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    Combination Treatment

    Approved in combination
    with solifenacin succinate1*

    *Marketed in the US as VESIcare®

    GO with two mechanisms of action

    Storage makes up the majority of the micturition cycle

    • The β-ARs belong to a family of G-protein-coupled receptors, which are involved with cellular signalling throughout the body and are made up of 3 subtypes (β1, β2, and β3)5,6
    • All 3 β‑AR subtypes are expressed in the human bladder, but β3‑messenger RNA (mRNA) predominates, accounting for 97% of β‑AR mRNA in the bladder7
      • The β1-AR and β2-AR subtypes make up 1.5% and 1.4% of the total β‑AR mRNA, respectively

    Overactive bladder (OAB) is characterized by involuntary contraction of the detrusor muscle during storage phase2

    Myrbetriq is the first and only FDA-approved β3-AR agonist.

    It is indicated as monotherapy or in combination with the antimuscarinic solifenacin succinate for the treatment of OAB symptoms of urge urinary incontinence, urgency, and urinary frequency1

    Diagram illustrating mirabegron and solifenacin succinate mechanisms of action

    A β3-AR agonist combined with an antimuscarinic targets 2 different receptor pathways within the urinary bladder1,8

    • Mirabegron is an agonist of the human β3‑AR as demonstrated by in vitro laboratory experiments using the cloned human β3‑AR1
    • Although mirabegron showed very low intrinsic activity for cloned human β1‑AR and β2‑AR, results in humans indicate that β1‑AR stimulation occurred at a mirabegron dose of 200mg1

    GO with combination therapy
    to treat OAB symptoms

    Study Design

    Co-administration of Myrbetriq with solifenacin succinate was evaluated in a 12 week, double blind, randomized, placebo controlled, parallel group, multicenter clinical trial in patients with OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency (SYNERGY Study; NCT01972841).

    Combination therapy 12 week study design Combination therapy 12 week study design
    Incontinence

    Demonstrated reduction in incontinence

    Myrbetriq combined with solifenacin succinate showed measurable reduction in incontinence episodes per 24 hours1,9

    Co-Primary Endpoint

    Adjusted change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours1

    The first statistical comparison within the pre-specified sequential testing was between the solifenacin 5 mg and mirabegron 50 mg group and its monotherapy components for incontinence. While the 5 + 50 mg group was superior to solifenacin 5 mg for incontinence, superiority versus mirabegron 50 mg could not be demonstrated (p=0.052). Therefore, the primary objective for the 5 + 50 mg therapy was not met. Because the null hypothesis for this test could not be rejected, the subsequent hypotheses for mean number of micturitions per 24 hours and mean volume voided per micturition could not be tested. Also, no hypothesis testing could be performed for the 5 + 25 mg group. Although formal hypothesis testing could not continue, nominal p values were assigned.1,9

    Demonstrated reduction in incontinence Demonstrated reduction in incontinence

    a Combination therapy (25 mg/5 mg) demonstrated significant improvement vs Myrbetriq 25 mg (-0.34*, p=0.001†).

    b Combination therapy (25 mg/5 mg) did not demonstrate significant improvement vs solifenacin succinate 5 mg (-0.25*, p=0.072†).

    c Combination therapy (50 mg/5 mg) did not demonstrate significant improvement vs Myrbetriq 50 mg (-0.23*, p=0.052).

    d Combination therapy (50 mg/5 mg) demonstrated significant improvement vs solifenacin succinate 5 mg (-0.20*, p=0.033).

    *Adjusted mean difference.

    †Nominal p values.

    CI=confidence interval; EoT=end of treatment.

    • 50.7% of patients receiving Myrbetriq 25 mg + solifenacin succinate 5 mg combination therapy achieved zero incontinence vs 40.6% and 42.9% of patients receiving Myrbetriq 25 mg monotherapy and solifenacin succinate 5 mg monotherapy, respectively (odds ratio vs Myrbetriq 25 mg, 1.50 (CI 1.16, 1.93); odds ratio vs solifenacin succinate 5 mg, 1.31 (CI 1.02, 1.69))9
    • 52.2% of patients receiving Myrbetriq 50 mg + solifenacin succinate 5 mg combination therapy achieved zero incontinence vs 46.3% and 42.9% of patients receiving Myrbetriq 50 mg monotherapy and solifenacin succinate 5 mg monotherapy, respectively (odds ratio vs Myrbetriq 50 mg, 1.34 (CI 1.04, 1.73); odds ratio vs solifenacin succinate 5 mg, 1.40 (CI 1.09, 1.81))9
    Micturitions

