英文药名：Bydureon（EXENATIDE injection in pre-filled pen）

中文药名：艾塞那肽缓释剂注射用混悬液预充笔

生产厂家：Amylin Pharmaceuticals，Inc./Alkermes plc
药品介绍
Bydureon为长效注射剂。艾塞那肽为人胰高血糖素样肽-1（GLP-1）的类似物，与GLP-1具有相同的生理功能
适应症和用途
BYDUREON是一种胰高血糖素样肽-1(GLP-1)受体激动剂适用作为膳食和运动的辅助改善血糖控制在2型糖尿病成年在多种临床情况中。
BYDUREON是艾塞那肽的一种缓释剂制剂。不要与BYETTA同时给予。
使用的重要限制
● 不推荐对膳食和运动控制不佳患者作为一线治疗。
● 不应使用治疗1型糖尿病或糖尿病酮症酸中毒。
● 尚未研究与胰岛素和不推荐。
● 尚未在有胰腺炎史患者中研究。有胰腺炎史患者考虑其他抗糖尿病治疗。
剂量和给药方法
● 通过皮下注射每7天1次(每周)给予2mg，在白天任何事件和有或无进餐。
● 在粉悬浮后立即给药。
剂型和规格
BYDUREON是2mg艾塞那肽为缓释剂可注射悬液。
禁忌症
● 如髓性甲状腺癌个人或家庭史或有多发性内分泌肿瘤综合征2型患者中不要使用。
● 如对艾塞那肽或任何产品成分严重超敏性史不要使用。
批准上市时间
2011年6月在欧盟获批
2012年1月27日获得FDA批准上市
上市许可持有人
阿斯利康AB

