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利那洛肽胶囊|Constella(Linaclotide capsules)

2014-07-07 01:27:32  作者:新特药房  来源:互联网  浏览次数:426  文字大小:【】【】【
简介: 英文药名:Constella(Linaclotide capsules) 中文药名:利那洛肽胶囊 生产厂家:Ironwood制药药品介绍Almirall, S.A.公司 (ALM:MC)和Ironwood制药公司共同宣布其新药Constella®(利那洛肽胶囊290 ...

英文药名:Constella(Linaclotide capsules)

中文药名:利那洛肽胶囊

生产厂家:Ironwood制药
药品介绍
Almirall, S.A.公司 (ALM:MC)和Ironwood制药公司共同宣布其新药Constella®(利那洛肽胶囊290mcg 口服1/日)上市,该药物是首个获批用于治疗中重度IBS-C成人患者新型处方药物,在欧洲,Constella®现已在德国、英国以及北欧国家中上市,且在2013年内有望在数个其他欧洲国家中上市。
在欧盟内,Constella是首个也是仅有的一个获批用于成人IBS-C的治疗药物,已被临床试验证实可以改善患者的腹痛症状——IBS-C的标志性症状,同时也可以改善便秘相关的其他症状。IBS是一种易复发的功能性慢性胃肠道疾病,在欧洲其发病率超过10%。据估计,在IBS患者中,约有1/3为不同严重程度的IBS-C患者。IBS-C相关性症状包括腹痛和/或腹部不适、腹部胀气以及便秘等。
“利那洛肽的上市对于1/3的IBS患者(具有便秘症状)来说是一个好消息。该疾病的相关症状可对患者的生活产生负面影响。对于患者和临床医师来说,IBS-C特异性靶向治疗药物的出现都是极受欢迎的,现今,该药物可以更好地控制这种令人讨厌的慢性疾病。” 胃肠病学家Eamonn Quigley教授表示。
IBS-C诊断
对于患者和临床医师来说,IBS-C的诊断和治疗都是比较令人困惑的。在内科临床诊疗中,具有胃肠道不适主诉的患者有30%是IBS患者,但其中只有19%的患者在首次就诊时即已明确诊断,另有56%的患者需要就诊5次才能获得明确诊断。
与健康个体相比较,IBS-C成人患者不仅健康相关生活质量显著降低,而且与哮喘、偏头痛以及其他不同的疾病状态相似。
Constella获批之前,IBS-C患者的治疗还主要依赖于对个体患者症状的治疗上,例如解痉药物,以及未经许可的抗抑郁药物阵痛治疗和利用缓泻剂治疗便秘。
