Mirabegron

Usage

• Mirabegron is prescribed for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.
• Pharmacological classification: Beta-3 adrenergic agonist.
• Mechanism of Action: Mirabegron relaxes the detrusor smooth muscle of the bladder during the storage phase of the micturition cycle by stimulating beta-3 adrenergic receptors. This increases bladder capacity and reduces the urge to urinate.

Alternate Names

• International Nonproprietary Name (INN): Mirabegron.
• Brand names: Myrbetriq, Betmiga.

How It Works

• Pharmacodynamics: Mirabegron is a selective beta-3 adrenergic receptor agonist. Stimulation of these receptors in the bladder leads to relaxation of the detrusor muscle, increasing bladder capacity and reducing OAB symptoms.
• Pharmacokinetics:
  • Absorption: Mirabegron is absorbed orally with an absolute bioavailability ranging from 29% to 35%. Food does not significantly affect absorption.
  • Metabolism: Primarily metabolized in the liver via multiple CYP isoenzymes, including CYP2D6 and CYP3A4.
  • Elimination: Excreted primarily in the urine (50-70%) and feces (approximately 20%). The elimination half-life is approximately 50 hours.
• Mode of Action: Mirabegron selectively binds to and activates beta-3 adrenergic receptors located on the detrusor muscle of the bladder. This activation stimulates adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP) levels. Elevated cAMP levels lead to smooth muscle relaxation and an increase in bladder capacity.
• Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Mirabegron acts as a beta-3 adrenergic receptor agonist. There is no significant inhibition of other CYP isoenzymes or relevant interaction with neurotransmitter systems.
• Elimination Pathways: Primarily renal excretion (50-70%) with some fecal excretion (approximately 20%). Hepatic metabolism plays a significant role, involving CYP2D6 and CYP3A4.

Dosage

Standard Dosage

Adults:

• Initial dose: 25 mg orally once daily.
• Maintenance dose: May be increased to 50 mg orally once daily after 4-8 weeks if needed, based on individual efficacy and tolerability.

Children (≥3 years old):

• Oral Suspension: Dosing is based on body weight:
  • ≥35 kg: 48 mg (6 mL) PO once daily, may be increased to 80 mg (10 mL) after 4-8 weeks
  • 22 kg to <35 kg: 32 mg (4 mL) PO once daily, may be increased to a maximum of 64 mg (8 mL)
  • 11 kg to <22 kg: 24 mg (3 mL) PO once daily, may be increased to a maximum of 48 mg (6 mL)
• Tablets: Usage and dosage must be determined by the doctor.

Special Cases:

• Elderly Patients: No specific dose adjustment is generally required. However, consider starting with a lower dose and monitoring closely.
• Patients with Renal Impairment:
  • Mild to moderate (eGFR 30-89 mL/min/1.73 m²): Maximum dose of 50 mg once daily. If co-administered with a strong CYP3A inhibitor reduce to 25 mg once daily.
  • Severe (eGFR 15-29 mL/min/1.73 m²): Maximum dose of 25 mg once daily. If co-administered with a strong CYP3A inhibitor Mirabegron is not recommended.
  • End-stage renal disease (ESRD) or dialysis: Not recommended.
• Patients with Hepatic Dysfunction:
  • Mild (Child-Pugh A): No dose adjustment needed. If co-administered with a strong CYP3A inhibitor reduce to 25 mg once daily.
  • Moderate (Child-Pugh B): Maximum dose of 25 mg once daily. If co-administered with a strong CYP3A inhibitor Mirabegron is not recommended.
  • Severe (Child-Pugh C): Not recommended.
• Patients with Comorbid Conditions: Caution is advised in patients with uncontrolled hypertension, QT prolongation, or clinically significant bladder outlet obstruction. Monitor blood pressure regularly.

Clinical Use Cases

Mirabegron is specifically indicated for the treatment of overactive bladder symptoms and is not typically used in the clinical settings listed (Intubation, Surgical Procedures, Mechanical Ventilation, ICU Use, Emergency Situations).

Dosage Adjustments

Dose adjustments may be necessary based on individual patient response, tolerability, renal function, hepatic function, and concomitant medications, especially strong CYP3A inhibitors.

Side Effects

Common Side Effects:

• Tachycardia/Increased heart rate
• Urinary tract infections (UTIs)
• Headache
• Dizziness
• Dry mouth
• Nasal congestion or inflammation
• Constipation or diarrhea
• Nausea

Rare but Serious Side Effects:

• Angioedema
• Allergic reactions
• Hypertension
• Atrial fibrillation
• Urinary retention
• QT Prolongation
• Severe skin reactions (Stevens-Johnson syndrome, Toxic Epidermal Necrolysis)

Long-Term Effects:

Limited data are available on the long-term effects of mirabegron.

