BETMIGA 50mg prolonged tablets medication leaflet

Betmiga 25 mg prolonged-release tablets

Betmiga 50 mg prolonged-release tablets

Betmiga 25 mg prolonged-release tablets:

Each tablet contains 25 mg of mirabegron.

Betmiga 50 mg prolonged-release tablets:

Each tablet contains 50 mg of mirabegron.

For the full list of excipients, see section 6.1.

Prolonged-release tablet.

Betmiga 25 mg tablets:

Oval, brown tablet, debossed with the company logo and “325” on the same side.

Betmiga 50 mg tablets:

Oval, yellow tablet, debossed with the company logo and “355” on the same side.

Overactive bladder in adults

Betmiga prolonged-release tablets are indicated for symptomatic treatment of urgency, increasedmicturition frequency and/or urgency incontinence as may occur in adult patients with overactivebladder (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.

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 Betmigaprolonged-release tablets or Betmiga granules for prolonged-release oral suspension based on the bodyweight of the patient. The prolonged-release tablets may be administered to patients weighing 35 kg ormore; 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 patientsadministered 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. Ifneeded, the dose may be increased to a maximum dose of 50 mg once daily with food after 4 to8 weeks. During long-term therapy, patients should be periodically evaluated for treatmentcontinuation and for potential dose adjustment, at least annually or more frequently if indicated.

Patients should be instructed to take any missed doses, unless more than 12 hours have passed sincethe missed dose. If more than 12 hours have passed, the missed dose can be skipped, and the next doseshould be taken at the usual time.

Betmiga has not been studied in patients with end stage renal disease (ESRD) (estimated glomerularfiltration rate (eGFR) < 15 ml/min/1.73 m2), patients requiring haemodialysis, or patients with severehepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in these patientpopulations (see sections 4.4 and 5.2).

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

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

Parameter Classification Dose(mg)

Mild/Moderate* 50

Renal impairment(1) Severe** 25

ESRD Not recommended

Mild* 50

Hepatic impairment(2) Moderate** 25

Severe Not recommended1. 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 concomitantlyreceiving 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 impairmentconcomitantly receiving strong CYP3A inhibitors.

The following table provides the daily dosing recommendations for paediatric NDO patients aged 3 toless 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 than18 years with renal or hepatic impairment weighing 35 kg or more

Parameter Classification Starting dose Maximum dose(mg) (mg)

Mild/Moderate* 25 50

Renal impairment(1) Severe** 25 25

ESRD Not recommended

Mild* 25 50

Hepatic impairment(2) Moderate** 25 25

Severe Not recommended1. 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 tomoderate 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 concomitantlyreceiving 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 impairmentconcomitantly receiving strong CYP3A inhibitors.

No dose adjustment is necessary according to gender.

Overactive bladder

The safety and efficacy of mirabegron in children below 18 years of age with OAB have not yet beenestablished. No data are available.

Neurogenic detrusor overactivity

The safety and efficacy of mirabegron in children below 3 years of age have not yet been established.

Overactive bladder in adults

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

- 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 diastolicblood pressure ≥ 110 mm Hg.

Betmiga has not been studied in patients with ESRD (eGFR < 15 ml/min/1.73 m2) or patients requiringhaemodialysis and, therefore, it is not recommended for use in this patient population. Data are limitedin patients with severe renal impairment (eGFR 15 to 29 ml/min/1.73 m2); based on a pharmacokineticstudy (see section 5.2) a dose of 25 mg once daily is recommended in this population. This medicinalproduct is not recommended for use in patients with severe renal impairment (eGFR15 to 29 ml/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors (see section 4.5).

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 notrecommended for use in patients with moderate hepatic impairment (Child-Pugh B) concomitantlyreceiving strong CYP3A inhibitors (see section 4.5).

Overactive bladder in adults

Mirabegron can increase blood pressure. Blood pressure should be measured at baseline andperiodically during treatment with mirabegron, especially in hypertensive patients.

Data are limited in patients with stage 2 hypertension (systolic blood pressure ≥ 160 mm Hg ordiastolic 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 largerin children (3 to less than 12 years of age) than in adolescents (12 to less than 18 years of age). Bloodpressure 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 clinicalstudies (see section 5.1). However, since patients with a known history of QT prolongation or patientswho are taking medicinal products known to prolong the QT interval were not included in thesestudies, the effects of mirabegron in these patients is unknown. Caution should be exercised whenadministering 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 takingantimuscarinic medicinal products for the treatment of OAB has been reported in post-marketingexperience in patients taking mirabegron. A controlled clinical safety study in patients with BOO didnot demonstrate increased urinary retention in patients treated with Betmiga; however, Betmiga shouldbe administered with caution to patients with clinically significant BOO. Betmiga should also beadministered with caution to patients taking antimuscarinic medicinal products for the treatment of

OAB.

In vitro data

Mirabegron is transported and metabolised through multiple pathways. Mirabegron is a substrate forcytochrome P450 (CYP) 3A4, CYP2D6, butyrylcholinesterase,uridine diphospho-glucuronosyltransferases (UGT), the efflux transporter P-glycoprotein (P-gp) andthe influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Studies of mirabegron usinghuman liver microsomes and recombinant human CYP enzymes showed that mirabegron is a moderateand time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron inhibited

P-gp-mediated drug transport at high concentrations.