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled pen
1. Name of the medicinal product
Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled pen
2. Qualitative and quantitative composition
Each pre-filled pen contains 2 mg of exenatide. After reconstitution, each pen delivers a dose of 2 mg in 0.65 ml.
For the full list of excipients, see section 6.1.
3. 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.
4. Clinical particulars
4.1 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.
4.2 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. For the next injection patients can return to their chosen injection day. However, only one injection should be taken in a 24 hour period.
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 patients
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 Bydureone in children and adolescents aged under 18 years have not yet been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.
Method of administration
Bydureon is for self administration by the patient. Each pen should be used by one person only and is for single use.
Prior to initiation of Bydureon, it is strongly recommended that patients be trained by their healthcare professional. 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”.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 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
Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. There have been rare, spontaneously reported events of acute pancreatitis with Bydureon. Resolution of pancreatitis has been observed with supportive treatment, but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, Bydureon should be discontinued; if acute pancreatitis is confirmed, Bydureon should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
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, e.g. cholelithiasis.
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.
4.5 Interaction with other medicinal products and other forms of interaction
The results of a study using paracetamol as a marker of gastric emptying suggest that the effect of Bydureon to slow gastric emptying is minor and not expected to cause clinically significant reductions in the rate and extent of absorption of concomitantly administered oral medicinal products. Therefore, no dose adjustments for medicinal products sensitive to delayed gastric emptying are required.
When 1,000 mg paracetamol tablets were administered, either with or without a meal, following 14 weeks of Bydureon therapy, no significant changes in paracetamol AUC were observed compared to the control period. Paracetamol Cmax decreased by 16 % (fasting) and 5 % (fed) and tmax was increased from approximately 1 hour in the control period to 1.4 hours (fasting) and 1.3 hours (fed).
Sulphonylureas
The dose of a sulphonylurea may require adjustment due to the increased risk of hypoglycaemia associated with sulphonylurea therapy (see sections 4.2 and 4.4).
The following interaction studies have been conducted using 10 mcg exenatide twice daily but not exenatide once weekly:
Hydroxy Methyl Glutaryl Coenzyme A reductase inhibitors
Lovastatin AUC and Cmax were decreased approximately 40 % and 28 %, respectively, and tmax was delayed about 4 h when exenatide twice daily was administered concomitantly with a single dose of lovastatin (40 mg) compared with lovastatin administered alone. In exenatide twice daily 30-week placebo-controlled clinical trials, concomitant use of exenatide and HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles (see section 5.1). No predetermined dose adjustment is required; however lipid profiles should be monitored as appropriate.
Warfarin
A delay in tmax of about 2 h was observed when warfarin was administered 35 min after exenatide twice daily. No clinically relevant effects on Cmax or AUC were observed. Increased INR has been reported during concomitant use of warfarin and exenatide twice daily. INR should be monitored during initiation of Bydureon therapy in patients on warfarin and/or cumarol derivatives (see section 4.8).
Digoxin and lisinopril
In interaction studies of the effect of exenatide twice daily on digoxin and lisinopril there were no clinical relevant effects on Cmax or AUC, however a delay in tmax of about 2 h was observed.
Ethinyl estradiol and levonorgestrel
Administration of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) one hour before exenatide twice daily did not alter the AUC, Cmax or Cmin of either ethinyl estradiol or levonorgestrel. Administration of the oral contraceptive 35 minutes after exenatide did not affect AUC but resulted in a reduction of the Cmax of ethinyl estradiol by 45 %, and Cmax of levonorgestrel by 27-41 %, and a delay in tmax by 2-4 h due to delayed gastric emptying. The reduction in Cmax is of limited clinical relevance and no adjustment of dosing of oral contraceptives is required.
Paediatric population
Interaction studies with exenatide have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Due to the long washout period of Bydureon, women of childbearing potential should use contraception during treatment with Bydureon. Bydureon should be discontinued at least 3 months before a planned pregnancy.
Pregnancy
There are no adequate data from the use of Bydureon in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Bydureon should not be used during pregnancy and the use of insulin is recommended.
Breast-feeding
It is unknown whether exenatide is excreted in human milk. Bydureon should not be used during breast-feeding.
Fertility
No fertility studies in humans have been conducted.
4.7 Effects on ability to drive and use machines
No studies on the effects of the ability to drive and use machines have been performed. When Bydureon is used in combination with a sulphonylurea, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines.
4.8 Undesirable effects
Summary of the safety profile
The most frequent adverse reactions (≥ 5 % of Bydureon treatment) were mainly gastrointestinal related (nausea, vomiting, diarrhoea and constipation). The most frequently reported single adverse reaction was nausea, which was associated with the initiation of treatment and decreased over time. In addition, injection site reactions (pruritus, nodules, erythema), hypoglycaemia (with a sulphonylurea), and headache occurred. Most adverse reactions associated with Bydureon were mild to moderate in intensity.
Acute pancreatitis and acute renal failure have been reported rarely since exenatide twice daily has been marketed (see section 4.4).
Tabulated summary of adverse reactions
The frequency of adverse reactions of Bydureon identified from clinical trials and spontaneous reports are summarised in Table 1 below.
The data source comprises two placebo controlled studies (10 and 15 weeks) and 3 trials comparing Bydureon to either exenatide twice daily (a 30 week study), sitagliptin and pioglitazone (a 26 week study) and insulin glargine (a 26 week study). Background therapies included diet and exercise, metformin, a sulphonylurea, a thiazolidinedione or a combination of oral anti-diabetic agents.
In addition, Table 1 includes spontaneous reports of events that were either not observed in clinical trials (frequency considered not known) or that were observed in clinical trials using the clinical trials database to estimate frequency.
The reactions are listed below as MedDRA preferred term by system organ class and absolute frequency. Patient frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000) and not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1: Adverse reactions of Bydureon identified from clinical trials and spontaneous reports

System organ class /adverse reaction terms	Frequency of occurrence
	Very common	Common	Uncommon	Rare	Very rare	Not known
Immune system disorders
Anaphylactic reaction						X2
Metabolism and nutrition disorders
Hypoglycaemia (with a sulphonylurea)	X1,3
Decreased appetite		X1,3
Dehydration				X4
Nervous system disorders
Headache		X1,3
Dizziness		X1,3
Dysgeusia			X4
Gastrointestinal disorders
Intestinal obstruction			X4
Acute pancreatitis (see section 4.4)						X2
Nausea	X1,3
Vomiting	X1,3
Diarrhoea	X1,3
Dyspepsia		X1,3
Abdominal pain		X1,3
Gastroesophageal reflux disease		X1,3
Abdominal distension		X1
Eructation		X1
Constipation	X1
Flatulence		X1,3
Skin and subcutaneous tissue disorders
Macular and papular rash						X2
Pruritus, and/ or urticaria			X1
Angioneurotic oedema						X2
Injection site abscesses and cellulitis						X2
Hyperhidrosis			X4
Alopecia			X4
Renal and urinary disorders
Altered renal function, including acute renal failure, worsened chronic renal failure, renal impairment, increased serum creatinine (see section 4.4).						X2
General disorders and administration site conditions
Injection site pruritus	X1
Fatigue		X1,3
Injection site erythema		X1
Injection site rash		X1
Somnolence		X1
Asthenia		X4
Feeling jittery				X4
Investigations
International normalised ratio increased (see section 4.4)				X4