    Demonstrated reduction in micturition frequency

    Myrbetriq combined with solifenacin succinate showed meaningful reduction in micturition frequency per 24 hours1,9

    Co-Primary Endpoint

    Adjusted change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours1

    Demonstrated reduction in incontinence Demonstrated reduction in incontinence

    a Combination therapy (25 mg/5 mg) demonstrated significant improvement vs Myrbetriq 25 mg (-0.48*, p=0.001†).

    b Combination therapy (25 mg/5 mg) demonstrated significant improvement vs solifenacin succinate 5 mg (-0.29*, p=0.040†).

    c Combination therapy (50 mg/5 mg) demonstrated significant improvement vs Myrbetriq 50 mg (-0.56*, p>0.001†).

    d Combination therapy (50 mg/5 mg) demonstrated significant improvement vs solifenacin succinate 5 mg (-0.39*, p=0.006†).

    *Adjusted mean difference.

    †Nominal p values.

    CI=confidence interval; EoT=end of treatment.

    Volume Voided

    Demonstrated increase in volume voided per micturition

    Myrbetriq combined with solifenacin succinate increased the mean volume voided per micturition1,9

    Secondary Endpoint

    Adjusted change from baseline to end of treatment (Week 12) in mean volume voided per micturition1

    Demonstrated reduction in incontinence Demonstrated reduction in incontinence

    a Combination therapy (25 mg/5 mg) demonstrated significant improvement vs Myrbetriq 25 mg (21.52*, p>0.001†).

    b Combination therapy (25 mg/5 mg) did not demonstrate significant improvement vs solifenacin succinate 5 mg (3.85*, p=0.219†).

    c Combination therapy (50 mg/5 mg) demonstrated significant improvement vs Myrbetriq 50 mg (17.74*, p>0.001†).

    d Combination therapy (50 mg/5 mg) demonstrated significant improvement vs solifenacin succinate 5 mg (8.75*, p=0.005†).

    *Adjusted mean difference.

    †Nominal p values.

    CI=confidence interval; EoT=end of treatment.

    Add-on Therapy

    Study Design

    Myrbetriq add-on therapy was evaluated in a 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 (BESIDE; NCT 01908829).

    Add-on therapy infographic Add-on therapy infographic
    Incontinence

    Demonstrated reduction in incontinence

    Myrbetriq added on to solifenacin succinate showed meaningful reduction in
    incontinence episodes per 24 hours1,10

    Primary Endpoint

    Adjusted change from baseline to end of treatment (Week 12) in mean number of incontinence
    episodes per 24 hours1

    Demonstrated reduction in incontinence

    a Add-on therapy demonstrated significant improvement vs solifenacin succinate 5 mg (p=0.001).

    CI=confidence interval; EoT=end of treatment.

    *Patients in the add-on therapy treatment group received Myrbetriq 25 mg and solifenacin succinate 5 mg for 4 weeks. The Myrbetriq dose was increased to 50 mg after Week 4.1

    • 46% of patients receiving Myrbetriq add‑on therapy achieved zero incontinence vs 37.9% of patients receiving solifenacin succinate 5 mg alone (odds ratio 1.47 (CI 1.17, 1.84))10
    Micturitions

    Demonstrated reduction in micturition frequency

    Myrbetriq added on to solifenacin succinate showed
    meaningful reduction in micturition frequency per 24 hours1

    Secondary Endpoint

    Adjusted change from baseline to end of treatment (Week 12) in mean number
    of micturitions per 24 hours1

    Demonstrated reduction in incontinence

    a Add-on therapy demonstrated significant improvement vs solifenacin succinate 5 mg (p<0.001).

    CI=confidence interval; EoT=end of treatment.

