457114

2012

TAU461756287212457114Therapeutic Advances in UrologyE Sacco and R Bientinesi

Therapeutic Advances in Urology

Review

Mirabegron: a review of recent data

and its prospects in the management
of overactive bladder

Ther Adv Urol

(2012) 4(6) 315324
DOI: 10.1177/
1756287212457114
The Author(s), 2012.
Reprints and permissions:
http://www.sagepub.co.uk/
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Emilio Sacco and Riccardo Bientinesi

Abstract: Mirabegron is a novel, once-daily, orally active, first-in-class, potent 3adrenoceptor agonist recently approved by Food and Drug Administration for overactive
bladder therapy. Phase II studies and four large-scale phase III multinational randomized,
controlled trials have supported the efficacy and tolerability of mirabegron in the clinical trial
setting of patients with overactive bladder for up to 12 weeks of therapy and in the long term
(12 months). The reported incidence and severity of treatment-emergent and serious adverse
effects were similar to antimuscarinics, but with a more than threefold lower incidence of
dry mouth compared with tolterodine. However, the effects on the cardiovascular system,
pharmacokinetic interactions with other drugs, and increased incidence of new malignant
events will require careful evaluation in the near future.
Keywords: 3-adrenoceptor agonist, efficacy, mirabegron, overactive bladder, safety, urinary
incontinence

Introduction
Overactive bladder (OAB), defined by the
International Continence Society as urgency
with or without urinary incontinence, usually
associated with frequency and nocturia [Abrams
et al. 2002], is a multifactorial and common
health disorder associated with detrimental
effects on quality of life and huge economic burden [Irwin et al. 2006; Sacco et al. 2010].
Irrespective of the pathophysiology, the aim of
treatment of OAB is to obtain symptom relief
without affecting the empty phase of the micturition cycle. Current first-line treatment relies
mainly on conservative therapeutic strategies,
such as behavioural therapies, functional electrical stimulation, clean intermittent catheterization and pharmacological treatment. Second-line
treatment options in refractory patients are
neuromodulation, botulinum toxin and surgery.
Antimuscarinic drugs are US Food and Drug
Adminstration (FDA)-approved medications for
OAB and represent the mainstay of pharmacological treatment [Chapple et al. 2008a].
Unfortunately, antimuscarinics are not always
effective in controlling OAB symptoms and rarely
cure OAB. Furthermore, bothersome adverse

effects (AEs), including dry mouth, nausea,

constipation and central nervous system AEs,
due to their lack of bladder selectivity, cause poor
long-term adherence to treatment [Milsom et al.
2001; DSouza et al. 2008].
Recent advances in the understanding of the
physiopathology of OAB have driven a huge
amount of basic and clinical research into novel
pharmacological compounds. Among potential
novel peripherally acting drugs, 3-adrenoceptor
(AR) agonists appear very promising [Sacco et al.
2008].

Correspondence to:
Emilio Sacco, MD, PhD
Clinica Urologica,
Policlinico Gemelli, Largo
Gemelli 8, 00168 Roma,
Italy
emilio.sacco@gmail.com
Riccardo Bientinesi, MD
Urologic Clinic,
Department of Surgical
Sciences, A. Gemelli
Universitary Hospital,
Catholic University School
of Medicine of Rome,
Rome, Italy

Mirabegron (also known as YM178) is a novel,

once-daily orally active, first-in-class, potent 3AR agonist [Takasu et al. 2007]. Regulatory applications for mirabegron are under review in several
countries. In July 2011, mirabegron was granted
marketing approval in Japan and was launched in
September 2011. In June 2012 FDA also approved
mirabegron (Myrbetriq, Astellas Pharma US,
Inc.). Thereafter we reviewed clinical data on the
safety and efficacy of mirabegron by searching
English language full papers and abstracts in
MEDLINE, ClinicalTrials.gov, controlled-trials.

