英文药名: Onglyza(Saxagliptin filmcoated tablets) 中文药名: 沙格列汀片薄膜片 生产厂家: 百时美施贵宝 药品介绍 ONGLYZA™(saxagliptin,沙格列汀片)是一种高效二肽基肽酶-4（Dipeptidyl Peptidase 4，DPP-4）抑制剂，通过选择性抑制DPP-4，可以升高内源性胰高血糖素样肽-1（Glucagon-like Peptide-1，GLP-1）和葡萄糖依赖性促胰岛素释放多肽（Glucose-dependent Insulinotropic Peptide，GIP）水平，从而调节血糖。 适应症及用法 ONGLYZA是一种二肽基肽酶4抑制剂表示作为辅助饮食和运动改善血糖控制在成人2型糖尿病。 使用的重要限制： 不应该用于治疗1型糖尿病或糖尿病酮症酸中毒。 尚未研究与胰岛素合用。 用法用量 推荐剂量为2.5毫克，5毫克，每天一次的餐点。 2.5毫克，每日建议为中度或重度肾功能不全患者（肌酐清除率≤50毫升/分钟），或终末期肾脏疾病。之前开始ONGLYZA并在此后定期评估肾功能。 建议患者也服用2.5毫克，每日很强的细胞色素P450 3A4/5（CYP3A4/5）抑制剂（如酮康唑）。 剂型和优势 片剂：5毫克和2.5毫克 禁忌 无。 警告和注意事项 当一起使用的胰岛素促分泌剂（例如，磺酰脲），低剂量的胰岛素促分泌剂，可能需要减少低血糖的危险。 目前还没有临床研究建立ONGLYZA或任何其它抗糖尿病药物的大血管风险减少确凿的证据。 不良反应 ≥5％的ONGLYZA比用安慰剂治疗患者更常见的治疗的患者中报道的不良反应有：上呼吸道感染，泌尿道感染，头痛。 外周水肿ONGLYZA和噻唑烷二酮（TZD）相结合比相结合安慰剂和TZD治疗的患者，治疗的患者更常见的报道。 低血糖发生ONGLYZA和磺脲类药物相结合的治疗的患者与安慰剂组和磺脲类药物相结合的治疗的患者中更常见的。 与ONGLYZA治疗的患者比用安慰剂治疗患者中更常见的过敏相关的事件（例如，荨麻疹，面部水肿）。 药物相互作用 同时服用强CYP3A4 / 5抑制剂（如酮康唑）显着增加saxagliptin的浓度。建议限制ONGLYZA剂量为2.5毫克，每天一次。 特殊人群中使用 在孕妇有没有足够和良好对照的研究。 ONGLYZA 18岁以下儿童患者中的安全性和有效性尚未确立。 Onglyza 2.5mg & 5mg film-coated tablets 1. Name of the medicinal product Onglyza 2.5 mg film-coated tablets Onglyza 5 mg film-coated tablets 2. Qualitative and quantitative composition Each tablet contains 2.5 mg saxagliptin (as hydrochloride). Each tablet contains 5 mg saxagliptin (as hydrochloride). Excipients with known effect: Each tablet contains 99 mg lactose monohydrate. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Film-coated tablet (tablet). Onglyza 2.5 mg tablets are pale yellow to light yellow, biconvex, round, film-coated tablets, with “2.5” printed on one side and “4214” printed on the other side, in blue ink. Onglyza 5 mg tablets are pink , biconvex, round, film-coated tablet, with “5” printed on one side and “4215” printed on the other side, in blue ink. 4. Clinical particulars 4.1 Therapeutic indications Onglyza is indicated in adult patients aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control: as monotherapy • in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance. as dual oral therapy in combination with • metformin, when metformin alone, with diet and exercise, does not provide adequate glycaemic control. • a sulphonylurea, when the sulphonylurea alone, with diet and exercise, does not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate. • a thiazolidinedione, when the thiazolidinedione alone with diet and exercise, does not provide adequate glycaemic control in patients for whom use of a thiazolidinedione is considered appropriate. as triple oral therapy in combination with • metformin plus a sulphonylurea when this regimen alone, with diet and exercise, does not provide adequate glycaemic control. as combination therapy with insulin (with or without metformin), when this regimen alone, with diet and exercise, does not provide adequate glycaemic control. 4.2 Posology and method of administration Posology The recommended dose of Onglyza is 5 mg once daily. Onglyza tablets must not be split or cut. When Onglyza is used in combination with insulin or a sulphonylurea, a lower dose of the insulin or sulphonylurea may be required to reduce the risk of hypoglycaemia (see section 4.4). The safety and efficacy of saxagliptin as triple oral therapy in combination with metformin and a thiazolidinedione has not been established. Special populations Older people (≥65 years) No dose adjustment is recommended based solely on age. Experience in patients aged 75 years and older is very limited and caution should be exercised when treating this population (see also sections 4.4, 5.1 and 5.2). Renal impairment No dose adjustment is recommended for patients with mild renal impairment. The dose of Onglyza should be reduced to 2.5 mg once daily in patients with moderate or severe renal impairment. The experience in patients with severe renal impairment is very limited. Therefore, saxagliptin should be used with caution in this population. Onglyza is not recommended for patients with end-stage renal disease (ESRD) requiring haemodialysis (see section 4.4). Because the dose of Onglyza should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of Onglyza, and, in keeping with routine care, renal assessment should be done periodically thereafter (see sections 4.4 and 5.2). Hepatic impairment No dose adjustment is necessary for patients with mild or moderate hepatic impairment (see section 5.2). Saxagliptin should be used with caution in patients with moderate hepatic impairment, and is not recommended for use in patients with severe hepatic impairment (see section 4.4). Paediatric population The safety and efficacy of Onglyza in children aged birth to < 18 years have not yet been established. No data are available. Method of administration Onglyza can be taken with or without a meal at any time of the day. If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, or history of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock, and angioedema, to any dipeptidyl peptidase 4 (DPP4) inhibitor (see sections 4.4 and 4.8). 