Mirader 25

Indications

Mirader is prescribed for managing the symptomatic relief of urgency, increased frequency of urination, and urgency incontinence in adult patients diagnosed with overactive bladder (OAB) syndrome.

Pharmacology Mirabegron, the pioneering beta-3 adrenoceptor agonist, operates through a dual mechanism. It directly affects the bladder smooth muscle and influences the sensory nervous system. By increasing cyclic adenosine monophosphate (cyclic AMP) levels, it induces relaxation of the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle through the activation of beta-3 adrenoceptors, thereby enhancing bladder capacity.

Dosage For adults, including the elderly, the recommended initial dosage is one Mirabegron 25 mg tablet taken once daily, with or without food. Depending on individual patient response and tolerance, the dose may be increased to one Mirabegron 50 mg tablet once daily.

Renal or hepatic impairment

In patients with severe renal impairment (ClCr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2) or moderate hepatic impairment (Child-Pugh Class B), the daily Mirabegron dose should not exceed one 25 mg tablet once daily. Mirabegron is not recommended for use in patients with end-stage renal disease (GFR <15 mL/min/1.73 m2) or severe hepatic impairment (Child Pugh Class C).

Gender

No adjustment in dosage is required based on gender.

Pediatric population

The safety and efficacy of Mirabegron in children under 18 years old have not been established.

Administration Mirabegron tablets are to be taken once daily, with liquids, swallowed whole, and should not be chewed, divided, or crushed.

Interaction Effect of enzyme inhibitors

In the presence of the strong inhibitor of CYP3A/P-gp ketoconazole, Mirader exposure (AUC) was increased 1.8-fold in healthy volunteers. No dose adjustment is necessary when combining Mirader with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renal impairment or mild hepatic impairment concurrently receiving strong CYP3A inhibitors, such as itraconazole, ketoconazole, ritonavir, and clarithromycin, the recommended dose is 25 mg once daily with or without food. Mirader is not recommended in patients with severe renal impairment or patients with moderate hepatic impairment concurrently receiving strong CYP3A inhibitors.

Effect of enzyme inducers

Substances that induce CYP3A or P-gp decrease the plasma concentrations of Mirader. No dose adjustment is needed for Mirader when administered with therapeutic doses of rifampicin or other CYP3A or P-gp inducers.

Effect of Mirader on CYP2D6 substrates

Mirader exhibits moderate inhibitory potency towards CYP2D6 in healthy volunteers. The CYP2D6 activity typically returns to baseline within 15 days after discontinuation of Mirader. Caution is advised when co-administering Mirader with medicinal products metabolized significantly by CYP2D6, such as thioridazine, Type 1 C antiarrhythmics (e.g., flecainide, propafenone), and tricyclic antidepressants (e.g., imipramine, desipramine).

Effect of Mirader on transporters

Mirader weakly inhibits P-gp. In healthy volunteers, Mirader increased Cmax and AUC by 29% and 27%, respectively, of the P-gp substrate digoxin. For patients initiating a combination of Mirader and digoxin, the lowest digoxin dose should be prescribed initially, with serum digoxin concentrations monitored for titration of the digoxin dose to achieve the desired clinical effect.

Other interactions

No clinically relevant interactions have been observed when Mirader was co-administered with therapeutic doses of solifenacin, tamsulosin, warfarin, metformin, or a combined oral contraceptive product containing ethinylestradiol and levonorgestrel. Dose adjustment is not recommended.

Contraindications Mirabegron is contraindicated in patients with hypersensitivity to the active substance or any of the excipients and in those with severe uncontrolled hypertension, defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg.

Side Effects

The most common side effects reported in patients treated with Mirader 50 mg during phase 3 double-blind, placebo-controlled studies were tachycardia and urinary tract infections. Tachycardia occurred in 1.2% of patients receiving Mirader 50 mg, leading to discontinuation in 0.1% of patients. Urinary tract infections were reported in 2.9% of patients receiving Mirader 50 mg, with none leading to discontinuation. Serious adverse reactions included atrial fibrillation (0.2%).

Pregnancy & Lactation Limited data are available regarding the use of Mirabegron in pregnant women. Animal studies have shown reproductive toxicity. Mirabegron is not recommended during pregnancy or in women planning pregnancy. Mirabegron is excreted in the milk of rodents and is predicted to be present in human milk. No studies have been conducted to assess the impact of Mirabegron on human milk production or its effects on breastfed infants. Therefore, Mirabegron should not be administered during breastfeeding. Mirabegron had no treatment-related effects on fertility in animals, and its effect on human fertility has not been established.

Precautions & Warnings Renal impairment

Mirader has not been studied in patients with end-stage renal disease or those requiring hemodialysis and is not recommended for use in this patient population. Limited data are available in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on pharmacokinetic studies, a dose reduction to 25 mg is recommended in this population. Mirader is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concurrently receiving strong CYP3A inhibitors.

Hepatic impairment

Mirader has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and is not recommended for use in this patient population. Mirader is not recommended for use in patients with moderate hepatic impairment (Child-Pugh Class B) concurrently receiving strong CYP3A inhibitors.

Hypertension

Mirader can elevate blood pressure. Blood pressure should be monitored at baseline and periodically during treatment, especially in hypertensive patients. Limited data are available in patients with stage 2 hypertension (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg).

Patients with congenital or acquired QT prolongation: Caution is advised when administering Mirader in patients with congenital or acquired QT prolongation.

Patients with bladder outlet obstruction and those taking antimuscarinic medications for OAB: Mirader should be administered with caution to patients with clinically significant bladder outlet obstruction and those taking antimuscarinic medications for OAB.

Overdose Effects

Mirader has been administered to healthy volunteers at single doses up to 400 mg