Mirabegron

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Extended Release 24 Hour, Oral:

Myrbetriq: 25 mg, 50 mg

Pharmacology

Mechanism of Action

Mirabegron, a beta-3 adrenergic receptor agonist, activates beta-3 adrenergic receptors in the bladder resulting in relaxation of the detrusor smooth muscle during the urine storage phase, thus increasing bladder capacity. At usual doses, mirabegron is believed to display selectivity for the beta-3 adrenergic receptor subtype compared to its affinity for the beta-1 and -2 adrenoceptor subtypes. Data have shown that beta-adrenoceptors, predominately the beta-3 subtype, mediate detrusor smooth muscle tone and promote the storage function of the human bladder.

Pharmacokinetics/Pharmacodynamics

Distribution

V_ss: ~1670 L (following IV administration)

Metabolism

Extensive metabolism via multiple pathways (eg, dealkylation, oxidation, glucuronidation, amide hydrolysis) via multiple enzymes (eg, UGT, esterase, CYP3A4, CYP2D6); two major pharmacologically inactive metabolites produced

Excretion

Urine (radiolabeled drug: 55%; unchanged drug: ~25%); feces (radiolabeled drug: 34%; unchanged drug: 0%)

Onset of Action

Efficacy is seen within 8 weeks; steady state achieved within 7 days

Time to Peak

~3.5 hours

Half-Life Elimination

~50 hours

Protein Binding

~71%; binds mainly to albumin and alpha₁-acid glycoprotein

Use in Specific Populations

Special Populations: Renal Function Impairment

Following single dose administration of mirabegron 100 mg in volunteers with mild renal impairment (estimated glomerular filtration rate [eGFR] 60 to 89 mL/minute/1.73 m² as estimated by modification of diet in renal disease), mean mirabegron C_max and AUC were increased by 6% and 31% relative to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR 30 to 59 mL/minute/1.73 m²), C_max and AUC were increased by 23% and 66%, respectively. In patients with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m²), mean C_max and AUC values were 92% and 118% higher compared with healthy subjects with normal renal function.

Special Populations: Hepatic Function Impairment

Following single-dose administration of mirabegron 100 mg in volunteers with mild hepatic impairment (Child-Pugh class A), mean mirabegron C_max and AUC were increased by 9% and 19% relative to volunteers with normal hepatic function. In volunteers with moderate hepatic impairment (Child-Pugh class B), mean C_max and AUC values were 175% and 65% higher.

Special Populations: Gender

The C_max and AUC of mirabegron were approximately 40% to 50% higher in females than in males. When corrected for differences in body weight, the mirabegron systemic exposure is 20% to 30% higher in females compared with males.

Use: Labeled Indications

Overactive bladder: Treatment of overactive bladder (OAB) with symptoms of urinary frequency, urgency, or urge urinary incontinence as monotherapy or in combination with solifenacin

Contraindications

Hypersensitivity to mirabegron or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Severe uncontrolled hypertension (systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg); pregnancy

Dosage and Administration

Dosing: Adult

Overactive bladder (OAB): Oral: Initial: 25 mg once daily; efficacy is observed within 8 weeks for 25 mg dose. May increase to 50 mg once daily based on individual patient efficacy and tolerability.

Concomitant use with solifenacin: Initial: 25 mg once daily with solifenacin 5 mg once daily. May increase mirabegron dose to 50 mg once daily after 4 to 8 weeks.

Dosing: Geriatric

Refer to adult dosing.

Administration

Administer without regard to food. Swallow the tablet whole with water; do not chew, divide, or crush.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Ajmaline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Ajmaline. Monitor therapy

Amphetamines: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Amphetamines. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Mirabegron. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose. Monitor therapy

CloZAPine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Monitor therapy

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Monitor therapy

CYP2D6 Substrates (High risk with Inhibitors): CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Exceptions: Tamoxifen. Monitor therapy

Desipramine: Mirabegron may increase the serum concentration of Desipramine. Monitor therapy

Digoxin: Mirabegron may increase the serum concentration of Digoxin. Management: Consider using the lowest dose of digoxin when initiating concurrent mirabegron. Monitor serum digoxin concentrations closely to help guide digoxin dosing. Consider therapy modification

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Eliglustat: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

Flecainide: Mirabegron may increase the serum concentration of Flecainide. Management: Monitor clinical response to flecainide closely. Dose adjustment may be necessary. Canadian mirabegron labeling recommends restricting the maximum adult mirabegron dose to 25 mg/day in patients receiving flecainide. Monitor therapy