4.4 Special warnings and precautions for use General Onglyza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Onglyza is not a substitute for insulin in insulin-requiring patients. Pancreatitis In post-marketing experience there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of saxagliptin. If pancreatitis is suspected, Onglyza and other potentially suspect medicinal products should be discontinued. Renal impairment A single dosage adjustment is recommended in patients with moderate or severe renal impairment. Saxagliptin should be used with caution in patients with severe renal impairment, and is not recommended for use in patients with end-stage renal disease (ESRD) requiring haemodialysis. Assessment of renal function is recommended prior to initiation of Onglyza, and, in keeping with routine care, renal assessment should be done periodically thereafter (see sections 4.2 and 5.2). Hepatic impairment Saxagliptin should be used with caution in patients with moderate hepatic impairment, and is not recommended for use in patients with severe hepatic impairment (see section 4.2). Use with medicinal products known to cause hypoglycaemia Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, a lower dose of sulphonylurea or insulin may be required to reduce the risk of hypoglycaemia when used in combination with Onglyza. Hypersensitivity reactions Onglyza should not be used in patients who have had any serious hypersensitivity reaction to a dipeptidyl peptidase 4 (DPP4) inhibitor. During postmarketing experience, including spontaneous reports and clinical trials, the following adverse reactions have been reported with the use of saxagliptin: serious hypersensitivity reactions, including anaphylactic reaction, anaphylactic shock, and angioedema. If a serious hypersensitivity reaction to saxagliptin is suspected, discontinue Onglyza, assess for other potential causes for the event, and institute alternative treatment for diabetes (see sections 4.3 and 4.8). Elderly patients Experience in patients aged 75 years and older is very limited and caution should be exercised when treating this population (see sections 5.1 and 5.2). Skin disorders Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical toxicology studies (see section 5.3). Although skin lesions were not observed at an increased incidence in clinical trials, there is limited experience in patients with diabetic skin complications. Postmarketing reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an adverse event (AE) for Onglyza (see section 4.8). Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering, ulceration or rash, is recommended. Cardiac failure Experience in NYHA class I-II is limited, and there is no experience in clinical studies with saxagliptin in NYHA class III-IV. Immunocompromised patients Immunocompromised patients, such as patients who have undergone organ transplantation or patients diagnosed with human immunodeficiency syndrome, have not been studied in the Onglyza clinical program. Therefore, the efficacy and safety profile of saxagliptin in these patients has not been established. Use with potent CYP 3A4 inducers Using CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, and rifampicin may reduce the glycaemic lowering effect of Onglyza (see section 4.5). Lactose The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Clinical data described below suggest that the risk for clinically meaningful interactions with co-administered medicinal products is low. The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). In in vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4. In studies conducted in healthy subjects, neither the pharmacokinetics of saxagliptin and its major metabolite, were meaningfully altered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids or famotidine. In addition, saxagliptin did not meaningfully alter the pharmacokinetics of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, the active components of a combined oral contraceptive (ethinyl estradiol and norgestimate), diltiazem or ketoconazole. Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem, increased the Cmax and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the corresponding values for the active metabolite were decreased by 44% and 34%, respectively. Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole, increased the Cmax and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the corresponding values for the active metabolite were decreased by 95% and 88%, respectively. Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin, reduced Cmax and AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the plasma DPP4 activity inhibition over a dose interval were not influenced by rifampicin (see section 4.4). The co-administration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such as carbamazepine, dexamethasone, phenobarbital and phenytoin) have not been studied and may result in decreased plasma concentration of saxagliptin and increased concentration of its major metabolite. Glycaemic control should be carefully assessed when saxagliptin is used concomitantly with a potent CYP3A4 inducer. The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of saxagliptin have not been specifically studied. 4.6 Fertility, pregnancy and lactation Pregnancy The use of saxagliptin has not been studied in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Onglyza should not be used during pregnancy unless clearly necessary. Breast-feeding It is unknown whether saxagliptin is excreted in human breast milk. Animal studies have shown excretion of saxagliptin and/or metabolite in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy to the woman. Fertility The effect of saxagliptin on fertility in humans has not been studied. Effects on fertility were observed in male and female rats at high doses producing overt signs of toxicity (see section 5.3). 4.7 Effects on ability to drive and use machines Onglyza may have a negligible influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed. However, when driving or using machines, it should be taken into account that dizziness has been reported in studies with saxagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when Onglyza is used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. insulin, sulphonylureas). 4.8 Undesirable effects Summary of the safety profile There were 4,148 patients with type 2 diabetes, including 3,021 patients treated with Onglyza, randomised in six double-blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control. In a pooled analysis, the overall incidence of adverse events in patients treated with saxagliptin 5 mg was similar to placebo. Discontinuation of therapy due to adverse events was higher in patients who received saxagliptin 5 mg as compared to placebo (3.3% as compared to 1.8%). Tabulated list of adverse reactions Adverse reactions reported in ≥5% of patients treated with saxagliptin 5 mg and more commonly than in patients treated with placebo or that were reported in ≥2% of patients treated with saxagliptin 5 mg and ≥1% more frequently compared to placebo are shown in Table 1. The adverse reactions are listed by system organ class and absolute frequency. Frequencies 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), or Very rare (<1/10,000), not known (cannot be estimated from the available data). Table 1 Frequency of adverse reactions by system organ class System organ class Adverse Reaction Frequency of adverse reactions by treatment regimen Saxagliptin monotherapy Saxagliptin with metformin1 Saxagliptin with a sulphonylurea (glibenclamide) Saxagliptin with a thiazolidinedione Infections and infestations         Upper respiratory infection Common Common Common Common Urinary tract infection Common Common Common Common Gastroenteritis Common Common Common Common Sinusitis Common Common Common Common Nasopharyngitis   Common2     Metabolism and nutrition disorders         Hypoglycaemia     Very common3   Nervous system disorders         Headache Common Common Common Common Gastrointestinal disorders         Vomiting Common Common Common Common General disorders and administration site conditions         Oedema peripheral       Common4 1Includes saxagliptin in add-on to metformin and initial combination with metformin. 2Only in the initial combination therapy. 3There was no statistically significant difference compared to placebo. The incidence of confirmed hypoglycaemia was uncommon for Onglyza 5 mg (0.8%) and placebo (0.7%). 4All of the reported adverse drug reactions of peripheral oedema were of mild to moderate intensity and none resulted in study drug discontinuation. Postmarketing experience from clinical trials and spontaneous reports Table 2 shows additional adverse reactions which have been reported in postmarketing experience. The frequencies are based on the experience from clinical trials. Table 2 Frequency of additional adverse reactions by system organ class System organ class Adverse Reaction Frequency of adverse reactions1 Gastrointestinal disorders   Diarrhoea2 Common Nausea Pancreatitis Abdominal pain Common Uncommon Unknown Immune system disorders   Hypersensitivity reactions3 (see sections 4.3 and 4.4) Uncommon Anaphylactic reactions including anaphylactic shock (see sections 4.3 and 4.4) Rare Skin and subcutaneous tissue disorders   Angioedema (see sections 4.3 and 4.4) Dermatitis Pruritus Rash2 Urticaria Rare Uncommon Uncommon Common Uncommon 1 Frequency estimates are based on the pooled analysis of the saxagliptin monotherapy, add-on to metformin and initial combination with metformin, add-on to sulphonylurea, and add-on to thiazolidinedione clinical trials. 