In vivo data

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

Clinically relevant drug interactions between mirabegron and medicinal products that inhibit, induce orare a substrate for one of the CYP isozymes or transporters are not expected except for the inhibitoryeffect 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 iscombined with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renalimpairment (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 andclarithromycin, the recommended dose is 25 mg once daily (see section 4.2). Betmiga is notrecommended in patients with severe renal impairment (eGFR 15 to 29 ml/min/1.73 m2) or patientswith moderate hepatic impairment (Child-Pugh Class B) concomitantly receiving strong CYP3Ainhibitors (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. Nodose adjustment is needed for mirabegron when administered with therapeutic doses of rifampicin orother CYP3A or P-gp inducers.

Effect of CYP2D6 polymorphism

CYP2D6 genetic polymorphism has minimal impact on the mean plasma exposure to mirabegron (seesection 5.2). Interaction of mirabegron with a known CYP2D6 inhibitor is not expected and was notstudied. No dose adjustment is needed for mirabegron when administered with CYP2D6 inhibitors orin 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 dailydosing of mirabegron IR resulted in a 90% increase in Cmax and a 229% increase in AUC of a singledose of metoprolol. Multiple once daily dosing of mirabegron resulted in a 79% increase in Cmax and a241% increase in AUC of a single dose of desipramine.

Caution is advised if mirabegron is co-administered with medicinal products with a narrow therapeuticindex and significantly metabolised by CYP2D6, such as thioridazine, Type 1C antiarrhythmics (e.g.,flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is alsoadvised 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 acombination 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 obtainthe desired clinical effect. The potential for inhibition of P-gp by mirabegron should be consideredwhen Betmiga is combined with sensitive P-gp substrates e.g. dabigatran.

No clinically relevant interactions have been observed when mirabegron was co-administered withtherapeutic doses of solifenacin, tamsulosin, warfarin, metformin or a combined oral contraceptivemedicinal product containing ethinylestradiol and levonorgestrel. Dose-adjustment is notrecommended.

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

Interaction studies have only been performed in adults.

Betmiga is not recommended in women of childbearing potential not using contraception.

There are no or limited amount of data from the use of mirabegron in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3). Betmiga is not recommended duringpregnancy.

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 milkproduction in humans, its presence in human breast milk, or its effects on the breast-fed child.

Betmiga should not be used during breast-feeding.

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

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

The safety of Betmiga was evaluated in 8 433 adult patients with OAB, of which 5 648 received atleast one dose of mirabegron in the phase 2/3 clinical program, and 622 patients received Betmiga forat 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 discontinueddue 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 thethree 12-week phase 3 double blind, placebo-controlled studies are tachycardia and urinary tractinfections. The frequency of tachycardia was 1.2% in patients receiving Betmiga 50 mg. Tachycardialed to discontinuation in 0.1% patients receiving Betmiga 50 mg. The frequency of urinary tractinfections was 2.9% in patients receiving Betmiga 50 mg. Urinary tract infections led todiscontinuation in none of the patients receiving Betmiga 50 mg. Serious adverse reactions includedatrial 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.

The table below reflects the adverse reactions observed with mirabegron in adults with OAB in thethree 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) andnot known (cannot be established from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

MedDRA Common Uncommon Rare Very rare Not known

System organ (cannot beclass estimatedfrom theavailabledata)

Infections and Urinary tract Vaginal infectioninfestations infection Cystitis

Psychiatric Insomnia*disorders Confusionalstate*

Nervous system Headache*disorders Dizziness*

Eye disorders Eyelid oedema

Cardiac Tachycardia Palpitationdisorders Atrial fibrillation

Vascular Hypertensivedisorders crisis*

Gastrointestinal Nausea* Dyspepsia Lip oedemadisorders Constipation* Gastritis

Diarrhoea*

Hepatobiliary GGT increaseddisorders AST increased

ALT increased

Skin and Urticaria Leukocytoclasticsubcutaneous Rash vasculitistissue disorders Rash macular Purpura

Rash papular Angioedema*

Pruritus

Musculoskeletal Joint swellingand connectivetissue disorders

Renal and Urinaryurinary retention*disorders

Reproductive Vulvovaginalsystem and pruritusbreast disorders

Investigations Blood pressureincreased

*observed during post-marketing experience

The safety of mirabegron tablets and oral suspension was evaluated in 86 paediatric patients aged 3 toless than 18 years with NDO in a 52-week, open-label, baseline-controlled, multicentre, dose titrationstudy. The most commonly reported adverse reactions observed in the paediatric population wereurinary tract infection, constipation, and nausea.

In the paediatric patients with NDO, no severe adverse reactions were reported.

Overall, the safety profile in children and adolescents is similar to that observed in adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Mirabegron has been administered to healthy adult volunteers at single doses up to 400 mg. At thisdose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding100 beats per minute (bpm) (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for10 days showed increases in pulse rate and systolic blood pressure when administered to healthy adultvolunteers.

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

Pharmacotherapeutic group: Urologicals, drugs for urinary frequency and incontinence, ATC code:

G04BD12

Mirabegron is a potent and selective beta 3-adrenoceptor agonist. Mirabegron showed relaxation ofbladder 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 bladderfunction models. Mirabegron increased mean voided volume per micturition and decreased thefrequency of non-voiding contractions, without affecting voiding pressure, or residual urine in ratmodels of bladder overactivity. In a monkey model, mirabegron showed decreased voiding frequency.

These results indicate that mirabegron enhances urine storage function by stimulatingbeta 3-adrenoceptors in the bladder.

During the urine storage phase, when urine accumulates in the bladder, sympathetic nerve stimulationpredominates. Noradrenaline is released from nerve terminals, leading predominantly to betaadrenoceptor activation in the bladder musculature, and hence bladder smooth muscle relaxation.