Indoramin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Indoramin. Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Mirabegron. Monitor therapy

Metoprolol: Mirabegron may diminish the antihypertensive effect of Metoprolol. Mirabegron may increase the serum concentration of Metoprolol. Monitor therapy

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Monitor therapy

Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Consider therapy modification

Pitolisant: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Pitolisant. Monitor therapy

Propafenone: Mirabegron may increase the serum concentration of Propafenone. Management: Monitor clinical response to propafenone closely. Dose adjustment may be necessary. Canadian mirabegron labeling recommends restricting the maximum adult mirabegron dose to 25 mg/day in patients receiving propafenone. Monitor therapy

RifAMPin: May decrease the serum concentration of Mirabegron. Monitor therapy

Solifenacin: Mirabegron may enhance the adverse/toxic effect of Solifenacin. Specifically, the risk of acute urinary retention may be enhanced. Monitor therapy

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Consider therapy modification

Tamsulosin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin. Monitor therapy

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Monitor therapy

Adverse Reactions

>10%: Cardiovascular: Hypertension (9% to 11%)

1% to 10%:

Cardiovascular: Tachycardia (2%)

Central nervous system: Headache (2% to 4%), dizziness (1% to 3%)

Gastrointestinal: Constipation (1% to 3%), xerostomia (4%), diarrhea (2%), abdominal pain (1%)

Genitourinary: Urinary tract infection (3% to 6%), cystitis (2%)

Infection: Influenza (3%)

Neuromuscular & skeletal: Back pain (3%), arthralgia (2%)

Respiratory: Nasopharyngitis (4%), sinusitis (3%)

<1%, postmarketing, and/or case reports: Abdominal distension, angioedema, anxiety, atrial fibrillation, bladder pain, blurred vision, breast cancer, cerebrovascular accident, confusion, dry eye syndrome, dyspepsia, gastritis, elevated gamma-glutamyl transferase, genital pruritus, glaucoma, hallucination, hypersensitivity angiitis, increased lactate dehydrogenase, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, insomnia, lip edema, malignant neoplasm of lung, malignant neoplasm of prostate, nausea, nephrolithiasis, nonthrombocytopenic purpura, osteoarthritis, palpitations, pruritus, rhinitis, skin rash, urinary retention, urticaria, vaginal infection

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported; some cases have occurred after the first dose. May be life-threatening. Immediately discontinue and institute supportive care if the tongue, hypopharynx, or larynx is involved.
• Blood pressure effects: Dose-related increases in blood pressure have been reported; monitor blood pressure periodically during therapy. Not recommended in patients with severe uncontrolled hypertension (SBP ≥180 and/or DBP ≥110 mm Hg); if used in patients with controlled and less severe hypertension, use with caution and monitor blood pressure closely; exacerbation of preexisting hypertension has been infrequently reported.

Disease-related concerns:

• Bladder flow obstruction: Use with caution in patients with bladder outlet obstruction (BOO) and in patients using concomitant muscarinic antagonists; the risk of urinary retention may be increased.
• Hepatic impairment: Use with caution in patients with mild to moderate hepatic impairment; dosage adjustment is required in patients with moderate hepatic impairment. Use is not recommended in severe hepatic impairment.
• QT prolongation: Use with caution in patients with a history of QT interval prolongation or those receiving medications known to prolong the QT interval. In one thorough QT study, supratherapeutic doses prolonged the QTc interval based on the individual subject-specific correction method (QTcI) in females but not in males (Malik 2012). In general, mirabegron at the recommended dose has a low risk of QT interval prolongation (Sanford 2013).
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment is required in patients with severe renal impairment. Use is not recommended in ESRD.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Monitor blood pressure at baseline and then periodically during therapy; signs and symptoms of urinary retention

Pregnancy

Pregnancy Considerations

Adverse effects have been observed in some animal reproduction studies.

Patient Education

What is this drug used for?

• It is used to treat an overactive bladder.

Frequently reported side effects of this drug

• Dry mouth
• Flu-like signs
• Back pain
• Joint pain
• Constipation
• Stuffy nose
• Sore throat

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.
• Fast heartbeat
• Abnormal heartbeat
• Bladder irritation
• Swelling in your throat
• Vision changes
• Severe dizziness
• Passing out
• Severe headache
• Difficult urination
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

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