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Therapeutic Advances in Urology 4 (6)

com, clinicaltrialsfeeds.org and proceedings of
international scientific meetings. The reports of
the Division of Reproductive and Urologic
Products Office of the FDA [FDA, 2012], which
recently reviewed efficacy and safety of mirabegron for marketing approval, has also been used as
a source of data.

Consequently, several pharmaceutical companies

are developing a number of 3-AR selective agonists aimed at treating OAB. In particular, an
extensive clinical development and clinical pharmacology programs which consist of 41 studies
were involved in the development of mirabegron
by Astellas Pharma (Ibaraki, Japan).

Mechanism of action
In mammalian species detrusor relaxation is
mainly mediated by the cyclic adenosine
monophosphate pathway, which is activated via
the fixation of noradrenalin to -ARs [Andersson
et al. 2009]. 1,2,3-ARs have all been demonstrated in both animal and human bladder
[Andersson et al. 2009]. However, 3-ARs
account for more than 95% of all -AR mRNA in
the human bladder and are thought to be the
main -ARs mediating human detrusor relaxation
[Takeda et al. 1999, 2000; Igawa et al. 2010]. 3ARs have been found to be highly and preferentially expressed on urinary bladder tissues,
including the urothelium, interstitial cells, and
detrusor smooth muscle [Andersson et al. 2009;
Andersson and Arner, 2004; Otsuka et al. 2008;
Limberg et al. 2010; Fujimura et al. 1999].

Pharmacokinetics
The manufacturer conducted 23 human phar
macocynetic studies, including extensive phar
macocynetic/pharmacodynamic modelling and
simulation [FDA, 2012]. The plasma protein binding is 71%. The drug is widely distributed in the
body with a large volume of distribution of approximately 1670 liters. The terminal elimination half
life of mirabegron is approximately 50 h. The time
to reach maximum concentration (Tmax) is 34 h.
The absolute bioavailability is approximately 29%
at a 25 mg dose and 35% at a 50 mg dose. The bioavailability appears to be higher in women (40
50% higher exposure) than in men; however, when
normalized for body weight the difference is
reduced to around 2030%. The bioavailability is
reduced when given with food, depending on fat
content, with low-fat food having greater effect on
the absorption than high-fat food [FDA, 2012].

In animal studies 3-AR agonists directly cause

dose-dependent detrusor relaxation during the
storage phase of the micturition cycle and inhibited
neurogenic detrusor overactivity and experimentally induced or bladder outlet obstruction (BOO)associated OAB [Woods et al. 2001; Hicks et al.
2007; Takasu et al. 2007]. It has been shown that,
compared with other agents (including antimuscarinics), 3-AR agonists increase bladder capacity
with no change in micturition pressure and residual volume, supporting the principle of 3-AR agonism as a new therapeutic approach to OAB.
Receptors on smooth muscle are thought to be
the main site of action for these agents in treating
detrusor overactivity, although they also promote
relaxation by directly influencing urothelial functions [Yamaguchi and Chapple, 2007; Birder et al.
1998]. In addition, it has been demonstrated that
3-AR agonists can directly inhibit afferent nerve
firing in spinal cord transected rats [Kanai et al.
2011]. These drugs have many fewer, if any, cardiovascular side effects compared with 1,2-AR
agonists [Kaidoh et al. 2002]. Pilot studies already
reported beneficial effects with terbutaline
[Lindholm and Lose, 1986] and clenbuterol
[Gruneberger, 1984] in patients with OAB.

Absorption and elimination kinetics and metabolite profiles of mirabegron were investigated in
four healthy men by Takusagawa and colleagues
[Takusagawa et al. 2012]. Mirabegron, administered as an oral solution (160 mg of radiolabelled
[14C]mirabegron, 1.85 MBq) was rapidly
absorbed. A double-peak phenomenon in the
plasma mirabegron concentrationtime profile
was seen with distinct peaks at approximately
0.51 h and 24 h after administration, likely
caused by two separated absorption windows
along the small intestine. Unchanged mirabegron
was the most abundant fraction of radioactivity,
accounting for approximately 22% of plasma
radioactivity. The mean cumulative excretion of
radioactivity by 408 h after dosing was 55.0% in
urine, 34.2% in faeces and 89.2% in total, showing that at least a 55.0% dose of mirabegron
was absorbed from the gastrointestinal tract.
Mirabegron was recovered in urine and faeces
mainly in the unchanged form. Thus, unchanged
mirabegron excreted in urine accounted for 45%
of the excreted radioactivity, while 10 metabolites
accounted for most of the remainder of the urinary radioactivity.The unchanged form accounted
for almost all radioactivity in the faeces. Eight