During the urine voiding phase, the bladder is predominantly under parasympathetic nervous systemcontrol. Acetylcholine, released from pelvic nerve terminals, stimulates cholinergic M2 and M3receptors, inducing bladder contraction. The activation of the M2 pathway also inhibitsbeta 3-adrenoceptor induced increases in cAMP. Therefore, beta 3-adrenoceptor stimulation should notinterfere with the voiding process. This was confirmed in rats with partial urethral obstruction, wheremirabegron decreased the frequency of non-voiding contractions without affecting the voided volumeper micturition, voiding pressure, or residual urine volume.

Urodynamics

Betmiga at doses of 50 mg and 100 mg once daily for 12 weeks in men with lower urinary tractsymptoms (LUTS) and bladder outlet obstruction (BOO) showed no effect on cystometry parametersand was safe and well tolerated. The effects of mirabegron on maximum flow rate and detrusorpressure at maximum flow rate were assessed in this urodynamic study consisting of 200 male patientswith LUTS and BOO. Administration of mirabegron at doses of 50 mg and 100 mg once daily for12 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 oftreatment in post void residual volume (ml) was 0.55 (10.702), 17.89 (10.190), 30.77 (10.598) for theplacebo, mirabegron 50 mg and mirabegron 100 mg treatment groups.

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

A thorough QT (TQT) study (n=164 healthy male and n=153 healthy female volunteers with a meanage of 33 years) evaluated the effect of repeat oral dosing of mirabegron at the indicated dose (50 mgonce daily) and two supra-therapeutic doses (100 and 200 mg once daily) on the QTcI interval. Thesupra-therapeutic doses represent approximately 2.6- and 6.5-fold the exposure of the therapeutic dose,respectively. A single 400 mg dose of moxifloxacin was used as a positive control. Each dose level ofmirabegron and moxifloxacin was evaluated in separate treatment arms each including placebo-control(parallel cross-over design). For both males and females administered mirabegron at 50 mg and100 mg, the upper bound of the one-sided 95% confidence interval did not exceed 10 msec at any timepoint for the largest time-matched mean difference from placebo in the QTcI interval. In femalesadministered mirabegron at the 50 mg dose, the mean difference from placebo on QTcI interval at5 hours post dose was 3.67 msec (upper bound of the one-sided 95% CI 5.72 msec). In males, thedifference was 2.89 msec (upper bound of the one-sided 95% CI 4.90 msec). At a mirabegron dose of200 mg, the QTcI interval did not exceed 10 msec at any time point in males, while in females theupper bound of the one-sided 95% confidence interval did exceed 10 msec between 0.5-6 hours, witha maximum difference from placebo at 5 hours where the mean effect was 10.42 msec (upper bound ofthe one-sided 95% CI 13.44 msec). Results for QTcF and QTcIf were consistent with QTcI.

In this TQT study, mirabegron increased heart rate on ECG in a dose dependent manner across the50 mg to 200 mg dose range examined. The maximum mean difference from placebo in heart rateranged from 6.7 bpm with mirabegron 50 mg up to 17.3 bpm with mirabegron 200 mg in healthysubjects.

Effects on pulse rate and blood pressure in adult patients with OAB

In OAB patients (mean age of 59 years) across three 12-week phase 3 double blind, placebo-controlledstudies receiving Betmiga 50 mg once daily, an increase in mean difference from placebo ofapproximately 1 bpm for pulse rate and approximately 1 mm Hg or less in systolic bloodpressure/diastolic blood pressure (SBP/DBP) was observed. Changes in pulse rate and blood pressureare reversible upon discontinuation of treatment.

Effects on blood pressure in paediatric patients with NDO

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

Effect on intraocular pressure (IOP)

Mirabegron 100 mg once daily did not increase IOP in healthy adult subjects after 56 days oftreatment. In a phase 1 study assessing the effect of Betmiga on IOP using Goldmann applanationtonometry in 310 healthy subjects, a dose of mirabegron 100 mg was non-inferior to placebo for theprimary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; the upper bound of the two-sided 95% CI of the treatment difference betweenmirabegron 100 mg and placebo was 0.3 mm Hg.

Overactive bladder in adult patients

Efficacy of mirabegron was evaluated in three phase 3 randomised, double blind, placebo-controlled,12-week studies for the treatment of overactive bladder with symptoms of urgency and frequency withor without incontinence. Female (72%) and male (28%) patients with a mean age of 59 years (range18 - 95 years) were included. The study population consisted of approximately 48% antimuscarinictreatment naïve patients as well as approximately 52% patients previously treated with antimuscarinicmedicinal products. In one study, 495 patients received an active control (tolterodine prolonged releaseformulation).

The co-primary efficacy endpoints were (1) change from baseline to end of treatment in mean numberof incontinence episodes per 24 hours and (2) change from baseline to end of treatment in meannumber of micturitions per 24 hours based on a 3-day micturition diary. Mirabegron demonstratedstatistically significant larger improvements compared to placebo for both co-primary endpoints aswell as secondary endpoints (see Tables 3 and 4).

Table 3: Co-primary and selected secondary efficacy endpoints at end of treatment for pooledstudies in adults

Pooled studies

Parameter (046, 047, 074)

Placebo Mirabegron50 mg

Mean number of incontinence episodes per 24 hours (FAS-I) (Co-primary)n 878 862

Mean baseline 2.73 2.71

Mean change from baseline* -1.10 -1.49

Mean difference from placebo* (95% CI) -- -0.40 (-0.58, -0.21)p-value -- < 0.001‡

Mean number of micturitions per 24 hours (FAS) (Co-primary)n 1 328 1 324

Mean baseline 11.58 11.70

Mean change from baseline* -1.20 -1.75

Mean difference from placebo* (95% CI) -- -0.55 (-0.75, -0.36)p-value -- < 0.001‡

Mean volume voided (ml) per micturition (FAS) (Secondary)n 1 328 1 322

Mean baseline 159.2 159.0

Mean change from baseline* 9.4 21.4

Mean difference from placebo* (95% CI) -- 11.9 (8.3, 15.5)p-value -- < 0.001‡

Mean level of urgency (FAS) (Secondary)n 1 325 1 323

Mean baseline 2.39 2.42

Mean change from baseline* -0.15 -0.26

Mean difference from placebo* (95% CI) -- -0.11 (-0.16, -0.07)p-value -- < 0.001‡

Mean number of urgency incontinence episodes per 24 hours (FAS-I) (Secondary)n 858 834

Mean baseline 2.42 2.42

Mean change from baseline* -0.98 -1.38

Mean difference from placebo* (95% CI) -- -0.40 (-0.57, -0.23)p-value -- < 0.001‡

Mean number of episodes with urgency grades 3 or 4 per 24 hours (FAS) (Secondary)n 1 324 1 320

Mean baseline 5.61 5.80

Mean change from baseline* -1.29 -1.93

Mean difference from placebo* (95% CI) -- -0.64 (-0.89, -0.39)p-value -- < 0.001‡

Treatment satisfaction - visual analogue scale (FAS) (Secondary)n 1 195 1 189

Mean baseline 4.87 4.82

Mean change from baseline* 1.25 2.01

Mean difference from placebo* (95% CI) -- 0.76 (0.52, 1.01)p-value -- < 0.001†

Pooled studies consisted of studies 046 (Europe/Australia), 047 (North America [NA]) and 074(Europe/NA).

* Least squares mean adjusted for baseline, gender, and study.† Statistically significantly superior compared to placebo at the 0.05 level without multiplicityadjustment.‡ Statistically significantly superior compared to placebo at the 0.05 level with multiplicityadjustment.

FAS: Full analysis set, all randomised patients who took at least 1 dose of double blind study drugand who had a micturition measurement in the baseline diary and at least 1 post-baseline visit diarywith a micturition measurement.

FAS-I: Subset of FAS who also had at least 1 incontinence episode in the baseline diary.

CI: Confidence Interval

Table 4: Co-primary and selected secondary efficacy endpoints at end of treatment for studies046, 047 and 074 in adults

Study 046 Study 047 Study 074

Parameter

Placebo Mirabegron Tolterodine Placebo Mirabegron50 mg ER 4 mg 50 mg Placebo Mirabegron50 mg

Mean number of incontinence episodes per 24 hours (FAS-I) (Co-primary)n 291 293 300 325 312 262 257

Meanbaseline 2.67 2.83 2.63 3.03 2.77 2.43 2.51

Meanchangefrom -1.17 -1.57 -1.27 -1.13 -1.47 -0.96 -1.38baseline*

Meandifferencefrom -- -0.41 -0.10 -- -0.34 -- -0.42placebo*95%

Confidence -- (-0.72, -0.09) (-0.42, 0.21) -- (-0.66, -0.03) -- (-0.76, -0.08)

Intervalp-value -- 0.003‡ 0.11 -- 0.026‡ -- 0.001‡

Mean number of micturitions per 24 hours (FAS) (Co-primary)n 480 473 475 433 425 415 426

Meanbaseline 11.71 11.65 11.55 11.51 11.80 11.48 11.66

Meanchangefrom -1.34 -1.93 -1.59 -1.05 -1.66 -1.18 -1.60baseline*

Meandifferencefrom -- -0.60 -0.25 -- -0.61 -- -0.42placebo*95%

Confidence -- (-0.90, -0.29) (-0.55, 0.06) -- (-0.98, -0.24) -- (-0.76, -0.08)

Intervalp-value -- < 0.001‡ 0.11 -- 0.001‡ -- 0.015‡

Study 046 Study 047 Study 074

Parameter

Placebo Mirabegron Tolterodine Mirabegron Mirabegron50 mg ER 4 mg Placebo 50 mg Placebo 50 mg

Mean volume voided (ml) per micturition (FAS) (Secondary)n 480 472 475 433 424 415 426

Meanbaseline 156.7 161.1 158.6 157.5 156.3 164.0 159.3

Meanchangefrom 12.3 24.2 25.0 7.0 18.2 8.3 20.7baseline*

Meandifferencefrom -- 11.9 12.6 -- 11.1 -- 12.4placebo*95%

Confidence -- (6.3, 17.4) (7.1, 18.2) -- (4.4, 17.9) -- (6.3, 18.6)

Intervalp-value -- < 0.001‡ < 0.001† -- 0.001‡ -- < 0.001‡

Mean level of urgency (FAS) (Secondary)n 480 472 473 432 425 413 426

Meanbaseline 2.37 2.40 2.41 2.45 2.45 2.36 2.41

Meanchangefrom -0.22 -0.31 -0.29 -0.08 -0.19 -0.15 -0.29baseline*

Meandifferencefrom -- -0.09 -0.07 -- -0.11 -- -0.14placebo*95%

Confidence -- (-0.17, -0.02) (-0.15, 0.01) -- (-0.18, -0.04) -- (-0.22, -0.06)

Intervalp-value -- 0.018† 0.085 -- 0.004† -- < 0.001§

Mean number of urgency incontinence episodes per 24 hours (FAS-I) (Secondary)n 283 286 289 319 297 256 251

Meanbaseline 2.43 2.52 2.37 2.56 2.42 2.24 2.33

Meanchangefrom -1.11 -1.46 -1.18 -0.89 -1.32 -0.95 -1.33baseline*

Meandifferencefrom -- -0.35 -0.07 -- -0.43 -- -0.39placebo*95%

Confidence -- (-0.65, -0.05) (-0.38, 0.23) -- (-0.72, -0.15) -- (-0.69, -0.08)

Intervalp-value -- 0.003† 0.26 -- 0.005† -- 0.002§

Study 046 Study 047 Study 074

Parameter

Placebo Mirabegron Tolterodine Placebo Mirabegron Mirabegron50 mg ER 4 mg 50 mg Placebo 50 mg

Mean number of episodes with urgency grades 3 or 4 per 24 hours (FAS) (Secondary)n 479 470 472 432 424 413 426

Meanbaseline 5.78 5.72 5.79 5.61 5.90 5.42 5.80

Meanchangefrom -1.65 -2.25 -2.07 -0.82 -1.57 -1.35 -1.94baseline*

Meandifferencefrom -- -0.60 -0.42 -- -0.75 -- -0.59placebo*95%

Confidence -- (-1.02, -0.18) (-0.84, -0.00) -- (-1.20, -0.30) -- (-1.01, -0.16)

Intervalp-value -- 0.005† 0.050† -- 0.001† -- 0.007§

Treatment satisfaction - visual analogue scale (FAS) (Secondary)n 428 414 425 390 387 377 388

Meanbaseline 4.11 3.95 3.87 5.5 5.4 5.13 5.13

Meanchangefrom 1.89 2.55 2.44 0.7 1.5 1.05 1.88baseline*

Meandifferencefrom -- 0.66 0.55 -- 0.8 -- 0.83placebo*95%

Confidence -- (0.25, 1.07) (0.14, 0.95) -- (0.4, 1.3) -- (0.41, 1.25)

Intervalp-value -- 0.001† 0.008† -- < 0.001† -- < 0.001†

* Least squares mean adjusted for baseline, gender and geographical region.† Statistically significantly superior compared with placebo at the 0.05 level without multiplicityadjustment.‡ Statistically significantly superior compared with placebo at the 0.05 level with multiplicityadjustment.§ Not statistically significantly superior compared to placebo at the 0.05 level with multiplicityadjustment.

FAS: Full analysis set, all randomised patients who took at least 1 dose of double blind study drugand who had a micturition measurement in the baseline diary and at least 1 post-baseline visit diarywith a micturition measurement.

FAS-I: Subset of FAS who also had at least 1 incontinence episode in the baseline diary.

Betmiga 50 mg once daily was effective at the first measured time point of week 4, and efficacy wasmaintained throughout the 12-week treatment period. A randomised, active controlled, long term studydemonstrated that efficacy was maintained throughout a 1-year treatment period.

Subjective improvement in health-related quality of life measurements

In the three 12-week phase 3 double blind, placebo-controlled studies, treatment of the symptoms of

OAB with mirabegron once daily resulted in a statistically significant improvement over placebo onthe following health-related quality of life measures: treatment satisfaction and symptom bother.

Efficacy in patients with or without prior OAB antimuscarinic therapy

Efficacy was demonstrated in patients with and without prior OAB antimuscarinic therapy. In addition,mirabegron showed efficacy in patients who previously discontinued OAB antimuscarinic therapy dueto insufficient effect (see Table 5).

Table 5: Co-primary efficacy endpoints for adult patients with prior OAB antimuscarinictherapy

Pooled studies

Parameter (046, 047, 074) Study 046

Placebo Mirabegron Placebo Mirabegron Tolterodine50 mg 50 mg ER 4 mg

Patients with prior OAB antimuscarinic therapy

Mean number of incontinence episodes per 24 hours (FAS-I)n 518 506 167 164 160

Mean baseline 2.93 2.98 2.97 3.31 2.86

Mean change from baseline* -0.92 -1.49 -1.00 -1.48 -1.10

Mean difference from placebo* -- -0.57 -- -0.48 -0.1095% Confidence Interval -- (-0.81, -0.33) -- (-0.90, -0.06) (-0.52, 0.32)

Mean number of micturitions per 24 hours (FAS)n 704 688 238 240 231

Mean baseline 11.53 11.78 11.90 11.85 11.76

Mean change from baseline* -0.93 -1.67 -1.06 -1.74 -1.26

Mean difference from placebo* -- -0.74 -- -0.68 -0.2095% Confidence Interval -- (-1.01, -0.47) -- (-1.12, -0.25) (-0.64, 0.23)

Patients with prior OAB antimuscarinic therapy who discontinued due to insufficient effect

Mean number of incontinence episodes per 24 hours (FAS-I)n 336 335 112 105 102

Mean baseline 3.03 2.94 3.15 3.50 2.63

Mean change from baseline* -0.86 -1.56 -0.87 -1.63 -0.93

Mean difference from placebo* -- -0.70 -- -0.76 -0.0695% Confidence Interval -- (-1.01, -0.38) -- (-1.32, -0.19) (-0.63, 0.50)

Mean number of micturitions per 24 hours (FAS)n 466 464 159 160 155

Mean baseline 11.60 11.67 11.89 11.49 11.99

Mean change from baseline* -0.86 -1.54 -1.03 -1.62 -1.11

Mean difference from placebo* -- -0.67 -- -0.59 -0.0895% Confidence Interval -- (-0.99, -0.36) -- (-1.15, -0.04) (-0.64, 0.47)

Pooled studies consisted of 046 (Europe/Australia), 047 (North America [NA]) and 074(Europe/NA).

* Least squares mean adjusted for baseline, gender, study, subgroup, and subgroup by treatmentinteraction for Pooled Studies and least squares mean adjusted for baseline, gender, geographicalregion, subgroup, and subgroup by treatment interaction for Study 046.