2 The incidence of diarrhoea was 4.1% (36/882) in the saxagliptin 5 mg group and 6.1% (49/799) in the placebo group. 3 These reactions were also identified in the pre-approval clinical trials, but do not meet the criteria for Table 1. Description of selected adverse reactions Adverse events, considered by the investigator to be at least possibly drug-related and reported in at least two more patients treated with saxagliptin 5 mg compared to control, are described below by treatment regimen. As monotherapy: dizziness (common) and fatigue (common). As add-on to metformin: dyspepsia (common) and myalgia (common). As add-on to sulphonylurea (glibenclamide): fatigue (uncommon), dyslipidemia (uncommon) and hypertriglyceridemia (uncommon). As initial combination with metformin: gastritis (common), arthralgia (uncommon), myalgia (uncommon), and erectile dysfunction (uncommon). As add-on to metformin plus a sulphonylurea: dizziness (common), fatigue (common) and flatulence (common). Hypoglycaemia Adverse reactions of hypoglycaemia were based on all reports of hypoglycaemia; a concurrent glucose measurement was not required. When used as add-on combination therapy with metformin plus sulphonylurea, the overall incidence of reported hypoglycemia was 10.1 % for Onglyza 5 mg and 6.3% for placebo. When used as add-on to insulin (with or without metformin), the overall incidence of reported hypoglycaemia was 18.4% for Onglyza 5 mg and 19.9% for placebo. Investigations Across clinical studies, the incidence of laboratory adverse events was similar in patients treated with saxagliptin 5 mg compared to patients treated with placebo. A small decrease in absolute lymphocyte count was observed. From a baseline mean absolute lymphocyte count of approximately 2,200 cells/μl, a mean decrease of approximately 100 cells/μl relative to placebo was observed in the placebo-controlled-pooled analysis. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The clinical significance of this decrease in lymphocyte count relative to placebo is not known. 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 IMB Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie Malta ADR Reporting The Medicines Authority Post-Licensing Directorate 203 Level 3, Rue D'Argens GŻR-1368 Gżira Website: www.medicinesauthority.gov.mt e-mail: postlicensing.medicinesauthority@gov.mt 4.9 Overdose Onglyza has been shown to be safe and well-tolerated with no clinically meaningful effect on QTc interval or heart rate at oral doses up to 400 mg daily for 2 weeks (80 times the recommended dose). In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. Saxagliptin and its major metabolite can be removed by haemodialysis (23% of dose over 4 hours). 5. Pharmacological properties 5.1 Pharmacodynamic properties  Pharmacotherapeutic group: Drugs used in diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH03 Mechanism of action and pharmacodynamic effects Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible, competitive, DPP-4 inhibitor. In patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load, this DPP-4 inhibition resulted in a 2-to 3-fold increase in circulating levels of active incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations and increased glucose-dependent beta-cell responsiveness, which resulted in higher insulin and C-peptide concentrations. The rise in insulin from pancreatic beta-cells and the decrease in glucagon from pancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal. Saxagliptin improves glycaemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes. Clinical efficacy and safety A total of 4,148 patients with type 2 diabetes, including 3,021 patients treated with, saxagliptin were randomised in 6 double-blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control. In these studies 634 patients were 65 years and older, while 59 patients were 75 years and older. Treatment with saxagliptin 5 mg once daily produced clinically relevant and statistically significant improvements in haemoglobin A1c (HbA1c), fasting plasma glucose (FPG) and postprandial glucose (PPG) compared to placebo in monotherapy, in combination with metformin (initial or add-on therapy), in combination with a sulphonylurea, and in combination with a thiazolidinedione (see Table 3). There was also no apparent change in body weight associated with saxagliptin. Reductions in HbA1c were seen across subgroups including gender, age, race, and baseline body mass index (BMI) and higher baseline HbA1c was associated with a greater adjusted mean change from baseline with saxagliptin. Saxagliptin as monotherapy Two double-blind, placebo-controlled studies of 