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E Sacco and R Bientinesi

urinary metabolites were also detected in the
plasma. There appear to be several metabolic
pathways involved in the metabolism of mirabegron, including dealkylation, oxidation, glucuronidation, and amide hydrolysis. Also, these
pathways involve multiple enzymes and isoenzymes such as butyrylcholinesterase, uridine
diphospho-glucuronosyltransferase, cytochrome
P450 (CYP3A4) (the primary responsible isoenzyme), CYP2D6, and alcohol dehydrogenase. As
a result, the possibility that coadministered drugs
with the potential to inhibit/induce one specific
enzyme or transporter may affect the pharmacokinetics of mirabegron is low. Polymorphism of
CYP2D6 has been shown to cause pharmacokinetic differences between poor and extensive
metabolizers, although they are not considered
clinically relevant [van Gelderen et al. 2009].
Recently, methods for the determination of mirabegron and its metabolites in human plasma have
been developed and validated [Teijlingen et al.
2012]. Systemic exposure was higher in patients
with severe renal impairment or moderate hepatic
impairment than in healthy controls; the dose
proposed by the manufacturer is 25 mg in these
patients.
Mirabegron is formulated as oral controlled
absorption system (OCAS) tablets. OCAS is a
modified release system (also referred to as
extended release or prolonged release) that allows
the release of drug from the tablets for an
extended period. The drug product is available in
two strengths of 50 mg (recommended, to be
marketed orally once daily dose, with or without
food) and 25 mg (for patients with severe renal or
moderate hepatic impairment).
Clinical efficacy
Mirabegron has been studied extensively in more
than 10,000 individuals over the last 10 years.
The safety and efficacy in patients with OAB
were evaluated in six global, 12-week, phase IIb
and phase III studies; however, most of these
studies are still unpublished as full-paper articles
in peer-reviewed journals.
Chapple and colleagues reported the results of
a proof-of-concept, randomized, double-blind,
parallel group, phase IIa dose-ranging trial
(BLOSSOM trial) with mirabegron in patients
with OAB [Chapple et al. 2008b]. Tolterodine
and placebo were used as controls. Thirty-one
sites of six European countries enrolled 260

patients who, after a 2-week placebo run-in

period, were randomly assigned to four study
groups: placebo (n = 66), mirabegron 100 mg
twice daily (n = 65), mirabegron 150 mg twice
daily (n = 65), and tolterodine 4 mg four times
daily (n = 64) for a 4-week period. Analysis of the
primary efficacy measure showed a statistically
significant reduction from baseline in mean
micturition frequency with 100 and 150 mg of
mirabegron (17% and 18% respectively) compared with placebo (9%) and tolterodine
(11%). Mirabegron was also significantly superior than placebo with regard to mean volume
voided per micturition, mean number of incontinence episodes, nocturia episodes, urgency incontinence episodes, and urgency episodes per 24 h.
Based on these results, Chapple and colleagues
conducted a European dose-ranging phase IIb trial
(DRAGON trial) enrolling 919 patients randomized in five study groups: placebo, once-daily
mirabegron 25 mg, 50 mg, 100 mg, and 200 mg
for a 12-week period [Chapple et al. 2010]. Analysis
of the primary efficacy measure showed statistically
significant dose-dependent reduction in mean micturition frequency with 50, 100, and 200 mg of
mirabegron compared with placebo (2.1, 2.1,
and 2.2 respectively; p < 0.05). Furthermore,
compared with placebo, mirabegron significantly
increased mean volume voided per micturition
(dose-dependent effect), decreased the mean number of incontinence episodes, urgency incontinence
episodes, and urgency episodes per 24 h.
Three pivotal large-scale phase III studies conducted by Astellas have been considered for the
efficacy analysis in the report of the Division of
Reproductive and Urologic Products of FDA
[FDA, 2012; Khullar et al. 2011; Nitti et al. 2011].
Efficacy analysis of these studies and of pooled
results were based on two coprimary efficacy endpoints: the change from baseline to endpoint in the
mean number of incontinence episodes per 24 h;
and the mean change from baseline to endpoint
in the mean number of micturitions per 24 h.
Khullar et al. carried out a EuropeanAustralian
multicentre, randomized, double-blind, parallel-group, placebo and active controlled phase
III trial (SCORPIO trial) [Khullar et al. 2011].
The study enrolled 1978 patients with OAB
who, after a 2-week placebo run-in period, were
randomized to receive one of the following once
daily for 12 weeks: placebo (n = 494), mirabegron
50 mg (n = 493), mirabegron 100 mg (n = 496),