FAS: Full analysis set, all randomised patients who took at least 1 dose of double blind study drugand who had a micturition measurement in the baseline diary and at least 1 post-baseline visit diarywith a micturition measurement.

FAS-I: Subset of FAS who also had at least 1 incontinence episode in the baseline diary.

Neurogenic detrusor overactivity in paediatric patients

Efficacy of mirabegron tablets and oral suspension was evaluated in a 52-week, open-label, baseline-controlled, multicentre, dose titration study for the treatment of NDO in paediatric patients. Patientshad a diagnosis of NDO with involuntary detrusor contractions with detrusor pressure increase greaterthan 15 cm H2O and performed clean intermittent catheterisation (CIC). Patients ≥ 35 kg receivedtablets and patients < 35 kg (or ≥ 35 kg but unable to tolerate tablets) received oral suspension. For allpatients, mirabegron was administered orally once daily with food. The starting dose (PED25) was a25 mg tablet or between 3-6 ml of oral suspension (depending on patient weight). This dose wasup-titrated to PED50, a 50 mg tablet or between 6-11 ml of oral suspension (depending on bodyweight). The dose titration period was a maximum of 8 weeks followed by a dose maintenance periodof at least 52 weeks.

A total of 86 patients aged 3 to less than 18 years of age received mirabegron. Of these, 71 patientscompleted treatment through week 24 and 70 completed 52 weeks of treatment. A total of 68 patientshad valid urodynamic measurements for evaluation of efficacy. The study population included 39(45.3%) males and 47 (54.7%) females. The optimised maintenance dose within this study populationincluded 94% of patients at the maximum dose, and 6% of patients at the starting dose.

The most common (in greater than 10% of all patients) background medical conditions related to NDOin children and adolescents included in the study were congenital central nervous system anomaly(54.5% and 48.4%, respectively), meningomyelocele (27.3% and 19.4%, respectively), and spinabifida (10.9% and 12.9%, respectively). In adolescents, 12.9% had a spinal cord injury.

The primary efficacy endpoint was change from baseline in maximum cystometric capacity (MCC)after 24 weeks of mirabegron treatment. Improvements in MCC were observed in all patient groups(see Table 6).

Table 6: Primary efficacy endpoint in paediatric patients with NDO

Children Adolescents

Parameter aged 3 to < 12 years aged 12 to < 18 years(N=43)* (N=25)*

Mean (SD) Mean (SD)

Maximum cystometric capacity (ml)

Baseline 158.6 (94.5) 238.9 (99.1)

Week 24 230.7 (129.1) 352.1 (125.2)

Change from baseline 72.0 (87.0) 113.2 (82.9)95% Confidence Interval (45.2, 98.8) (78.9, 147.4)

* N is the number of patients who took at least one dose and provided valid values for MCC atbaseline and week 24.

The secondary efficacy endpoints were change from baseline in bladder compliance, number ofoveractive detrusor contractions, detrusor pressure at end of bladder-filling, bladder volume prior tofirst detrusor contraction, maximum catheterised urine volume per day, and number of leakageepisodes per day after 24 weeks of mirabegron treatment (see Table 7).

Table 7: Secondary efficacy endpoints in paediatric patients with NDO

Children Adolescents

Parameter aged 3 to < 12 years aged 12 to < 18 years(N=43)* (N=25)*

Mean (SD) Mean (SD)

Bladder compliance (ml/cm H2O)†

Baseline 14.5 (50.7) 11.0 (10.0)

Week 24 29.6 (52.8) 23.8 (15.3)

Change from baseline 14.6 (42.0) 13.5 (15.0)95% Confidence Interval (-0.3, 29.5) (6.7, 20.4)

Number of overactive detrusor contractions (> 15 cm H2O)†

Baseline 3.0 (3.8) 2.0 (2.9)

Week 24 1.0 (2.2) 1.4 (2.3)

Change from baseline -1.8 (4.1) -0.7 (3.8)95% Confidence Interval (-3.2, -0.4) (-2.4, 0.9)

Detrusor pressure (cm H2O) at end of bladder-filling†

Baseline 42.2 (26.2) 38.6 (17.9)

Week 24 25.6 (21.2) 27.8 (27.8)

Change from baseline -18.1 (19.9) -13.1 (19.9)95% Confidence Interval (-24.8, -11.3) (-22.0, -4.3)

Bladder volume prior to first detrusor contraction (> 15 cm H2O)†

Baseline 115.8 (87.0) 185.2 (121.2)

Week 24 207.9 (97.8) 298.7 (144.4)

Change from baseline 93.1 (88.1) 121.3 (159.8)95% Confidence Interval (64.1, 122.1) (53.8, 188.8)

Maximum catheterised urine volume per day (ml)†

Baseline 300.1 (105.7) 367.5 (119.0)

Week 24 345.9 (84.6) 449.9 (146.6)

Change from baseline 44.2 (98.3) 81.3 (117.7)95% Confidence Interval (13.2, 75.2) (30.4, 132.3)

Number of leakage episodes per day†

Baseline 3.2 (3.7) 1.8 (1.7)

Week 24 0.7 (1.2) 0.9 (1.2)

Change from baseline -2.0 (3.2) -1.0 (1.1)95% Confidence Interval (-3.2, -0.7) (-1.5, -0.5)

* N is the number of patients who took at least one dose and provided valid values for MCC atbaseline and week 24.