“数以千计的IBS-C患者正在寻求针对其症状的治疗措施,例如腹部不适和便秘,但直到现在,该疾病尚无特异性的治疗药物。通过许多人的共同努力,针对许多的此类成人患者,现今我们终于可以缓他们的病痛了。该疾病还可以对患者带来严重的苦恼和庞大的治疗费用,在欧洲,总体上来说该疾病造成了巨大的经济负担。” Almirall的首席运营官Luciano Conde表示。
Ironwood 的首席商务官Tom McCourt 表示:“为全世界范围内符合适应证的患者带来利那洛肽药物治疗,是Ironwood公司的重要任务之一。基于此前利那洛肽在美国上市时的良好情况,我们希望它也能够为饱受此种高发病率疾病折磨的欧洲成人IBS-C患者带来生活质量改善。”
Constella®于2012年11月获欧洲委员会批准,在瑞士,该药物也处于正式批准的注册过程之中。
关于Constella® (利那洛肽)
利那洛肽是一种鸟苷酸环化酶-C受体激动剂(GCCA),同时具有内脏镇痛效应和内分泌活性。利那洛肽是一种含有14个氨基酸的合成肽类结构,与内源性鸟苷肽家族相关。利那洛肽及其活性代谢产物都可以与小肠上皮管腔表面的鸟苷酸环化酶-C(GC-C)受体结合。在动物模型中,通过GC-C的活化,利那洛肽可以减轻内脏疼痛,提高胃肠道转运速度,在人类中,该药物也可以提高结肠的转运速度。GC-C活化的结果即细胞内外cGMP(环鸟苷酸)浓度升高。细胞外cGMP可以降低疼痛神经纤维的活性,可减轻模型动物的内脏疼痛。细胞内cGMP可通过激活CFTR(囊性纤维化跨膜传导调节因子),增加小肠腔内氯化物和碳酸氢盐的分泌量,最终导致小肠液分泌增多和小肠转运速度增快。
利那洛肽是由Ironwood公司的科学家发明的,在欧洲,Almirall公司获批对该药物进行市场营销。Constella®是该药物的商标,由Ironwood制药公司所有。
关于便秘型肠易激综合征(IBS-C)
IBS是一种功能性的肠道疾病,主要症状是与排便相关的腹部疼痛或腹部不适,以及以排便紊乱为特征的肠道习惯改变。IBS-C是IBS的4种不同亚型之一。现今人们认为,1/3的IBS患者是IBS-C患者,具有慢性腹痛和便秘症状。功能性胃肠道疾病Rome III诊断标准中包含IBS的诊断标准,即在过去3个月内具有反复发作性腹痛或腹部不适每周至少3天,症状开始于诊断前至少6个月,同时具有以下2种或2种以上表现:症状发作与排便频次改变相关;排便后症状改善;症状发作与排便性状改变相关。
在欧洲人群中,IBS的估计发病率超过10%。IBS对患者的日常生活会带来负面影响,造成了巨大的社会-经济压力,也导致了患者不良的心理预后,在基层医疗体系和二级医疗体系中,该疾病在胃肠道疾病工作中占有绝大部分的比例。鉴于此疾病的复杂性,IBS尚无治愈手段,现有的治疗选择也极少。
包装规格:(2013年6月18日在欧洲上市)
290ugx10片/瓶
290ugx28片/瓶
290ugx60片/瓶
290ugx90片/瓶

