The format of this leaflet was determined by the Ministry of Health and its content was checked and

approved in 08.2016.
The content of this leaflet was updated according to guidelines of the Ministry of Health in January 2018

1. NAME OF THE MEDICINAL PRODUCT

Betmiga 25 mg.
Betmiga 50 mg.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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.

3. PHARMACEUTICAL FORM

Prolonged-release tablet.

Betmiga 25 mg prolonged-release tablets

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

Betmiga 50 mg prolonged-release tablets

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may
occur in adult patients with overactive bladder (OAB) syndrome.

4.2 Posology and method of administration

Posology

Adults (including elderly patients)

The recommended dose is 50 mg once daily.

Special populations
Renal and hepatic impairment
Betmiga has not been studied in patients with end stage renal disease (GFR < 15 mL/min/1.73 m2 or patients
requiring haemodialysis) or severe hepatic impairment (Child-Pugh Class C) and it is therefore not
recommended for use in these patient populations (see sections 4.4 and 5.2).

The following table provides the daily dosing recommendations for subjects with renal or hepatic
impairment in the absence and presence of strong CYP3A inhibitors (see sections 4.4, 4.5 and 5.2).

1
Table 1: Daily dosing recommendations for subjects with renal or hepatic impairment in the
absence and presence of strong CYP3A inhibitors
Strong CYP3A inhibitors(3)
Without inhibitor With inhibitor
Renal impairment(1) Mild 50 mg 25 mg
Moderate 50 mg 25 mg
Severe 25 mg Not recommended
Hepatic impairment(2) Mild 50 mg 25 mg
Moderate 25 mg Not recommended
1. Mild: GFR 60 to 89 mL/min/1.73 m2; moderate: GFR 30 to 59 mL/min/1.73 m2; severe: GFR
15 to 29 mL/min/1.73 m2.
2. Mild: Child-Pugh Class A; Moderate: Child-Pugh Class B.
3. Strong CYP3A inhibitors see section 4.5

Gender
No dose adjustment is necessary according to gender.

Paediatric population
The safety and efficacy of mirabegron in children below 18 years of age have not yet been established.
No data are available.

Method of administration

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.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood
pressure ≥110 mm Hg.

4.4 Special warnings and precautions for use

Renal impairment

Betmiga has not been studied in patients with end stage renal disease (GFR < 15 mL/min/1.73 m2 or patients
requiring haemodialysis) and, therefore, it is not recommended for use in this patient population. Data are
limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a
pharmacokinetic study (see section 5.2) a dose reduction to 25 mg is recommended in this population. This
medicinal product is not recommended for use in patients with severe renal impairment (GFR 15 to 29
mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors (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

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).

2
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 postmarketing 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.

4.5 Interaction with other medicinal products and other forms of interaction

In vitro data

Mirabegron is transported and metabolised through multiple pathways. Mirabegron is a substrate for
cytochrome P450 (CYP) 3A4, CYP2D6, butyrylcholinesterase, uridine diphospho-glucuronosyltransferases
(UGT), the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1,
OCT2, and OCT3. Studies of mirabegron using human liver microsomes and recombinant human CYP
enzymes showed that mirabegron is a moderate and timedependent 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 (GFR
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 with or without food (see section 4.2). Betmiga is not recommended in patients with
severe renal impairment (GFR 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.

3
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 Betmiga
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.

4.6 Fertility, pregnancy and lactation

Woman of childbearing potential

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

Pregnancy

There are limited amount of data from the use of Betmiga in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). This medicinal product 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 administered during breast-feeding.

Fertility

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

4
4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The safety of Betmiga was evaluated in 8433 patients with OAB, of which 5648 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 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 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.

5
MedDRA Common Uncommon Rare Very rare Not known
System organ class (cannot be
estimated
from the
available
data)
Infections and Urinary tract Vaginal
infestations infection infection
Cystitis
Psychiatric Insomnia*
disorders
Nervous system Headache*
disorders Dizziness*
Eye disorders Eyelid oedema
Cardiac disorders Tachycardia Palpitation
Atrial
fibrillation
Vascular Hypertensive
disorders crisis*
Gastrointestinal Nausea* Dyspepsia Lip oedema
disorders Constipation* Gastritis
Diarrhoea*
Skin and Urticaria Leukocytoclastic
subcutaneous Rash vasculitis
tissue disorders Rash macular Purpura
Rash papular Angioedema*
Pruritus
Musculoskeletal Joint swelling
and connective
tissue disorders
Renal and urinary Urinary
disorders retention*
Reproductive Vulvovaginal
system and breast pruritus
disorders
Investigations Blood pressure
increased
GGT increased
AST increased
ALT increased
*observed during post-marketing experience

Any suspected adverse events should be reported to the Ministry of Health according to the National
Regulation by using an online form:
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.health.g
ov.il ) or by email (adr@MOH.HEALTH.GOV.IL).

