英文药名：Lyxumia(Lixisenatide) 中文药名：利西拉来注射液 生产厂家：赛诺菲 药品介绍 2013年2月4日表示，赛诺菲新药产品Lyxumia在欧洲获得上市批准，该药物是一种胰高血糖素样肽1（GLP-1）受体激动剂，属注射用糖尿病治疗药物。 Lyxumia的通用名为利司那肽，该药物一天注射一次，连同其它药物或者胰岛素一块使用，用于治疗只能通过药物来控制血糖水平的患者。 之前赛诺菲失去了几个重磅炸弹药物的专利，面临着仿制药的激烈竞争，而利西拉来正是公司押注的的几个新产品之一。根据5000名2型糖尿病患者参与的11项临床试验结果，Lyxumia在血糖水平与血糖控制以及减肥方面表现出有益的疗效。 Lyxumia的上市批准适用于欧盟27个成员国，以及冰岛、Lichtenstein和挪威，同时该药物上市申请在其他几个国家处于待定状态。 药用产品名称 Lyxumia 10µg注射用溶液 剂型 注射用溶液(注射液). 透明，无色溶液。 治疗适应证 Lyxumia适用于为治疗有2型糖尿病成年与口服降糖药用产品和/或基础胰岛素联用达到血糖控制，当这些，与饮食和运动在一起不能提供适当提供适当血糖控制(对可得到的不同联用资料见节4.4和5.1)。 剂量学和给药方法 剂量学 开始剂量：在10 µg Lyxumia每天1次开始给药共14天。 维持剂量：在第15天开始一个固定的维持剂量20 µg Lyxumia每天1次。 为维持剂量可得到Lyxumia 20 µg注射用溶液。 Lyxumia是每天1次给予，在该天首次进餐或旁晚餐前1小时内。如果丢失1剂Lyxumia，应在下一餐前1小时内注射。当Lyxumia被添加至存在的二甲双胍治疗，同时二甲双胍给药可继续不变。 当Lyxumia被添加至的已存在一种磺脲类[sulphonylurea]或一种基础胰岛素治疗，减低低血糖的风险，可考虑减低磺脲类或基础胰岛素的剂量。由于低血糖的增加风险，Lyxumia不应与基础胰岛素和一种磺脲类联合给予(见节)。 Lyxumia的使用不需要特殊监视血糖。但是，当与一种磺脲类或一种基础胰岛素联合使用时，可能变得有必要监测血糖或自身监测血糖以调整磺脲类或基础胰岛素的剂量。 特殊人群 老年患者(≥65岁) 无需根据年龄调整剂量。≥75岁患者中临床经验有限。 肾受损患者 对有轻度肾受损患者(肌酐清除率: 50-80 ml/min)无需调整剂量. 有中度肾受损患者治疗经验有限(肌酐：30-50 ml/min)和在这个人群应谨慎使用Lyxumia。 没有在有严重肾受损(肌酐清除率小于30 ml/min)或肾病终末期患者的治疗经验和因此不推荐Lyxumia在这些人群中使用。 肝受损患者 在有肝受损患者中无需调整剂量。 儿童人群 尚未确定lixisenatide在小于18岁儿童和青少年中的安全性和疗效。没有可供利用资料。 给药方法 Lyxumia将在大腿，腹部或上臂皮下注射。不应静脉或肌肉注射Lyxumia。 禁忌证 对活性物质或对节6.1中列出任何赋形剂超敏性。 包装规格[Lyxumia 利西拉来] 3mlx1支/盒 3mlx2支/盒 3mlx6支/盒 Lyxumia 10 micrograms solution for injection Lyxumia 20 micrograms solution for injection Lyxumia Treatment Initiation Pack ------------------------------------------------------ Lyxumia 10 micrograms solution for injection 1. Name of the medicinal product Lyxumia 10 micrograms solution for injection 2. Qualitative and quantitative composition Each dose (0.2 ml) contains 10 micrograms (mcg) of lixisenatide (50 mcg per ml). Excipient(s) with known effects: Each dose contains 54 micrograms of metacresol. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Solution for injection (injection). Clear, colourless solution. 4. Clinical particulars 4.1 Therapeutic indications Lyxumia is indicated for the treatment of adults with type 2 diabetes mellitus to achieve glycaemic control in combination with oral glucose-lowering medicinal products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4 and 5.1 for available data on the different combinations). 4.2 Posology and method of administration Posology Starting dose: dosing is initiated at 10 mcg Lyxumia once daily for 14 days. Maintenance dose: a fixed maintenance dose of 20 mcg Lyxumia once daily is started on Day 15. Lyxumia 20 micrograms solution for injection is available for the maintenance dose. Lyxumia is administered once daily, within the hour prior to the first meal of the day or the evening meal. If a dose of Lyxumia is missed, it should be injected within the hour prior to the next meal. When Lyxumia is added to existing metformin therapy, the current metformin dose can be continued unchanged. When Lyxumia is added to existing therapy of a sulphonylurea or a basal insulin, a reduction in the dose of the sulphonylurea or the basal insulin may be considered to reduce the risk of hypoglycaemia. Lyxumia should not be given in combination with basal insulin and a sulphonylurea due to increased risk of hypoglycaemia (see section 4.4). The use of Lyxumia does not require specific blood glucose monitoring. However, when used in combination with a sulphonylurea or a basal insulin, blood glucose monitoring or blood glucose self-monitoring may become necessary to adjust the doses of the sulphonylurea or the basal insulin. Special populations Elderly patients(≥65 years) No dose adjustment is required based on age. The clinical experience in patients ≥75 years is limited (see sections 5.1 and 5.2). Patients with renal impairment No dose adjustment is required for patients with mild renal impairment (creatinine clearance : 50-80 ml/min). There is limited therapeutic experience in patients with moderate renal impairment (creatinine clearance: 30-50 ml/min) and Lyxumia should be used with caution in this population. There is no therapeutic experience in patients with severe renal impairment (creatinine clearance less than 30 ml/min) or end-stage renal disease and therefore, it is not recommended to use Lyxumia in these populations (see section 5.2). Patients with hepatic impairment No dose adjustment is needed in patients with hepatic impairment (see section 5.2) Paediatric population The safety and efficacy of lixisenatide in children and adolescents less than 18 years of age have not yet been established. No data are available. Method of administration Lyxumia is to be injected subcutaneously in the thigh, abdomen or upper arm. Lyxumia should not be administered intravenously or intramuscularly. 