1 Rate based on Bydureon clinical trial database n= 592 total, (patients on sulphonylurea n= 135).
2 Rate based on Bydureon spontaneous reports data.
3 Reactions were in the same frequency grouping in the exenatide twice-daily treatment group.
4 Rate based on Bydureon clinical trial database n=3,111 (including all completed long-term efficacy and safety studies).
Description of selected adverse reactions
Hypoglycaemia
The incidence of hypoglycaemia was increased when Bydureon was used in combination with a sulphonylurea (15.9 % versus 2.2 %) (see section 4.4). To reduce the risk of hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea may be considered (see sections 4.2 and 4.4).
Bydureon was associated with a significantly lower incidence of episodes of hypoglycaemia than insulin glargine in patients also receiving metformin therapy (3 % versus 19 %) and in patients also receiving metformin plus sulphonylurea therapy (20 % versus 42 %).
Across all studies most episodes (96.8 % n=32) of hypoglycaemia were minor, and resolved with oral administration of carbohydrate. One patient was reported with major hypoglycaemia since he had a low blood glucose value (2.2 mmol/l) and requested assistance with oral carbohydrate treatment which resolved the event.
Nausea
The most frequently reported adverse reaction was nausea. In patients treated with Bydureon, generally 20 % reported at least one episode of nausea compared to 34 % of exenatide twice-daily patients. Most episodes of nausea were mild to moderate. With continued therapy, the frequency decreased in most patients who initially experienced nausea.
The incidence of withdrawal due to adverse events during the 30-week controlled trial was 6 % for Bydureon-treated patients, 5 % for exenatide twice-dailytreated patients. The most common adverse events leading to withdrawal in either treatment group were nausea and vomiting. Withdrawal due to nausea or vomiting each occurred in < 1 % for Bydureon-treated patients and 1 % for exenatide twice daily treated patients.
Injection site reactions
Injection site reactions were observed more frequently in Bydureon-treated patients versus comparator treated patients (16 % versus range of 2-7 %) during the 6 month controlled phase of studies. These injection site reactions were generally mild and usually did not lead to withdrawal from studies. Patients may be treated to relieve symptoms, while continuing treatment. Subsequent injections should use a different site of injection each week. In post marketing experiences, cases with injection site abscesses and cellulitis have been reported.
Small subcutaneous injection site nodules were observed very frequently in clinical trials, consistent with the known properties of poly (D,L-lactide co-glycolide) polymer microsphere formulations. Most individual nodules were asymptomatic, did not interfere with study participation and resolved over 4 to 8 weeks.
Immunogenicity
Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop antibodies to exenatide following treatment with Bydureon. In most patients who develop antibodies, antibody titres diminish over time.
The presence of antibodies (high or low titres) is not predictive of glycaemic control for an individual patient.
In clinical studies of Bydureon, approximately 45 % of patients had low titre antibodies to exenatide at study endpoint. Overall the percentage of antibody positive patients was consistent across clinical trials. Overall, the level of glycaemic control (HbA1c) was comparable to that observed in those without antibody titres. On average in the phase 3 studies, 12 % of the patients had higher titre antibodies. In a proportion of these the glycaemic response to Bydureon was absent at the end of the controlled period of studies; 2.6 % of patients showed no glucose improvement with higher titre antibodies while 1.6 % showed no improvement while antibody negative.
Patients who developed antibodies to exenatide tend to have more injection site reactions (for example: redness of skin and itching), but otherwise similar rates and types of adverse events as those with no antibodies to exenatide.
For Bydureon-treated patients, the incidence of potentially immunogenic injection site reactions (most commonly pruritus with or without erythema) during the 30-week and the two 26-week studies, was 9 %. These reactions were less commonly observed in antibody-negative patients (4 %) compared with antibody-positive patients (13 %), with a greater incidence in those with higher titre antibodies.
Examination of antibody-positive specimens revealed no significant cross-reactivity with similar endogenous peptides (glucagon or GLP-1).
Rapid weight loss
In a 30-week study, approximately 3 % (n=4/148) of Bydureon-treated patients experienced at least one time period of rapid weight loss (recorded body weight loss between two consecutive study visits of greater than 1.5 kg/week).
Increased heart rate
A mean increase in heart rate (HR) of 2.6 beats per minute (bpm) from baseline (74 bpm) was observed in pooled Bydureon clinical studies. Fifteen percent of Bydureon treated patients had mean increases in HR of ≥10 bpm; approximately 5% to 10% of subjects within the other treatment groups had mean increases in HR of ≥10 bpm.
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:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
Malta
ADR Reporting
Website: www.medicinesauthority.gov.mt/adrportal
4.9 Overdose
Effects of overdoses with exenatide (based on exenatide twice daily clinical studies) included severe nausea, severe vomiting and rapidly declining blood glucose concentrations. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, other blood glucose lowering drugs, excl. insulins, ATC code: A10BX04.
Mechanism of action
Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that exhibits several antihyperglycaemic actions of glucagon-like peptide-1 (GLP-1). The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind to and activate the known human GLP-1 receptor in vitro, its mechanism of action mediated by cyclic AMP and/or other intracellular signaling pathways.
Exenatide increases, on a glucose-dependent basis, the secretion of insulin from pancreatic beta cells. As blood glucose concentrations decrease, insulin secretion subsides. When exenatide was used in combination with metformin and/or a thiazolidinedione, no increase in the incidence of hypoglycaemia was observed over that of placebo in combination with metformin and/or a thiazolidinedione which may be due to this glucose-dependent insulinotropic mechanism (see section 4.4).
Exenatide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output. However, exenatide does not impair the normal glucagon response and other hormone responses to hypoglycaemia.
Exenatide slows gastric emptying thereby reducing the rate at which meal-derived glucose appears in the circulation.
Administration of exenatide has been shown to reduce food intake, due to decreased appetite and increased satiety.
Pharmacodynamic effects
Exenatide improves glycaemic control through the sustained effects of lowering both postprandial and fasting glucose concentrations in patients with type 2 diabetes. Unlike native GLP-1, Bydureon has a pharmacokinetic and pharmacodynamic profile in humans suitable for once weekly administration.
A pharmacodynamic study with exenatide demonstrated in patients with type 2 diabetes (n=13) a restoration of first phase insulin secretion and improved second phase insulin secretion in response to an intravenous bolus of glucose.
Clinical efficacy and safety
The results of long-term clinical studies of Bydureon are presented below; these studies comprised 1628 subjects (804 treated with Bydureon), 54 % men and 46 % women, 281 subjects (141 treated with Bydureon) were ≥ 65 years of age.
Glycaemic control
In two studies Bydureon 2 mg once weekly has been compared to exenatide twice daily 5 mcg for 4 weeks followed by exenatide twice daily 10 mcg. One study was of 24 weeks in duration (n= 252) and the other of 30 weeks (n= 295) followed by an open labelled extension where all patients were treated with Bydureon 2 mg once weekly for a further 22 weeks (n= 243). In both studies, decreases in HbA1c were evident in both treatment groups as early as the first post-treatment HbA1c measurement (weeks 4 or 6).
Bydureon resulted in a statistically significant reduction in HbA1c compared to patients receiving exenatide twice daily (Table 2).
A clinically relevant effect of Bydureon and exenatide twice-daily treated subjects was observed on HbA1c, regardless of the background anti-diabetic therapy in both studies.
Clinically and statistically significantly more subjects on Bydureon compared to exenatide twice-daily patients achieved an HbA1c reduction of ≤ 7 % or < 7 % in the two studies (p < 0.05 and p=< 0.0001 respectively).
Both Bydureon and exenatide twice daily patients achieved a reduction in weight compared to baseline, although the difference between the two treatment arms was not significant.
Further reductions in HbA1c and sustained weight loss were observed for at least 52 weeks in the patients completing both the controlled 30-week study and the uncontrolled study extension. The evaluable patients who switched from exenatide twice daily to Bydureon (n= 121) achieved the same improvement in HbA1c of - 2.0 % , at the end of the 22 week extension compared to the initial baseline, as the patients treated with Bydureon for 52 weeks.
Table 2: Results of two trials of Bydureon versus exenatide twice daily in combination with diet and exercise alone, metformin and/or sulphonylurea and metformin and/or thiazolidinedione (intent to treat patients).