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Therapeutic Advances in Urology 4 (6)

Figure 1. Coprimary efficacy variables in the SCORPIO trial. Mean change from baseline to final visit in the
number of (a) incontinence episodes per 24 h and (b) micturitions per 24 h. Data are least squares mean
adjusted for baseline, sex and geographical region. Statistically significantly superior versus placebo at the
0.05 level with multiplicity adjustment. FAS, full analysis set; FAS-I, all full analysis set patients who had at
least one incontinence episode at baseline; NS, not statistically significant versus placebo. Reprinted from
[Khullar et al. 2012], with permission from Elsevier.

or tolterodine slow release (SR) 4 mg (n = 495).

Analysis of the coprimary efficacy measures
showed a statistically significant decrease from
baseline in mean number of micturitions with
50 mg and 100 mg of mirabegron (1.93, 1.77,
respectively) and mean number of incontinence
episodes (1.57, 1.46, respectively ) per 24 h
compared with placebo (Figure 1). Although
improvements in both coprimary endpoints
were also observed with tolterodine SR, these
did not reach statistical significance.
Nitti et al. confirmed the aforementioned results in
a multicentre, randomized, double-blind, parallel-group, placebo-controlled phase III trial (the
ARIES trial) conducted in North America [Nitti et
al. 2011]. This study enrolled 1328 patients with
OAB and randomly assigned to them three treatment arms: placebo, mirabegron 50 mg and mirabegron 100 mg for 12 weeks. Statistically significant
reductions from baseline were observed with both
doses of mirabegron in the number of incontinence episodes (1.13, 1.47, and 1.63 for placebo, mirabegron 50 mg, and 100 mg, respectively;
p < 0.05) and in the number of micturitions per 24
h (1.05, 1.66, and 1.75 for placebo, mirabegron 50 mg, and 100 mg, respectively; p < 0.05) .
A post hoc analysis of the SORPIO trial [Khullar
et al. 2011] showed that both mirabegron doses

(50 mg and 100 mg once daily) were effective in

improving coprimary efficacy endpoints versus
placebo in antimuscarinic treatment-nave
patients and in patients whose condition failed to
respond to previous antimuscarinic therapy,
regardless of the reason for discontinuation
[Khullar et al. 2012].
The third pivotal phase III study is a European
North American, randomized, double-blind,
placebo-controlled trial (the CAPRICORN
trial) comparing mirabegron 25 mg and 50 mg
with placebo. The results of this trial, submitted
to FDA by Astellas, are still unpublished [FDA,
2012].
Tables 1 and 2 display the results of a primary
pooled efficacy analysis performed by FDA and
including data from the three aforementioned
pivotal phase III studies [FDA, 2012]. The data
relate to the 50 mg mirabegron OCAS once daily
regimen, the proposed dosing regimen under
evaluation for FDA marketing approval.
Further data coming from subpopulation analyses showed that mirabegron 25 mg and 50 mg
was effective in men and women, although a
larger reduction versus placebo in mean number
of incontinence episodes was observed in women
compared with men. In addition, mirabegron

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E Sacco and R Bientinesi

Table 1. Pooled phase III pivotal studies: mean number of micturitions per 24 h.

