MIRABEGRON ASTELLAS

Posology Paediatric patients 3 to less than 18 years of age with NDO may be administered Mirabegron Astellas granules for prolonged-release oral suspension or Mirabegron Astellas prolonged-release tablets based on the body weight of the patient.

The recommended dose of Mirabegron Astellas granules for prolonged-release oral suspension is determined based on patient weight and should be administered once daily with food. Treatment should be initiated at the recommended starting dose.

Thereafter, the dose may be increased to the lowest effective dose. The maximum dose should not be exceeded. Patients who reach 35 kg or more while on treatment may be switched from oral suspension to tablet formulation if they can swallow tablets.

Patients administered 6 ml oral suspension dose may be switched to 25 mg tablet dose and patients administered 10 ml oral suspension dose may be switched to 50 mg tablet dose. During long-term therapy, patients should be periodically evaluated for treatment continuation and for potential dose adjustment, at least annually or more frequently if indicated.

The following table provides the doses for oral suspension by body weight range.

Table 1:

Daily oral suspension dosing recommendations for paediatric NDO patients aged 3 to less than 18 years according to patient body weight Body weight range (kg) Starting dose (ml) Maximum dose (ml) 11 to < 22 3 6 22 to < 35 4 8 ≥ 35 6 10 Missed dose Patients should be instructed to take any missed doses, unless more than 12 hours have passed since the missed dose.

If more than 12 hours have passed, the missed dose can be skipped, and the next dose should be taken at the usual time. 2). 2).

Table 2:

Daily oral suspension dosing recommendations for paediatric NDO patients aged 3 to less than 18 years with renal or hepatic impairment according to patient body weight Parameter Classification Body weight range (kg) Starting dose (ml) Maximum dose (ml) 11 to < 22 3 6 22 to < 35 4 8Mild/Moderate* ≥ 35 6 10 11 to < 22 3 3 22 to < 35 4 4Severe** ≥ 35 6 6 Renal impairment(1) ESRD Not recommended 11 to < 22 3 6 22 to < 35 4 8Mild* ≥ 35 6 10 11 to < 22 3 3 22 to < 35 4 4Moderate** ≥ 35 6 6 Hepatic impairment(2) Severe Not recommended 1.

73 m2. No dose adjustment is necessary for patients with mild to moderate renal impairment. 2.

Mild:

Child-Pugh Class A; Moderate: Child-Pugh Class B; Severe: Child-Pugh Class C. * In patients with mild to moderate renal impairment or mild hepatic impairment concomitantly receiving strong CYP3A inhibitors, the recommended dose is no more than the starting dose.

** Not recommended for use in patients with severe renal impairment or moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors. Gender No dose adjustment is necessary according to gender. Paediatric population Overactive bladder The safety and efficacy of mirabegron in children below 18 years of age with OAB have not been established.

1 but no recommendation on a posology can be made. Neurogenic detrusor overactivity The safety and efficacy of mirabegron in children below 3 years of age have not yet been established. Method of administration Mirabegron Astellas granules for prolonged-release oral suspension is intended for oral use and should be taken once daily with food.

The granules should be reconstituted with 100 ml water prior to administration. If a measuring cup is provided, it should be used to measure the water volume to use for reconstitution. 6. After reconstitution, the oral suspension is pale brownish yellow suspension.

The oral syringe and adaptor provided with Mirabegron Astellas granules for prolonged-release oral suspension should be used to measure and administer the correct dose.

Summary of the safety profile The safety of mirabegron tablets was evaluated in 8 433 adult patients with OAB, of which 5 648 received at least one dose of mirabegron in the phase 2/3 clinical program, and 622 patients received mirabegron for at least 1 year (365 days).

In the three 12-week phase 3 double-blind, placebo-controlled studies, 88% of the patients completed treatment with this medicinal product, and 4% of the patients discontinued due to adverse events. Most adverse reactions were mild to moderate in severity.