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 There is no therapeutic experience with lixisenatide in patients with type 1 diabetes mellitus and it should not be used in these patients. Lixisenatide should not be used for treatment of diabetic ketoacidosis. Acute pancreatitis Use of glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, lixisenatide should be discontinued ; if acute pancreatitis is confirmed, lixisenatide should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Severe gastrointestinal disease Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions. Lixisenatide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis and therefore, the use of lixisenatide is not recommended in these patients. Renal impairment There is limited therapeutic experience in patients with moderate renal impairment (creatinine clearance: 30-50 ml/min) and no therapeutic experience in patients with severe renal impairment (creatinine clearance less than 30 ml/min) or end-stage renal disease. Lyxumia should be used with caution in patients with moderate renal impairment. Use is not recommended in patients with severe renal impairment or end-stage renal disease (see sections 4.2 and 5.2). Hypoglycaemia Patients receiving Lyxumia with a sulphonylurea or with a basal insulin may have an increased risk of hypoglycaemia. Reduction of the dose of the sulphonylurea or the basal insulin may be considered to reduce the risk of hypoglycaemia (see section 4.2). Lyxumia should not be given in combination with basal insulin and a sulphonylurea due to increased risk of hypoglycaemia. Concomitant medicinal products The delay of gastric emptying with lixisenatide may reduce the rate of absorption of orally administered medicinal products. Lyxumia should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption, require careful clinical monitoring or have a narrow therapeutic ratio. Specific recommendations regarding intake of such medicinal products are given in section 4.5. Populations not studied Lixisenatide has not been studied in combination with dipeptidyl peptidase 4 (DPP-4) inhibitors. There is limited experience in patients with congestive heart failure. Dehydration Patients treated with Lyxumia should be advised of the potential risk of dehydration in relation to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Excipients This medicinal product contains metacresol, which may cause allergic reactions. 4.5 Interaction with other medicinal products and other forms of interaction Lixisenatide is a peptide and is not metabolised by cytochrome P450. In in vitro studies, lixisenatide did not affect the activity of cytochrome P450 isozymes or human transporters tested. The delay of gastric emptying with lixisenatide may reduce the rate of absorption of orally administered medicinal products. Patients receiving medicinal products of either a narrow therapeutic ratio or medicinal products that require careful clinical monitoring should be followed closely, especially at the time of initiation of lixisenatide treatment. These medicinal products should be taken in a standardised way in relation to lixisenatide. If such medicinal products are to be administered with food, patients should be advised to, if possible, take them with a meal when lixisenatide is not administered. For oral medicinal products that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, patients should be advised to take those medicinal products at least 1 hour before or 4 hours after lixisenatide injection. Gastro-resistant formulations containing substances sensitive to stomach degradation, should be administered 1 hour before or 4 hours after lixisenatide injection. Paracetamol Paracetamol was used as a model medicinal product to evaluate the effect of lixisenatide on gastric emptying. Following administration of a single dose of paracetamol 1000 mg, paracetamol AUC and t1/2 were unchanged whatever the timing of its administration (before or after the lixisenatide injection). When administered 1 or 4 hours after 10 mcg lixisenatide, Cmax of paracetamol was decreased by 29% and 31% respectively and median tmax was delayed by 2.0 and 1.75 hours respectively. A further delay in tmax and a reduced Cmax of paracetamol have been predicted with the 20 mcg maintenance dose. No effects on paracetamol Cmax and tmax were observed when paracetamol was administered 1 hour before lixisenatide. Based on these results, no dose adjustment for paracetamol is required but the delayed tmax observed when paracetamol is administered 1-4 hours after lixisenatide should be taken into account when a rapid onset of action is required for efficacy. Oral contraceptives Following administration of a single dose of an oral contraceptive medicinal product (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) 1 hour before or 11 hours after 10 mcg lixisenatide, the