Baseline (SE)
Endpoint (SE)
Change from baseline
LSM difference versus placebo
95% two-sided CI
p Value

Mirabregon 50 mg
N = 1324

Placebo
N = 1328

11.7 (0.09)
9.9 (0.09)
1.8 (0.08)
0.55 (0.10)
(0.75, 0.36)
<0.001*

11.6 (0.09)
10.4 (0.09)
1.2 (0.08)

p Values are nominal from paired comparisons versus placebo within stratified rank analysis of covariance model.
Reprinted from [FDA, 2012].
*Statistically significantly superior compared with placebo at the 0.05 level with multiplicity adjustment.
CI, confidence interval; LSM, least square mean; SE, standard error.

Table 2. Pooled phase III pivotal studies: mean number of incontinence episodes per 24 h.

Baseline (SE)
Endpoint (SE)
Change from baseline
LSM difference versus placebo
95% two-sided CI
p Value

Mirabregon 50 mg
N = 862

Placebo
N = 878

2.7 (0.09)
1.2 (0.09)
1.5 (0.08)
0.40 (0.09)
(0.58, 0.21)
<0.001*

2.7 (0.09)
1.6 (0.09)
1.1 (0.08)

p Values are nominal from paired comparisons versus placebo within stratified rank analysis of covariance model.
Reprinted from [FDA, 2012].
*Statistically significantly superior compared with placebo at the 0.05 level with multiplicity adjustment.
CI, confidence interval; LSM, least square mean; SE, standard error.

25 mg and 50 mg resulted in reduction in mean

number of incontinence episodes per 24 h that
was significantly lower in the age group under 65
years compared with those aged 65 years and
over. Mirabegron 50 mg and 100 mg did not
appear effective in decreasing the mean number
of incontinence episodes in men with benign prostatic hyperplasia [FDA, 2012].
Another multinational randomized, double-blind,
parallel group, active-controlled, phase III trial has
been conducted in North America, Europe and
other countries (the TAURUS trial) and assessed
the long-term (12 months) safety and efficacy of
mirabegron 50 mg and 100 mg and tolterodine SR
4 mg [Chapple et al. 2012]. The study was not
designed to demonstrate a statistically significant
difference in efficacy between treatment groups.
After a single-blind placebo run-in period of
2 weeks, 2444 patients with OAB were randomized to the four study groups for 12 months.

The authors reported that for both doses impro

vements in OAB symptoms were observed by
month 1, with continued improvement until at
least month 3 and maintenance of the effect
through month 12, as measured by the change
from baseline for mean number of micturitions per
24 h, mean number of incontinence episodes per
24 h, and improvements in mean volume voided/
micturition (Figure 2) [Chapple et al. 2012].
Results from further studies are awaited, such as
those from a phase II trial evaluating mirabegron
and solifenacin alone and in combination for
treating OAB (ClinicalTrials.gov identifier:
NCT01340027).
Safety and tolerability
Chapple and colleagues reported in the
BLOSSOM trial an incidence of treatment-
emergent adverse effects (TEAEs) of 39.2%

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Therapeutic Advances in Urology 4 (6)

Figure 2. Coprimary efficacy variables in the long-term (12 months) TAURUS trial. Mean number of (a)
incontinence episodes per 24 h and (b) micturitions per 24 h. Adjusted mean changes from baseline at each
visit, based on the repeated measures model. Reprinted from [Chapple et al. 2012], with permission from
Elsevier.

