mirabegron: prescribing information – dosing, contraindications, interactions, side effects

Overactive bladder in adults

Betmiga 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

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

Betmiga granules for prolonged-release oral suspension is indicated for treatment of neurogenic detrusor overactivity (NDO) in paediatric patients aged 3 to less than 18 years.

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 Betmiga prolonged-release tablets or Betmiga 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 Betmiga 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
Betmiga 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* Severe** ESRD Not recommended Hepatic impairment(2) Mild* Moderate** 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*
Severe**
ESRD
Not recommended
Hepatic impairment(2)
Mild*
Moderate**
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.

Posology

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

The recommended dose of Betmiga 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 22 to < 35 ≥ 35

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
Betmiga granules for prolonged-release oral suspension 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 paediatric NDO patients aged 3 to less than 18 years with renal or hepatic impairment based on body weight (see sections 4.4 and 5.2).

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) Renal impairment(1) Mild/Moderate* 11 to < 22 22 to < 35 ≥ 35 Severe** 11 to < 22 22 to < 35 ≥ 35 ESRD Not recommended Hepatic impairment(2) Mild* 11 to < 22 22 to < 35 ≥ 35 Moderate** 11 to < 22 22 to < 35 ≥ 35 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

Mirabegron 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. Instructions on reconstitution of the medicinal product before administration are provided in section 6.6. After reconstitution, the oral suspension is pale brownish yellow suspension.

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

• 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.

Summary of the safety profile

The safety of Betmiga 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 Betmiga 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 Betmiga 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 Betmiga 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Betmiga 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Betmiga 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Betmiga 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 national reporting system listed in Appendix V.

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. 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 national reporting system listed in Appendix V.

Renal impairment

Betmiga 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

Betmiga 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

Betmiga, 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 Betmiga; however, Betmiga should be administered with caution to patients with clinically significant BOO. Betmiga should also be administered with caution to patients taking antimuscarinic medicinal products for the treatment of OAB.

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 no more than the starting dose 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

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 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 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’.

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 Betmiga 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). Betmiga 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 Betmiga 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.

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 no more than the starting dose (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.

Women of childbearing potential

Betmiga 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). Betmiga 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.

Betmiga 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.

Women of childbearing potential

Betmiga granules for prolonged-release oral suspension 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). Betmiga granules for prolonged-release oral suspension 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.

Betmiga granules for prolonged-release oral suspension 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.

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

Betmiga granules for prolonged-release oral suspension has no or negligible influence on the ability to drive and use machines.

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.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Urologicals, drugs for urinary frequency and incontinence, ATC code:
G04BD12.
Mechanism of action

Mirabegron is a potent and selective beta 3-adrenoceptor agonist. Mirabegron showed relaxation of bladder smooth muscle in rat and human isolated tissue, increased cyclic adenosine monophosphate (cAMP) concentrations in rat bladder tissue and showed a bladder relaxant effect in rat urinary bladder function models. Mirabegron increased mean voided volume per micturition and decreased the frequency of non-voiding contractions, without affecting voiding pressure, or residual urine in rat models of bladder overactivity. In a monkey model, mirabegron showed decreased voiding frequency.
These results indicate that mirabegron enhances urine storage function by stimulating beta 3-adrenoceptors in the bladder.

During the urine storage phase, when urine accumulates in the bladder, sympathetic nerve stimulation predominates. Noradrenaline is released from nerve terminals, leading predominantly to beta adrenoceptor activation in the bladder musculature, and hence bladder smooth muscle relaxation.
During the urine voiding phase, the bladder is predominantly under parasympathetic nervous system control. Acetylcholine, released from pelvic nerve terminals, stimulates cholinergic M2 and M3 receptors, inducing bladder contraction. The activation of the M2 pathway also inhibits beta 3-adrenoceptor induced increases in cAMP. Therefore, beta 3-adrenoceptor stimulation should not interfere with the voiding process. This was confirmed in rats with partial urethral obstruction, where mirabegron decreased the frequency of non-voiding contractions without affecting the voided volume per micturition, voiding pressure, or residual urine volume.

Pharmacodynamic effects

Urodynamics
Betmiga at doses of 50 mg and 100 mg once daily for 12 weeks in men with lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO) showed no effect on cystometry parameters and was safe and well tolerated. The effects of mirabegron on maximum flow rate and detrusor pressure at maximum flow rate were assessed in this urodynamic study consisting of 200 male patients with LUTS and BOO. Administration of mirabegron at doses of 50 mg and 100 mg once daily for 12 weeks did not adversely affect the maximum flow rate or detrusor pressure at maximum flow rate.
In this study in male patients with LUTS/BOO, the adjusted mean (SE) change from baseline to end of treatment in post void residual volume (ml) was 0.55 (10.702), 17.89 (10.190), 30.77 (10.598) for the placebo, mirabegron 50 mg and mirabegron 100 mg treatment groups.