Cmax, AUC, t1/2 and tmax of ethinylestradiol and levonorgestrel were unchanged. Administration of the oral contraceptive 1 hour or 4 hours after lixisenatide did not affect AUC and t1/2 of ethinylestradiol and levonorgestrel, whereas Cmax of ethinylestradiol was decreased by 52% and 39% respectively and Cmax of levonorgestrel was decreased by 46% and 20%, respectively and median tmax was delayed by 1 to 3 hours. The reduction in Cmax is of limited clinical relevance and no dose adjustment for oral contraceptives is required. Atorvastatin When lixisenatide 20 mcg and atorvastatin 40 mg were co-administered in the morning for 6 days, the exposure to atorvastatin was not affected, while Cmax was decreased by 31% and tmax was delayed by 3.25 hours. No such increase for tmax was observed when atorvastatin was administered in the evening and lixisenatide in the morning but the AUC and Cmax of atorvastatin were increased by 27% and 66% respectively. These changes are not clinically relevant and therefore, no dose adjustment for atorvastatin is required when co-administered with lixisenatide. Warfarin and other coumarin derivatives After concomitant administration of warfarin 25 mg with repeated dosing of lixisenatide 20 mcg, there were no effects on AUC or INR (International Normalised Ratio) while Cmax was reduced by 19% and tmax was delayed by 7 hours. Based on these results, no dose adjustment for warfarin is required when co-administered with lixisenatide; however, frequent monitoring of INR in patients on warfarin and/or coumarin derivatives is recommended at the time of initiation or ending of lixisenatide treatment. Digoxin After concomitant administration of lixisenatide 20 mcg and digoxin 0.25 mg at steady state, the AUC of digoxin was not affected. The tmax of digoxin was delayed by 1.5 hour and the Cmax was reduced by 26%. Based on these results, no dose adjustment for digoxin is required when co-administered with lixisenatide. Ramipril After concomitant administration of lixisenatide 20 mcg and ramipril 5 mg during 6 days, the AUC of ramipril was increased by 21% while the Cmax was decreased by 63%. The AUC and Cmax of the active metabolite (ramiprilat) were not affected. The tmax of ramipril and ramiprilat were delayed by approximately 2.5 hours. Based on these results, no dose adjustment for ramipril is required when co-administered with lixisenatide. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Lyxumia is not recommended in women of childbearing potential not using contraception. Pregnancy There are no adequate data from the use of Lyxumia in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Lyxumia should not be used during pregnancy. The use of insulin is recommended instead. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Lyxumia should be discontinued. Breast-feeding It is unknown if Lyxumia is excreted in human milk. Lyxumia should not be used during breast-feeding. Fertility Animal studies do not indicate direct harmful effects with respect to fertility. 4.7 Effects on ability to drive and use machines Lyxumia has no or negligible influence on the ability to drive or use machines. When used in combination with a sulphonylurea or a basal insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines. 4.8 Undesirable effects Summary of the safety profile Over 2,600 patients have received Lyxumia either alone or in combination with metformin, a sulphonylurea (with or without metformin) or a basal insulin (with or without metformin, or with or without a sulphonylurea) in 8 large placebo- or active-controlled phase III studies. The most frequently reported adverse reactions during clinical studies were nausea, vomiting and diarrhoea. These reactions were mostly mild and transient. In addition, hypoglycaemia (when Lyxumia was used in combination with a sulphonylurea and/or a basal insulin) and headache occurred. Allergic reactions have been reported in 0.4% of Lyxumia patients. Tabulated list of adverse reactions Adverse reactions reported from placebo- and active-controlled phase III studies over the entire treatment period are presented in Table 1. The table presents adverse reactions that occurred with an incidence >5% if the frequency was higher among Lyxumia treated patients than patients treated with all comparators. The table also includes adverse reactions with a frequency ≥1% in the Lyxumia group if the frequency was greater than 2 times the frequency for all comparators group. Frequencies of adverse reactions are defined as: 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 system organ class, adverse reactions are presented in order of decreasing frequency. Table 1: Adverse reactions reported in placebo- and active-controlled phase III studies during the entire treatment period (including