Safety

GO with a safe and tolerable option1

Evaluation of Safety: Monotherapy

The safety profile of Myrbetriq® (mirabegron) has been evaluated in patients with overactive bladder (OAB) in three 12-week trials and a 1-year safety study1*

Safety and tolerability studied in three 12-week phase III trials1

Percent of patients with adverse reactions derived from all adverse events, exceeding placebo rate and reported by ≥1% of patients treated with Myrbetriq 25 mg or 50 mg once daily in Studies 1, 2, and 31

Chart showing results of 12 week safety study

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

Myrbetriq was evaluated in three 12‑week, double‑blind, randomized, placebo‑controlled,
parallel‑group, multicenter clinical trials in patients with OAB.1

  • 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 >1 patient and at a rate greater than placebo.
Study Design

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

Percent of patients with adverse reactions derived from all adverse events, reported by >2% of patients treated with Myrbetriq 50 mg once daily in the 1 year safety study1

Chart showing results of 1 year safety study in elderly patients

bThe active control in this study was tolterodine extended-release (ER) 4 mg.2

Myrbetriq was evaluated in a 1-year, randomized, fixed‑dose, double‑blind, active‑controlled study1

  • Adverse reactions leading to discontinuation in patients treated with Myrbetriq 50 mg (reported by >2 patients and >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 ≥2 patients and >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; these markers subsequently returned to baseline while both patients continued Myrbetriq
  • Serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, 100 mg, and active control once daily, respectively. 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.
Study Design

*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 study in patients with OAB (Study 4). Of these patients, 731 received Myrbetriq in a previous 12‑week study. In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.

12 Week Safety

Safety and tolerability studied in three 12-week phase III trials1

Percent of patients with adverse reactions derived from all adverse events, exceeding placebo rate and reported by ≥1% of patients treated with Myrbetriq 25 mg or 50 mg once daily in Studies 1, 2, and 31

Chart showing results of 12 week safety study

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

Myrbetriq was evaluated in three 12‑week, double‑blind, randomized, placebo‑controlled, parallel‑group, multicenter clinical trials in patients with OAB.1

  • 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 >1 patient and at a rate greater than placebo
Study Design
*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 study in patients with OAB (Study 4). • Of these patients, 731 received Myrbetriq in a previous 12‑week study. • In Study 4, 1385 patients received Myrbetriq continuously for at least 6 months, 1311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.
1-Year Safety

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

Percent of patients with adverse reactions derived from all adverse events, reported by >2% of patients treated with Myrbetriq 50 mg once daily in the 1 year safety study1

Chart showing results of 1 year safety study in elderly patients

bThe active control in this study was tolterodine extended-release (ER) 4 mg.2

Myrbetriq was evaluated in a 1‑year, randomized, fixed‑dose, double‑blind, active‑controlled study1

  • Adverse reactions leading to discontinuation in patients treated with Myrbetriq 50 mg (reported by >2 patients and >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 ≥2 patients and >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; these markers subsequently returned to baseline while both patients continued Myrbetriq
  • Serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, 100 mg, and active control once daily, respectively. 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.
Study Design

Hear from a peer

Dr. Christopher R. Chapple discusses the results of a 1‑year study examining the safety profile of Myrbetriq.

Play video of Dr Christopher R. Chapple, MD, DHC, FRCS
References

References

  1. Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci 2008;9(6):453-66.
  2. Igawa Y, Yamazaki Y, Takeda H, et al. Functional and molecular biological evidence for a possible β3-adrenoceptor in the human detrusor muscle. Br J Pharmacol 1999;126(3):819-25.
  3. Ursino MG, Vasina V, Raschi E, Crema F, De Ponti F. The β3-adrenoceptor as a therapeutic target: current perspectives. Pharmacol Res 2009;59(4):221-34.
  4. Westfall TC, Macarthur H, Westfall, DP. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems. In: Brunton L, Hilal-Dandan R, Knollman B, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw Hill, 2018.
  5. Yamaguchi O. β3-adrenoceptors in human detrusor muscle. Urology 2002;59(suppl):25-29.
  6. Chu FM, Dmochowski R. Pathophysiology of overactive bladder. Am J Med 2006;119(3A):3S-8S.
  7. Myrbetriq [Prescribing Information]. Northbrook, IL: Astellas Pharma US, Inc.
  8. Chapple CR, Kaplan SA, Mitcheson D, et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β3-adrenoceptor agonist, in overactive bladder. Eur Urol 2013,63(2):296-305.

Hear from a peer

Dr. Christopher R. Chapple discusses the results of a 1‑year study examining the safety profile of Myrbetriq.

The Safety Profile of Myrbetriq® (mirabegron) in Elderly Patients: Monotherapy

Safety evaluated in 12-week analysis3,4

Pre-specified subgroup analysis in patients ≥65 years (n=1674 of 4427) and ≥75 years (n=478 of 4427) of age

Percent of patients ≥65 and ≥75 years of age with adverse reactions derived from all adverse events, exceeding placebo rate and reported by ≥3% of patients in any treatment group in the ≥65 year subgroup4

Chart showing results of 12 week safety study in elderly patients

Pre-specified subgroup analysis in patients ≥65 years (n=1674 of 4427) and ≥75 years (n=478 of 4427) of age3

  • The frequency of serious AEs was generally greater in patients ≥65 years of age than patients <65 years of age3
  • The frequency of serious AEs was generally greater in patients ≥75 years of age than patients <75 years of age3
  • Adverse events leading to discontinuation among patients ≥65 years of age were numerically similar for Myrbetriq 25 mg, Myrbetriq 50 mg, and placebo (4.5%, 5.6% and 5.0%, respectively)4
Study Design

Safety evaluated in 1-year study3,4

Pre-specified subgroup analysis in patients ≥65 years (n=1674 of 4427) and ≥75 years (n=478 of 4427) of age

Percent of patients ≥65 and ≥75 years of age with adverse reactions derived from all adverse events, exceeding placebo rate and reported by ≥3% of patients in any treatment group in the ≥65 year subgroup4

Chart showing results of 1 year safety study in elderly patients
  • The frequency of serious AEs was generally greater in patients ≥65 years of age than patients <65 years of age3
  • The frequency of serious AEs was generally greater in patients ≥75 years of age than patients <75 years of age3

Safety Evaluated at Week 12 and at 1 Year3,4

Pre-specified subgroup analysis in patients ≥65 years (n=1674 of 4427) and ≥75 years (n=478 of 4427) of age3,4

  • At both Week 12 and 1 year, the frequency of serious AEs was generally greater in patients ≥65 years of age than patients <65 years of age4
  • At Week 12, adverse events leading to discontinuation among patients ≥65 years of age were numerically similar for Myrbetriq 25 mg, Myrbetriq 50 mg, and placebo (4.5%, 5.6% and 5.0%, respectively)4
  • The pharmacokinetics of Myrbetriq were similar in elderly and adult volunteers, and no dose adjustment is necessary for elderly patients.
Study Design

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 Pharma US, Inc. 2. Khullar V, Amarenco G, Angulo JC, et al. Efficacy and tolerability of mirabegron, a β3-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European–Australian phase 3 trial. Eur Urol. 2013;63:283‑295. 3. Astellas. Myrbetriq. Data on File. 4. Wagg A, Cardozo L, Nitti VW, et al. The efficacy and tolerability of the β3-adrenoceptor agonist mirabegron for the treatment of symptoms of overactive bladder in older patients. Age Ageing. 2014:43(5):666-675.

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).