The most common adverse reactions reported for adult patients treated with mirabegron 50 mg during the three 12-week phase 3 double-blind, placebo-controlled studies are tachycardia and urinary tract infections. 2% in patients receiving mirabegron 50 mg.

1% patients receiving mirabegron 50 mg. 9% in patients receiving mirabegron 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving mirabegron 50 mg. 2%). Adverse reactions observed during the 1-year (long term) active controlled (muscarinic antagonist) study were similar in type and severity to those observed in the three 12-week phase 3 double-blind, placebo-controlled studies.

Tabulated list of adverse reactions The table below reflects the adverse reactions observed with mirabegron in adults with OAB in the three 12-week phase 3 double-blind, placebo-controlled studies. The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000) and not known (cannot be established from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. MedDRA System organ class Common Uncommon Rare Very rare Not known (cannot be estimated from the available data) Infections and infestations Urinary tract infection Vaginal infection Cystitis Psychiatric disorders Insomnia* Confusion al state* Nervous system disorders Headache* Dizziness* Eye disorders Eyelid oedema Cardiac disorders Tachycardi a Palpitation Atrial fibrillation Vascular disorders Hypertensi ve crisis* Gastrointestin al disorders Nausea* Constipatio n* Diarrhoea* Dyspepsia Gastritis Lip oedema Hepatobiliary disorders GGT increased AST increased ALT increased Skin and subcutaneous tissue disorders Urticaria Rash Rash macular Rash papular Pruritus Leukocytoclas tic vasculitis Purpura Angioedema* Musculoskele tal and connective tissue disorders Joint swelling Renal and urinary disorders Urinary retention* Reproductive system and breast disorders Vulvovaginal pruritus Investigations Blood pressure increased *observed during post-marketing experience Paediatric population The safety of mirabegron oral suspension and tablets was evaluated in 86 paediatric patients aged 3 to less than 18 years with neurogenic detrusor overactivity in a 52- week, open-label, baseline-controlled, multicentre, dose titration study.

The most commonly reported adverse reactions observed in the paediatric population were urinary tract infection, constipation, and nausea. In the paediatric patients with NDO, no severe adverse reactions were reported. The safety of mirabegron tablets and oral suspension was evaluated in 26 paediatric patients aged 5 to less than 18 years of age with overactive bladder in a 12-week, double-blind, randomised, multicentre, parallel group, placebo-controlled sequential dose titration study.

The most commonly reported adverse reactions observed in the paediatric population were nasopharyngitis, fatigue and mood swing. Overall, the safety profile in children and adolescents is similar to that observed in adults. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

73 m2) or patients requiring haemodialysis and, therefore, it is not recommended for use in this patient population. 2) a dose no more than the starting dose is recommended in this population. 5). Hepatic impairment Mirabegron 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.

5). Hypertension Mirabegron can increase blood pressure in paediatric patients. Blood pressure increases may be larger in children (3 to less than 12 years of age) than in adolescents (12 to less than 18 years of age). Blood pressure should be measured at baseline and periodically during treatment with mirabegron.

1). However, since patients with a known history of QT prolongation or patients who are taking medicinal products known to prolong the QT interval were not included in these studies, the effects of mirabegron in these patients is unknown.

Caution should be exercised when administering mirabegron in these patients. Patients with bladder outlet obstruction and patients taking antimuscarinics medicinal products for overactive bladder (OAB) Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medicinal products for the treatment of OAB has been reported in post-marketing experience in patients taking mirabegron.

A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients treated with mirabegron; however, mirabegron should be administered with caution to patients with clinically significant BOO.

Mirabegron should also be administered with caution to patients taking antimuscarinic medicinal products for the treatment of OAB. Excipients Mirabegron Astellas granules for prolonged-release oral suspension contains ethyl parahydroxybenzoate (E214) and methyl parahydroxybenzoate (E218).

This may cause allergic reactions (possibly delayed). This medicinal product contains less than 1 mmol sodium (23 mg) per 10 ml of oral suspension, that is to say essentially ‘sodium-free’.

1. - Severe uncontrolled hypertension defined as systolic blood pressure ≥ 180 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg.