Mirabegron

Introduction Overview

Generic Name

mirabegron

Brand Name

Myrbetriq

Dosage Form

Oral tablet; Oral granules suspension

Drug Class

Urinary antispasmodics

Pharmacokinetics

Absorption:
Mirabegron is well absorbed following oral administration with peak plasma concentrations generally reached within 3 to 4 hours post-dose. The bioavailability of mirabegron depends on the dose and exhibits nonlinear kinetics, likely due to presystemic metabolism and efflux transporters. Food intake can reduce the rate of absorption; however, it does not significantly affect overall exposure, allowing mirabegron tablets to be taken with or without food in adults. In pediatric patients, granule formulations should be administered with food to optimize absorption. The time to peak concentration (Tmax) is generally between 2.5 and 4 hours, reflecting rapid absorption.

Distribution:
Mirabegron demonstrates moderate protein binding in plasma, approximately 71%, primarily to albumin and alpha-1-acid glycoprotein. The apparent volume of distribution is high, suggesting extensive extravascular distribution and tissue penetration. Extensive distribution into bladder tissues aligns with its pharmacodynamic effect on detrusor muscle relaxation. Mirabegron crosses biological membranes and distributes into various tissues but has limited data regarding cerebrospinal fluid penetration.

Metabolism:
Mirabegron is extensively metabolized in the liver primarily by cytochrome P450 enzymes, including CYP3A4 and CYP2D6 isoforms. Additionally, it undergoes phase II metabolism via uridine diphosphate glucuronosyltransferases (UGTs). Multiple metabolic pathways contribute to clearance, forming several inactive metabolites. This metabolism is subject to interindividual variability due to genetic polymorphisms and concomitant medications influencing enzyme activity. Clinical drug interaction studies indicate that mirabegron acts as a moderate CYP2D6 inhibitor and may affect drugs metabolized by this enzyme.

Elimination:
Mirabegron and its metabolites are eliminated via renal and fecal routes. Approximately 55% of the drug is excreted in urine primarily as metabolites, while 34% is eliminated via feces. The elimination half-life ranges from 50 to 70 hours, permitting once-daily dosing. Clearance is reduced in patients with renal or moderate hepatic impairment, necessitating caution or dose adjustment. In severe renal impairment or end-stage renal disease, use is contraindicated. Plasma clearance may also be affected by age-related physiological changes.

Dosage Forms

Available Dosage Forms:
- Oral extended-release tablets: 25 mg, 50 mg
- Oral granule formulation (suspension): Packaged as granules for suspension, dose prepared and administered as directed by pharmacist, used especially in pediatric patients 3 years and older weighing at least 35 kg (77 pounds).

Dosages for Adults and Adolescents:
- Adults with overactive bladder: 25 mg once daily initially; may increase to 50 mg once daily based on efficacy and tolerability.
- Tablets may be taken with or without food.
- Dose adjustments may be necessary in special populations.

Specific Patient Populations:
- Pediatric patients (≥3 years old and ≥35 kg): Granule suspension is used; dosing individualized by healthcare provider, with administration alongside food to enhance absorption.
- Renal impairment: Not recommended in end-stage renal disease or severe renal impairment; dose adjustment may be considered in mild to moderate impairment.
- Hepatic impairment: Use with caution in moderate hepatic impairment; avoid in severe liver disease.
- Elderly: Dose adjustments may be required due to altered pharmacokinetics.

Clinical guidelines emphasize adherence to prescribed formulation due to differences in bioavailability between tablets and suspension. Frequent blood pressure monitoring is indicated during treatment, given the drug's potential hypertensive effects.

Mechanism Of Action

Mirabegron is a selective beta-3 adrenergic receptor agonist that exerts its therapeutic effects primarily by relaxing the detrusor muscle of the urinary bladder. Its binding to beta-3 adrenergic receptors activates adenylate cyclase via stimulation of Gs proteins, leading to increased cyclic adenosine monophosphate (cAMP) levels within bladder smooth muscle cells. Elevated cAMP promotes smooth muscle relaxation through activation of protein kinase A pathways that decrease intracellular calcium levels, thereby reducing detrusor muscle contractility.

Unlike antimuscarinic agents traditionally used for overactive bladder, mirabegron's unique mechanism targets sympathetic pathways without antagonizing muscarinic receptors, resulting in an improved side effect profile with less risk of dry mouth, constipation, and cognitive effects. This adrenergic receptor selectivity limits effects on heart rate and blood pressure but necessitates monitoring due to potential hypertensive impacts in susceptible individuals.

