繁体中文
设为首页
加入收藏
当前位置:药品说明书与价格首页 >> 男性科 >> 新药推存 >> Betmiga prolongedrelease tablets(Mirabegron)

Betmiga prolongedrelease tablets(Mirabegron)

2014-09-07 09:14:37  作者:新特药房  来源:互联网  浏览次数:967  文字大小:【】【】【
简介: 英文药名:Betmiga(mirabegron tablets) 中文药名:米拉贝隆片 生产厂家:安斯泰来药品介绍2013年1月14日,安斯泰来(Astellas)生产的Betmiga(mirabegron)获欧盟委员会(EC)批准,用于膀胱过度 ...

部份中文米拉贝隆处方资料(仅供参考)
米拉贝隆片:Myrbetriq(mirabegron) [美国商品名]  Betanis Tablets(Mirabegron)[日本商品名] Betmiga Tablets(Mirabegron)[欧洲商品名]
【药品名称】米拉贝隆缓释片
【规    格】25mg;50mg
【剂    型】缓释片剂
【适 应 症】用于治疗膀胱过度活动症(OAB)。
【用法用量】剂量为25mg,每天一次,可随食或不随食服用。
【药理及作用机制】 
体外研究表明,米拉贝隆为β-3肾上腺素能受体的激动剂,米拉贝隆能激动β-3肾上腺素能受体,在储存期至排空期间松弛逼尿肌平滑肌,从而增加膀胱的容量,减少遗尿、尿急、尿频等症状,米拉贝隆对β-1和β-2受体显示非常低的内在活性,200mg米拉贝隆才能产生对β-1的刺激作用。
【上市及国内情况】 
上市情况:米拉贝隆,是由日本安斯泰来(Astel-las)制药公司研发的新型OAB治疗药,2011年9月16日在日本上市,商品名为Betanis,2012年6月获美国FDA批准上市,用于治疗成年人膀胱过度活动症(OAB),商品名为Myrbetriq,上市规格为25mg和50mg。2013年1月,米拉贝隆获EC批准上市,商品名为Betmiga。目前,该品种没有在中国上市。
【疗效评价】
米拉贝隆是30年来FDA批准的首个以新机制治疗OAB的药物,一线药物抗胆碱能药物以毒蔁碱M3受体为靶点,对膀胱收缩力有影响,引起眼干,口干和排尿困难等副作用,耐受性较差,米拉贝隆是一种新的治疗OAB的药物,具有良好的疗效和耐受性,以β-3肾上腺素能受体为靶点,起效的同时,并不影响膀胱收缩力,特别适用于伴有膀胱逼尿肌力的OAB患者。目前,已是被多个指南的*用药。
2013年1月14日,安斯泰来(Astellas)生产的Betmiga(mirabegron)获欧盟委员会(EC)批准,用于膀胱过度活动症(OAB)的治疗。
mirabegron可选择性地与膀胱肌肉的β-3肾上腺素受体结合并将其激活,这有助于促进膀胱充盈和储尿,这是膀胱控制药物的一种新机制。
目前的标准治疗是一类名为抗毒蕈碱类的药物,但该药会引起致严重的口干、便秘等副作用,从而导致许多患者停止用药。


Betmiga 25mg & 50mg prolonged-release tablets
1. Name of the medicinal product
Betmiga 25 mg prolonged-release tablets
Betmiga 50 mg prolonged-release tablets
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 tablets
Oval, brown tablet, debossed with the company logo and “325” on the same side.
Betmiga 50 mg tablets
Oval, yellow tablet, debossed with the company logo and “355” on the same side.
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 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).

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 once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed.
4.3 Contraindications
Mirabegron is contraindicated in patients with
- 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. 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 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 medications 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 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 (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.
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
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.
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 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.
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.