Constella 290 micrograms hard capsules
1. Name of the medicinal product
Constella 290 micrograms hard capsules
2. Qualitative and quantitative composition
Each capsule contains 290 micrograms of linaclotide.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Hard capsule.
White to off-white-orange opaque capsule (18 mm x 6.35 mm) marked “290” with grey ink.
4. Clinical particulars
4.1 Therapeutic indications
Constella is indicated for the symptomatic treatment of moderate to severe irritable bowel syndrome with constipation (IBS-C) in adults.
4.2 Posology and method of administration
Posology
The recommended dose is one capsule (290 micrograms) once daily.
Physicians should periodically assess the need for continued treatment. The efficacy of linaclotide has been established in double-blind placebo-controlled studies for up to 6 months. If patients have not experienced improvement in their symptoms after 4 weeks of treatment, the patient should be re-examined and the benefit and risks of continuing treatment reconsidered.
Special populations
Patients with renal or hepatic impairment
No dose adjustments are required for patients with hepatic or renal impairment (see section 5.2).
Elderly patients
For elderly patients, although no dose adjustment is required the treatment should be carefully monitored and periodically re-assessed (see section 4.4).
Paediatric population
The safety and efficacy of linaclotide in children aged 0 to18 years have not yet been established. No data are available.
Constella should not be used in children and adolescents (see sections 4.4 and 5.1).
Method of administration
Oral use. The capsule should be taken at least 30 minutes before a meal (see section 4.5).
4.3 Contraindications
Hypersensitivity to linaclotide or to any of the excipients listed in section 6.1.
Patients with known or suspected mechanical gastrointestinal obstruction.
4.4 Special warnings and precautions for use
Constella should be used after organic diseases have been ruled out and a diagnosis of moderate to severe IBS-C (see section 5.1) is established.
Patients should be aware of the possible occurrence of diarrhoea during treatment. They should be instructed to inform their physician if severe or prolonged diarrhoea occurs (see section 4.8).
Should prolonged (e.g. more than 1 week) or severe diarrhoea occur, medical advice should be sought and temporary discontinuation of linaclotide until diarrhoea episode is resolved may be considered. Additional caution should be exercised in patients who are prone to a disturbance of water or electrolyte balance (e.g. elderly, patients with CV diseases, diabetes, hypertension), and electrolyte control should be considered.
Linaclotide has not been studied in patients with chronic inflammatory conditions of the intestinal tract, such as Crohn's disease and ulcerative colitis; therefore it is not recommended to use Constella in these patients.
Elderly patients
There are limited data in elderly patients (see section 5.1). Because of the higher risk of diarrhoea seen in the clinical trials (see section 4.8), special attention should be given to these patients and the treatment benefit-risk ratio should be carefully and periodically assessed.
Paediatric population
Constella should not be used in children and adolescents as it has not been studied in this population. As GC-C receptor is known to be overexpressed at early ages, children younger than 2 years may be particularly sensitive to linaclotide effects.
4.5 Interaction with other medicinal products and other forms of interaction
No drug-drug interaction studies have been performed. Linaclotide is rarely detectable in plasma following administration of the recommended clinical doses and in vitro studies have shown that linaclotide is neither a substrate nor an inhibitor/inducer of the cytochrome P450 enzyme system and does not interact with a series of common efflux and uptake transporters (see section 5.2).
A food interaction clinical study in healthy subjects showed that linaclotide was not detectable in plasma either in fed or in fasted conditions at the therapeutic doses. Taking Constella in the fed condition produced more frequent and looser stools, as well as more gastrointestinal adverse events, than when taking it under fasting conditions (see section 5.1). The capsule should be taken 30 minutes before a meal (see section 4.2).
Concomitant treatment with proton pump inhibitors, laxatives or NSAIDs may increase the risk of diarrhoea.
In cases of severe or prolonged diarrhoea, absorption of other oral medicinal products may be affected. The efficacy of oral contraceptives may be reduced and the use of an additional contraceptive method is recommended to prevent possible failure of oral contraception (see the prescribing information of the oral contraceptive). Caution should be exercised when prescribing medicinal products absorbed in the intestinal tract with a narrow therapeutic index such as levothyroxine as their efficacy may be reduced.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is limited amount of data from the use of linaclotide in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use during pregnancy.
Breast-feeding
As systemic exposure to linaclotide is minimal, excretion in breast milk is not likely, although it has not been evaluated. Although at therapeutic doses no effects on the breastfed newborn/infant are anticipated, in the absence of human data, the use during breast-feeding is not recommended.
Fertility
Animal studies indicate that there is no effect on male or female fertility.
4.7 Effects on ability to drive and use machines
 Constella has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of safety profile
Linaclotide has been given orally to 1,166 patients with IBS-C in controlled clinical studies. Of these patients, 892 patients received linaclotide at the recommended dose of 290 micrograms per day. Total exposure in the clinical development plan exceeded 1,500 patient-years. The most frequently reported adverse reaction associated with Constella therapy was diarrhoea, mainly mild to moderate in intensity, occurring in less than 20% of patients. In rare and more severe cases, this may – as a consequence – lead to the occurrence of dehydration, hypokalaemia, blood bicarbonate decrease, dizziness, and orthostatic hypotension.
Other common adverse reactions (>1%) were abdominal pain, abdominal distension and flatulence.
Tabulated list of adverse reactions
The following adverse reactions were reported in controlled clinical studies at the recommended dose of 290 micrograms per day with frequencies corresponding to: 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) and very rare (<1/10,000) and not known (cannot be estimated from the available data).