    *Patients in the add-on therapy treatment group received Myrbetriq 25 mg and solifenacin succinate 5 mg for 4 weeks. The Myrbetriq dose was increased to 50 mg after Week 4.1

    Volume Voided

    Demonstrated increase in volume voided
    per micturition

    Myrbetriq added on to solifenacin succinate increased the mean volume voided per micturition1

    Secondary Endpoint

    Adjusted change from baseline to end of treatment (Week 12) in mean volume voided per micturition1

    Demonstrated reduction in incontinence

    a Add-on therapy demonstrated significant improvement vs solifenacin succinate 5 mg (p<0.001).

    CI=confidence interval; EoT=end of treatment.

    *Patients in the add-on therapy treatment group received Myrbetriq 25 mg and solifenacin succinate 5 mg for 4 weeks. The Myrbetriq dose was increased to 50 mg after Week 4.1

    GO with a safe and tolerable option

    Evaluated in patients with overactive bladder (OAB) in three 12‑week trials and a 1‑year safety study1

    12 Week Safety

    Safety evaluated in three 12-week, double-blind, randomized, active-controlled safety studies1

    Percent of patients with adverse reactions derived from all adverse events >placebo and
    comparator (at same dose level) rate and reported by ≥1% of patients treated with combination
    therapy in Studies 5, 6 and 7*†

    • The most commonly reported adverse reactions (>2% of patients treated with combination therapy of Myrbetriq and solifenacin succinate 5 mg and >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 co‑administration trials were dry mouth and urinary retention
    • No serious adverse reactions were reported by >2 patients

    *Adverse reactions occurring in patients treated with co-administration 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.

    †Study 5=SYMPHONY (NCT01340027); Study 6=SYNERGY (NCT01972841); Study 7=BESIDE (NCT01908829).9

    ‡Includes any recorded treatment-emergent UTI.

    1-Year Safety

    Safety evaluated in a 1‑year, double‑blind, randomized, active‑controlled study1

    Percent of patients with adverse reactions derived from all adverse events exceeding
    comparator rate and reported ≥2% of patients treated with combination therapy in Study 8*

    One year safety: combination therapy chart showing adverse events: placebo and comparators

    *Study 8=SYNERGY II (NCT02045862).10

    †Includes any recorded treatment-emergent UTI.

    • The most common adverse reactions (>2% of patients treated with co-administration 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%)
    • Serious adverse events of neoplasm were reported by 0.7%, 0.3%, and 0% of patients who received co‑administration of Myrbetriq 50 mg and solifenacin succinate 5 mg, Mybetriq 50 mg monotherapy, and solifenacin succinate 5 mg monotherapy, respectively
    • Neoplasms reported by >1 patient who received co‑administration of 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 co‑administration of Myrbetriq plus solifenacin succinate and these reported neoplasms has not been established

    Blood Pressure and Urinary Retention

    Effects on blood pressure studied in a 12-week, double-blind, placebo-controlled safety/efficacy study1

    • No consistent differences in 24-hour mean SBP/DBP were observed compared to placebo, Myrbetriq, or solifenacin succinate monotherapy as assessed with 24-hour ABPM
    • Similar frequencies of categorical changes were observed for combination treatment vs placebo in 24-hour me an SBP/DBP

    Myrbetriq and urinary retention1

    • In patients taking Myrbetriq, urinary retention has been reported to occur in patients with BOO and in patients taking muscarinic antagonist medications for the treatment of OAB
    • Myrbetriq should be administered with caution to patients taking muscarinic antagonist medications for the treatment of OAB, including solifenacin succinate
    • A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should still be administered with caution to patients with clinically significant BOO

    ABPM=ambulatory blood pressure monitoring;

    BOO=bladder outlet obstruction;

    SBP/DBP=systolic blood pressure/diastolic blood pressure;

    UTI=urinary tract infection

    12 Week Safety

    Safety evaluated in three 12-week, double-blind, randomized, active-controlled safety studies1

    Percent of patients with adverse reactions derived from all adverse events >placebo and
    comparator (at same dose level) rate and reported by ≥1% of patients treated with combination
    therapy in Studies 5, 6 and 7*†

    Twelve week safety: combination therapy chart showing adverse events: placebo and comparators
    • The most commonly reported adverse reactions (>2% of patients treated with combination therapy of Myrbetriq and solifenacin succinate 5 mg and >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 co‑administration trials were dry mouth and urinary retention
    • No serious adverse reactions were reported by >2 patients

    *Adverse reactions occurring in patients treated with co-administration 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.