24 Week Study	Bydureon 2 mg	Exenatide 10 mcg twice daily
N	129	123
Mean HbA1c (%)
Baseline	8.5	8.4
Change from baseline ( ± SE)	-1.6 (±0.1)**	-0.9 (±0.1)
Mean difference change from baseline between treatments(95 % CI)	-0.67 (-0.94, -0.39) **
Patients (%) achieving HbA1c < 7 %	58	30
Change in fasting plasma glucose (mmol/l) ( ± SE)	-1.4 (±0.2)	-0.3 (±0.2)
Mean body weight (kg)
Baseline	97	94
Change from baseline ( ± SE)	-2.3 (±0.4)	-1.4 ( ± 0.4)
Mean difference change from baseline between treatments(95 % CI)	-0.95 (-1.91, 0.01)
30 Week Study
N	148	147
Mean HbA1c (%)
Baseline	8.3	8.3
Change from baseline( ± SE)	-1.9 (±0.1)*	-1.5 (±0.1)
Mean difference change from baseline between treatments(95 % CI)	-0.33 (-0.54, -0.12) *
Patients (%) achieving HbA1c≤7 %	73	57
Change in fasting plasma glucose (mmol/l) ( ± SE)	-2.3 (±0.2)	-1.4( ±0.2)
Mean body weight (kg)
Baseline	102	102
Change from baseline( ± SE)	-3.7 (±0.5)	-3.6 (±0.5)
Mean difference change from baseline between treatments(95 % CI)	-0.08 (-1.29, 1.12)