4.9 Overdose

Mirabegron has been administered to healthy 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 volunteers.

6
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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals, urinary antispasmodics 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.

A thorough QT (TQT) study (n = 164 healthy male and n = 153 healthy female volunteers with a mean age
of 33 years) evaluated the effect of repeat oral dosing of mirabegron at the indicated dose (50 mg once daily)
and two supra-therapeutic doses (100 and 200 mg once daily) on the QTcI interval. The supra-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 of mirabegron 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 and 100 mg, the upper bound of the
one-sided 95% confidence interval did not exceed 10 msec at any time point for the largest time-matched
mean difference from placebo in the QTcI interval. In females administered mirabegron at the 50 mg dose,
the mean difference from placebo on QTcI interval at 5 hours post dose was 3.67 msec (upper bound of the

7
one-sided 95% CI 5.72 msec). In males, the difference was 2.89 msec (upper bound of the one-sided 95% CI
4.90 msec). At a mirabegron dose of 200 mg, the QTcI interval did not exceed 10 msec at any time point in
males, while in females the upper bound of the one-sided 95% confidence interval did exceed 10 msec
between 0.5–6 hours, with a maximum difference from placebo at 5 hours where the mean effect was
10.42 msec (upper bound of the 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 the 50 mg to
200 mg dose range examined. The maximum mean difference from placebo in heart rate ranged from
6.7 bpm with mirabegron 50 mg up to 17.3 bpm with mirabegron 200 mg in healthy subjects.

Effects on pulse rate and blood pressure in patients with OAB

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

Effect on intraocular pressure (IOP)

Mirabegron 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase
1 study assessing the effect of Betmiga on IOP using Goldmann applanation tonometry in 310 healthy
subjects, a dose of mirabegron 100 mg was non-inferior to placebo for the primary 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 between mirabegron 100 mg and placebo was 0.3 mm Hg.

Clinical efficacy and safety

Efficacy of Betmiga was evaluated in three phase 3 randomized, double blind, placebo controlled, 12-week
studies for the treatment of overactive bladder with symptoms of urgency and frequency with or without
incontinence. Female (72%) and male (28%) patients with a mean age of 59 years (range 18 – 95 years) were
included. The study population consisted of approximately 48% antimuscarinic treatment naïve patients as
well as approximately 52% patients previously treated with antimuscarinic medicinal products. In one study,
495 patients received an active control (tolterodine prolonged release formulation).

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

8
Table 2: Co-primary and selected secondary efficacy endpoints at end of treatment for pooled
studies
Pooled studies
(046, 047, 074)
Placebo Mirabegron
Parameter 50 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 1328 1324
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 1328 1322
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 1325 1323
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 1324 1320
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 1195 1189
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 multiplicity adjustment.
# Statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment.
FAS: Full analysis set, all randomized patients who took at least 1 dose of double blind study drug and who had a
micturition measurement in the baseline diary and at least 1 post-baseline visit diary with a micturition
measurement.
FAS-I: Subset of FAS who also had at least 1 incontinence episode in the baseline diary.
CI: Confidence Interval
9
Table 3: Co-primary and selected secondary efficacy endpoints at end of treatment for studies 046,
047 and 074
Study 046 Study 047 Study 074
Parameter Placebo Mirabegron Tolterodine Placebo Mirabegron Placebo Mirabegron
50 mg ER 4 mg 50 mg 50 mg
Mean number of incontinence episodes per 24 hours (FAS-I) (Co-primary)
n 291 293 300 325 312 262 257
Mean baseline 2.67 2.83 2.63 3.03 2.77 2.43 2.51
Mean change
-1.17 -1.57 -1.27 -1.13 -1.47 -0.96 -1.38
from baseline†
Mean
difference -- -0.41 -0.10 -- -0.34 -- -0.42
from placebo†
95%
(-0.42, (-0.76,
Confidence -- (-0.72, -0.09) -- (-0.66, -0.03) --
0.21) -0.08)
Interval
p-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
Mean baseline 11.71 11.65 11.55 11.51 11.80 11.48 11.66
Mean change
-1.34 -1.93 -1.59 -1.05 -1.66 -1.18 -1.60
from baseline†
Mean
difference -- -0.60 -0.25 -- -0.61 -- -0.42
from placebo†
95%
(-0.55, (-0.76,
Confidence -- (-0.90, -0.29) -- (-0.98, -0.24) --
0.06) -0.08)
Interval
p-value -- <0.001# 0.11 -- 0.001# -- 0.015#
Mean volume voided (mL) per micturition (FAS) (Secondary)
n 480 472 475 433 424 415 426
Mean baseline 156.7 161.1 158.6 157.5 156.3 164.0 159.3
Mean change
12.3 24.2 25.0 7.0 18.2 8.3 20.7
from baseline†
Mean
difference -- 11.9 12.6 -- 11.1 -- 12.4
from placebo†
95%
Confidence -- (6.3, 17.4) (7.1, 18.2) -- (4.4, 17.9) -- (6.3, 18.6)
Interval
p-value -- <0.001# <0.001* -- 0.001# -- <0.001#
Mean level of urgency (FAS) (Secondary)
n 480 472 473 432 425 413 426
Mean baseline 2.37 2.40 2.41 2.45 2.45 2.36 2.41
Mean change
-0.22 -0.31 -0.29 -0.08 -0.19 -0.15 -0.29
from baseline†
Mean
difference -- -0.09 -0.07 -- -0.11 -- -0.14
from placebo†
95%
(-0.17, (-0.15, (-0.22,
Confidence -- -- (-0.18, -0.04) --
-0.02) 0.01) -0.06)
Interval
p-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
Mean baseline 2.43 2.52 2.37 2.56 2.42 2.24 2.33