the period beyond the main 24-week treatment period in studies with ≥76 weeks of total treatment). System Organ Class Frequency of occurrence   Very common Common Uncommon Infections and infestations   Influenza     Upper respiratory tract infection     Cystitis     Viral infection   Immune system disorders     Anaphylactic reaction Metabolism and nutrition disorders Hypoglycaemia (in combination with a sulphonylurea and / or a basal insulin) Hypoglycaemia (in combination with metformin alone)   Nervous system disorders Headache Dizziness     Somnolence   Gastrointestinal disorders Nausea Dyspepsia   Vomiting     Diarrhoea     Skin and subcutaneous tissue disorders     Urticaria Musculoskeletal and connective tissue disorders   Back pain   General disorders and administration site conditions   Injection site pruritus Description of selected adverse reactions Hypoglycaemia In patients taking Lyxumia in monotherapy, symptomatic hypoglycaemia occurred in 1.7% of lixisenatide treated patients and in 1.6% of placebo treated patients. When Lyxumia is used in combination with metformin alone, symptomatic hypoglycaemia occurred in 7.0% of lixisenatide patients and in 4.8% of placebo patients during the entire treatment period. In patients taking Lyxumia in combination with a sulphonylurea and metformin, symptomatic hypoglycaemia occurred in 22.0% of lixisenatide treated patients and in 18.4% of placebo treated patients during the entire treatment period (3.6% absolute difference). When Lyxumia is used in combination with a basal insulin with or without metformin, symptomatic hypoglycaemia occurred in 42.1% of lixisenatide patients and in 38.9% of placebo patients during the entire treatment period (3.2% absolute difference). During the entire treatment period, when Lyxumia was given with a sulphonylurea alone, symptomatic hypoglycaemia occurred in 22.7% of lixisenatide treated patients versus 15.2% with placebo (7.5% absolute difference). When Lyxumia was given with a sulphonylurea and a basal insulin, symptomatic hypoglycaemia occurred in 47.2% of lixisenatide treated patients compared to 21.6% with placebo (25.6% absolute difference). Overall, the incidence of severe symptomatic hypoglycaemia was uncommon (0.4% in lixisenatide patients and 0.2% in placebo patients) during the entire treatment period of the Phase III placebo-controlled studies. Gastrointestinal disorders Nausea and vomiting were the most frequently reported adverse reactions during the main 24-week treatment period. The incidence of nausea was higher in the lixisenatide group (26.1%) compared to the placebo group (6.2%) and the incidence of vomiting was higher in the lixisenatide group (10.5%) than in the placebo group (1.8%). They were mostly mild and transient and occured during the first 3 weeks after starting treatment. Thereafter, they progressively decreased during the following weeks. Injection site reactions Injections site reactions were reported in 3.9% of the patients receiving Lyxumia while they were reported in 1.4% of patients receiving placebo during the main 24-week treatment period. The majority of reactions were mild in intensity and usually did not result in discontinuation of the treatment. Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing proteins or peptides, patients may develop anti-lixisenatide antibodies following treatment with Lyxumia and, at the end of the main 24-week treatment period in placebo-controlled studies, 69.8% of lixisenatide patients had a positive antibody status. The percentage of patients who were antibody positive was similar at the end of the entire 76-week treatment period. At the end of the main 24-week treatment period, 32.2% of the patients having a positive antibody status had an antibody concentration above the lower limit of quantification, and at the end of the entire 76-week treatment period, 44.7% of the patients had an antibody concentration above the lower limit of quantification. After stopping the treatment, few antibody positive patients were followed-up for antibody status; the percentage decreased to approximately 90% within 3 months and 30% at 6 months or beyond. The change in HbA1c from baseline was similar regardless of the antibody status (positive or negative). Of lixisenatide-treated patients with HbA1c measurement, 79.3% had either a negative antibody status or an antibody concentration below the lower limit of quantification and the other 20.7% of patients had a quantified antibody concentration. In the subset of patients (5.2%) with the highest antibody concentrations, the mean improvement in HbA1c at Week 24 and at Week 76 was in a clinically relevant range; however there was variability in the glycaemic response and 1.9% had no decrease in HbA1c. The antibody status (positive or