24-week duration were conducted to evaluate the efficacy and safety of saxagliptin monotherapy in patients with type 2 diabetes. In both studies, once-daily treatment with saxagliptin provided significant improvements in HbA1c (see Table 3). The findings of these studies were confirmed with two subsequent 24-week regional (Asian) monotherapy studies comparing saxagliptin 5 mg with placebo. Saxagliptin add-on to metformin therapy An add-on to metformin placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of saxagliptin in combination with metformin in patients with inadequate glycaemic control (HbA1c 7-10%) on metformin alone. Saxagliptin (n=186) provided significant improvements in HbA1c, FPG and PPG compared to placebo (n=175). Improvements in HbA1c, PPG, and FPG following treatment with saxagliptin 5 mg plus metformin were sustained up to Week 102. The HbA1c change for saxagliptin 5 mg plus metformin (n=31) compared to placebo plus metformin (n=15) was -0.8% at Week 102. Saxagliptin add-on to metformin compared with SU add-on to metformin A 52-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin (428 patients) compared with sulphonylurea (glipizide, 5 mg titrated as needed to 20 mg, mean dose of 15 mg) in combination with metformin (430 patients) in 858 patients with inadequate glycaemic control (HbA1c 6.5%-10%) on metformin alone. The mean metformin dose was approximately 1900 mg in each treatment group. After 52 weeks, the saxagliptin and glipizide groups had similar mean reductions from baseline in HbA1c in the per-protocol analysis (-0.7% vs. –0.8%, respectively, mean baseline HbA1c of 7.5% for both groups). The intent-to-treat analysis showed consistent results. The reduction in FPG was slightly less in the saxagliptin-group and there were more discontinuations (3.5% vs. 1.2%) due to lack of efficacy based on FPG criteria during the first 24 weeks of the study. Saxagliptin also resulted in a significantly lower proportion of patients with hypoglycaemia, 3% (19 events in 13 subjects) vs. 36.3% (750 events in 156 patients) for glipizide. Patients treated with saxagliptin exhibited a significant decrease from baseline in body weight compared to a weight gain in patients administered glipizide (-1.1 vs. +1.1 kg). Saxagliptin add-on to metformin compared with sitagliptin add-on to metformin An 18-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin (403 patients), compared with sitagliptin 100 mg in combination with metformin (398 patients) in 801 patients with inadequate glycaemic control on metformin alone. After 18 weeks, saxagliptin was non-inferior to sitagliptin in mean reduction from baseline in HbA1c in both the per-protocol and the full analysis sets . The reductions from baseline in HbA1c respectively for saxagliptin and sitagliptin in the primary per-protocol analysis were -0.5% (mean and median) and -0.6% (mean and median). In the confirmatory full analysis set, mean reductions were -0.4% and -0.6% respectively for saxagliptin and sitagliptin, with median reductions of -0.5% for both groups. Saxagliptin in combination with metformin as initial therapy A 24-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin as initial combination therapy in treatment-naïve patients with inadequate glycaemic control (HbA1c 8-12%). Initial therapy with the combination of saxagliptin 5 mg plus metformin (n=306) provided significant improvements in HbA1c, FPG and PPG compared to with either saxagliptin (n=317) or metformin (n=313) alone as initial therapy. Reductions in HbA1c from baseline to Week 24 were observed in all evaluated subgroups defined by baseline HbA1c, with greater reductions observed in patients with a baseline HbA1c ≥10% (see Table 3). Improvements in HbA1c, PPG and FPG following initial therapy with saxagliptin 5 mg plus metformin were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg plus metformin (n=177) compared to metformin plus placebo (n=147) was -0.5% at Week 76. Saxagliptin add-on to glibenclamide therapy An add-on placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of saxagliptin in combination with glibenclamide in patients with inadequate glycaemic control at enrolment (HbA1c 7.5-10%) on a sub-maximal dose of glibenclamide alone. Saxagliptin in combination with a fixed, intermediate dose of a sulphonylurea (glibenclamide 7.5 mg) was compared to titration to a higher dose of glibenclamide (approximately 92% of patients in the placebo plus glibenclamide group were up-titrated to a final total daily dose of 15 mg). Saxagliptin (n=250) provided significant improvements in HbA1c, FPG and PPG compared to titration to a higher dose of glibenclamide (n=264). Improvements in HbA1c and PPG following treatment with saxagliptin 5 mg were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg (n=56) compared to uptitrated glibenclamide plus