MedDRA

System organ class

Common

Uncommon

Rare

Very rare

Not known (cannot be estimated from the available data)

Infections and infestations

Urinary tract infection

Vaginal infection

Cystitis

Psychiatric disorders

Insomnia*

Eye disorders

Eyelid oedema

Cardiac disorders

Tachycardia

Palpitation

Atrial fibrillation

Vascular disorders

Hypertensive crisis*

Gastrointestinal disorders

Nausea

Constipation

Diarrhoea

Dyspepsia

Gastritis

Lip oedema

Skin and subcutaneous tissue disorders

Urticaria

Rash

Rash macular

Rash papular

Pruritus

Leukocytoclastic vasculitis

Purpura

Angioedema*

Musculoskeletal and connective tissue disorders

Joint swelling

Reproductive system and breast disorders

Vulvovaginal pruritus

Investigations

Blood pressure increased

GGT increased

AST increased

ALT increased

Renal and urinary disorders

Urinary retention*

Nervous system disorders

Headache*

Dizziness*

observed during post-marketing experience
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
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.
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 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

Parameter

Pooled studies

(046, 047, 074)

Placebo

Mirabegron

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 placeb (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
Table 2: Co-primary and Selected Secondary Efficacy Endpoints at End of Treatment for Studies 046, 047 and 074

Parameter

Study 046

Study 047

Study 074

Placebo

Mirabegron 50 mg

Tolterodine ER 4 mg

Placebo

Mirabegron 50 mg

Placebo

Mirabegron 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 from baseline

-1.17

-1.57

-1.27

-1.13

-1.47

-0.96

-1.38

Mean difference from placebo

--

-0.41

-0.10

--

-0.34

--

-0.42

95% Confidence Interval

--

(-0.72, -0.09)

(-0.42, 0.21)

--

(-0.66, -0.03)

--

(-0.76, -0.08)

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 from baseline

-1.34

-1.93

-1.59

-1.05

-1.66

-1.18

-1.60

Mean difference from placebo†

--

-0.60

-0.25

--

-0.61

--

-0.42

95% Confidence Interval

--

(-0.90, -0.29)

(-0.55, 0.06)

--

(-0.98, -0.24)

--

(-0.76, -0.08)

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 from baseline

12.3

24.2

25.0

7.0

18.2

8.3

20.7

Mean difference from placebo

--

11.9

12.6

--

11.1

--

12.4

95% Confidence Interval

--

(6.3, 17.4)

(7.1, 18.2)

--

(4.4, 17.9)

--

(6.3, 18.6)

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 from baseline†

-0.22

-0.31

-0.29

-0.08

-0.19

-0.15

-0.29

Mean difference from placebo†

--

-0.09

-0.07

--

-0.11

--

-0.14

95% Confidence Interval

--

(-0.17,

-0.02)

(-0.15, 0.01)

--

(-0.18, -0.04)

--

(-0.22, -0.06)

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

Mean change from baseline†

-1.11

-1.46

-1.18

-0.89

-1.32

-0.95

-1.33

Mean difference from placebo†

--

-0.35

-0.07

--

-0.43

--

-0.39

95% Confidence Interval

--

(-0.65, -0.05)

(-0.38, 0.23)

--

(-0.72, -0.15)

--

(-0.69, -0.08)

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 from baseline†

-1.65

-2.25

-2.07

-0.82

-1.57

-1.35

-1.94

Mean difference from placebo†

--

-0.60

-0.42

--

-0.75

--

-0.59

95% Confidence Interval

--

(-1.02, -0.18)

(-0.84, -0.00)

--

(-1.20, -0.30)

--

(-1.01, -0.16)

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 from baseline

1.89

2.55

2.44

0.7

1.5

1.05

1.88

Mean difference from placebo

--

0.66

0.55

--

0.8

--

0.83

95% Confidence Interval

--

(0.25, 1.07)

(0.14, 0.95)

--

(0.4, 1.3)

--

(0.41, 1.25)

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.
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 3: Co-primary efficacy endpoints for patients with prior OAB antimuscarinic therapy

Parameter

Pooled studies

(046, 047, 074)