compared with 36.4% for the placebo group and

48.4% for the tolterodine group [Chapple et al.
2008b]. AEs were mild or moderate in intensity,
and headache and gastrointestinal disorders were
the most common (6.9%, 13.8%, respectively) in
the mirabegron group, but their incidence was
lower compared with the tolterodine group (9.4%,
23.4% respectively). Treatment-related dizziness
and palpitations were more common with mirabegron compared with placebo and tolterodine.
Of note, no episodes of acute urinary retention
were reported. Discontinuation rates caused by
adverse effects were 4.6% and 7.7% with mirabegron 100 mg and 150 mg, respectively, 1.5% with
placebo and 3.1% with tolterodine.
In the DRAGON trial [Chapple et al. 2010] the
incidence of one or more TEAEs in the mirabegron groups (25, 50,100, and 200 mg) was

between 43.8% and 47.9% compared with 43.2%

in the placebo group. The most commonly
reported class of TEAEs were gastrointestinal disorders, including constipation, dry mouth, dyspepsia and nausea (7.28.3% in the mirabegron
groups versus 5.3% in the placebo group). Of
note, the incidence of dry mouth was lower than
has been seen with antimuscarinics [Chapple
et al. 2008a] and, again, no episodes of acute urinary retention were reported. No differences
between treatment groups were observed in electrocardiogram (ECG) parameters but a statistically significant increase from baseline in mean
pulse rate versus placebo was observed with 100
mg and 200 mg mirabegron [1.6 and 4.1 beats
per minute (bpm) respectively in the morning;
2.7 and 4.7 bpm in the afternoon]; this change in
pulse rate was not associated with an increase in
cardiovascular AEs. Discontinuation rates were

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E Sacco and R Bientinesi

Table 3. Most frequent (2% in any treatment group) treatment-emergent adverse events (the TAURUS trial).
Preferred term

Mirabegron

Tolterodine SR 4 mg

Adverse event, n (%)

50 mg
(n = 812)

100 mg
(n = 820)

(n = 820)

Any AE
Hypertension
Urinary tract infection
Nasopharyngitis
Headache
Back pain
Constipation
Influenza
Dry mouth
Sinusitis
Diarrhoea
Arthralgia
Dizziness
Cystitis
Tachycardia

485 (59.7)
75 (9.2)
48 (5.9)
32 (3.9)
33 (4.1)
23 (2.8)
23 (2.8)
21 (2.6)
23 (2.8)
22 (2.7)
15 (1.8)
17 (2.1)
22 (2.7)
17 (2.1)
8 (1.0)

503 (61.3)
80 (9.8)
45 (5.5)
35 (4.3)
26 (3.2)
29 (3.5)
25 (3.0)
25 (3.0)
19 (2.3)
18 (2.2)
24 (2.9)
19 (2.3)
13 (1.6)
11 (1.3)
19 (2.3)

508 (62.6)
78 (9.6)
52 (6.4)
25 (3.1)
20 (2.5)
13 (1.6)
22 (2.7)
28 (3.4)
70 (8.6)
12 (1.5)
16 (2.0)
16 (2.0)
21 (2.6)
19 (2.3)
25 (3.1)

Reprinted from [Chapple et al. 2012], with permission from Elsevier.

AE, adverse event; SR, sustained release.

between 2.4% and 5.3% in the mirabegron

groups and 3.0% in the placebo group.
Khullar and colleagues reported in their largescale EuropeanAustralian trial an incidence of
TEAEs similar across the placebo, mirabegron 50
mg, mirabegron 100 mg, and tolterodine SR
groups (43.3, 42.8, 40.1, and 46.7%, respectively)
[Khullar et al. 2011]. The most common TEAEs
were hypertension (7.7, 5.9, 5.4, and 8.1%), dry
mouth (2.6, 2.8, 2.8, and 10.1%), headache (2.8,
3.7, 1.8, and 3.6%), and nasopharyngitis (1.6,
2.8, 2.8, and 2.8%). Although the incidence of
dry mouth was similar in the placebo and mirabegron groups, and markedly lower than observed
in patients receiving tolterodine SR, the incidence
of constipation was similar across all treatment
groups.
In the North American phase III trial a similar
incidence of TEAEs was observed for placebo,
mirabegron 50 mg and 100 mg groups (50.1%,
51.6% and 46.9% respectively) [Nitti et al. 2011].
The incidence of hypertension was 6.6%, 6.1%,
and 4.9%, and headache 2.0%, 3.2%, and 3.0%
in the placebo, mirabegron 50 mg, and 100 mg
groups respectively. Discontinuation rates due to
adverse events were 3.8%, 4.1%, and 4.4% in the
placebo, mirabegron 50 mg, and 100 mg groups.