† Number of patients (children/adolescents) with data available for both baseline and week 24;

Bladder compliance: n=33/21; Number of overactive detrusor contractions: n=36/22; Detrusorpressure at end of bladder-filling: n=36/22; Bladder volume prior to first detrusor contraction:n=38/24; Maximum catheterised urine volume per day: n=41/23; Number of leakage episodes perday: n=26/21.

Patient- or clinician-reported questionnaire endpoints included acceptability, change from baseline inthe Pediatric Incontinence Questionnaire (PIN-Q), change from baseline in the Patient Global

Impression of Severity Scale (PGI-S), and Clinician Global Impression of Change (CGI-C) (see

Table 8).

Table 8: Patient- or clinician-reported questionnaire endpoints in paediatric patients with

NDO

Children Adolescents

Parameter aged 3 to < 12 years aged 12 to < 18 years(N=43)* (N=25)*

Mean (SD) Mean (SD)

Pediatric Incontinence Questionnaire (PIN-Q) score†

Baseline 30.8 (15.7) 29.4 (14.6)

Week 24 30.6 (15.2) 25.2 (15.5)

Change from baseline 2.0 (10.5) -4.9 (14.1)95% Confidence Interval (-2.4, 6.4) (-11.3, 1.5)

Total Patient Global Impression of Severity Scale (PGI-S) score†

Baseline 2.2 (0.8) 2.3 (0.9)

Week 24 2.6 (0.8) 3.0 (0.7)

Change from baseline 0.3 (1.2) 0.6 (1.0)95% Confidence Interval (-0.1, 0.8) (0.1, 1.0)

Total Clinician Global Impression of Change (CGI-C) at week 24, N (%)†

Very Much Improved 6 (14.6%) 10 (41.7%)

Much Improved 24 (58.5%) 7 (29.2%)

Minimally Improved 6 (14.6%) 5 (20.8%)

No Change 4 (9.8%) 1 (4.2%)

Minimally Worse 1 (2.4%) 1 (4.2%)

Much Worse 0 0

Very Much Worse 0 0

* N is the number of patients who took at least one dose and provided valid values for MCC atbaseline and week 24.

† Number of patients (children/adolescents) with data available for both baseline and week 24. PIN-Qscore: n=24/21, Total PGI-S score: n=25/22; Total CGI-C at week 24: n=41/24.

The European Medicines Agency has waived the obligation to submit the results of studies with

Betmiga in all subsets of the paediatric population in “Treatment of idiopathic overactive bladder” (seesection 4.2 for information on paediatric use).

After oral administration of mirabegron in healthy volunteers mirabegron is absorbed to reach peakplasma 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 doseproportionally over the dose range. In the overall adult population of males and females, a 2-foldincrease 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 mirabegronincreased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady-state concentrations areachieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasmaexposure of mirabegron at steady-state is approximately double that seen after a single dose.

The median Tmax of mirabegron following oral administration of a single dose of mirabegron tablets ororal suspension in patients under fed state was 4-5 hours. Population pharmacokinetic analysispredicted 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 thepopulation mean exposure (AUCtau) of the oral suspension to the tablet is approximately 45%.

Effect of food on absorption

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 anddemonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at therecommended dose.

The population pharmacokinetic model predicted that the patients receiving mirabegron in the fed statewould have 44.7% of steady-state AUCtau relative to an equal dose administered in the fasted state.

This value is consistent with the AUCinf results seen in the single-dose food effects studies formirabegron. In the phase 3 paediatric study, mirabegron was administered with food and demonstratedboth safety and efficacy. Dosing recommendations are based upon the exposures expected in the fedstate. Therefore, in paediatric patients, mirabegron should be taken with food at the recommendeddose.

Mirabegron is extensively distributed. The volume of distribution at steady-state (Vss) is approximately1 670 l. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderateaffinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. In vitroerythrocyte concentrations of 14C-mirabegron were about 2-fold higher than in plasma.

Mirabegron volume of distribution was relatively large and increased with increasing body weight inaccordance with allometric principles based on population pharmacokinetic analysis. Age, sex andpatient population had no impact on volume of distribution after accounting for potential differences inbody weight.

Mirabegron is metabolised via multiple pathways involving dealkylation, oxidation, (direct)glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following asingle dose of 14C-mirabegron. Two major metabolites were observed in adult human plasma; both arephase 2 glucuronides representing 16% and 11% of total exposure. These metabolites are notpharmacologically active.

Based on in vitro studies, mirabegron is unlikely to inhibit the metabolism of co-administeredmedicinal products metabolised by the following cytochrome P450 enzymes: CYP1A2, CYP2B6,

CYP2C8, CYP2C9, CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of theseenzymes at clinically relevant concentrations. Mirabegron did not induce CYP1A2 or CYP3A.

Mirabegron is predicted not to cause clinically relevant inhibition of OCT-mediated drug transport.

Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism ofmirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination.

In vitro and ex vivo studies have shown the involvement from butyrylcholinesterase, UGT and possiblyalcohol dehydrogenase (ADH) in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6.

CYP2D6 polymorphism

In healthy adult subjects who are genotypically poor metabolisers of CYP2D6 substrates (used as asurrogate for CYP2D6 inhibition), mean Cmax and AUCinf of a single 160 mg dose of a mirabegron IRformulation were 14% and 19% higher than in extensive metabolisers, indicating that CYP2D6 geneticpolymorphism has minimal impact on the mean plasma exposure to mirabegron. Interaction ofmirabegron with a known CYP2D6 inhibitor is not expected and was not studied. No dose adjustmentis needed for mirabegron when administered with CYP2D6 inhibitors or in adult patients who are

CYP2D6 poor metabolisers.

