4.1. Therapeutic indications

Overactive bladder in adults

Mirabegron Astellas prolonged-release tablets are indicated for symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome.

Neurogenic detrusor overactivity in the paediatric population

Mirabegron Astellas prolonged-release tablets are indicated for treatment of neurogenic detrusor overactivity (NDO) in paediatric patients aged 3 to less than 18 years.

4.2. Posology and method of administration

Posology

Overactive bladder

Adults (including elderly patients)

The recommended dose is 50 mg once daily.

Neurogenic detrusor overactivity in the paediatric population

Paediatric patients 3 to less than 18 years of age with NDO may be administered Mirabegron Astellas prolonged-release tablets or Mirabegron Astellas granules for prolonged-release oral suspension based on the body weight of the patient. The prolonged-release tablets may be administered to patients weighing 35 kg or more; the granules for prolonged-release oral suspension are recommended for patients below 35 kg. 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.

The recommended starting dose of Mirabegron Astellas prolonged-release tablets is 25 mg once daily with food. If needed, the dose may be increased to a maximum dose of 50 mg once daily with food after 4 to 8 weeks. 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.

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.

Special populations

Renal and hepatic impairment

Mirabegron Astellas has not been studied in patients with end stage renal disease (ESRD) (estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m2), patients requiring haemodialysis, or patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in these patient populations (see sections 4.4 and 5.2).

The following table provides the daily dosing recommendations for adult OAB patients with renal or hepatic impairment (see sections 4.4, 4.5 and 5.2).

Table 1: Daily dosing recommendations for adult OAB patients with renal or hepatic impairment

Parameter

Classification

Dose

(mg)

Renal impairment(1)

Mild/Moderate*

50

Severe**

25

ESRD

Not recommended

Hepatic impairment(2)

Mild*

50

Moderate**

25

Severe

Not recommended

1. Mild/Moderate: eGFR 30 to 89 ml/min/1.73 m2; Severe: eGFR 15 to 29 ml/min/1.73 m2; ESRD: eGFR < 15 ml/min/1.73 m2.

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 25 mg.

** Not recommended for use in patients with severe renal impairment or moderate hepatic impairment concomitantly receiving strong CYP3A inhibitors.

The following table provides the daily dosing recommendations for paediatric NDO patients aged 3 to less than 18 years with renal or hepatic impairment weighing 35 kg or more (see sections 4.4 and 5.2).

Table 2: Daily dosing recommendations for paediatric NDO patients aged 3 to less than 18 years with renal or hepatic impairment weighing 35 kg or more

Parameter

Classification

Starting dose

(mg)

Maximum dose

(mg)

Renal impairment(1)

Mild/Moderate*

25

50

Severe**

25

25

ESRD

Not recommended

Hepatic impairment(2)

Mild*

25

50

Moderate**

25

25

Severe

Not recommended

1. Mild/Moderate: eGFR 30 to 89 ml/min/1.73 m2; Severe: eGFR 15 to 29 ml/min/1.73 m2; ESRD: eGFR < 15 ml/min/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. Currently available data are described in section 5.1 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

Overactive bladder in adults

The tablet is to be taken with liquids, swallowed whole, and is not to be chewed, divided, or crushed. It may be taken with or without food.

Neurogenic detrusor overactivity in the paediatric population

The tablet is to be taken with liquids, swallowed whole, and is not to be chewed, divided, or crushed. It should be taken with food.

4.3. Contraindications

- Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

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

4.4. Special warnings and precautions for use

Renal impairment

Mirabegron has not been studied in patients with ESRD (eGFR < 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 (eGFR 15 to 29 ml/min/1.73 m2); based on a pharmacokinetic study (see section 5.2) a dose of 25 mg once daily is recommended in this population. This medicinal product is not recommended for use in patients with severe renal impairment (eGFR 15 to 29 ml/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors (see section 4.5).

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. This medicinal product is not recommended for use in patients with moderate hepatic impairment (Child-Pugh B) concomitantly receiving strong CYP3A inhibitors (see section 4.5).

Hypertension

Overactive bladder in adults

Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with mirabegron, 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).

Neurogenic detrusor overactivity in the paediatric population

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.

Patients with congenital or acquired QT prolongation

Mirabegron, at therapeutic doses, has not demonstrated clinically relevant QT prolongation in clinical studies (see section 5.1). 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 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.