    †Study 5=SYMPHONY (NCT01340027); Study 6=SYNERGY (NCT01972841); Study 7=BESIDE (NCT01908829).9

    ‡Includes any recorded treatment-emergent UTI.

    1-Year Safety

    Safety evaluated in a 1‑year, double‑blind, randomized, active‑controlled study1

    Percent of patients with adverse reactions derived from all adverse events exceeding
    comparator rate and reported ≥2% of patients treated with combination therapy in Study 8*

    One year safety: combination therapy chart showing adverse events: placebo and comparators

    *Study 8=SYNERGY II (NCT02045862).10

    †Includes any recorded treatment-emergent UTI.

    • The most common adverse reactions (>2% of patients treated with co-administration 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%)
    • Serious adverse events of neoplasm were reported by 0.7%, 0.3%, and 0% of patients who received co‑administration of Myrbetriq 50 mg and solifenacin succinate 5 mg, Mybetriq 50 mg monotherapy, and solifenacin succinate 5 mg monotherapy, respectively
    • Neoplasms reported by >1 patient who received co‑administration of 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 co‑administration of Myrbetriq plus solifenacin succinate and these reported neoplasms has not been established

    Blood Pressure and Urinary Retention

    Effects on blood pressure studied in a 12-week, double-blind, placebo-controlled safety/efficacy study1

    • No consistent differences in 24-hour mean SBP/DBP were observed compared to placebo, Myrbetriq, or solifenacin succinate monotherapy as assessed with 24-hour ABPM
    • Similar frequencies of categorical changes were observed for combination treatment vs placebo in 24-hour me an SBP/DBP

    Myrbetriq and urinary retention1

    • In patients taking Myrbetriq, urinary retention has been reported to occur in patients with BOO and in patients taking muscarinic antagonist medications for the treatment of OAB
    • Myrbetriq should be administered with caution to patients taking muscarinic antagonist medications for the treatment of OAB, including solifenacin succinate
    • A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq should still be administered with caution to patients with clinically significant BOO

    ABPM=ambulatory blood pressure monitoring;

    BOO=bladder outlet obstruction;

    SBP/DBP=systolic blood pressure/diastolic blood pressure;

    UTI=urinary tract infection

    GO with a once-daily treatment option

    Oral therapy dosing only once per day1,8

    • The recommended starting doses for combination treatment are Myrbetriq 25 mg once daily and VESIcare® (solifenacin succinate) 5 mg once daily
    • Based on individual patient efficacy and tolerability, the Myrbetriq dose may be increased to 50 mg once daily after 4 to 8 weeks
    • Myrbetriq and VESIcare can be taken together with or without food
    • Myrbetriq and VESIcare should be taken with water and swallowed whole
    • Myrbetriq should not be chewed, divided, or crushed
    Combination therapy dosing options

    Dose adjustments in specific populations1

    • The daily dose of Myrbetriq should not exceed 25 mg once daily in the following populations:
      • Patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2)
      • Patients with moderate hepatic impairment (Child-Pugh Class B)
    • Myrbetriq is not recommended for use in patients with end-stage renal disease (ESRD) or in patients with severe hepatic impairment (Child-Pugh Class C)
    • No dose adjustment is necessary for the elderly
    • The safety and effectiveness of Myrbetriq, alone or in combination with VESIcare, in pediatric patients have not been established

    INDICATIONS AND USAGE

    Myrbetriq® (mirabegron), a beta-3 adrenergic agonist, is indicated as monotherapy or in combination with the muscarinic antagonist solifenacin succinate for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

    IMPORTANT SAFETY INFORMATION

    Do not use Myrbetriq® (mirabegron) in patients who have known hypersensitivity reactions to mirabegron or any component of the tablet.

    Solifenacin succinate is contraindicated in patients with urinary retention, gastric retention, uncontrolled narrow-angle glaucoma, and in patients with hypersensitivity to the product.

    Myrbetriq alone or in combination with solifenacin succinate can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in severe uncontrolled hypertensive patients (defined as systolic blood pressure ≥ 180mm Hg and/or diastolic blood pressure ≥ 110mm Hg). Worsening of hypertension was reported infrequently in Myrbetriq clinical trial patients with OAB.

