treatment of neurogenic detrusor overactivity (NDO). Study 9 included patients 3 to 17 years of age. Entry criteria required that patients had a diagnosis of neurogenic detrusor overactivity (NDO) with involuntary detrusor contractions with detrusor pressure increase greater than 15 cm H 2 O and that patients or their caregivers practiced clean intermittent catheterization (CIC).

    MYRBETRIQ/MYRBETRIQ Granules were administered orally once daily. All patients initially received a weight-based starting dose equivalent to 25 mg daily dose followed by dose titration to a dose equivalent of 50 mg daily dose. The duration of the dose titration period was up to 8 weeks and this period was followed by a dose maintenance period that continued for the duration of the 52-week study.

    The optimized maintenance dose within this study population included 94% of patients at the maximum dose, and 6% of patients at the starting dose. The primary efficacy endpoint was change from baseline in the patients’ maximum cystometric (bladder) capacity (MCC) after 24 weeks of treatment with MYRBETRIQ/MYRBETRIQ Granules. The magnitude of the observed changes from baseline in the primary and secondary efficacy endpoints were comparable between patients 3 to less than 12 years of age and patients 12 to 17 years of age.

    Table 16: Change from Baseline in Maximum Cystometric Capacity (MCC) at 24 Weeks in Pediatric Patients with Neurogenic Detrusor Overactivity (NDO) Treated with MYRBETRIQ/MYRBETRIQ Granules in Study 9 Parameter Children Aged 3 to Less than 12 Years (N=43) N is the number of patients who took at least one dose and provided valid values for MCC at Baseline and Week 24. Table 17: Changes from Baseline in Other Urodynamic Parameters at Week 24 in Pediatric Patients with Neurogenic Detrusor Overactivity (NDO) Treated with MYRBETRIQ/MYRBETRIQ Granules in Study Bladder Volume Prior To First Detrusor Contraction (> 15 cm H 2 O) Baseline Change from baseline Table 18: Changes from Baseline in Maximum Catheterized Urine Volume and Number of Leakage Episodes at Week 24 in Pediatric Patients with Neurogenic Detrusor Overactivity (NDO) Treated with MYRBETRIQ/MYRBETRIQ Granules in Study Number of Leakage Episodes per Day Baseline Change from baseline