placebo (n=27) was -0.7% at Week 76. Saxagliptin add-on combination therapy with insulin (with or without metformin) A total of 455 patients with type 2 diabetes participated in a 24-week randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of saxagliptin in combination with a stable dose of insulin (baseline mean: 54.2 Units) in patients with inadequate glycaemic control (HbA1c ≥ 7.5% and ≤ 11%) on insulin alone (n=141) or on insulin in combination with a stable dose of metformin (n=314). Saxagliptin 5 mg add-on to insulin with or without metformin provided significant improvements after 24 weeks in HbA1c and PPG compared with placebo add-on to insulin with or without metformin. Similar HbA1c reductions versus placebo were achieved for patients receiving saxagliptin 5 mg add-on to insulin regardless of metformin use (−0.4% for both subgroups). Improvements from baseline HbA1c were sustained in the saxagliptin add-on to insulin group compared to the placebo add-on to insulin group with or without metformin at Week 52. The HbA1c change for the saxagliptin group (n=244) compared to placebo (n=124) was -0.4% at Week 52. Saxagliptin add-on to thiazolidinedione therapy A placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of saxagliptin in combination with a thiazolidinedione (TZD) in patients with inadequate glycaemic control (HbA1c 7-10.5%) on TZD alone. Saxagliptin (n=183) provided significant improvements in HbA1c, FPG and PPG compared to placebo (n=180). Improvements in HbA1c, PPG and FPG following treatment with saxagliptin 5 mg were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg (n=82) compared to TZD plus placebo (n=53) was -0.9% at Week 76. Saxagliptin add-on combination therapy with metformin and sulphonylurea A total of 257 patients with type 2 diabetes participated in a 24-week randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of saxagliptin (5 mg once daily) in combination with metformin plus sulphonylurea (SU) in patients with inadequate glycemic control (HbA1c ≥7% and ≤10%). Saxagliptin (n=127) provided significant improvements in HbA1c and PPG compared with the placebo (n=128). The HbA1c change for saxagliptin compared to placebo was -0.7% at Week 24. Patients with renal impairment A 12 week, multi-centre, randomised, double-blind, placebo controlled study was conducted to evaluate the treatment effect of saxagliptin 2.5 mg once daily compared with placebo in 170 patients (85 patients on saxagliptin and 85 on placebo) with type 2 diabetes (HbA1c 7.0-11%) and renal impairment (moderate [n=90]; severe [n=41]; or ESRD [n=39]). In this study, 98.2% of the patients received other antihyperglycaemic treatments (75.3% on insulin and 31.2% on oral antihyperglycaemics; some received both). Saxagliptin significantly decreased HbA1c compared with placebo; the HbA1c change for saxagliptin was -0.9% at Week 12 (HbA1c change of -0.4% for placebo). Improvements in HbA1c following treatment with saxagliptin 2.5 mg were sustained up to Week 52, however the number of patients who completed 52 weeks without modification of other antihyperglycaemic treatments was low (26 subjects in the saxagliptin group versus 34 subjects in the placebo group). The incidence of confirmed hypoglycaemic events was somewhat higher in the saxagliptin group (9.4%) versus placebo group (4.7%) although the number of subjects with any hypoglycaemic event did not differ between the treatment groups. There was no adverse effect on renal function as determined by estimated glomerular filtration rate or CrCL at Week 12 and Week 52. Table 3 Key efficacy results of Onglyza 5 mg per day in placebo-controlled monotherapy trials and in add-on combination therapy trials Mean baseline HbA1c (%) Mean change2 from baseline HbA1c (%) at Week 24 Placebo-corrected mean change in HbA1c (%) at Week 24 (95% CI) MONOTHERAPY STUDIES       • Study CV181011 (n=103) 8.0 -0.5 -0.6 (-0.9, -0.4)3 • Study CV181038 (n=69) 7.9 -0.7 (morning) -0.4 (-0.7, -0.1) 4 (n=70) 7.9 -0.6 (evening) -0.4 (-0.6, -0.1) 5 ADD-ON/COMBINATION STUDIES       • Study CV181014: add-on to metformin (n=186) 8.1 -0.7 -0.8 (-1.0, -0.6)3 • Study CV181040: add-on to SU1 (n=250) 8.5 -0.6 -0.7 (-0.9, -0.6)3 • Study D1680L00006: add-on to metformin plus SU (n=257) 8.4 -0.7 -0.7(-0.9,-0.5) 3 • Study CV181013: add-on to TZD (n=183) 8.4 -0.9 -0.6 (-0.8, -0.4)3 • Study CV181039: initial combination with metformin6       Overall population (n=306) 9.4 -2.5 -0.5 (-0.7, -0.4) 7 Baseline HbA1c ≥10% stratum (n=107) 10.8 -3.3 -0.6 (-0.9, -0.3) 8 • Study CV181057: add-on to insulin (+/-metformin)       Overall population (n=300) 8.7 -0.7 -0.4 (-0.6, -0.2)3 n=Randomized patients (primary efficacy-intention-to-treat analysis) with data available. 1Placebo group had uptitration of glibenclamidefrom 7.5 to 15 mg total daily dose. 2 Adjusted mean change from baseline adjusted for baseline value (ANCOVA). 