Bydureon(exenatide，艾塞那肽缓释注射用混悬液)每周注射一次的疗法在欧盟获批上市

欧盟已经批准Bydureon®每周注射一次的疗法上市，该药将在欧盟国家逐一推出。
Bydureon®是2型糖尿病治疗中首个也是唯一的每周注射一次疗法，在欧盟获批也是世界首次。
　　
欧盟已经批准Bydureon®(艾塞那肽2毫克粉剂和注射用缓释悬剂)上市，礼来公司将与AmylinPharmaceuticals和Alkermes共同开发市场，在欧盟内的27个成员国逐一推出此药。
　　
重要性：胰高糖素样肽1受体激动剂Bydureon®是2型糖尿病治疗中首个也是唯一的每周注射一次疗法，在欧盟获批也是世界首次，只需要每周一次注射就可以很好地控制血糖。
　　
适应症：欧盟批准Bydureon与二甲双胍、磺脲类药物和噻唑烷二酮等单药或多药联合使用治疗2型糖尿病。
　　
礼来公司糖尿病业务副总裁EnriqueConterno说：“Bydureon是控制糖尿病一个全新的选择。全球的糖尿病发病状况以及疾病对各方面的影响都令人不容乐观，因此，创新性的治疗方案对病患会有很大帮助。”他接着说，Bydureon在欧盟获批是礼来糖尿病事业一个重要的里程碑。礼来糖尿病产品研发线上有6个化合物处于后期研发阶段，其中包括了在5月份在美国获批并上市的Tradjenta™。
　　
上市计划：Bydureon预计在2011年第三季度开始上市。在英国之后，德国也会推出。因为考虑到各国的医疗保险支付，礼来将在欧盟逐步推出此药。
　　
临床和安全数据：Bydureon欧盟的获批是基于包括DURATION临床研究结果的完整数据：在六个月内，使用Bydureon改善了血糖控制，糖化血红蛋白指标与基线相比下降1.5%-1.9%。主要的临床副反应是轻中度的恶心(约占20%的临床病人)、呕吐和腹泻。

药物：Bydureon（艾塞那肽缓释剂）

疾病：2型糖尿病

开发商：Amylin制药，礼来（Eli Lilly）和Alkermes

 BYDUREON® 2 mg powder and solvent for prolonged-release suspension for injection.

Go to top of the page2. QUALITATIVE AND QUANTITATIVE COMPOSITION
 Each vial contains 2 mg of exenatide.

For a full list of excipients, see section 6.1.

Go to top of the page3. PHARMACEUTICAL FORM
 Powder and solvent for prolonged-release suspension for injection.

Powder: white to off-white powder.

Solvent: clear, colourless to pale yellow to pale brown solution.

Go to top of the page4. CLINICAL PARTICULARS
  

Go to top of the page4.1 Therapeutic indications
 BYDUREON is indicated for treatment of type 2 diabetes mellitus in combination with

• Metformin

• Sulphonylurea

• Thiazolidinedione

• Metformin and sulphonylurea

• Metformin and thiazolidinedione

in adults who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies.

Go to top of the page4.2 Posology and method of administration
 Posology

The recommended dose is 2 mg exenatide once weekly.

Patients switching from exenatide twice daily (BYETTA) to BYDUREON may experience transient elevations in blood glucose concentrations, which generally improve within the first two weeks after initiation of therapy.

When BYDUREON is added to existing metformin and/or thiazolidinedione therapy, the current dose of metformin and/or thiazolidinedione can be continued. When BYDUREON is added to sulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered to reduce the risk of hypoglycaemia (see section 4.4).

BYDUREON should be administered once a week on the same day each week. The day of weekly administration can be changed if necessary as long as the next dose is administered at least one day (24 hours) later. BYDUREON can be administered at any time of day, with or without meals.

If a dose is missed, it should be administered as soon as practical. Thereafter, patients can resume their once weekly dosing schedule. Two injections should not be given on the same day.

The use of BYDUREON does not require additional self-monitoring. Blood glucose self-monitoring may be necessary to adjust the dose of sulphonylurea.

If a different antidiabetic treatment is started after the discontinuation of BYDUREON, consideration should be given to the prolonged release of BYDUREON (see section 5.2).

Special populations

Elderly

No dose adjustment is required based on age. However, as renal function generally declines with age, consideration should be given to the patient's renal function (see patients with renal impairment). The clinical experience in patients > 75 years is very limited (see section 5.2).

Patients with renal impairment

No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50 to 80 ml/min). Clinical experience in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min) is very limited (see section 5.2). BYDUREON is not recommended in these patients.

BYDUREON is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.4).

Patients with hepatic impairment

No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of BYDUREON in children and adolescents aged under 18 years have not yet been established (see section 5.2). No data are available.

Method of administration

BYDUREON is for self administration by the patient. Each kit should be used by one person only and is for single use.

Appropriate training is recommended for non-healthcare professionals administering the product. The “Instructions for the User”, provided in the carton, must be followed carefully by the patient.

Each dose should be administered in the abdomen, thigh, or the back of the upper arm as a subcutaneous injection immediately after suspension of the powder in the solvent.

For instructions on the suspension of the medicinal product before administration, see section 6.6 and the “Instructions for the User”.

Go to top of the page4.3 Contraindications
 Hypersensitivity to the active substance or to any of the excipients.

Go to top of the page4.4 Special warnings and precautions for use
 BYDUREON should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

BYDUREON must not be administered by intravenous or intramuscular injection.

This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially “sodium-free”.

Renal impairment

In patients with end-stage renal disease receiving dialysis, single doses of exenatide twice daily increased frequency and severity of gastrointestinal adverse reactions, therefore BYDUREON is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 ml/min). The clinical experience in patients with moderate renal impairment is very limited and the use of BYDUREON is not recommended.

There have been rare, spontaneously reported events of altered renal function with exenatide, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring haemodialysis. Some of these events occurred in patients experiencing events that may affect hydration, including nausea, vomiting, and/or diarrhoea and/or receiving medicinal products known to affect renal function/hydration status. Concomitant medicinal products included angiotensin converting enzymes inhibitors, angiotensin-II antagonists, non-steroidal anti-inflammatory medicinal products and diuretics. Reversibility of altered renal function has been observed with supportive treatment and discontinuation of potentially causative agents, including exenatide.

Severe gastrointestinal disease

BYDUREON has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Its use is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhoea. Therefore, the use of BYDUREON is not recommended in patients with severe gastrointestinal disease.

Acute pancreatitis

There have been rare, spontaneously reported events of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed with supportive treatment, but very rare cases of necrotizing or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, BYDUREON and other potentially suspect medicinal products should be discontinued. Treatment with BYDUREON should not be resumed after pancreatitis has been diagnosed.

Concomitant medicinal products

The concurrent use of BYDUREON with insulin, D-phenylalanine derivatives (meglitinides), alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors or other GLP-1 receptor agonists has not been studied. The concurrent use of BYDUREON and exenatide twice daily (BYETTA) has not been studied and is not recommended.

Hypoglycaemia

The risk of hypoglycaemia was increased when BYDUREON was used in combination with a sulphonylurea in clinical trials. Furthermore, in the clinical studies, patients on a sulphonylurea combination, with mild renal impairment had an increased incidence of hypoglycaemia compared to patients with normal renal function. To reduce the risk of hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea should be considered.

Rapid weight loss

Rapid weight loss at a rate of >1.5 kg per week has been reported in patients treated with exenatide. Weight loss of this rate may have harmful consequences.

Interaction with warfarin

There have been some reported cases of increased INR (International Normalized Ratio), sometimes associated with bleeding, with concomitant use of warfarin and exenatide (see section 4.5).

Discontinuation of treatment

After discontinuation, the effect of BYDUREON may continue as plasma levels of exenatide decline over 10 weeks. Choice of other medicinal products and dose selection should be considered accordingly, as adverse reactions may continue and efficacy may, at least partly, persist until exenatide levels decline.
 