Adverse Drug Reactions (ADR):

• Urinary retention requiring catheterization.
• Severe allergic reactions.
• Malignant hypertension.

Contraindications

• Severe uncontrolled hypertension (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg).
• Hypersensitivity to mirabegron or any of its components.
• End Stage Renal Disease or dialysis.
• Severe Hepatic Impairment (Child-Pugh Class C)

Drug Interactions

• Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin): May increase mirabegron plasma concentrations. Dose adjustment is necessary.
• Drugs that prolong the QT interval: Use with caution and monitor QT interval.
• Other drugs metabolized by CYP2D6 (e.g., thioridazine, metoprolol, desipramine, imipramine): Mirabegron is a weak inhibitor of CYP2D6; monitor for potential interactions.
• Digoxin: Combination may cause increases in digoxin plasma concentrations.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (US FDA). There are no adequate and well-controlled studies in pregnant women. Mirabegron should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Breastfeeding: Mirabegron is excreted in human milk. Caution should be exercised when administering mirabegron to a nursing woman.

Drug Profile Summary

• Mechanism of Action: Beta-3 adrenergic receptor agonist, relaxing the detrusor muscle of the bladder.
• Side Effects: Common: Tachycardia, UTI, headache, dizziness. Serious: Angioedema, allergic reactions, hypertension, atrial fibrillation, urinary retention.
• Contraindications: Severe uncontrolled hypertension, hypersensitivity, ESRD.
• Drug Interactions: Strong CYP3A inhibitors, QT interval prolonging drugs, CYP2D6 substrates, digoxin.
• Pregnancy & Breastfeeding: Category C; use with caution. Excreted in breast milk.
• Dosage: Adults: 25 mg once daily, may increase to 50 mg. Children: Dose adjusted according to weight. Renal/Hepatic impairment: Dose reductions necessary.
• Monitoring Parameters: Blood pressure, heart rate, renal function tests, hepatic function tests, electrocardiogram (ECG) if QT prolongation is a concern.

Popular Combinations

• Solifenacin succinate: Combining mirabegron with solifenacin, an antimuscarinic medication, can provide greater improvement in OAB symptoms compared to either drug alone.

Precautions

• General Precautions: Assess for pre-existing hypertension, bladder outlet obstruction, and QT prolongation. Monitor blood pressure regularly.
• Specific Populations: Pregnancy (Category C, use with caution), breastfeeding (excreted in breast milk, use with caution), children (dose based on weight), elderly (monitor closely).
• Lifestyle Considerations: Alcohol may exacerbate OAB symptoms.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Mirabegron?

A: Adults: Initially 25 mg orally once daily, which can be increased to 50 mg daily after 4-8 weeks based on response and tolerability. Children (3+): Dosing is weight based, as follows:

• ≥35 kg: 48 mg (6 mL) PO once daily, may be increased to 80 mg (10 mL) after 4-8 weeks
• 22 kg to <35 kg: 32 mg (4 mL) PO once daily, may be increased to a maximum of 64 mg (8 mL)
• 11 kg to <22 kg: 24 mg (3 mL) PO once daily, may be increased to a maximum of 48 mg (6 mL)

Q2: How does Mirabegron work?

A: Mirabegron is a beta-3 adrenergic agonist. It relaxes the detrusor muscle in the bladder, increasing bladder capacity and reducing OAB symptoms.

Q3: What are the common side effects of Mirabegron?

A: Common side effects include tachycardia, urinary tract infections, headache, dizziness, and dry mouth.

Q4: What are the serious side effects of Mirabegron?

A: Rare but serious side effects include angioedema, allergic reactions, hypertension, atrial fibrillation, and urinary retention.

Q5: Is Mirabegron safe to use during pregnancy or breastfeeding?

A: Mirabegron is Pregnancy Category C. It should only be used if the potential benefit outweighs the potential risk to the fetus. It is present in human breast milk. Caution should be exercised when administered to a nursing mother.

Q6: What are the contraindications for Mirabegron?

A: Contraindications include severe uncontrolled hypertension, hypersensitivity to mirabegron, end-stage renal disease (ESRD), and severe hepatic impairment (Child-Pugh C).

Q7: Does Mirabegron interact with other medications?

A: Yes, Mirabegron can interact with strong CYP3A inhibitors (requiring dose adjustment), drugs that prolong the QT interval, some CYP2D6 substrates, and digoxin.

Q8: How long does it take for Mirabegron to start working?

A: It may take 4-8 weeks to observe significant improvements in OAB symptoms.

Q9: Can Mirabegron be used in children?

A: Yes, but only in oral suspension form. Dosing is dependent upon body weight and should be determined by a physician.

Q10: What should I monitor in patients taking Mirabegron?

A: Monitor blood pressure, heart rate, and renal and hepatic function. Consider ECG monitoring if there is concern for QT prolongation or if the patient is on concomitant drugs known to prolong the QT interval.