Summary Basis of Decision for Myrbetriq

Clinical Pharmacology

Myrbetriq (mirabegron) is a potent and selective beta 3-adrenoceptor (AR) agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urgency, urgency incontinence, and urinary frequency. Beta 3-ARs are involved in bladder relaxation. Mirabegron demonstrated relaxation of bladder smooth muscle in rat and human isolated tissues, increased cyclic adenosine monophosphate (cAMP) concentrations in rat bladder tissue, and has shown a bladder relaxant effect in rat urinary bladder function models. Mirabegron demonstrated very low intrinsic activity for cloned human beta 1-AR and beta 2-AR.

The clinical pharmacology program consisted of 29 studies in 1,800 volunteers. The majority of studies were performed in healthy male and female volunteers aged 18 to 55 years. As the target OAB population consists of a large proportion of elderly patients, the program also included healthy elderly men and women >65 years of age.

Results showed that mirabegron was associated with dose-dependent increases in blood pressure, heart rate, and QTc prolongation. Therefore, an initial dose of 25 mg, rather than 50 mg, is recommended to minimize cardiac safety concerns. At the maximum recommended therapeutic dose of 50 mg, the largest mean difference from placebo in the QTc interval was <5 ms in healthy male and female subjects at steady-state.

Peak plasma concentrations (C_max) and increases in systemic exposure levels obtained with doses of 50 mg to 200 mg mirabegron were greater than dose-proportional. The exposures achieved at the supratherapeutic doses adequately covered those that would be anticipated in the target patient population, including individuals with compromised drug elimination. Because patients with severe renal impairment and moderate hepatic impairment are reported to result in 92% and 175% increases in the C_max, respectively, the maximum recommended dose in these special populations should not exceed 25 mg so that cardiovascular effects can be minimized.

The clinical pharmacology studies provided a thorough characterization of the clinical pharmacology of mirabegron and provided substantive support for labelling claims. Together, the clinical and pharmacological data support the use of Myrbetriq for the treatment of OAB with symptoms of urgency, urgency incontinence, and urinary frequency.

For further details, please refer to the Myrbetriq Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Myrbetriq was evaluated in three, Phase III, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicentre, clinical studies in patients with overactive bladder (OAB) with symptoms of urgency incontinence, urinary urgency, and urinary frequency (Studies 178-CL-046, -047, and -074). Entry criteria required that patients had symptoms of OAB for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urinary urgency with or without incontinence over a 3-day period. The majority of patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18-95 years). The population included both naïve patients who had not received prior antimuscarinic pharmacotherapy for OAB (48%) and those who had received prior antimuscarinic pharmacotherapy for OAB (52%).

In Study 178-CL-046, 1987 patients were randomized to placebo, Myrbetriq 50 mg, Myrbetriq 100 mg, or an active control (tolterodine ER 4 mg) once daily. In Study 178-CL-047, 1,329 patients were randomized to placebo, Myrbetriq 50 mg, or Myrbetriq 100 mg once daily. In Study 178-CL-074, 1,306 patients were randomized to placebo, Myrbetriq 25 mg, or Myrbetriq 50 mg once daily.

The co-primary efficacy endpoints in all three studies were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours; and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. Secondary endpoints included change from baseline to end of treatment (Week 12) in mean volume voided per micturition; change from baseline to Week 4 in mean number of incontinence episodes per 24 hours; change from baseline to Week 4 in mean number of micturitions per 24 hours; change from baseline to end of treatment (Week 12) in mean level of urgency, mean number of urgency incontinence episodes per 24 hours, mean number of urgency episodes, and quality of life measures.

Efficacy data from the three, Phase III studies showed that the co-primary efficacy endpoints (reduction in daily incontinence episode and micturition frequency) were achieved statistically in all three studies for Myrbetriq 50 mg once daily, as well as in Study 178-CL-074 for Myrbetriq 25 mg once daily. In Studies 178-CL-046, -047, and -074, the patients who were treated with Myrbetriq 50 mg demonstrated statistically significant improvements compared to placebo in the mean change from baseline in the number of incontinence episodes per 24 hours [-1.57, -1.47 and -1.38 versus (vs.) -1.17, -1.13 and -0.96], and statistically significant improvements compared to placebo in the mean change from baseline in the number of micturitions per 24 hours (-1.93, -1.66, and -1.65 vs. -1.34, -1.05, and -1.18).