Total body clearance (CLtot) from plasma is approximately 57 l/h. The terminal elimination half-life(t1/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 l/h, which corresponds tonearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretionalong with glomerular filtration. The urinary excretion of unchanged mirabegron is dose-dependentand ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of100 mg. Following the administration of 160 mg 14C-mirabegron to healthy volunteers, approximately55% of the radiolabel was recovered in the urine and 34% in the faeces. Unchanged mirabegronaccounted for 45% of the urinary radioactivity, indicating the presence of metabolites. Unchangedmirabegron accounted for the majority of the faecal radioactivity.

Mirabegron clearance was predicted to increase in patients with increasing body weight in accordancewith allometric principles based on population pharmacokinetic analysis. The apparent clearanceparameter was impacted significantly by dose, formulation, and food effects on relative bioavailability.

Values of apparent clearance were highly variable but generally similar between children andadolescents, despite body weight differences, because of these effects on bioavailability.

The Cmax and AUC of mirabegron and its metabolites following multiple oral doses in elderlyvolunteers (≥ 65 years) were similar to those in younger volunteers (18-45 years).

In patients 3 to less than 18 years of age, age was not predicted to have any impact on key mirabegronpharmacokinetic parameters after accounting for differences in body weight. Models including age didnot result in meaningful improvements to the paediatric population pharmacokinetic model, indicatingthat inclusion of body weight was sufficient to address differences in mirabegron pharmacokineticsdue to age.

The Cmax and AUC are approximately 40% to 50% higher in females than in males. Gender differencesin Cmax and AUC are attributed to differences in body weight and bioavailability.

Gender has no meaningful impact on mirabegron pharmacokinetics in the paediatric population from 3to less than 18 years of age.

The pharmacokinetics of mirabegron in adults are not influenced by race.

Following single dose administration of 100 mg Betmiga in adult volunteers with mild renalimpairment (eGFR-MDRD 60 to 89 ml/min/1.73 m2), mean mirabegron Cmax and AUC were increasedby 6% and 31% relative to adult volunteers with normal renal function. In adult volunteers withmoderate renal impairment (eGFR-MDRD 30 to 59 ml/min/1.73 m2), Cmax and AUC were increased by23% and 66%, respectively. In adult volunteers with severe renal impairment (eGFR-MDRD 15 to29 ml/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher. Mirabegron has not beenstudied in patients with ESRD (eGFR < 15 ml/min/1.73 m2) or patients requiring haemodialysis.

Following single dose administration of 100 mg Betmiga in adult volunteers with mild hepaticimpairment (Child-Pugh Class A), mean mirabegron Cmax and AUC were increased by 9% and 19%relative to adult volunteers with normal hepatic function. In adult volunteers with moderate hepaticimpairment (Child-Pugh Class B), mean Cmax and AUC values were 175% and 65% higher.

Mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Pre-clinical studies have identified target organs of toxicity that are consistent with clinicalobservations. Transient increases in liver enzymes and hepatocyte changes (necrosis and decrease inglycogen particles) were seen in rats and reduced plasma leptin levels were noted. An increase in heartrate was observed in rats, rabbits, dogs and monkeys. Genotoxicity and carcinogenicity studies haveshown no genotoxic or carcinogenic potential in vivo.

Mirabegron had no discernible effect on gonadotropic or sex steroid hormone levels. In addition, noeffects on fertility were seen at sub-lethal doses (human equivalent dose was 19-fold higher than themaximum human recommended dose (MHRD)). The main findings in rabbit embryofetal developmentstudies included malformations of the heart (dilated aorta, cardiomegaly) at systemic exposures36-fold higher than observed at the MHRD. In addition, malformations of the lung (absent accessorylobe of the lung) and increased post-implantation loss were observed in the rabbit at systemicexposures 14-fold higher than observed at the MHRD, while in the rat reversible effects on ossificationwere noted (wavy ribs, delayed ossification, decreased number of ossified sternebrae, metacarpi ormetatarsi) at systemic exposures 22-fold higher than observed at the MHRD. The observedembryofetal toxicity occurred at doses associated with maternal toxicity. The cardiovascularmalformations observed in the rabbit were shown to be mediated via activation of thebeta 1-adrenoceptor.

The overall safety profile seen in juvenile rats was comparable to that observed in adult animals.

Repeat dose safety studies performed in juvenile rats showed no effect on physical development orsexual maturation. Mirabegron administration from weaning through sexual maturation had no effecton mating ability, fertility or embryofoetal development. Mirabegron administration increasedlipolysis and food consumption in juvenile rats.

Pharmacokinetic studies performed with radio-labelled mirabegron have shown that the parentcompound and/or its metabolites are excreted in the milk of rats at levels that were approximately1.7-fold higher than plasma levels at 4 hours post administration (see section 4.6).

Core tablet

Macrogol 8000 and 2 000 000

Hydroxypropylcellulose

Butylhydroxytoluene

Magnesium stearate

Betmiga 25 mg prolonged-release tablets:

Hypromellose 2910, 6 mPa.s

Macrogol 8000

Iron oxide yellow (E172)

Iron oxide red (E172)

Betmiga 50 mg prolonged-release tablets:

Hypromellose 2910, 6 mPa.s

Macrogol 8000

Iron oxide yellow (E172)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

Alu-Alu blisters in cartons containing 10, 20, 30, 50, 60, 90, 100 or 200 tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Astellas Pharma Europe B.V.

Sylviusweg 622333 BE Leiden

The Netherlands

EU/1/12/809/001 - 006

EU/1/12/809/008 - 013

EU/1/12/809/015 - 018

Date of first authorisation: 20 December 2012

Date of latest renewal: 18 September 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.