3 p<0.0001 compared to placebo. 4 p=0.0059 compared to placebo. 5 p=0.0157 compared to placebo. 6 Metformin was uptitrated from 500 to 2000 mg per day as tolerated. 7 Mean HbA1c change is the difference between the saxagliptin+metformin and metformin alone groups (p<0.0001). 8 Mean HbA1c change is the difference between the saxagliptin+metformin and metformin alone groups. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Onglyza in one or more subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetics of saxagliptin and its major metabolite were similar in healthy subjects and in patients with type 2 diabetes. Absorption Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and 4 hours (Tmax), respectively. The Cmax and AUC values of saxagliptin and its major metabolite increased proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its major metabolite were 78 ng·h/ml and 214 ng·h/ml, respectively. The corresponding plasma Cmax values were 24 ng/ml and 47 ng/ml, respectively. The intra-subject coefficients of variation for saxagliptin Cmax and AUC were less than 12%. The inhibition of plasma DPP-4 activity by saxagliptin for at least 24 hours after oral administration of saxagliptin is due to high potency, high affinity, and extended binding to the active site. Interaction with food Food had relatively modest effects on the pharmacokinetics of saxagliptin in healthy subjects. Administration with food (a high-fat meal) resulted in no change in saxagliptin Cmax and a 27% increase in AUC compared with the fasted state. The time for saxagliptin to reach Cmax (Tmax) was increased by approximately 0.5 hours with food compared with the fasted state. These changes were not considered to be clinically meaningful. Distribution The in vitro protein binding of saxagliptin and its major metabolite in human serum is negligible. Thus, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin. Biotransformation The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a selective, reversible, competitive DPP-4 inhibitor, half as potent as saxagliptin. Elimination The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metabolite are 2.5 hours and 3.1 hours respectively, and the mean t1/2 value for plasma DPP-4 inhibition was 26.9 hours. Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its major metabolite, and total radioactivity respectively. The average renal clearance of saxagliptin (230 ml/min) was greater than the average estimated glomerular filtration rate (120 ml/min), suggesting some active renal excretion. For the major metabolite, renal clearance values were comparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivity was recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed medicinal product from the gastrointestinal tract. Linearity The Cmax and AUC of saxagliptin and its major metabolite increased proportionally to the saxagliptin dose. No appreciable accumulation of either saxagliptin or its major metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence was observed in the clearance of saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg. Special populations Renal impairment A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a 10 mg oral dose of saxagliptin in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The study included patients with renal impairment classified on the basis of creatinine clearance (based on the Cockcroft-Gault formula) as mild (>50 to ≤80 ml/min), moderate (≥30 to ≤50 ml/min), or severe (<30 ml/min), as well as patients with ESRD on haemodialysis. The degree of renal impairment did not affect the Cmax of saxagliptin or its major metabolite. In subjects with mild renal impairment, the mean AUC values of saxagliptin and its major metabolite were 1.2- and 1.7 -fold higher, respectively, than mean AUC values in subjects with normal renal function. Because increases of this magnitude are not clinically relevant, dose adjustment in patients with mild renal impairment is not recommended. In subjects with moderate or severe renal impairment or in subjects with ESRD on haemodialysis, the AUC values of saxagliptin and its major metabolite were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal function. The dose of Onglyza should be reduced to 2.5 mg once daily in patients with moderate or severe renal impairment (see sections 4.2 and 4.4). Hepatic impairment In subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment the exposures to saxagliptin were 1.1-, 1.4- and 1.8-fold higher, respectively, and the exposures to BMS-510849 were 22%, 7%, and 33% lower, respectively, than those observed in healthy subjects. Older people (≥65 years) Elderly patients (65-80 years) had about 60% higher saxagliptin AUC than young patients (18-40 years). This is not considered clinically meaningful, therefore, no dose adjustment for Onglyza is recommended on the basis of age alone. 