10
 Study 046 Study 047 Study 074
Parameter Placebo Mirabegron Tolterodine Placebo Mirabegron Placebo Mirabegron
50 mg ER 4 mg 50 mg 50 mg
Mean change
-1.11 -1.46 -1.18 -0.89 -1.32 -0.95 -1.33
from baseline†
Mean
difference -- -0.35 -0.07 -- -0.43 -- -0.39
from placebo†
95%
(-0.38, (-0.72, (-0.69,
Confidence -- (-0.65, -0.05) -- --
0.23) -0.15) -0.08)
Interval
p-value -- 0.003* 0.26 -- 0.005* -- 0.002‡
Mean number of episodes with urgency grades 3 or 4 per 24 hours (FAS) (Secondary)
n 479 470 472 432 424 413 426
Mean baseline 5.78 5.72 5.79 5.61 5.90 5.42 5.80
Mean change
-1.65 -2.25 -2.07 -0.82 -1.57 -1.35 -1.94
from baseline†
Mean
difference -- -0.60 -0.42 -- -0.75 -- -0.59
from placebo†
95%
(-0.84, (-1.01,
Confidence -- (-1.02, -0.18) -- (-1.20, -0.30) --
-0.00) -0.16)
Interval
p-value -- 0.005* 0.050* -- 0.001* -- 0.007‡
Treatment satisfaction – visual analogue scale (FAS) (Secondary)
n 428 414 425 390 387 377 388
Mean baseline 4.11 3.95 3.87 5.5 5.4 5.13 5.13
Mean change
1.89 2.55 2.44 0.7 1.5 1.05 1.88
from baseline†
Mean
difference -- 0.66 0.55 -- 0.8 -- 0.83
from placebo†
95%
(0.14,
Confidence -- (0.25, 1.07) -- (0.4, 1.3) -- (0.41, 1.25)
0.95)
Interval
p-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 multiplicity adjustment.
# Statistically significantly superior compared with placebo at the 0.05 level with multiplicity adjustment.
‡ Not statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment.
FAS: Full analysis set, all randomized patients who took at least 1 dose of double blind study drug and who had a
micturition measurement in the baseline diary and at least 1 post-baseline visit diary with 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 was
maintained throughout the 12-week treatment period. A randomized, active controlled, long term study
demonstrated 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 on the following
health-related quality of life measures: treatment satisfaction and symptom bother.

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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 due to
insufficient effect (see Table 3).

Table 4: Co-primary efficacy endpoints for patients with prior OAB antimuscarinic therapy
Pooled studies
(046, 047, 074) Study 046
Placebo Mirabegron Placebo Mirabegron Tolterodine
Parameter 50 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 -0.10
95% 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 -0.20
95% 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 -0.06
95% 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 -0.08
95% 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 treatment interaction for
Pooled Studies and least squares mean adjusted for baseline, gender, geographical region, subgroup, and subgroup
by treatment interaction for Study 046.
FAS: Full analysis set, all randomized patients who took at least 1 dose of double blind study drug and who had a
micturition measurement in the baseline diary and at least 1 post-baseline visit diary with a micturition
measurement.
FAS-I: Subset of FAS who also had at least 1 incontinence episode in the baseline diary.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Betmiga in
one or more subsets of the paediatric population in “Treatment of idiopathic overactive bladder” and
“Treatment of neurogenic detrusor overactivity” (see section 4.2 for information on paediatric use).

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5.2 Pharmacokinetic properties

Absorption

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 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.

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 and demonstrated both safety and
efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose.

