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

Posology
Adults (including elderly patients)
The recommended dose is 50 mg once daily with or without food.
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)

Gender
No dose adjustment is necessary according to gender.
Pediatric 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 once daily, with liquids, swallowed whole and is not to be chewed, divided, or
crushed
 

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.
Betmiga 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. Betmiga 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 Betmiga, 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).
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 medications for OAB
Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic
medications for the treatment of OAB has been reported in post marketing experience in patients taking
mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary
retention in patients treated with Betmiga; however, Betmiga should be administered with caution to
patients with clinically significant BOO. Betmiga should also be administered with caution to patients
taking antimuscarinic medications for the treatment of OAB
 

In vitro data
Mirabegron is transported and metabolised through multiple pathways. Mirabegron is a substrate for
cytochrome P450 (CYP) 3A4, CYP2D6, butyrylcholinesterase, uridine diphospho-glucuronosyltransferases
(UGT), the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT)
OCT1, OCT2, and OCT3. Studies of mirabegron using human liver microsomes and recombinant human
CYP enzymes showed that mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak
inhibitor of CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations.
In vivo data
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.
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 (GFR15 to 29 mL/min/1.73 m2) or patients with moderate hepatic impairment
(Child-Pugh Class B) concomitantly receiving strong CYP3A inhibitors (see sections 4.2 and 4.4).
Effect of enzyme inducers
Substances that are inducers of CYP3A or P-gp decrease the plasma concentrations of mirabegron. No dose
adjustment is needed for mirabegron when administered with therapeutic doses of rifampicin or other
CYP3A or P-gp inducers.
Effect of 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
 

Pregnancy Category: C
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). Betmiga is not recommended during pregnancy and in
women of childbearing potential not using contraception.
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
 

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

A. SUMMARY OF SIDE EFFECTS
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 Betmiga, 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.
B. 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). Within each
frequency grouping, adverse reactions are presented in order of decreasing seriousness

C. DESCRIPTION OF SELECTED ADVERSE REACTIONS:
Not Applicable
D. PEDIATRIC POPULATION:
The safety and efficacy of mirabegron in children below 18 years of age have not yet been established.
No data are available.
E. OTHER SPECIAL POPULATION:
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.
Betmiga 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. Betmiga 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 Betmiga, 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).
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 medications for OAB
Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic
medications for the treatment of OAB has been reported in post marketing experience in patients taking
mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary
retention in patients treated with Betmiga; however, Betmiga should be administered with caution to
patients with clinically significant BOO. Betmiga should also be administered with caution to patients
taking antimuscarinic medications for the treatment of OAB

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.
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, 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 nonvoiding 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 nonvoiding 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 supratherapeutic 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 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 medication. 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).
Table 1: Co-primary and Selected Secondary Efficacy Endpoints at End of Treatment for Pooled Studies

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 metabolized 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 metabolized 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.
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 (eGFRMDRD 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 (eGFRMDRD 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)
 

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 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)
 

Core tablet
Macrogol
Hydroxypropylcellulose
Butylhydroxytoluene
Magnesium stearate
Film coating Betmiga 25 mg prolonged release film-coated tablets
Hypromellose
Macrogol
Iron oxide yellow (E172)
Iron oxide red (E172)
Film coating Betmiga 50 mg prolonged release film-coated tablets
Hypromellose
Macrogol
Iron oxide yellow (E172)
 

Not applicable
 

Store below 30 °C
This medicinal product does not require any special storage conditions
 

Alu-Alu blisters in cartons containing 30 tablets
 

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