negative) is not predictive of the reduction of HbA1c for an individual patient. There was no difference in the overall safety profile in patients regardless of the antibody status with the exception of an increase of the incidence of injection site reactions (4.7% in antibody positive patients compared to 2.5% in antibody-negative patients during the entire treatment period). The majority of injection site reactions were mild, regardless of antibody status. There was no cross-reactivity versus either native glucagon or endogenous GLP-1. Allergic reactions Allergic reactions possibly associated with lixisenatide (such as anaphylactic reaction, angioedema and urticaria) have been reported in 0.4% of lixisenatide patients while possibly associated allergic reactions occurred in less than 0.1% of placebo patients during the main 24-week treatment period. Anaphylactic reactions were reported in 0.2% of the lixisenatide treated patients vs. none in the placebo group. Most of these reported allergic reactions were mild in severity. One case of anaphylactoid reaction was reported during clinical trials with lixisenatide. Heart rate In a study in healthy volunteers, a transient rise in heart rate has been observed after administration of lixisenatide 20 mcg. Cardiac arrhythmias particularly tachycardia (0.8% vs <0.1%) and palpitations (1.5% vs 0.8%) have been reported in lixisenatide patients compared to placebo treated patients. Withdrawal The incidence of treatment discontinuation due to adverse events was 7.4% for Lyxumia compared to 3.2% in the placebo group during the main 24-week treatment period. The most common adverse reactions which led to treatment discontinuation in the lixisenatide group were nausea (3.1%) and vomiting (1.2%). 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 During clinical studies, doses up to 30 mcg of lixisenatide twice a day were administered to type 2 diabetic patients in a 13-week study. An increased incidence of gastrointestinal disorders was observed. In case of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms and the lixisenatide dose should be reduced to the prescribed dose. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other blood glucose lowering drugs, excl. insulins, ATC code: A10BX10. Mechanism of action Lixisenatide is a selective GLP-1 receptor agonist. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells. Lixisenatide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP). Lixisenatide stimulates insulin secretion when blood glucose is increased but not at normoglycaemia, which limits the risk of hypoglycaemia. In parallel, glucagon secretion is suppressed. In case of hypoglycaemia, the rescue mechanism of glucagon secretion is preserved. Lixisenatide slows gastric emptying thereby reducing the rate at which meal-derived glucose appears in the circulation. Pharmacodynamic effects When administered once daily, lixisenatide improves glycaemic control through the immediate and sustained effects of lowering both post-prandial and fasting glucose concentrations in patients with type 2 diabetes. This effect on post-prandial glucose was confirmed in a 4-week study versus liraglutide 1.8 mg once a day. Reduction from baseline in the AUC 0:30-4:30h of plasma glucose after a test-meal was: -227.25 h*mg/dL (-12,61 h*mmol/L) in the lixisenatide group and -72.83 h*mg/dL (-4.04 h*mmol/L) in the liraglutide group. Clinical efficacy and safety The effects of Lyxumia on glycaemic control were evaluated in six randomised double-blind, placebo-controlled clinical studies and one randomised, open-label, active-controlled study versus exenatide. These studies included 3,825 patients with type 2 diabetes (2,445 patients randomised to lixisenatide), 48.2% men and 51.8% women. 768 subjects (447 randomised to lixisenatide) were ≥65 years of age and 103 subjects (57 randomised to lixisenatide) were ≥75 years of age. In the completed Phase III studies, it was observed that more than 90% of the patient population was able to remain on the once daily maintenance dose of 20 mcg Lyxumia at the end of the main 24-week treatment period. • Glycaemic control Add-on combination therapy with oral antidiabetics Lyxumia in combination with metformin, a sulphonylurea, pioglitazone or a combination of these agents showed statistically significant reductions in HbA1c, in fasting plasma glucose and in 2-hour post-prandial glucose after a test-meal compared to placebo at the end of the main 24-week treatment period (tables 2 and 3). The HbA1c reduction was significant with once-daily administration, whether administered morning or evening. This effect on HbA1c was sustained in long term studies for up to 76 weeks. Add-on treatment to metformin alone Table 2: Placebo-controlled studies in combination with