Distribution

Mirabegron is extensively distributed. The volume of distribution at steady state (Vss) is approximately
1670 L. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity
for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. In vitro erythrocyte
concentrations of 14C-mirabegron were about 2-fold higher than in plasma.

Biotransformation

Mirabegron is metabolised via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation,
and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-
mirabegron. Two major metabolites were observed in human plasma; both are phase 2 glucuronides
representing 16% and 11% of total exposure. These metabolites are not pharmacologically active.

Based on in vitro studies, mirabegron is unlikely to inhibit the metabolism of co-administered medicinal
products metabolised by the following cytochrome P450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9,
CYP2C19 and CYP2E1 because mirabegron did not inhibit the activity of these enzymes 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 of
mirabegron, 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 possibly alcohol
dehydrogenase (ADH) in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6.

CYP2D6 polymorphism
In healthy subjects who are genotypically poor metabolisers of CYP2D6 substrates (used as a surrogate for
CYP2D6 inhibition), mean Cmax and AUCinf of a single 160 mg dose of a mirabegron IR formulation were
14% and 19% higher than in extensive metabolisers, indicating that CYP2D6 genetic polymorphism has
minimal impact on the mean plasma exposure to mirabegron. 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.

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Elimination

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 to nearly 25% of
CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular
filtration. The urinary excretion of unchanged mirabegron is dose-dependent and ranges from approximately
6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of
160 mg 14C-mirabegron to healthy volunteers, approximately 55% of the radiolabel was recovered in the
urine and 34% in the faeces. Unchanged mirabegron accounted for 45% of the urinary radioactivity,
indicating the presence of metabolites. Unchanged mirabegron accounted for the majority of the faecal
radioactivity.

Age

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

Gender

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

Race

The pharmacokinetics of mirabegron are not influenced by race.

Renal impairment

Following single dose administration of 100 mg Betmiga in volunteers with mild renal impairment (eGFR-
MDRD 60 to 89 mL/min/1.73 m2), mean mirabegron Cmax and AUC were increased by 6% and 31% relative
to volunteers with normal renal function. In volunteers with moderate renal impairment (eGFR-MDRD 30 to
59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In volunteers with severe
renal impairment (eGFR-MDRD 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and
118% higher. Mirabegron has not been studied in patients with end stage renal disease (GFR
< 15 mL/min/1.73 m2 or patients requiring haemodialysis).

Hepatic impairment

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

5.3 Preclinical safety data

Pre-clinical studies have identified target organs of toxicity that are consistent with clinical observations.
Transient increases in liver enzymes and hepatocyte changes (necrosis and decrease in glycogen particles)
were seen in rats. An increase in heart rate was observed in rats, rabbits, dogs and monkeys. Genotoxicity
and carcinogenicity studies have shown no genotoxic or carcinogenic potential in vivo.

No effects on fertility were seen at sub-lethal doses (human equivalent dose was 19-fold higher than the
maximum human recommended dose (MHRD)). The main findings in rabbit embryofetal development
studies included malformations of the heart (dilated aorta, cardiomegaly) at systemic exposures 36-fold
higher than observed at the MHRD. In addition, malformations of the lung (absent accessory lobe of the
lung) and increased post-implantation loss were observed in the rabbit at systemic exposures 14-fold higher
than observed at the MHRD, while in the rat reversible effects on ossification were noted (wavy ribs, delayed

14
ossification, decreased number of ossified sternebrae, metacarpi or metatarsi) at systemic exposures 22-fold
higher than observed at the MHRD. The observed embryofetal toxicity occurred at doses associated with
maternal toxicity. The cardiovascular malformations observed in the rabbit were shown to be mediated via
activation of the beta 1-adrenoceptor.

Pharmacokinetic studies performed with radio-labelled mirabegron have shown that the parent compound
and/or its metabolites are excreted in the milk of rats at levels that were approximately 1.7-fold higher than
plasma levels at 4 hours post administration (see section 4.6).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core tablet
Macrogol 8,000 and 2,000,000
Hydroxypropylcellulose
Butylhydroxytoluene
Magnesium stearate

Film coating
Betmiga 25 mg prolonged-release tablets
Hypromellose 2910, 6 mPa.s
Macrogol 8,000
Iron oxide yellow (E172)
Iron oxide red (E172)

Betmiga 50 mg prolonged-release tablets

Hypromellose 2910, 6 mPa.s
Macrogol 8,000
Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store below 25 oc.

6.5 Nature and contents of container

Alu-Alu blisters in cartons containing 30 tablets.

6.6 Special precautions for disposal

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

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7. Name of manufacturer

Astellas Pharma Europe B.V., Leiden, the Netherlands

8. Name of registration holder

Astellas Pharma International B.V. Israel.

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