 

MedDRa system organ class

Very common

Common

Uncommon

Rare

Unknown

Infections and infestations

 

Gastroenteritis viral

   

 

Gastrointestinal disorders

Diarrhoea

Abdominal pain

Flatulence

Abdominal distension

Faecal incontinence

Defecation urgency

 

 

Skin and subcutaneous tissue disorders

 

 

 

 

Rash

Metabolism and nutrition disorders

   

Hypokalaemia

Dehydration

Decreased appetite

 

 

Nervous system disorders

 

Dizziness

   

 

Vascular disorders

   

Orthostatic hypotension

 

 

Investigations

     

Blood bicarbonate decreased

Description of selected adverse reactions
Diarrhoea is the most common adverse reaction and is consistent with the pharmacological action of the active substance. 2% of treated patients experienced severe diarrhoea and 5% of patients discontinued treatment due to diarrhoea in clinical studies.
The majority of reported cases of diarrhoea were mild (43%) to moderate (47%); 2% of treated patients experienced severe diarrhoea. Approximately half of the diarrhoea episodes started within the first week of treatment.
Regarding duration of diarrhoea, duration of more than 28 days was reported in 21% of patients with diarrhoea; approximately one third of diarrhoea cases resolved within 7 days.
Five percent of patients discontinued treatment due to diarrhoea in clinical studies. In those patients in which diarrhoea led to discontinuation, it resolved after a few days of discontinuing treatment.
Elderly (>65 years), hypertensive and diabetic patients reported diarrhoea more frequently as compared to the overall IBS-C population included in the clinical trials.
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 (see details below).
United Kingdom
Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard
Ireland
IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.imb.ie, e-mail: imbpharmacovigilance@imb.ie
4.9 Overdose
An overdose may result in symptoms resulting from an exaggeration of the known pharmacodynamic effects of the medicinal product, mainly diarrhoea. In a study in healthy volunteers receiving a single dose of 2,897 micrograms (up to 10-fold the recommended therapeutic dose) the safety profile in these subjects was consistent with that in the overall population, with diarrhoea being the most commonly reported adverse event.
Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted as required.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other drugs for constipation, ATC Code: A06AX04
Mechanism of action
Linaclotide is a Guanylate Cyclase-C receptor agonist (GCCA) with visceral analgesic and secretory activities.
Linaclotide is a 14-amino acid synthetic peptide structurally related to the endogenous guanylin peptide family. Both linaclotide and its active metabolite bind to the GC-C receptor, on the luminal surface of the intestinal epithelium. Through its action at GC-C, linaclotide has been shown to reduce visceral pain and increase GI transit in animal models and increase colonic transit in humans. Activation of GC-C results in an increase in concentrations of cyclic guanosine monophosphate (cGMP), both extracellularly and intracellularly. Extracellular cGMP decreases pain-fiber activity, resulting in reduced visceral pain in animal models. Intracellular cGMP causes secretion of chloride and bicarbonate into the intestinal lumen, through activation of the cystic fibrosis transmembrane conductance regulator (CFTR), which results in increased intestinal fluid and accelerated transit.
Pharmacodynamic effects
In a cross-over food interaction study, 18 healthy subjects were administered Constella 290 micrograms for 7 days both in the fasting and fed state. Taking Constella immediately after a high fat breakfast resulted in more frequent and looser stools, as well as more gastrointestinal adverse events, compared with taking it in the fasted state.
Clinical efficacy and safety
The efficacy of linaclotide was established in two randomised, double-blind, placebo-controlled Phase 3 clinical studies in patients with IBS-C. In one clinical study (study 1), 802 patients were treated with Constella 290 micrograms or placebo once daily for 26 weeks. In the second clinical study (study 2), 800 patients were treated for 12 weeks, and then re-randomised for an additional 4 weeks treatment period. During the 2-weeks pre-treatment baseline period, patients had a mean abdominal pain score of 5.6 (0-10 scale) with 2.2% of abdominal pain-free days, a mean bloating score of 6.6 (0-10 scale), and an average of 1.8 spontaneous bowel movements (SBM)/week.
The characteristics of the patient population included in Phase 3 clinical trials were as follows: mean age of 43.9 years [range 18 - 87 years with 5.3% ≥ 65 years of age], 90.1% female. All patients met Rome II criteria for IBS-C and were required to report a mean abdominal pain score of ≥ 3 on a 0-to-10-point numeric rating scale (criteria that correspond to a moderate to severe IBS population), < 3 complete spontaneous bowel movements and ≤ 5 SBMs per week during a 2-week baseline period.
The co-primary endpoints in both clinical studies were 12-week IBS degree of relief responder rate and 12 week abdominal pain/discomfort responder rate. An IBS degree of relief responder was a patient that was considerably or completely relieved for at least 50% of the treatment period; an abdominal pain/discomfort responder was a patient that had an improvement of 30% or more for at least 50% of the treatment period.
For the 12 weeks data, study 1 shows that 39% of the patients treated with linaclotide compared with 17% of the patients treated with placebo showed response to IBS degree of relief (p<0.0001) and 54% of the patients treated with linaclotide compared with 39% of the patients treated with placebo showed response to abdominal pain/discomfort (p<0.0001). Study 2 shows that 37% of the patients treated with linaclotide compared with 19% of the patients treated with placebo showed response to IBS degree of relief (p<0.0001) and 55% of the patients treated with linaclotide compared with 42% of the patients treated with placebo showed response to abdominal pain/discomfort (p=0.0002).
For the 26 weeks data, study 1 shows that 37% and 54% of the patients treated with linaclotide compared with 17% and 36% of the patients treated with placebo showed response to IBS degree of relief (p<0.0001) and abdominal pain/discomfort (p<0.0001) respectively.
In both studies, these improvements were seen by week 1 and sustained over the entire treatment periods (Figures 1 and 2). Linaclotide has been shown not to cause rebound effect when the treatment was stopped after 3 months continuous treatment.

