Side Effects of Myrbetriq (mirabegron)

Myrbetriq (mirabegron) is a beta-3 adrenergic agonist used to treat overactive bladder with symptoms of urgency (a strong need to urinate that is difficult to control), frequency (urinating often), and leakage (accidental urination due to a sudden or uncontrollable urge) in adults.

Common side effects of Myrbetriq include

• headache,
• increased blood pressure,
• constipation,
• dizziness,
• diarrhea,
• back pain,
• dry mouth,
• joint pressure, and
• common cold symptoms.

Less commonly, some patients have problems emptying their bladder while taking Myrbetriq.

Serious side effects of Myrbetriq include

• heart problems,
• eye problems,
• Stevens-Johnson syndrome,
• vaginal infections, cancer, and
• urinary tract infections (UTIs).

Drug interactions of Myrbetriq include medications that are metabolized or broken down by the CYP2D6 enzymes, because it can result in an increase in their blood levels. Taking Myrbetriq with digoxin causes an increase in digoxin blood levels. In clinical studies when Myrbetriq was administered with warfarin, blood levels of warfarin were increased. 

Use of Myrbetriq during pregnancy has not been adequately evaluated. Due to the lack of conclusive safety data, Myrbetriq should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. 

It is unknown if Myrbetriq is excreted in human breast milk. As many drugs are excreted into human milk and have the potential of causing harm to the nursing infant, Myrbetriq should only be used during breastfeeding if it is clearly needed.

The most common side effects of mirabegron are:

• Headache
• Increased blood pressure
• Constipation
• Dizziness
• Diarrhea
• Back pain
• Dry mouth
• Joint pressure
• Common cold symptoms

Less commonly, some patients have experienced problems with emptying their bladder while taking mirabegron.

Possible serious side effects include:

• Heart problems
• Eye problems
• Stevens-Johnson syndrome
• Vaginal infections
• Cancer
• Urinary tract infection

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. 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.

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.

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

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 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

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).

Postmarketing Experience

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, 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. A causal relationship between mirabegron and these disorders has not been established.

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

Urologic: urinary retention

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). 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.

Digoxin

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.

Warfarin

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.