In Study 178-CL-074, the 25 mg and 50 mg doses of Myrbetriq were both statistically significant to placebo for both co-primary endpoints within 8 weeks, and the efficacy was maintained through the 12-week treatment period. At the end of 12 weeks, the mean differences from placebo for the 25 mg dose and the 50 mg of Myrbetriq were -0.40 and -0.42, respectively, for the mean number of incontinence episodes; and -0.47 and -0.42, respectively, for the mean number of micturitions. Some secondary endpoints also showed comparability between the 25 mg and 50 mg dose; however, a modest benefit of the 50 mg dose compared to the 25 mg dose was observed for several secondary endpoints.

In a 52-week, randomized, active-controlled, long-term, safety study (Study 178-CL-049), the efficacy appeared to be maintained through 12 months of Myrbetriq therapy. The efficacy results between Myrbetriq and the comparator drug appeared to be comparable; however, this study was conducted as a safety study, and not an efficacy study.

Overall, the efficacy results of the three Phase III studies are statistically significant, clinically relevant, and considered acceptable to support the use of Myrbetriq for treating the symptoms of OAB. The indication originally sought by the sponsor stated a dose of 50 mg Myrbetriq once daily with or without food. Instead, Health Canada recommended an initial dose and usual therapeutic dose of 25 mg Myrbetriq once daily, and based on individual patient efficacy and tolerability, the dosage may be increased to a maximum recommended dose of 50 mg once daily with or without food. The lower dose of 25 mg gives patients who have a clinical response to Myrbetriq 25 mg the possibility to have a more favourable benefit/risk profile.

For more information on the efficacy of Myrbetriq, refer to the Myrbetriq Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety data for Myrbetriq (mirabegron) to support once daily use for the treatment of overactive bladder (OAB) were primarily derived from 41 clinical studies, and post-marketing data available from Japan.

In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 178-CL-046,178-CL-47 and 178-CL-074, described in Clinical Efficacy), Myrbetriq was evaluated for safety in 2,736 patients with OAB. In the three studies combined, 432 patients received Myrbetriq 25 mg, 1,375 received Myrbetriq 50 mg, and 929 received Myrbetriq 100 mg once daily.

Myrbetriq was also evaluated for safety in 1,632 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 178-CL-049). Of these patients, 731 received Myrbetriq in a previous 12-week study. In Study 178-CL-049, 1,385 patients received Myrbetriq continuously for at least 6 months, 1,311 patients received Myrbetriq for at least 9 months, and 564 patients received Myrbetriq for at least 1 year.

In Studies 178-CL-046, 178-CL-47, and 178-CL-074, the most commonly reported adverse events (≥1% of Myrbetriq patients and >placebo) were hypertension, nasopharyngitis, urinary tract infection, headache, constipation, upper respiratory tract infection, arthralgia, diarrhoea, tachycardia, abdominal pain, and fatigue. The most frequent adverse events (AEs) leading to discontinuation 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 AEs by more than 1 patient and at a rate greater than placebo. Other adverse reactions reported by less than 1% of patients treated with Myrbetriq included the following:

• Cardiac disorders: palpitations, atrial fibrillation, blood pressure increased.
• Eye disorders: eyelid edema, glaucoma.
• Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension.
• Infections and Infestations: sinusitis, rhinitis.
• Investigations: increased serum levels of gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH).
• Musculoskeletal and connective tissue disorders: joint swelling.
• 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.

In the long-term Study 178-CL-049, the most commonly reported adverse events (>2% of Myrbetriq patients) in patients treated with Myrbetriq 50 mg for up to 52 weeks were hypertension, urinary tract infection, headache, nasopharyngitis, back pain, constipation, dry mouth, dizziness, sinusitis, influenza, arthralgia and cystitis. For Myrbetriq 50 mg once daily, AEs leading to discontinuation reported by more than 2 patients and at a rate greater than the active control included: constipation (0.9%); headache (0.6%); dizziness (0.5%); hypertension (0.5%); dry eyes (0.4%); nausea (0.4%); blurred vision (0.4%); and urinary tract infection (0.4%). Serious AEs reported by at least 2 patients and exceeding the active control included: cerebrovascular accident (0.4%); and osteoarthritis (0.2%). Serum ALT/AST levels increased from baseline by greater than 10-fold in 2 patients (0.3%) treated with Myrbetriq 50 mg. Serious AEs of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Myrbetriq 50 mg, Myrbetriq 100 mg, and the active control once daily, respectively. Neoplasms reported by 2 patients treated with Myrbetriq 100 mg included breast cancer, malignant lung neoplasm, and prostate cancer. The sponsor is conducting a post-marketing study to further assess the occurrence of neoplasms with the administration of Myrbetriq.