    In patients taking Myrbetriq, urinary retention has been reported in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq and solifenacin succinate 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 antimuscarinic medications for the treatment of OAB, including solifenacin succinate.

    Angioedema of the face, lips, tongue and/or larynx has been reported with Myrbetriq and with solifenacin succinate. Cases of angioedema 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 and/or solifenacin succinate and initiate appropriate therapy and/or measures necessary to ensure a patent airway.

    Solifenacin succinate should be administered with caution to patients with decreased gastrointestinal motility, controlled narrow-angle glaucoma or reduced renal or hepatic function. Doses of solifenacin succinate higher than 5mg are not recommended in patients with severe renal impairment, moderate hepatic impairment, or when administered with ketoconazole or other potent CYP3A4 inhibitors. Use of solifenacin succinate in patients with severe hepatic impairment is not recommended.

    Anticholinergic central nervous system (CNS) effects have been reported with solifenacin succinate use, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing dose, and be advised not to drive or operate heavy machinery until they know how solifenacin succinate affects them. If a patient experiences these effects, dose reduction or drug discontinuation should be considered.

    Since Myrbetriq is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with Myrbetriq. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.

    In solifenacin succinate monotherapy studies, for the 5mg dose one serious adverse event (angioneurotic edema) was reported. For the 10mg dose, three intestinal serious adverse events were reported (one fecal impaction, one colonic obstruction and one intestinal obstruction).

    In clinical trials, the most commonly reported adverse reactions (> 2% and > placebo) for Myrbetriq 25mg and 50mg versus placebo, respectively, were hypertension (11.3%, 7.5% vs. 7.6%), nasopharyngitis (3.5%, 3.9% vs. 2.5%), urinary tract infection (4.2%, 2.9% vs. 1.8%), and headache (2.1%, 3.2% vs. 3.0%).

    In clinical trials, the most commonly reported adverse reactions (> 2% and > placebo and > comparator) for Myrbetriq in combination with solifenacin succinate 25mg + 5mg and 50mg + 5mg versus Myrbetriq 25mg, Myrbetriq 50mg, solifenacin succinate 5mg and placebo, respectively, were dry mouth (9.3%, 7.2% vs. 3.8%, 3.6%, 6.5%, 2.2%), urinary tract infection (7.0%, 4.0% vs. 4.0%, 4.2%, 3.6%, 5.3%), constipation (4.2%, 3.9% vs. 1.2%, 2.8%, 2.4%, 1.2%), and tachycardia (2.2%, 0.9% vs. 1.6%, 1.6%, 0.7%, 0.8%).

    In postmarketing experience with mirabegron, the following events have also occurred: atrial fibrillation, nausea, constipation, diarrhea, and dizziness.

    Please see accompanying complete Prescribing Information for Myrbetriq® (mirabegron) and VESIcare® (solifenacin succinate).

    References

    1. Myrbetriq [Prescribing Information]. Northbrook, IL: Astellas, Inc.
    2. Chu FM, Dmochowski R. Pathophysiology of overactive bladder. Am J Med 2006; 119(3A):3S-8S.
    3. Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci
      2008;9(6):453-66.
    4. Igawa Y, Yamazaki Y, Takeda H, et al. Functional and molecular biological evidence for a possible beta3‑adrenoceptor in the human detrusor muscle. Br J Pharmacol 1999;126(3):819‑25.
    5. Ursino MG, Vasina V, Raschi E, Crema F, De Ponti F. The B3‑adrenoceptor as a therapeutic target: current perspectives. Pharmacol Res 2009;59(4):221-34.
    6. Westfall TC, Macarthur H, Westfall DP. Neurotransmission: the autonomic and somatic motor nervous systems. In: Brunton LL, Hilal-Dandan R, Knollman BC, editors. Goodman & Gilman’s the pharmacological basis of therapeutics 13th ed. New York: McGraw-Hill, 2018.
    7. Yamaguchi O. B3‑adrenoceptors in human detrusor muscle. Urology 2002;59(5 Supp 1):25-9.
    8. VESIcare® [Prescribing Information]. Northbrook, IL: Astellas Pharma US, Inc
    9. Herschorn S, Chapple CR, Abrams P, et al. Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study). BJU Int 2017;120(4):562-75.
    10. Drake MJ, Chapple C, Esen AA, et al. Efficacy and safety of mirabegron add‑on therapy to solifenacin in incontinent overactive bladder patients with an inadequate response to initial 4-week solifenacin monotherapy: a randomised double‑blind multicentre phase 3B study (BESIDE). Eur Urol 2016;70(1):136-45.
    Important Safety Information,
    Indications and Usage