SE = standard error, CI= confidence interval), * p< 0.05, **p< 0.0001
A study of 26-week duration has been conducted, in which Bydureon 2 mg is compared to insulin glargine once daily. Bydureon demonstrated a superior change in HbA1c compared to insulin glargine. Compared with insulin glargine treatment, Bydureon treatment significantly lowered mean body weight and was associated with fewer hypoglycaemic events (Table 3).
Table 3: Results of one 26 week trial of Bydureon versus insulin glargine in combination with metformin alone or metformin and sulphonylurea (intent to treat patients).

Bydureon 2 mg	Insulin Glargine1
N	233	223
Mean HbA1c (%)
Baseline	8.3	8.3
Change from baseline ( ± SE)	-1.5 ( ± 0.1)*	-1.3 ( ± 0.1)*
Mean difference change from baseline between treatments(95 % CI)	-0.16 (-0.29, -0.03)*
Patients (%) achieving HbA1c≤7 %	62	54
Change in fasting serum glucose (mmol/l) ( ± SE)	-2.1 ( ± 0.2)	-2.8 ( ± 0.2)
Mean body weight (kg)
Baseline	91	91
Change from baseline ( ± SE)	-2.6 ( ± 0.2)	+1.4 ( ±0.2)
Mean difference change from baseline between treatments (95 % CI)	-4.05 (-4.57, -3.52) *

SE = standard error, CI= confidence interval), * p<0.05
1 Insulin glargine was dosed to a target glucose concentration of 4.0 to 5.5 mmol/l (72 to 100 mg/dl). The mean dose of insulin glargine at the beginning of treatment was 10.1 IU/day rising to 31.1 IU/day for insulin glargine-treated patients.
The 156-week results were consistent with those previously reported in the 26-week interim report. Treatment with Bydureon persistently significantly improved glycaemic control and weight control, compared to the insulin glargine treatment. Safety findings at 156 weeks were consistent with those reported at 26 weeks.
In a 26-week double-blind study Bydureon was compared to maximum daily doses of sitagliptin and pioglitazone in subjects also using metformin. All treatment groups had a significant reduction in HbA1c compared to baseline. Bydureon demonstrated superiority to both sitagliptin and pioglitazone with respect to change in HbA1c from baseline.
Bydureon demonstrated significantly greater weight reductions compared to sitagliptin. Patients on pioglitazone gained weight (Table 4).
Table 4: Results of one 26-week trial of Bydureon versus sitagliptin and versus pioglitazone in combination with metformin (intent to treat patients).

Bydureon 2 mg	Sitagliptin 100 mg	Pioglitazone 45 mg
N	160	166	165
Mean HbA1c (%)
Baseline	8.6	8.5	8.5
Change from baseline ( ± SE)	-1.6 (± 0.1)*	-0.9 (± 0.1)*	-1.2 (± 0.1)*
Mean difference change from baseline between treatments (95 % CI) versus sitagliptin	-0.63 ( -0.89, -0.37)**
Mean difference change from baseline between treatments(95 % CI) versus pioglitazone	-0.32 (-0.57, -0.06,)*
Patients (%) achieving HbA1c≤7 %	62	36	49
Change in fasting serum glucose (mmol/l) ( ± SE)	-1.8 (± 0.2)	-0.9 (± 0.2)	-1.5 (± 0.2)
Mean body weight (kg)
Baseline	89	87	88
Change from baseline ( ± SE)	-2.3 (± 0.3)	-0.8 (± 0.3)	+2.8 (± 0.3)
Mean difference change from baseline between treatments(95 % CI) versus sitagliptin	-1.54 (-2.35, -0.72)*
Mean difference change from baseline between treatments(95 % CI) versus pioglitazone	-5.10 (-5.91, -4.28)**