Study 046

Placebo

Mirabegron 50 mg

Placebo

Mirabegron 50 mg

Tolterodine 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 baselin

-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).
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.
Biotransfrmation
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 (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 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
Macrogols
Hydroxypropylcellulose
Butylhydroxytoluene
Magnesium stearate
Film coating Betmiga 25 mg prolonged-release tablets
Hypromellose
Macrogol
Iron oxide yellow (E172)
Iron oxide red (E172)
Film coating Betmiga 50 mg prolonged-release tablets
Hypromellose
Macrogol
Iron oxide yellow (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
Shelf life after first opening of the bottle: 6 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Alu-Alu blisters in cartons containing 10, 20, 30, 50, 60, 90, 100 or 200 tablets.
HDPE bottles with child-resistant polypropylene (PP) caps and a silica gel desiccant containing 90 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
The Netherlands
8. Marketing authorisation number(s)
EU/1/12/809/001 – 018
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 20 December 2012
10. Date of revision of the text
31 March 2016
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
---------------------------------------------------
产地国家:瑞士  
原产地英文商品名:
Betmiga Retard Tabletten 25mg/tab 30tabs/box 
原产地英文药品名:
Mirabegron
中文参考商品译名:
Betmiga缓释片 25毫克/片 30片/盒
中文参考药品译名:
米拉贝隆
生产厂家中文参考译名:
安斯泰来制药
生产厂家英文名:
Astellas Pharma AG
---------------------------------------------------
产地国家:瑞士 
原产地英文商品名:
Betmiga Retard Tabletten 50mg/tab 30tabs/box
原产地英文药品名:
Mirabegron
中文参考商品译名:
Betmiga缓释片 50毫克/片 30片/盒
中文参考药品译名:
米拉贝隆
生产厂家中文参考译名:
安斯泰来制药
生产厂家英文名:
Astellas Pharma AG
---------------------------------------------------
产地国家:瑞士  
原产地英文商品名:
Betmiga Retard Tabletten 25mg/tab 90tabs/box 
原产地英文药品名:
Mirabegron
中文参考商品译名:
Betmiga缓释片 25毫克/片 90片/盒
中文参考药品译名:
米拉贝隆
生产厂家中文参考译名:
安斯泰来制药
生产厂家英文名:
Astellas Pharma AG
---------------------------------------------------
产地国家:瑞士 
原产地英文商品名:
Betmiga Retard Tabletten 50mg/tab 90tabs/box
原产地英文药品名:
Mirabegron
中文参考商品译名:
Betmiga缓释片 50毫克/片 90片/盒
中文参考药品译名:
米拉贝隆
生产厂家中文参考译名:
安斯泰来制药
生产厂家英文名:
Astellas Pharma AG
---------------------------------------------------
产地国家:德国
原产地英文商品名:
Betmiga Retard Tabletten 50mg/tab 100tabs/box
原产地英文药品名:
Mirabegron
中文参考商品译名:
Betmiga缓释片 50毫克/片 100片/盒
中文参考药品译名:
米拉贝隆
生产厂家中文参考译名:
安斯泰来制药
生产厂家英文名:
Astellas Pharma AG
---------------------------------------------------
产地国家:荷兰 
原产地英文商品名:
Betmiga prolonged-release tablets 25mg/tab 30tabs/box 
原产地英文药品名:
Mirabegron
中文参考商品译名:
Betmiga缓释片 25毫克/片 30片/盒
中文参考药品译名:
米拉贝隆
生产厂家中文参考译名:
安斯泰来制药
生产厂家英文名:
Astellas Pharma Ltd
---------------------------------------------------
产地国家:荷兰 
原产地英文商品名:
Betmiga prolonged-release tablets 50mg/tab 30tabs/box
原产地英文药品名:
Mirabegron
中文参考商品译名:
Betmiga缓释片 50毫克/片 30片/盒
中文参考药品译名:
米拉贝隆
生产厂家中文参考译名:
安斯泰来制药
生产厂家英文名:
Astellas Pharma Europe B.V.

责任编辑:admin


相关文章
Vesicare(Solifenacin succinate Tablet)
 

最新文章

更多

· GELNIQUE 3% GEL(Oxybut...
· BUP-4 tablet/fine gran...
· 睾酮素凝胶|AndroGel(te...
· Xiaflex(注射用胶原酶溶...
· DESMOPRESSIN Spray(醋...
· 马尿酸乌洛托品片|Hipre...
· Uracyst solution vials...
· Vitaros cream(alprosta...
· Natesto(testosterone) ...
· SILDENAFIL OD TABLETS(...

推荐文章

更多

· GELNIQUE 3% GEL(Oxybut...
· BUP-4 tablet/fine gran...
· 睾酮素凝胶|AndroGel(te...
· Xiaflex(注射用胶原酶溶...
· DESMOPRESSIN Spray(醋...
· 马尿酸乌洛托品片|Hipre...
· Uracyst solution vials...
· Vitaros cream(alprosta...
· Natesto(testosterone) ...
· SILDENAFIL OD TABLETS(...

热点文章

更多