Effect on QT interval
Betmiga at doses of 50 mg or 100 mg had no effect on the QT interval individually corrected for heart rate (QTcI interval) when evaluated either by sex or by the overall group.

Pharmacotherapeutic group: Urologicals, drugs for urinary frequency and incontinence, ATC code:
G04BD12.
Mechanism of action

Mirabegron is a potent and selective beta 3-adrenoceptor agonist. Mirabegron showed relaxation of bladder smooth muscle in rat and human isolated tissue, increased cyclic adenosine monophosphate (cAMP) concentrations in rat bladder tissue and showed a bladder relaxant effect in rat urinary bladder function models. Mirabegron increased mean voided volume per micturition and decreased the frequency of non-voiding contractions, without affecting voiding pressure, or residual urine in rat models of bladder overactivity. In a monkey model, mirabegron showed decreased voiding frequency.
These results indicate that mirabegron enhances urine storage function by stimulating beta 3-adrenoceptors in the bladder.

During the urine storage phase, when urine accumulates in the bladder, sympathetic nerve stimulation predominates. Noradrenaline is released from nerve terminals, leading predominantly to beta adrenoceptor activation in the bladder musculature, and hence bladder smooth muscle relaxation. During the urine voiding phase, the bladder is predominantly under parasympathetic nervous system control.
Acetylcholine, released from pelvic nerve terminals, stimulates cholinergic M2 and M3 receptors, inducing bladder contraction. The activation of the M2 pathway also inhibits beta 3-adrenoceptor induced increases in cAMP. Therefore, beta 3-adrenoceptor stimulation should not interfere with the voiding process. This was confirmed in rats with partial urethral obstruction, where mirabegron decreased the frequency of non-voiding contractions without affecting the voided volume per micturition, voiding pressure, or residual urine volume.

Pharmacodynamic effects

Urodynamics
Mirabegron at doses of 50 mg and 100 mg once daily for 12 weeks in men with lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO) showed no effect on cystometry parameters and was safe and well tolerated. The effects of mirabegron on maximum flow rate and detrusor pressure at maximum flow rate were assessed in this urodynamic study consisting of 200 male patients with LUTS and BOO. Administration of mirabegron at doses of 50 mg and 100 mg once daily for 12 weeks did not adversely affect the maximum flow rate or detrusor pressure at maximum flow rate.
In this study in male patients with LUTS/BOO, the adjusted mean (SE) change from baseline to end of treatment in post void residual volume (ml) was 0.55 (10.702), 17.89 (10.190), 30.77 (10.598) for the placebo, mirabegron 50 mg and mirabegron 100 mg treatment groups.

Effect on QT interval
Mirabegron at doses of 50 mg or 100 mg had no effect on the QT interval individually corrected for heart rate (QTcI interval) when evaluated either by sex or by the overall group.

Absorption

Adults

After oral administration of mirabegron in healthy volunteers mirabegron is absorbed to reach peak plasma concentrations (Cmax) between 3 and 4 hours. The absolute bioavailability increased from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increased more than dose proportionally over the dose range. In the overall adult population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 mg to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady-state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady-state is approximately double that seen after a single dose.

Paediatric population

The median Tmax of mirabegron following oral administration of a single dose of mirabegron tablets or oral suspension in patients under fed state was 4-5 hours. Population pharmacokinetic analysis predicted that the median Tmax of mirabegron tablets or oral suspension at steady-state was 3-4 hours.

The bioavailability of the oral suspension formulation is lower than that of the tablet. The ratio of the population mean exposure (AUCtau) of the oral suspension to the tablet is approximately 45%.

Effect of food on absorption

Adults

Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies, mirabegron was administered with or without food and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose.

Paediatric population

Absorption

Tablets

Adults

After oral administration of mirabegron in healthy adult volunteers mirabegron is absorbed to reach peak plasma concentrations (Cmax) between 3 and 4 hours. The absolute bioavailability increased from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increased more than dose proportionally over the dose range. In the overall adult population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 mg to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady-state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady-state is approximately double that seen after a single dose.

Tablets or granules for oral suspension

Paediatric population

The median Tmax of mirabegron following oral administration of a single dose of mirabegron oral suspension or tablets in patients under fed state was 4-5 hours. Population pharmacokinetic analysis predicted that the median Tmax of mirabegron oral suspension or tablets at steady-state was 3-4 hours.

The bioavailability of the oral suspension formulation is lower than that of the tablet. The ratio of the population mean exposure (AUCtau) of the oral suspension to the tablet is approximately 45%.

Effect of food on absorption

Tablets

Adults

Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. In the phase 3 studies in adults, mirabegron was administered with or without food and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose.

Tablets or granules for oral suspension

Paediatric population