4.5. Interaction with other medicinal products and other forms of interaction

In vitro data

Mirabegron is transported and metabolised through multiple pathways. Mirabegron is a substrate for cytochrome P450 (CYP) 3A4, CYP2D6, butyrylcholinesterase, uridine diphospho‑glucuronosyltransferases (UGT), the efflux transporter P-glycoprotein (P‑gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Studies of mirabegron using human liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron inhibited P‑gp‑mediated drug transport at high concentrations.

In vivo data

Drug-drug interactions

The effect of co-administered medicinal products on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of other medicinal products was studied in single and multiple dose studies. Most drug‑drug interactions were studied using a dose of 100 mg mirabegron given as oral controlled absorption system (OCAS) tablets. Interaction studies of mirabegron with metoprolol and with metformin used mirabegron immediate‑release (IR) 160 mg.

Clinically relevant drug interactions between mirabegron and medicinal products that inhibit, induce or are a substrate for one of the CYP isozymes or transporters are not expected except for the inhibitory effect of mirabegron on the metabolism of CYP2D6 substrates.

Effect of enzyme inhibitors

Mirabegron 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 mirabegron is combined with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renal impairment (eGFR 30 to 89 ml/min/1.73 m2) or mild hepatic impairment (Child‑Pugh Class A) concomitantly receiving strong CYP3A inhibitors, such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended dose is 25 mg once daily (see section 4.2). Mirabegron is not recommended in patients with severe renal impairment (eGFR 15 to 29 ml/min/1.73 m2) or patients with moderate hepatic impairment (Child‑Pugh Class B) concomitantly receiving strong CYP3A inhibitors (see sections 4.2 and 4.4).

Effect of enzyme inducers

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

Effect of CYP2D6 polymorphism

CYP2D6 genetic polymorphism has minimal impact on the mean plasma exposure to mirabegron (see section 5.2). Interaction of mirabegron with a known CYP2D6 inhibitor is not expected and was not studied. No dose adjustment is needed for mirabegron when administered with CYP2D6 inhibitors or in patients who are CYP2D6 poor metabolisers.

Effect of mirabegron on CYP2D6 substrates

In healthy volunteers, the inhibitory potency of mirabegron towards CYP2D6 is moderate and the CYP2D6 activity recovers within 15 days after discontinuation of mirabegron. Multiple once daily dosing of mirabegron 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 mirabegron resulted in a 79% increase in Cmax and a 241% increase in AUC of a single dose of desipramine.

Caution is advised if mirabegron is co-administered with medicinal products with a narrow therapeutic index and significantly metabolised by CYP2D6, such as thioridazine, Type 1C antiarrhythmics (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated.

Effect of mirabegron on transporters

Mirabegron is a weak inhibitor of P-gp. Mirabegron 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 mirabegron 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. The potential for inhibition of P-gp by mirabegron should be considered when mirabegron is combined with sensitive P-gp substrates e.g., dabigatran.

Other interactions

No clinically relevant interactions have been observed when mirabegron 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.

Increases in mirabegron exposure due to drug-drug interactions may be associated with increases in pulse rate.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Mirabegron Astellas is not recommended in women of childbearing potential not using contraception.

Pregnancy

There are no or limited amount of data from the use of mirabegron in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Mirabegron Astellas is not recommended during pregnancy.

Breast-feeding

Mirabegron is excreted in the milk of rodents and therefore is predicted to be present in human milk (see section 5.3). 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 Astellas should not be used during breast‑feeding.

Fertility

There were no treatment-related effects of mirabegron on fertility in animals (see section 5.3). The effect of mirabegron on human fertility has not been established.

4.7. Effects on ability to drive and use machines

Mirabegron Astellas has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The safety of mirabegron 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. The frequency of tachycardia was 1.2% in patients receiving mirabegron 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving mirabegron 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving mirabegron 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving mirabegron 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

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*

Confusional state*

Nervous system disorders

Headache*

Dizziness*

Eye disorders

Eyelid oedema

Cardiac disorders

Tachycardia

Palpitation

Atrial fibrillation

Vascular disorders

Hypertensive crisis*

Gastrointestinal disorders

Nausea*

Constipation*

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

Leukocytoclastic vasculitis

Purpura

Angioedema*

Musculoskeletal 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 tablets and oral suspension 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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Mirabegron has been administered to healthy adult volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 beats per minute (bpm) (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy adult volunteers.

Treatment for overdose should be symptomatic and supportive. In the event of overdose, pulse rate, blood pressure, and ECG monitoring is recommended.