    Table 13: Mean Baseline and Change from Baseline at Week 12 Week 12 is the last observation on treatment. for Incontinence Episodes, Micturition Frequency, and Volume Voided per Micturition in Patients with Overactive Bladder in Studies 1, 2, and 3
    ParameterStudy 1Study 2Study 3
    PlaceboMYRBETRIQ 50 mgPlaceboMYRBETRIQ 50 mgPlaceboMYRBETRIQ 25 mgMYRBETRIQ 50 mg
    Number of Incontinence Episodes per 24 Hours For incontinence episodes per 24 hours, the analysis population is restricted to patients with at least 1 episode of incontinence at baseline.
    n291293325312262254257
    Baseline (mean)2.672.833.032.772.432.652.51
    Change from baseline (adjusted mean Least squares mean adjusted for baseline, gender, and geographical region. )-1.17-1.57-1.13-1.47-0.96-1.36-1.38
    Difference from placebo (adjusted mean )---0.41---0.34---0.40-0.42
    95% Confidence Interval--(-0.72, -0.09)--(-0.66, -0.03)--(-0.74, -0.06)(-0.76, -0.08)
    p-value--0.003 Statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment.--0.026--0.0050.001
    Number of Micturitions per 24 Hours
    n480473433425415410426
    Baseline (mean)11.7111.6511.5111.8011.4811.6811.66
    Change from baseline (adjusted mean )-1.34-1.93-1.05-1.66-1.18-1.65-1.60
    Difference from placebo (adjusted mean )---0.60---0.61---0.47-0.42
    95% Confidence Interval--(-0.90, -0.29)--(-0.98, -0.24)--(-0.82, -0.13)(-0.76, -0.08)
    p-value--< 0.001--0.001--0.0070.015
    Volume Voided (mL) per Micturition
    n480472433424415410426
    Baseline (mean)156.7161.1157.5156.3164.0165.2159.3
    Change from baseline (adjusted mean )12.324.27.018.28.312.820.7
    Difference from placebo (adjusted mean )--11.9--11.1--4.612.4
    95% Confidence Interval--(6.3, 17.4)--(4.4, 17.9)--(-1.6, 10.8)(6.3, 18.6)
    p-value--< 0.001--0.001--0.15< 0.001
    Table 14: Mean Baseline and Change from Baseline at Week 12 Week 12 is the last observation on treatment. for Incontinence Episodes, Micturition Frequency, and Volume Voided per Micturition Overall Population with Overactive Bladder in Study 6
    ParameterPlaceboMYRBETRIQ 25 mgMYRBETRIQ 50 mgSolifenacin Succinate 5 mgMYRBETRIQ 25 mg + Solifenacin Succinate 5 mgMYRBETRIQ 50 mg + Solifenacin Succinate 5 mg
    Number of Incontinence Episodes per 24 Hours
    n412409406413823816
    Baseline (mean)3.403.423.163.593.213.15
    Change from baseline (adjusted mean Least squares mean adjusted for baseline, gender, age group (< 65, ≥ 65 years), previous OAB medication (yes, no), and geographical region using an ANCOVA model. )-1.34-1.70-1.76-1.79-2.04-1.98
    Difference from Solifenacin Succinate (adjusted mean )---------0.25-0.20
    95% Confidence Interval--------(-0.49, -0.01)(-0.44, 0.04)
    Difference from MYRBETRIQ (at the same MYRBETRIQ dose, adjusted mean )---------0.34-0.23
    95% Confidence Interval--------(-0.58, -0.10)(-0.47, 0.01)
    Number of Micturitions per 24 Hours
    n412409406413823816
    Baseline (mean)10.9710.8111.1910.7410.7210.72
    Change from baseline (adjusted mean )-1.64-2.00-2.03-2.20-2.49-2.59
    Difference from Solifenacin Succinate (adjusted mean )---------0.29-0.39
    95% Confidence Interval--------(-0.57, -0.01)(-0.67, -0.11)
    Difference from MYRBETRIQ (at the same MYRBETRIQ dose, adjusted mean )---------0.48-0.56
    95% Confidence Interval--------(-0.76, -0.21)(-0.84, -0.28)
    Volume Voided (mL) per Micturition
    n413407408411821821
    Baseline (mean)157.82152.46155.35151.86159.19153.83
    Change from baseline (adjusted mean )8.4413.3221.9930.9934.8439.73
    Difference from Solifenacin Succinate (adjusted mean )--------3.858.75
    95% Confidence Interval--------(-2.29, 10.00)(2.61, 14.89)
    Difference from MYRBETRIQ (at the same MYRBETRIQ dose, adjusted mean )--------21.5217.74
    95% Confidence Interval--------(15.35, 27.68)(11.58, 23.90)
    ANCOVA: Analysis of covariance
    Table 15: Change from Baseline at Week 12 Week 12 is the last observation on treatment. for Incontinence Episodes, Micturition Frequency, and Volume Voided per Micturition in Patients with Overactive Bladder in Study 7