At the cellular level, mirabegron’s stimulation of beta-3 receptors also influences bladder compliance during the storage phase of micturition, increasing bladder capacity without impeding normal voiding function. Clinical studies have demonstrated its efficacy in reducing urinary urgency and incontinence episodes by modulating bladder sensory and motor pathways.

Comparatively, mirabegron offers a novel pharmacologic strategy relative to anticholinergic agents and has been utilized both as monotherapy and adjunctively with antimuscarinics to optimize symptom control. Research continues into its long-term safety, particularly cardiovascular effects, and potential applications in neurogenic detrusor overactivity and other bladder dysfunctions.

Pharmacological Actions

Selective agonist of beta-3 adrenergic receptors in bladder detrusor muscle
Induces relaxation of bladder smooth muscle via cAMP-mediated signaling pathways
Increases functional bladder capacity by reducing spontaneous detrusor contractions
Does not antagonize muscarinic receptors, minimizing anticholinergic side effects
Modulates sympathetic nervous system activity in the lower urinary tract
Improves symptoms of overactive bladder such as urgency, frequency, and urge incontinence
May affect cardiovascular system causing mild increases in blood pressure and heart rate
Metabolized primarily by hepatic enzymes CYP3A4 and CYP2D6
Excreted via renal and fecal elimination pathways
Acts as a moderate inhibitor of CYP2D6, potentially altering coadministered drugs' metabolism
Utilized in both adult and pediatric populations for treatment of overactive bladder and neurogenic detrusor overactivity
Demonstrates sustained efficacy with once-daily oral dosing regimen
Minimal central nervous system penetration, thus minimal cognitive effects
Can be combined with antimuscarinic agents like solifenacin for additive therapeutic effects
Has advantage over anticholinergic drugs in tolerability and patient compliance

Therapeutic Or Clinical Uses

Treatment of overactive bladder symptoms in adults including urinary urgency, frequency, and urge urinary incontinence
Management of neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years and older weighing at least 35 kg
Adjunctive therapy in conjunction with antimuscarinic agents such as solifenacin for refractory overactive bladder
Symptomatic treatment to reduce urinary incontinence episodes and improve quality of life in patients with bladder hyperactivity
Off-label use in some clinical settings for bladder dysfunction secondary to neurological disorders such as multiple sclerosis or spinal cord injury
Alternative for patients intolerant to anticholinergic therapies due to side effect profiles
Improves bladder storage phase compliance without impairing voiding function
Potential option in elderly patients with overactive bladder with cautious monitoring
May be used where antimuscarinic contraindications exist or cause adverse effects
Long-term management of bladder symptoms requiring sustained pharmacotherapy

Side Or Adverse Effects

Increased blood pressure (hypertension), requiring periodic monitoring
Headache, often mild to moderate in intensity
Constipation, occurring less frequently than with antimuscarinics
Dry mouth, particularly when used in combination with antimuscarinic agents
Sinus pain and upper respiratory tract symptoms including sore throat
Urinary tract infection episodes reported in some patients
Rare reports of angioedema including facial, lip, tongue, and throat swelling necessitating emergency care
Palpitations and tachycardia especially if combined with other cardiovascular drugs
Potential urinary retention or difficulty in emptying bladder in susceptible individuals
Rare hypersensitivity reactions including rash and pruritus
Fatigue and dizziness in some patients during initial therapy
Abdominal pain and nausea occasionally observed
Increased risk for urinary discomfort including dysuria
Orthostatic hypotension infrequently reported, requiring caution in patients predisposed
Elevations in heart rate when administered with solifenacin due to additive autonomic effects

Precautions

Screen for existing hypertension before initiating therapy and monitor blood pressure regularly
Use cautiously in patients with bladder outlet obstruction or those prone to urinary retention
Avoid in patients with severe uncontrolled hypertension or severe renal impairment
Careful dose titration and monitoring in elderly patients and those with moderate hepatic impairment
Assess renal function periodically due to renal excretion of metabolites
Caution in patients with a history of hypersensitivity to mirabegron or related compounds
Not recommended for children under 3 years of age or under 35 kg body weight
Advise patients regarding potential delayed onset of action; therapeutic effects may take up to 8 weeks
Monitor for signs of angioedema; instruct patients to seek emergency care if symptoms develop
Adjust dosing regimen carefully when switching between tablet and granule formulations to avoid dosing errors
Inform patients about possible side effects such as headache and constipation and management strategies
Use caution when co-administered with medications that increase blood pressure or have cardiovascular effects
Not established safety profile during pregnancy; weigh benefits and risks before use
Monitor heart rate especially if combined with other agents that affect autonomic function
Warn about potential drug interactions with CYP2D6 substrates or inhibitors