metformin (24-week results). Metformin as background therapy   Lixisenatide 20 mcg Placebo Lixisenatide 20 mcg Placebo   (N= 160)   (N= 159) Morning (N= 255) Evening (N= 255)   (N= 170) Mean HbA1c (%)           Baseline 7.99 8.03 8.07 8.07 8.02 LS mean change from baseline -0.92 -0.42 -0.87 -0.75 -0.38 Patients (%) achieving HbA1c <7.0% 47.4 24.1 43.0 40.6 22.0 Mean body weight (kg)           Baseline 90.30 87.86 90.14 89.01 90.40 LS mean change from baseline -2.63 -1.63 -2.01 -2.02 -1.64 In an active-controlled study, Lyxumia once daily showed an HbA1c reduction of -0.79% compared to -0.96% with exenatide twice daily at the end of the main 24-week treatment period with a mean treatment difference of 0.17% (95% CI: 0.033, 0.297) and a similar percentage of patients achieved an HbA1c less than 7% in the lixisenatide group (48.5%) and in the exenatide group (49.8%). The incidence of nausea was 24.5% in the lixisenatide group compared to35.1% in the exenatide twice daily group and the incidence of symptomatic hypoglycaemia with lixisenatide was 2.5% during the 24-week main treatment period compared to 7.9% in the exenatide group. Add-on treatment to a sulphonylurea alone or in combination with metformin Table 3: Placebo-controlled study in combination with a sulphonylurea (24-week results) Sulphonylurea as background therapy with or without metformin   Lixisenatide 20 mcg Placebo (N= 570) (N= 286) Mean HbA1c (%)     Baseline 8.28 8.22 LS mean change from baseline -0.85 -0.10 Patients (%) achieving HbA1c <7.0% 36.4 13.5 Mean body weight (kg)     Baseline 82.58 84.52 LS mean change from baseline -1.76 -0.93 Add-on treatment to pioglitazone alone or in combination with metformin In a clinical study, the addition of lixisenatide to pioglitazone with or without metformin, in patients not adequately controlled with pioglitazone, resulted in an HbA1c decrease from baseline of 0.90%, compared to a decrease from baseline of 0.34% in the placebo group at the end of the 24-week main treatment period. At the end of the 24-week main treatment period, 52.3% of the lixisenatide patients achieved an HbA1c less than 7 % compared to 26.4% in the placebo group. During the 24-week main treatment period, nausea was reported in 23.5% in the lixisenatide group compared to 10.6% in the placebo group and symptomatic hypoglycaemia was reported in 3.4% of the lixisenatide patients compared to 1.2% in the placebo group. Add-on combination therapy with a basal insulin Lyxumia given with a basal insulin alone, or with a combination of a basal insulin and metformin, or a combination of a basal insulin and a sulphonylurea resulted in statistically significant reductions in HbA1c and in 2-hour post-prandial glucose after a test-meal compared to placebo. Table 4: Placebo-controlled studies in combination with a basal insulin (24-week results) Basal insulin as background therapy Alone or in combination with metformin Basal insulin as background therapy Alone or in combination with a sulphonylurea *   Lixisenatide 20 mcg Placebo Lixisenatide 20 mcg Placebo   (N= 327) (N= 166) (N= 154) (N= 157) Mean HbA1c (%)         Baseline 8.39 8.38 8.53 8.53 LS mean change from baseline -0.74 -0.38 -0.77 0.11 Patients (%) achieving HbA1c <7.0% 28.3 12.0 35.6 5.2 Mean duration of treatment with basal insulin at baseline (years) 3.06 3.2 2.94 3.01 Mean change in basal insulin dose (U)         Baseline 53.62 57.65 24.87 24.11 LS mean change from baseline -5.62 -1.93 -1.39 -0.11 Mean body weight (kg)         Baseline 87.39 89.11 65.99 65.60 LS mean change from baseline -1.80 -0.52 -0.38 0.06 *performed in Asian population A clinical study was conducted in insulin-naive patients insufficiently controlled on oral antidiabetic agents. This study consisted of a 12-week run-in period with introduction and titration of insulin glargine and of a 24-week treatment period during which patients receive either lixisenatide or placebo in combination with insulin glargine and metformin with or without thiazolidinediones. Insulin glargine was continuously titrated during this period. During the 12-week run-in period, addition and titration of insulin glargine resulted approximately in an HbA1c decrease of 1%. The addition of lixisenatide led to a significantly greater HbA1c decrease of 0.71% in the lixisenatide group compared to 0.40% in the placebo group. At the end of the 24-week treatment period, 56.3% of the lixisenatide patients achieved an HbA1c less than 7 % compared to 38.5% in the placebo group. During the 24-week treatment period, 22.4% lixisenatide patients reported at least one symptomatic hypoglycaemic event compared to 13.5% in the placebo group. The incidence of hypoglycaemia was mainly increased in the lixisenatide group during the first 6 weeks of treatment and thereafter, was