Mirasol XR Tablet (Extended Release)

Mirasol XR tablet is indicated for the symptomatic treatment of urgency, increased micturition frequency and urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome.

Mirabegron is the first beta-3 adrenoceptor agonist. Mirabegron exerts its effect via a dual mechanism, both directly acts on the bladder smooth muscle and also via the sensory nervous system, it increases the levels of cyclic adenosine monophosphate (cyclic AMP) and leads to relaxation of the detrusor smooth muscle during storage phase of urinary bladder fill-void cycle by activation of beta-3 adrenoceptor which increase bladder capacity.

Adults including elderly: The recommended starting dose is Mirabegron 25 mg tablet once daily with or without food. Based on individual patient efficacy and tolerability the dose may be increased to Mirabegron 50 mg tablet once daily.

Renal or hepatic impairment:

• 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 dose of Mirabegron should not exceed 25 mg tablet once daily.
• Mirabegron has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) or severe hepatic impairment (Child Pugh Class C) and it is therefore not recommended for use in these patient populations.

Gender: No dose adjustment is necessary according to gender.

Paediatric population: The safety and efficacy of Mirabegron in children below 18 years of age have not yet been established.

Mirabegron tablet is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed.

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

Effect of enzyme inducers: Substances that are inducers of CYP3A or P-gp decrease the plasma concentrations of Mirasol XR. No dose adjustment is needed for Mirasol XR when administered with therapeutic doses of rifampicin or other CYP3A or P-gp inducers.

Effect of Mirasol XR on CYP2D6 substrates: In healthy volunteers, the inhibitory potency of Mirasol XR towards CYP2D6 is moderate and the CYP2D6 activity recovers within 15 days after discontinuation of Mirasol XR. Multiple once daily dosing of Mirasol XR IR resulted in a 90% increase in Cmax and a 229% increase in AUC of a single dose of metoprolol. Multiple once daily dosing of Mirasol XR resulted in a 79% increase in Cmax and a 241% increase in AUC of a single dose of desipramine. Caution is advised if Mirasol XR is co-administered with medicinal products with a narrow therapeutic index and significantly metabolised by CYP2D6, such as thioridazine, Type 1 C antiarrhythmics (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if Mirasol XR is co-administered with CYP2D6 substrates that are individually dose titrated.

Effect of Mirasol XR on transporters: Mirasol XR is a weak inhibitor of P-gp. Mirasol XR increased Cmax and AUC by 29% and 27%, respectively, of the P-gp substrate digoxin in healthy volunteers. For patients who are initiating a combination of Mirasol XR and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.

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

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

The most common side effects reported for patients treated with Mirasol XR 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients receiving Mirasol XR 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Mirasol XR 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Mirasol XR 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Mirasol XR 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

There are limited amount of data from the use of Mirabegron in pregnant women. Studies in animals have shown reproductive toxicity. Mirabegron is not recommended during pregnancy and in women is planning to be pregnant. Mirabegron is excreted in the milk of rodents and therefore is predicted to be present in human milk. No studies have been conducted to assess the impact of Mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Mirabegron should not be administered during breast-feeding. There were no treatment-related effects of Mirabegron on fertility in animals. The effect of Mirabegron on human fertility has not been established.

Renal impairment: Mirasol XR has not been studied in patients with end stage renal disease (GFR <15 mL/min/1.73 m2 or patients requiring haemodialysis) and therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a pharmacokinetic study a dose reduction to 25 mg is recommended in this population. Mirasol XR is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors.

Hepatic impairment: Mirasol XR has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in this patient population. Mirasol XR is not recommended for use in patients with moderate hepatic impairment (Child-Pugh Class B) concomitantly receiving strong CYP3A inhibitors.

Hypertension: Mirasol XR can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with Mirasol XR, especially in hypertensive patients. Data are limited 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 should be exercised when administering Mirasol XR in patients with congenital or acquired QT prolongation.

Patients with bladder outlet obstruction and patients taking antimuscarinics medications for OAB: A controlled clinical safety study in patients with bladder outlet obstruction (BOO) did not demonstrate increased urinary retention in patients treated with Mirasol XR; however, Mirasol XR should be administered with caution to patients with clinically significant bladder outlet obstruction. Mirasol XR should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.

Mirasol XR has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations and increased pulse rate exceeding 100 beats per minute (bpm). Multiple doses of Mirasol XR up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdose should be symptomatic and supportive. In the event of overdose, pulse rate, blood pressure, and ECG monitoring is recommended.

BPH/ Urinary retention/ Urinary incontinence

Store in a cool and dry place, protected from light.