    INDICATIONS AND USAGE

    Myrbetriq® (mirabegron), a beta-3 adrenergic agonist, is indicated as monotherapy or in combination with the muscarinic antagonist solifenacin succinate for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

    IMPORTANT SAFETY INFORMATION

    Do not use Myrbetriq® (mirabegron) in patients who have known hypersensitivity reactions to mirabegron or any component of the tablet.

    Solifenacin succinate is contraindicated in patients with urinary retention, gastric retention, uncontrolled narrow-angle glaucoma, and in patients with hypersensitivity to the product.

    Myrbetriq alone or in combination with solifenacin succinate can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Myrbetriq is not recommended for use in severe uncontrolled hypertensive patients (defined as systolic blood pressure ≥ 180mm Hg and/or diastolic blood pressure ≥ 110mm Hg). Worsening of hypertension was reported infrequently in Myrbetriq clinical trial patients with OAB.

    In patients taking Myrbetriq, urinary retention has been reported in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Myrbetriq patients; however, Myrbetriq and solifenacin succinate 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 antimuscarinic medications for the treatment of OAB, including solifenacin succinate.

    Angioedema of the face, lips, tongue and/or larynx has been reported with Myrbetriq and with solifenacin succinate. Cases of angioedema 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 and/or solifenacin succinate and initiate appropriate therapy and/or measures necessary to ensure a patent airway.

    Solifenacin succinate should be administered with caution to patients with decreased gastrointestinal motility, controlled narrow-angle glaucoma or reduced renal or hepatic function. Doses of solifenacin succinate higher than 5mg are not recommended in patients with severe renal impairment, moderate hepatic impairment, or when administered with ketoconazole or other potent CYP3A4 inhibitors. Use of solifenacin succinate in patients with severe hepatic impairment is not recommended.

    Anticholinergic central nervous system (CNS) effects have been reported with solifenacin succinate use, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing dose, and be advised not to drive or operate heavy machinery until they know how solifenacin succinate affects them. If a patient experiences these effects, dose reduction or drug discontinuation should be considered.

    Since Myrbetriq is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with Myrbetriq. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.

    In solifenacin succinate monotherapy studies, for the 5mg dose one serious adverse event (angioneurotic edema) was reported. For the 10mg dose, three intestinal serious adverse events were reported (one fecal impaction, one colonic obstruction and one intestinal obstruction).

    In clinical trials, the most commonly reported adverse reactions (> 2% and > placebo) for Myrbetriq 25mg and 50mg versus placebo, respectively, were hypertension (11.3%, 7.5% vs. 7.6%), nasopharyngitis (3.5%, 3.9% vs. 2.5%), urinary tract infection (4.2%, 2.9% vs. 1.8%), and headache (2.1%, 3.2% vs. 3.0%).

    In clinical trials, the most commonly reported adverse reactions (> 2% and > placebo and > comparator) for Myrbetriq in combination with solifenacin succinate 25mg + 5mg and 50mg + 5mg versus Myrbetriq 25mg, Myrbetriq 50mg, solifenacin succinate 5mg and placebo, respectively, were dry mouth (9.3%, 7.2% vs. 3.8%, 3.6%, 6.5%, 2.2%), urinary tract infection (7.0%, 4.0% vs. 4.0%, 4.2%, 3.6%, 5.3%), constipation (4.2%, 3.9% vs. 1.2%, 2.8%, 2.4%, 1.2%), and tachycardia (2.2%, 0.9% vs. 1.6%, 1.6%, 0.7%, 0.8%).

    In postmarketing experience with mirabegron, the following events have also occurred: atrial fibrillation, nausea, constipation, diarrhea, and dizziness.

    Please see accompanying complete Prescribing Information for Myrbetriq® (mirabegron) and VESIcare® (solifenacin succinate).