similar to the placebo group. • Fasting plasma glucose The reductions in fasting plasma glucose obtained with Lyxumia treatment ranged from 0.42 mmol/L to 1.19 mmol/L (7.6 to 21.4 mg/dl) from baseline at the end of the main 24-week treatment period in placebo-controlled studies. • Post-prandial glucose Treatment with Lyxumia resulted in reductions in 2-hour post-prandial glucose after a test-meal statistically superior to placebo whatever the background treatment. The reductions with Lyxumia ranged from 4.51 to 7.96 mmol/L (81.2 to 143.3 mg/dl) from baseline at the end of the main 24-week treatment period across all studies in which post-prandial glucose was measured; 26.2% to 46.8% of patients had a 2-hour post-prandial glucose value below 7.8 mmol/L (140.4 mg/dl). • Body weight Treatment with Lyxumia in combination with metformin and/or a sulphonylurea resulted in a sustained body weight change from baseline in all controlled studies in a range from -1.76 kg to -2.96 kg at the end of the main 24-week treatment period. Body weight change from baseline in a range from -0.38 kg to -1.80 kg was also observed in lixisenatide patients receiving stable basal insulin dose, alone or in combination with metformin or a sulphonylurea. In patients newly started on insulin, body weight remained almost unchanged in the lixisenatide group while an increase was shown in the placebo group. Body weight reduction was sustained in long term studies up to 76 weeks. The body weight reduction is independent from the occurrence of nausea and vomiting. • Beta cell function Clinical studies with Lyxumia indicate improved beta-cell function as measured by the homeostasis model assessment for beta-cell function (HOMA-β). Restoration of first phase insulin secretion and improved second phase insulin secretion in response to an intravenous bolus of glucose were demonstrated in patients with type 2 diabetes (n=20) after a single dose of Lyxumia. • Cardiovascular evaluation No increase in mean heart rate in patients with type 2 diabetes was seen in all placebo controlled phase III studies. Mean systolic and diastolic blood pressure reductions up to 2.1 mmHg and up to 1.5 mmHg respectively were observed in phase III placebo-controlled studies. A meta-analysis of all independently adjudicated cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure and coronary revascularization procedure) from 8 phase III placebo-controlled studies which included 2673 type 2 diabetes patients treated with lixisenatide and 1448 patients treated with placebo showed a hazard ratio of 1.03 (95% confidence interval 0.64, 1.66) for lixisenatide versus placebo. The number of events in the clinical studies was low (1.9% in lixisenatide treated patients and 1.8% in placebo treated patients), precluding firm conclusions. The incidence of the individual CV events (lixisenatide vs placebo) was: CV death (0.3% vs 0.3%), non-fatal myocardial infarction (0.4% vs 0.4%), non-fatal stroke (0.7% vs 0.4%), hospitalization for unstable angina (zero vs 0.1%), hospitalization for heart failure (0.1% vs zero), and coronary revascularization procedure (0.7% vs 1.0%). Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Lyxumia 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 Absorption Following subcutaneous administration to patients with type 2 diabetes, the rate of lixisenatide absorption is rapid and not influenced by the dose administered. Irrespective of the dose and whether lixisenatide was administered as single or multiple doses, the median tmax is 1 to 3.5 hours in patients with type 2 diabetes. There are no clinically relevant differences in the rate of absorption when lixisenatide is administered subcutaneously in the abdomen, thigh, or arm. Distribution Lixisenatide has a moderate level of binding (55%) to human proteins. The apparent volume of distribution after subcutaneous administration of lixisenatide (Vz/F) is approximately 100 L. Biotransformation and elimination As a peptide, lixisenatide is eliminated through glomerular filtration, followed by tubular reabsorption and subsequent metabolic degradation, resulting in smaller peptides and amino acids, which are reintroduced in the protein metabolism. After multiple dose administration in patients with type 2 diabetes, mean terminal half-life was approximately 3 hours and the mean apparent clearance (CL/F) about 35 L/h. Special populations Patients with renal impairment There were no relevant differences in mean Cmax and AUC of lixisenatide between subjects with normal renal function and subjects with mild impaired renal function (creatinine clearance calculated by the Cockcroft-Gault formula 50-80 ml/min). In subjects with moderate renal impairment (creatinine clearance 30-50 ml/min) AUC was increased by 24% and in