Changes in laboratory assessments, vital signs,

physical examination, electrocardiograms, and
post-void residual volume were small and consistent across treatment groups.
Long-term (12 months) safety and tolerability
were the primary outcome of the TAURUS trial
[Chapple et al. 2012], showing that the incidence
and severity of treatment-emergent and serious
AEs were similar across the mirabegron 50 mg
(59.7%), mirabegron 100 mg (61.3%), and
tolterodine SR 4 mg (62.6%) groups (Table 3).
The most frequent TEAEs were hypertension,
dry mouth, constipation, and headache, which
occurred at a similar incidence across all treatment groups, while the incidence of dry mouth
was more than threefold lower compared with the
tolterodine SR 4 mg group [Chapple et al. 2012].
Most TEAEs were mild or moderate in severity
across all treatment groups. Five deaths were
reported; three in the mirabegron 50 mg group
and two in the tolterodine SR 4 mg group, but all
were considered unrelated to the study drug. No
consistent trends in ECG changes were identified
and there was no prolongation of the QTc interval in mirabegron-treated patients compared
with tolterodine-treated patients. Incidentally, a
thorough QT study showed no QT prolongation
at the 50 mg dose [FDA, 2012].

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Therapeutic Advances in Urology 4 (6)

Although mirabegron appeared to be well tolerated in patients with OAB and exhibited a low
incidence of TEAEs across the reported trials,
some safety issues still need to be clarified. A
mirabegron-related, dose-responsive elevation in
blood pressure of approximately 3-4 mmHg was
observed at Tmax in phase I studies and raised concerns, although the mirabegron-related elevation
in systolic and diastolic blood pressures was only
approximately 1 mmHg in phase III studies, generally comparable across all treatment groups. A
similar discrepancy exists between findings in
phase I studies and phase III studies relating to
effects on heart rate. The reasons for these discrepancies and the extent and clinical relevance of
these cardiovascular effects are not completely
clear, and according to FDA [FDA, 2012], represent a potential cardiovascular safety signal. In
relation to its mechanism of action, mirabegron
also increases the incidence of mild-severity urinary tract infections and there have been postmarketing reports of urinary retention. Furthermore,
in the phase III trials, an increased incidence of a
variety of neoplasms occurred in the mirabegron
100 mg group compared with the placebo group,
but not in the to-be-marketed mirabegron 50 mg
group; whether these data represent a true mirabegron-related effect is still unknown [FDA,
2012]. Finally, evidence of CYP2D6 moderate
inhibition in clinical trials highlighted a concern
for pharmacokinetic interaction with other drugs
that are CYP2D6 substrates; therefore mirabegron increases the systemic exposure of desipramine [Krauwinkel et al. 2010].
Conclusion
Overall, the results of phase III trials are promising for mirabegron becoming a novel effective
and safe drug for patients with OAB. Treatment
with the to-be-marketed dose of 50 mg achieved
the primary efficacy objectives, although it resulted
only in a reduction of 0.55 micturitions per 24 h
and 0.40 incontinence episodes per 24 h compared with placebo. The drug is well tolerated
overall, with a lower incidence of the well known
side effects of antimuscarinics, such as dry mouth,
constipation, and blurred vision.
However, some critical safety issues are still to be
clarified. The increase in blood pressure and
heart rate, mainly observed in phase I studies,
pharmacokinetic interaction with other drugs,
and the increased incidence of new malignant
events observed with the 100 mg dose have raised

concerns. Further clinical and long-term studies

are especially needed for a thorough representation of the safety profile.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or notfor-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest in
preparing this article.

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