Other signs and symptoms of IBS-C including bloating, complete spontaneous bowel movement (CSBM) frequency, straining, stool consistency, were improved in linaclotide treated patients vs. placebo (p<0.0001) as shown in the following table. These effects were reached at 1 week and sustained over the entire treatment periods.
Effect of Constella on IBS-C symptoms during the first 12 weeks of treatment in the pooled phase 3 efficacy clinical studies (studies 1 and 2).

Main secondary efficacy parameters

Placebo

(N =797)

Linaclotide

(N =805)

 

Baseline Mean

12-weeks Mean

Change from baseline Mean

Baseline Mean

12-weeks Mean

Change from baseline Mean

LS Mean Difference

Bloating

(11-point NRS)

6.5

5.4

–1.0

6.7

4.6

–1.9

–0.9*

CSBM/week

0.2

1.0

0.7

0.2

2.5

2.2

1.6*

Stool consistency

(BSFS Score)

2.3

3.0

0.6

2.3

4.4

2.0

1.4*

Straining

(5-point ordinal scale)

3.5

2.8

– 0.6

3.6

2.2

–1.3

–0.6*

*p<0.0001, Linaclotide vs Placebo. LS: Least Square
CSBM: Complete Spontaneous Bowel Movement
Treatment with linaclotide also resulted in significant improvements in validated and disease-specific Quality of Life measure (IBS-QoL; p<0.0001), and EuroQoL (p = 0.001). Clinically meaningful response in overall IBS-QoL (> 14 points difference) was achieved in 54% of linaclotide treated patients vs. 39% in placebo treated patients.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of clinical studies with Constella in one or more subsets of the paediatric population in functional constipation. See section 4.2 for information on paediatric use.
5.2 Pharmacokinetic properties
Absorption
In general, linaclotide is minimally detectable in plasma following therapeutic oral doses and therefore standard pharmacokinetic parameters cannot be calculated.
Following single doses of up to 966 micrograms and multiple doses up to 290 micrograms of linaclotide, there were no detectable plasma levels of parent compound or the active metabolite (des-tyrosine). When 2,897 micrograms was administered on day 8, following a 7-day course of 290 micrograms/day, linaclotide was detectable in only 2 of 18 subjects at concentrations just above the lower limit of quantification of 0.2 ng/ml (concentrations ranged from 0.212 to 0.735 ng/ml). In the two pivotal phase 3 studies in which patients were dosed with 290 micrograms of linaclotide once daily, linaclotide was only detected in 2 out of 162 patients approximately 2 h following the initial linaclotide dose (concentrations were 0.241 ng/ml to 0.239 ng/ml) and in none of the 162 patients after 4 weeks of treatment. The active metabolite was not detected in any of the 162 patients at any time point.
Distribution
As linaclotide is rarely detectable in plasma following therapeutic doses, standard distribution studies have not been conducted. It is expected that linaclotide is negligibly or not systemically distributed.
Biotransformation
Linaclotide is metabolised locally within the gastrointestinal tract to its active primary metabolite, des-tyrosine. Both linaclotide and des-tyrosine active metabolite are reduced and enzymatically proteolyzed within the gastrointestinal tract to smaller peptides and naturally occurring amino acids.