    ParameterSolifenacin Succinate 5 mgMYRBETRIQ 25 mg/50 mg + Solifenacin Succinate 5 mg
    Number of Incontinence Episodes per 24 Hours
    n704706
    Baseline (mean)3.153.24
    Change from baseline (adjusted mean Least squares mean adjusted for baseline, gender, age group (< 65, ≥ 65 years), geographical region, and 4-week incontinence reduction group using ANCOVA model. )-1.53-1.80
    Difference (MYRBETRIQ + Solifenacin Succinate) from Solifenacin Succinate (adjusted mean Differences of adjusted means are calculated by subtracting the adjusted mean of solifenacin succinate monotherapy groups from adjusted mean of MYRBETRIQ + Solifenacin Succinate group based on ANCOVA model described above. )-0.26--
    95% Confidence Interval(-0.47, -0.05)
    Number of Micturitions per 24 Hours
    n704706
    Baseline (mean)8.909.13
    Change from baseline (adjusted mean )-1.14-1.59
    Difference (MYRBETRIQ + Solifenacin Succinate) from Solifenacin Succinate (adjusted mean )-0.45 (0.12)--
    95% Confidence Interval(-0.67, -0.22)
    Volume Voided (mL) per Micturition
    n682680
    Baseline (mean)170.92172.93
    Change from baseline (adjusted mean )16.5228.05
    Difference (MYRBETRIQ + Solifenacin Succinate) from Solifenacin Succinate (adjusted mean )11.52--
    95% Confidence Interval(6.06, 16.99)
    ANCOVA: Analysis of covariance
    Table 16: Change from Baseline in Maximum Cystometric Capacity (MCC) at 24 Weeks in Pediatric Patients with Neurogenic Detrusor Overactivity (NDO) Treated with MYRBETRIQ/MYRBETRIQ Granules in Study 9
    ParameterChildren Aged 3 to Less than 12 Years (N=43) N is the number of patients who took at least one dose and provided valid values for MCC at Baseline and Week 24. Mean (SD)Adolescents Aged 12 to 17 Years (N=25) Mean (SD)
    Maximum Cystometric Capacity (mL)
    Baseline Week 24 Change from baseline 95% CI159 (95) 231 (129) 72 (87) (45, 99)239 (99) 352 (125) 113 (83) (79, 147)
    Table 17: Changes from Baseline in Other Urodynamic Parameters at Week 24 in Pediatric Patients with Neurogenic Detrusor Overactivity (NDO) Treated with MYRBETRIQ/MYRBETRIQ Granules in Study 9
    ParameterChildren Aged 3 to Less than 12 Years (N=43) N is the number of patients who took at least one dose and provided valid values for MCC at Baseline and Week 24. Mean (SD)Adolescents Aged 12 to 17 Years (N=25) Mean (SD)
    Bladder Compliance (mL/cm H 2 O) Number of patients (Children/Adolescents) with data available for both Baseline and Week 24; Bladder Compliance: n=33/21; Number of Overactive Detrusor Contractions: n=36/22; Bladder Volume Prior To First Detrusor Contraction: n=38/24.
    Baseline Change from baseline
    16.0 (55.8) 14.6 (42.1) 95% CI: -0.3, 29.511.1 (10.7) 13.6 (15.0) 95% CI: 6.7, 20.4
    Number of Overactive Detrusor Contractions (> 15 cm H 2 O)
    Baseline Change from baseline
    3.0 (4.0) -1.9 (4.2) 95% CI: -3.3, -0.42.1 (3.1) -0.8 (3.9) 95% CI: -2.5, 0.9
    Bladder Volume Prior To First Detrusor Contraction (> 15 cm H 2 O)
    Baseline Change from baseline115 (83) 93 (88) 95% CI: 64, 122177 (117) 121 (160) 95% CI: 54, 189
    Table 18: Changes from Baseline in Maximum Catheterized Urine Volume and Number of Leakage Episodes at Week 24 in Pediatric Patients with Neurogenic Detrusor Overactivity (NDO) Treated with MYRBETRIQ/MYRBETRIQ Granules in Study 9
    ParameterChildren Aged 3 to Less than 12 Years (N=43) N is the number of patients who took at least one dose and provided valid values for MCC at Baseline and Week 24. Mean (SD)Adolescents Aged 12 to 17 Years (N=25) Mean (SD)
    Maximum Catheterized Urine Volume per Day (mL) Number of patients (Children/Adolescents) with data available for both Baseline and Week 24; Maximum Catheterized Urine Volume per Day: n=41/23; Number of Leakage Episodes per Day: n=26/21.
    Baseline Change from baseline
    304 (109) 50 (104) 95% CI: 17, 83360 (111) 84 (122) 95% CI: 32, 137
    Number of Leakage Episodes per Day
    Baseline Change from baseline2.8 (3.7) -2.0 (3.2) 95% CI: -3.2, -0.71.8 (1.7) -1.0 (1.1) 95% CI: -1.5, -0.5

    Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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