SE = standard error, CI= confidence interval), * p< 0.05, **p< 0.0001
Body weight
A reduction in body weight compared to baseline has been observed in all Bydureon studies. This reduction in body weight was seen in patients treated with Bydureon irrespective of the occurrence of nausea although the reduction was larger in the group with nausea (mean reduction - 2.9 kg to - 5.2 kg with nausea versus - 2.2 kg to -2.9 kg without nausea).
The proportion of patients who had both a reduction in weight and HbA1c ranged from 70 to 79 % (the proportion of patients who had a reduction of HbA1c ranged from 88 to 96 %).
Plasma/serum glucose
Treatment with Bydureon resulted in significant reductions in fasting plasma/serum glucose concentrations, these reductions were observed as early as 4 weeks. Additional reductions in postprandial concentrations were also observed. The improvement in fasting plasma glucose concentrations was durable through 52 weeks.
Beta-cell function
Clinical studies with Bydureon have indicated improved beta-cell function, using measures such as the homeostasis model assessments (HOMA-B). The durability of effect on beta-cell function was maintained through 52 weeks.
Blood pressure
A reduction in systolic blood pressure was observed in Bydureon studies (2.9 mmHg to 4.7 mmHg). In the 30 week exenatide twice daily comparator study both Bydureon and exenatide twice daily significantly reduced systolic blood pressure from base line (4.7±1.1 mmHg and 3.4±1.1 mmHg respectively) the difference between the treatments was not significant. Improvements in blood pressure were maintained through 52 weeks.
Fasting lipids
Bydureon has shown no adverse effects on lipid parameters.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Bydureon in one or more subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
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 patients
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 mcg) 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 mcg) 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 tumor 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
sodium dihydrogen phosphate monohydrate
disodium phosphate heptahydrate
water for injections
sodium hydroxide (for pH adjustment)
6.2 Incompatibilities
In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
3 years
The suspension must be injected immediately after mixing the powder and the solvent.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).
Do not freeze.
The pens may be kept for up to 4 weeks below 30°C prior to use. At the end of this period Bydureon should be used or discarded.
Store in the original package in order to protect from light.
For storage conditions after mixing of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Each dual-chamber pen contains exenatide powder and solvent in a Type 1 glass cartridge sealed at one end with a chlorobutyl rubber stopper and an aluminum seal, and at the other end with a chlorobutyl rubber piston. The two chambers are separated by a second chlorobutyl rubber piston. There is one needle supplied per pen. Each carton also contains one spare needle. Use only the supplied needles with the pen.
Pack size of 4 single-dose pre-filled pens and a multipack containing 12 (3 packs of 4) single-dose pre-filled pens.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Pre-filled pen is for single-use only.
The powder in one chamber must be mixed with the solvent in the other chamber of the pre-filled pen. 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 reconstitution, the mixture should only be used if it is white to off white and cloudy. Please see the package leaflet and Instructions for the User for additional information on suspension and administration.
Use only the supplied custom needles with the pen.
Bydureon must be injected subcutaneously immediately after mixing of the powder and the solvent.
Bydureon that has been frozen must not be used.
The patient should be instructed to discard the pen safely, with the needle still attached, after each injection.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
AstraZeneca AB
SE-151 85 Södertälje
Sweden
8. Marketing authorisation number(s)
EU/1/11/696/003 4 pre-filled pens
EU/1/11/696/004 3 x 4 pre-filled pens
9. Date of first authorisation/renewal of the authorisation
24th July 2014
10. Date of revision of the text
19th January 2015
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
BYDUREON 2 mg powder and solvent for prolonged-release suspension for injection（http://www.medicines.org.uk/emc/medicine/24665）
http://www.oneyao.net
http://www.120ty.nt

糖尿病新疗法 Bydureon每周注射一次在欧洲获批上市
•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。
2011年7月5日,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 Amylin Pharmaceuticals 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 Enrique Conterno 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。
在其他国家申请获批：在日本，Bydureon 已经提出批准申请。在美国，下半年礼来将对食品药品监督局提出的一些关于产品的问题给予全面的答复。