In a separate clinical study in Japan, a single case of Stevens-Johnson syndrome was reported with increased levels of serum ALT, AST and bilirubin in a patient taking Myrbetriq 100 mg as well as an herbal medication (Kyufu Gold).

Serious AEs that were identified throughout the review of this submission included hypersensitivity (allergic) reactions, hepatic AEs, urinary tract AEs, neoplastic AEs, and cardiovascular adverse effects. These potential risks have been adequately addressed in the Myrbetriq Product Monograph including the dose recommendation of 25 mg as the initial and usual therapeutic dose with a maximum recommended dose of 50 mg.

Cardiovascular Effects

Increases in heart rate and blood pressure were reported in the Phase III clinical studies conducted in OAB patients. According to pulse rate self-measurements performed after waking up in the morning before taking the study drug, the placebo-adjusted mean increases from baseline in pulse rate were 0.9 beats per minute (bpm) for the 25 mg dose of Myrbetriq; 1.0 bpm for the 50 mg dose; 1.9 bpm for the 100 mg dose; and 1.0 bpm for tolterodine extended-release (ER) 4 mg at the final visit in the 12-week studies. Mean placebo-adjusted changes from baseline in self-measured systolic blood pressure performed after waking up in the morning before taking the study drug were  0.5 mm Hg for the 25 mg dose; 0.6 mm Hg for the 50 mg dose; 0.4 mm Hg for the 100 mg dose; and -0.1 mm Hg for tolterodine ER 4 mg at the final visit.

In the global OAB 12-week Phase II/III population, the incidence of treatment-emergent AEs in the System Order Class (SOC) of cardiac disorders tended to be higher with both Myrbetriq (2.7%) and tolterodine ER 4 mg (3.1%) than with placebo (1.8%). The most common AEs during Myrbetriq 25 mg and 50 mg treatment were tachycardia and palpitations, both of which occurred at a higher incidence than in the placebo group or the tolterodine group (tachycardia: placebo 0.4%, 25 mg Myrbetriq 1.2%, 50 mg Myrbetriq 1.1%, tolterodine ER 4 mg 0.1%; palpitations: placebo 0.2%, 25 mg Myrbetriq 0.9%, 50 mg Myrbetriq 0.6%, tolterodine ER 4 mg 0.4%). These events are predictable considering the positive chronotropic effects of Myrbetriq. Atrial fibrillation occurred at a higher rate with Myrbetriq 50 mg than with placebo or Myrbetriq 25 mg, but was similar to tolterodine (atrial fibrillation:  placebo 0.1% 25 mg Myrbetriq 0%, 50 mg Myrbetriq 0.2%, 4 mg tolterodine ER 0.2%).

In the global OAB 12-week Phase II/III population, the incidence of patients with a serious AE in the cardiac disorders SOC was not higher for Myrbetriq (0.2%) and tolterodine ER 4 mg (0.1%) than for placebo (0.3%). The only serious cardiac disorder SOC events occurring in more than one Myrbetriq-treated patients were atrial fibrillation and cardiac failure (atrial fibrillation: placebo 0.05%, 25 mg Myrbetriq 0%, 50 mg Myrbetriq 0.1%, and tolterodine ER 4 mg 0%). Serious events of cardiac failure occurred in 0.1% of patients in the Myrbetriq 50 mg group and 0.1% in the Myrbetriq 100 mg group, but not in the other treatment groups.

The effects of Myrbetriq on heart rate, blood pressure, and the QTc interval were demonstrated to be dose-dependent in the Phase I clinical pharmacology studies. For this reason, an initial dose of 25 mg, rather than 50 mg, is recommended to minimize cardiac safety concerns. Dosage may be increased to a maximum recommended dose of 50 mg based on individual safety and tolerability considerations. Blood pressure should be monitored during Myrbetriq treatment to ensure that increases above the threshold of normal are promptly identified and treated.

Health Canada is aware that the sponsor is undertaking a long-term observational study using electronic healthcare databases to evaluate the incidence of serious cardiovascular outcomes (both individual and composite outcomes) in patients that are being treated with Myrbetriq. These results will be available for further assessment once the study is completed.

Appropriate warnings and precautions are in place in the approved Myrbetriq Product Monograph to address the identified safety concerns.

For more information, refer to the Myrbetriq Product Monograph, approved by Health Canada and available through the Drug Product Database.