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Mirabegron

Pronunciation

(mir a BEG ron)

Index Terms

  • YM-178

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

Brand Names: U.S.

  • Myrbetriq

Pharmacologic Category

  • Beta3 Agonist

Pharmacology

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.

Distribution

Vss: ~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: Labeled Indications

Overactive bladder: Treatment of overactive bladder (OAB) with symptoms of urinary frequency, urgency, or urge urinary incontinence

Contraindications

Hypersensitivity to mirabegron or any component of the formulation

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

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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl 30 to 89 mL/minute or eGFR 30 to 89 mL/minute/1.73 m2: No dosage adjustment necessary.

CrCl 15 to 29 mL/minute or eGFR 15 to 29 mL/minute/1.73 m2: Do not exceed 25 mg once daily.

CrCl <15 mL/minute or eGFR <15 mL/minute/1.73 m2: Not recommended (has not been studied).

Hemodialysis: Not recommended (has not been studied).

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate impairment (Child-Pugh class B): Do not exceed 25 mg once daily.

Severe impairment (Child-Pugh class C): Not recommended (has not been studied).

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

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: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. 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

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

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

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. 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

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. Mirabegron may increase the serum concentration of Solifenacin. 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

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 (4%), dizziness (3%)

Gastrointestinal: Constipation (2% to 3%), xerostomia (3%), 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% (Limited to important or life-threatening): Abdominal distension, angioedema (angioedema of the face, angioedema of the lips, angioedema of the throat, angioedema of the tongue with or without respiratory symptoms), atrial fibrillation, bladder pain, blurred vision, breast cancer, cerebrovascular accident, dry eye syndrome, dyspepsia, gastritis, elevated gamma-glutamyl transferase, glaucoma, increased lactate dehydrogenase, increased serum ALT, increased serum AST, leukocytoclastic vasculitis, lip edema, malignant neoplasm of lung, malignant neoplasm of prostate, nausea, nephrolithiasis, osteoarthritis, palpitations, pruritus, purpura, rhinitis, skin rash, Stevens-Johnson syndrome, urinary retention, urticaria, vaginal infection, vulvovaginal pruritus

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 reported.

Disease-related concerns:

• Bladder flow obstruction: Use with caution in patients with bladder outlet obstruction (BOO); 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

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects have been observed in some animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience rhinitis or pharyngitis. Have patient report immediately to prescriber signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), tachycardia, abnormal heartbeat, angioedema, vision changes, severe dizziness, passing out, severe headache, or difficult urination (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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