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.
In three, 12 week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), MYRBETRIQ® was evaluated for safety in 2736 patients [see Clinical Studies ]. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received MYRBETRIQ® 25 mg, 1375 received MYRBETRIQ® 50 mg, and 929 received MYRBETRIQ® 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).
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 overactive bladder (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.
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.
Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with MYRBETRIQ® 25 mg or 50 mg once daily for up to 12 weeks. 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 1: Percentages of Patients with Adverse
Reactions, Derived from All Adverse Events, Exceeding Placebo Rate and Reported
by 1% or More Patients Treated With MYRBETRIQ® 25 mg or 50 mg Once Daily in Studies 1, 2, and 3
|Placebo (%)||MYRBETRIQ® 25 mg (%)||MYRBETRIQ® 50 mg (%)|
|Number of Patients||1380||432||1375|
|Urinary Tract Infection||1.8||4.2||2.9|
|Upper Respiratory Tract Infection||1.7||2.1||1.5|
|*Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring predominantly in subjects with baseline hypertension.|
Other adverse reactions reported by less than 1% of patients treated with MYRBETRIQ® in Studies 1, 2, or 3 included:
Investigations: GGT increased, AST increased, ALT increased, LDH increased
Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection
Table 2 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. The most commonly reported adverse reactions ( > 3% of MYRBETRIQ® patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.
Table 2: Percentages of Patients with Adverse
Reactions, Derived from all Adverse Events, Reported by Greater Than 2% of
Patients Treated With MYRBETRIQ® 50
mg Once Daily in Study 4
|MYRBETRIQ® 50 mg (%)||Active Control (%)|
|Number of Patients||812||812|
|Urinary Tract Infection||5.9||6.4|
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 (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 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® .
In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with MYRBETRIQ® 50 mg, MYRBETRIQ® 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.
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).
Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.
The following events have been reported in association with mirabegron use in worldwide postmarketing experience:
Gastrointestinal disorders: nausea
Urologic: urinary retention [see WARNINGS AND PRECAUTIONS]
Read the Myrbetriq (mirabegron) Side Effects Center for a complete guide to possible side effects
Drug interaction studies were conducted to investigate the effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs (e.g., ketoconazole, rifampin, solifenacin, tamsulosin, and oral contraceptives) [see CLINICAL PHARMACOLOGY]. No dose adjustment is recommended when these drugs are co-administered with mirabegron.
The following are drug interactions for which monitoring is recommended:
Drugs Metabolized By CYP2D6
Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when MYRBETRIQ® is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (27%). Therefore, 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 [see CLINICAL PHARMACOLOGY].
The mean Cmax 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 [see CLINICAL PHARMACOLOGY].
Read the Myrbetriq Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/13/2015
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