The potential inhibitory activity of linaclotide and its active primary metabolite MM-419447 on the human efflux transporters BCRP, MRP2, MRP3, and MRP4 and the human uptake transporters OATP1B1, OATP1B3, OATP2B1, PEPT1 and OCTN1 was investigated in vitro. Results of this study showed that neither peptide is an inhibitor of the common efflux and uptake transporters studied at clinically relevant concentrations.
The effect of linaclotide and its metabolites to inhibit the common intestinal enzymes (CYP2C9 and CYP3A4) and liver enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) or to induce liver enzymes (CYP1A2, 2B6, and 3A4/5) was investigated in vitro. Results of these studies showed that linaclotide and des-tyrosine metabolite are not inhibitors or inducers of the cytochrome P450 enzyme system.
Elimination
Following a single oral dose of 2,897 micrograms linaclotide on day 8, after a 7-day course of 290 micrograms/day in 18 healthy volunteers, approximately 3 to 5% of the dose was recovered in the faeces, virtually all of it as the des-tyrosine active metabolite.
Age and gender
Clinical studies to determine the impact of age and gender on the clinical pharmacokinetics of linaclotide have not been conducted because it is rarely detectable in plasma. Gender is not expected to have any impact on dosing. For age related information, please see sections 4.2., 4.4., and 4.8.
Renal impairment
Constella has not been studied in patients who have renal impairment. Linaclotide is rarely detectable in plasma, therefore, renal impairment would not be expected to affect clearance of the parent compound or its metabolite.
Hepatic impairment
Constella has not been studied in patients who have hepatic impairment. Linaclotide is rarely detectable in plasma and is not metabolised by liver cytochrome P450 enzymes, therefore, hepatic impairment would not be expected to affect the metabolism or clearance of the parent drug or its metabolite.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.
6. Pharmaceutical particulars
6.1 List of excipients
Capsule contents
Cellulose, microcrystalline
Hypromellose
Calcium chloride dihydrate
Leucine
Capsule shell
Titanium dioxide (E 171)
Gelatin
Red iron oxide (E172)
Yellow iron oxide (E172)
Capsule ink
Shellac
Propylene glycol
Ammonia solution, concentrated
Potassium hydroxide
Titanium dioxide (E 171)
Black iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Unopened bottle: 3 years.
Once the bottle is opened, the capsules should be used within 18 weeks.
6.4 Special precautions for storage
Do not store above 30°C. Keep the bottle tightly closed in order to protect from moisture.
The bottle contains one or more sealed canisters containing silica gel to keep the capsules dry. Keep the canisters in the bottle.
6.5 Nature and contents of container
White, high density polyethylene (HDPE) bottle with a tamper evident seal and a child-resistant screw cap, together with one or more desiccant canisters containing silica gel.
Pack sizes: 10, 28, 60 and 90 capsules. 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
Almirall, S.A.
Ronda General Mitre, 151
08022 Barcelona
Spain
8. Marketing authorisation number(s)
EU/1/12/801/001
EU/1/12/801/002
EU/1/12/801/003
EU/1/12/801/004
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 26 November 2012
10. Date of revision of the text
03/2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

责任编辑:admin


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