The absorption properties of exenatide reflect the extended release properties of the BYDUREON formulation. Once absorbed into the circulation, exenatide is distributed and eliminated according to its known systemic pharmacokinetic properties (as described in this section). Absorption Following weekly administration of 2 mg BYDUREON, mean exenatide concentrations exceeded minimal efficacious concentrations (~ 50 pg/ml) in 2 weeks with gradual increase in the average plasma exenatide concentration over 6 to 7 weeks. Subsequently, exenatide concentrations of approximately 300 pg/ml were maintained indicating that steady-state was achieved. Steady-state exenatide concentrations are maintained during the one week interval between doses with minimal peak to trough fluctuation from this average therapeutic concentration. Distribution The mean apparent volume of distribution of exenatide following subcutaneous administration of a single dose of exenatide is 28 l. Biotransformation and elimination Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide is 9 l/h. These pharmacokinetic characteristics of exenatide are independent of the dose. Approximately 10 weeks after discontinuation of BYDUREON therapy, mean plasma exenatide concentrations fell below minimal detectable concentrations. Special populations Patients with renal impairment Population pharmacokinetic analysis of renal impaired patients receiving 2 mg BYDUREON indicate that there may be an increase in systemic exposure of approximately 74 % and 23 % (median prediction in each group) in moderate (N=10) and mild (N=56) renal impaired patients, respectively as compared to normal (N=84) renal function patients. Patients with hepatic insufficiency No pharmacokinetic study has been performed in patients with hepatic insufficiency. Exenatide is cleared primarily by the kidney, therefore hepatic dysfunction is not expected to affect blood concentrations of exenatide. Gender, race and body weight Gender, race and body weight have no clinically relevant influence on exenatide pharmacokinetics. Elderly Data in elderly are limited, but suggest no marked changes in exenatide exposure with increased age up to about 75 years old. In a pharmacokinetic study of exenatide twice daily in patients with type 2 diabetes, administration of exenatide (10 µg) resulted in a mean increase of exenatide AUC by 36 % in 15 elderly subjects aged 75 to 85 years compared to 15 subjects aged 45 to 65 years likely related to reduced renal function in the older age group (see section 4.2). Paediatric population In a single-dose pharmacokinetic study of exenatide twice daily in 13 patients with type 2 diabetes and between the ages of 12 and 16 years, administration of exenatide (5 μg) resulted in slightly lower mean AUC (16 % lower) and Cmax (25 % lower) compared to those observed in adults. No pharmacokinetics study of BYDUREON has been conducted in the paediatric population.

5.3 Preclinical safety data

Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, or genotoxicity conducted with exenatide twice daily or BYDUREON. In a 104-week carcinogenicity study with BYDUREON a statistically significant increase in thyroid c - cell tumour incidence (adenomas and / or carcinomas) was observed in rats at all doses (1.4- to 26-fold the human clinical exposure with BYDUREON). The human relevance of these findings is currently unknown. Animal studies with exenatide did not indicate harmful effects with respect to fertility; high doses of exenatide caused skeletal effects and reduced foetal and neonatal growth.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder poly (D,L-lactide-co-glycolide) sucrose Solvent carmellose sodium sodium chloride polysorbate 20 monobasic sodium phosphate, monohydrate dibasic sodium phosphate, heptahydrate water for injections

6.2 Incompatibilities

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

2 years After reconstitution The suspension must be injected immediately.

6.4 Special precautions for storage

Store in a refrigerator (2ºC - 8ºC). Do not freeze. The kit may be kept for up to 4 weeks below 30ºC prior to use. Store in the original package in order to protect from light.

6.5 Nature and contents of container

The powder is packaged in a 3ml Type I glass vial sealed with a chlorobutyl rubber stopper and an aluminum seal with a plastic flip-off cap. The solvent is packaged in a 1.5ml Type 1 glass pre-filled syringe sealed with a bromobutyl rubber cap and a rubber plunger. Each single-dose kit contains one vial of 2mg exenatide, one pre-filled syringe of 0.65ml solvent, one vial connector, and two injection needles (one spare). Pack size of 4 single-dose kits and a multipack consisting of 3 x 4 single-dose kits. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The patient should be instructed to discard the syringe safely, with the needle still attached after each injection. The patient should recap the needle. The patient does not need to save any part of the single-use kit. The solvent should be visually inspected prior to use. The solvent should only be used if it is clear and free of particulate matter. After suspension, BYDUREON should only be used if the mixture is white to off white and cloudy. BYDUREON must be injected immediately after suspension of the powder in the solvent. BYDUREON that has been frozen must not be used. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Eli Lilly Nederland B.V., Grootslag 1-5, NL-3991 RA Houten, The Netherlands.

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/11/696/001 4 single-dose kits EU/1/11/696/002 3 x 4 single-dose kits

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17 June 2011

10. DATE OF REVISION OF THE TEXT

17 June 2011 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

LEGAL CATEGORY

POM BYDUREON® (exenatide) is a registered trade mark of Amylin Pharmaceuticals, Inc.