subjects with severe renal impairment (creatinine clearance 15-30 ml/min) AUC was increased by 46%. Patients with hepatic impairment As lixisenatide is cleared primarily by the kidney, no pharmacokinetic study has been performed in patients with acute or chronic hepatic impairment. Hepatic dysfunction is not expected to affect the pharmacokinetics of lixisenatide. Gender Gender has no clinically relevant effect on the pharmacokinetics of lixisenatide. Race Ethnic origin had no clinically relevant effect on the pharmacokinetics of lixisenatide based on the results of pharmacokinetic studies in Caucasian, Japanese and Chinese subjects. Elderly Age has no clinically relevant effect on the pharmacokinetics of lixisenatide. In a pharmacokinetic study in elderly non-diabetic subjects, administration of lixisenatide 20 mcg resulted in a mean increase of lixisenatide AUC by 29% in the elderly population (11 subjects aged 65 to 74 years and 7 subjects aged ≥75 years) compared to 18 subjects aged 18 to 45 years, likely related to reduced renal function in the older age group. Body weight Body weight has no clinically relevant effect on lixisenatide AUC. 5.3 Preclinical safety data Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology and toxicology. In 2-year subcutaneous carcinogenicity studies, non-lethal C-cell thyroid tumors were seen in rats and mice and are considered to be caused by a non-genotoxic GLP-1 receptor-mediated mechanism to which rodents are particularly sensitive. C-cell hyperplasia and adenoma were seen at all doses in rats and a no observed adverse effect level (NOAEL) could be not defined. In mice, these effects occurred at exposure ratio above 9.3-fold when compared to human exposure at the therapeutic dose. No C-cell carcinoma was observed in mice and C-cell carcinoma occurred in rats with an exposure ratio relative to exposure at human therapeutic dose of about 900-fold. In 2-year subcutaneous carcinogenicity study in mice, 3 cases of adenocarcinoma in the endometrium were seen in the mid dose group with a statistically significant increase, corresponding to an exposure ratio of 97-fold. No treatment-related effect was demonstrated. Animal studies did not indicate direct harmful effects with respect to male and female fertility in rats. Reversible testicular and epididymal lesions were seen in dogs treated with lixisenatide. No related effect on spermatogenesis was seen in healthy men. In embryo-foetal development studies, malformations, growth retardation, ossification retardation and skeletal effects were observed in rats at all doses (5-fold exposure ratio compared to human exposure) and in rabbits at high doses (32-fold exposure ratio compared to human exposure) of lixisenatide. In both species, there was a slight maternal toxicity consisting of low food consumption and reduced body weight. Neonatal growth was reduced in male rats exposed to high doses of lixisenatide during late gestation and lactation, with a slightly increased pup mortality observed. 6. Pharmaceutical particulars 6.1 List of excipients Glycerol 85% Sodium acetate trihydrate Methionine Metacresol Hydrochloric acid (for pH adjustment) Sodium hydroxide solution (for pH adjustment) 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 first use: 14 days 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. Store away from the freezer compartment. After first use Store below 30°C. Do not freeze. Do not store with attached needle. Keep the cap on the pen in order to protect from light. 6.5 Nature and contents of container Type I glass cartridge with a (bromobutyl) rubber plunger, flanged caps (aluminium) with inserted laminated sealing disks (bromobutyl rubber on the product side and polyisoprene on the outside). Each cartridge is assembled into a disposable pen. Each green pre-filled pen contains 3 ml solution, delivering 14 doses of 10 mcg. Pack containing 1 green pre-filled pen. 6.6 Special precautions for disposal and other handling Lyxumia should not be used if it has been frozen. Lyxumia can be used with 29 to 32 gauge disposable pen needles. Pen needles are not included. The patient should be instructed to discard the needle after each use in accordance with local requirements and to store the pen without the needle attached. This helps prevent contamination and potential needle blockage. The pen is to be used for one patient only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder sanofi-aventis groupe 54, rue La Boétie F – 75008 Paris France 8. Marketing authorisation number(s)  EU/1/12/811/001 (1 pre-filled pen) 9. Date of first authorisation/renewal of the authorisation  Date of first authorisation: 01 February 2013 10. Date of revision of the text 4 October 2013 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.