Warnings

Contraindicated in end-stage renal disease and severe renal impairment
Do not use in patients with severe uncontrolled hypertension
Serious risk of angioedema involving face, lips, tongue, and throat can be fatal; seek immediate medical help
May take up to 8 weeks for symptom improvement; continue therapy as prescribed
Use caution in patients with bladder outlet obstruction due to risk of urinary retention
Avoid use in patients with known hypersensitivity to mirabegron or formulation excipients
Monitor blood pressure regularly due to potential hypertensive effects
Potential interactions with drugs metabolized by CYP2D6 necessitate vigilance
Avoid abrupt discontinuation without physician guidance
Not recommended during pregnancy or breastfeeding unless clearly necessary
Do not use in pediatric patients under 3 years of age or under 35 kg body weight
Risk of elevated heart rate when used concurrently with antimuscarinic agents
Use with caution in patients with liver dysfunction
Monitor for hypersensitivity reactions including anaphylaxis
Patients should be advised not to drive or operate machinery if dizziness occurs

Contraindication

Known hypersensitivity or allergy to mirabegron or any product component
Severe renal impairment or end-stage renal disease
Severe uncontrolled hypertension (blood pressure above recommended thresholds)
Use in pediatric patients younger than 3 years of age or weighing less than 35 kg
Patients experiencing angioedema related to previous mirabegron exposure
Concurrent use with medications that are contraindicated due to profound CYP2D6 interactions in certain cases
Patients with bladder outlet obstruction causing retention risk without proper clearance
Use is not advised in severe hepatic impairment
Patients with known severe cardiovascular disorders unless benefits outweigh risks
Hypersensitivity to any inactive components of the formulation

Drug Interactions

Mirabegron is a moderate inhibitor of CYP2D6; can increase plasma levels of CYP2D6 substrates such as digoxin, flecainide, and propafenone
Concomitant use with solifenacin may increase incidence of anticholinergic adverse effects and cardiovascular side effects like tachycardia
Potential additive effects on blood pressure when combined with other antihypertensive or hypertensive agents
Concomitant administration with thioridazine requires caution due to risk of QT prolongation and elevated plasma concentration
Drugs that inhibit CYP3A4 or CYP2D6 may affect mirabegron metabolism altering its plasma levels
Use with P-glycoprotein substrates may alter their absorption or elimination
Caution when combined with digoxin due to increased serum digoxin concentrations requiring monitoring
Additive cardiac effects can occur with antiarrhythmic agents like flecainide and propafenone
Potential interaction with herbal supplements and over-the-counter medications metabolized by CYP enzymes
Drugs causing urinary retention may exacerbate adverse effects when used with mirabegron
Co-administration with potent CYP3A4 inducers may reduce mirabegron effectiveness by increasing metabolism
Concurrent use with other urinary antispasmodics requires careful management to avoid excessive pharmacodynamic effects
Interactions may necessitate dose adjustments of mirabegron or concomitant drugs
Clinicians should review comprehensive medication lists to avoid adverse interactions
Monitoring for adverse reactions is advised when starting or stopping interacting medications

Preparations Of The Drug

Extended-release oral tablets available in 25 mg and 50 mg strengths for once-daily dosing
Granule formulation supplied for oral suspension, suitable for pediatric patients meeting age and weight criteria
Pharmacy-prepared suspension with dosing syringe provided for accurate administration
Tablets are film-coated to facilitate swallowing and protect active drug integrity
Granules mixed into suspension should be shaken well before use; unused suspension discarded after labeled expiration
Storage recommended at room temperature, away from moisture and heat for both tablets and granules
Packaging includes detailed instructions for patients and caregivers for both formulations
Prescriptions specify formulation based on patient age, weight, and clinical condition
Approved for monotherapy and combination use with solifenacin succinate in adults
Not suitable for crushing, chewing, or breaking tablets; granules must be mixed as directed
Pharmaceutical preparations manufactured under stringent quality control to ensure dose uniformity
Available commercially as brand-name Myrbetriq and multiple generic equivalents
Formulations manufactured according to regulatory approvals with ongoing pharmacovigilance
Instructions include guidance on missed doses, storage, and disposal of unused medication
Patient access facilitated by coupons, pricing programs, and support groups specialized for urinary disorders