5.3 Preclinical safety data In cynomolgus monkeys saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) in extremities (tail, digits, scrotum and/or nose) at doses ≥3 mg/kg/day. The no effect level (NOEL) for the lesions is 1 and 2 times the human exposure of saxagliptin and the major metabolite respectively, at the recommended human dose of 5 mg/day (RHD). The clinical relevance of the skin lesions is not known, however clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin. Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes and bone marrow with no adverse sequelae have been reported in all species tested at exposures starting from 7 times the RHD. Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces and enteropathy at higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and the major metabolite, respectively, at RHD. Saxagliptin was not genotoxic in a conventional battery of genotoxicity studies in vitro and in vivo. No carcinogenic potential was observed in two-year carcinogenicity assays with mice and rats. Effects on fertility were observed in male and female rats at high doses producing overt signs of toxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats, saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis and decreased foetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the human exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects of saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL 158 and 224 times the human exposure for saxagliptin and the major metabolite, respectively at RHD). In a pre- and postnatal developmental study in rats, saxagliptin caused decreased pup weight at maternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and the major metabolite, respectively at RHD. The effect on offspring body weights were noted until postnatal day 92 and 120 in females and males, respectively. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core: Lactose monohydrate Cellulose microcrystalline (E460i) Croscarmellose sodium (E468) Magnesium stearate Film coating: Polyvinyl alcohol Macrogol/3350 Titanium dioxide (E171) Talc (E553b) Iron oxide red (E172) 5 mg Tablets only Iron oxide yellow (E172) 2.5 mg Tablets only Printing ink: Shellac Indigo carmine aluminium lake (E132) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container 2.5 mg Tablet Alu/Alu blister. Pack sizes of 14, 28, and 98 film-coated tablets in non-perforated calendar blisters. Pack sizes of 30x1 and 90x1 film-coated tablets in perforated unit dose blisters. Not all pack sizes may be marketed. 5mg Tablets Alu/Alu blister. Pack sizes of 14, 28, 56 and 98 film-coated tablets in non-perforated blisters. Pack sizes of 14, 28, 56 and 98 film-coated tablets in non-perforated calendar blisters. Pack sizes of 30x1 and 90x1 film-coated tablets in perforated unit dose blisters. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Bristol-Myers Squibb/AstraZeneca EEIG Bristol-Myers Squibb House Uxbridge Business Park Sanderson Road Uxbridge Middlesex UB8 1DH United Kingdom 8. Marketing authorisation number(s)  EU/1/09/545/012 - Onglyza 2.5 mg film-coated tablet oral use non-perforated calendar blister (Alu/Alu)-28 tablets EU/1/09/545/006 - Onglyza 5 mg film-coated tablet oral use non-perforated calendar blister (Alu/Alu)-28 tablet 9. Date of first authorisation/renewal of the authorisation 5 mg Tablets- 1st October 2009 2.5 mg Tablets – 28th February 2011 10. Date of revision of the text 23rd April 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 欧洲药监局肯定糖尿病新药Onglyza的疗效 2011年11月30日,糖尿病新药Onglyza近日得到了欧洲药监局的肯定，该药由阿斯利康和百时美-施贵宝联合推出。可以说这种糖尿病在未来几个月进入欧洲市场的障碍被扫清，因为通常情况下欧盟会采纳欧洲药监局的意见。 欧洲药监局专家认可了Onglyza作为辅助药物与常用老药（如甲福明二甲双胍、噻唑烷二酮或磺脲）联用治疗2型糖尿病的效果。 自2003推出降醇药Crestor之后，阿斯利康还未出品任何新药，而Onglyza成为了该公司近年来面世的第一种新产品，它被寄以厚望抢夺一定的市场份额，与美国默克极为畅销的同类药物Januvia展开竞争，后者在2008年的全球销售额达14亿美元。 Onglyza和Januvia均属于二肽基肽酶-4（DPP-4）类药物，通过增强人体调控血糖水平的能力而达到治疗效果。 尽管目前市场上的糖尿病治疗药种类繁多，但有些产品会导致患者体重增加或其他并发症，并且多数患者用药后未能将体内血糖控制在最佳水平，因此市场上对新型药物的需求还较为迫切。 阿斯利康和百时美-施贵宝还希望Onglyza在7月30日之前获准进入美国市场。今年4月份，该药也得到了FDA顾问团的支持，但FDA最终还是决定延期批准药物上市销售，最终的审批意见将自4月30日之后的3个月内确定。 ---------------------------------------------------- 产地国家：欧洲共同体 原产地英文商品名: ONGLYZA 2.5mg/tab 28tabs/bottle 原产地英文药品名: SAXAGLIPTIN HYDROCHLORIDE 中文参考商品译名: ONGLYZA 2.5毫克/膜包衣片 28片/盒 中文参考药品译名: 盐酸沙格列汀 生产厂家中文参考译名: 百时美施贵宝 生产厂家英文名: BRISTOL MYERS SQUIBB ---------------------------------------------------- 产地国家：欧洲共同体 原产地英文商品名: ONGLYZA 5mg/tab 28tabs/bottle 原产地英文药品名: SAXAGLIPTIN HYDROCHLORIDE 中文参考商品译名: ONGLYZA 5毫克/膜包衣片 28片/盒 中文参考药品译名: 盐酸沙格列汀 生产厂家中文参考译名: 百时美施贵宝 生产厂家英文名: BRISTOL MYERS SQUIBB ---------------------------------------------------- 产地国家：美国 原产地英文商品名: ONGLYZA 2.5mg/tab 30tabs/bottle 原产地英文药品名: SAXAGLIPTIN HYDROCHLORIDE 中文参考商品译名: ONGLYZA 2.5毫克/片 30片/瓶 中文参考药品译名: 盐酸沙格列汀 生产厂家中文参考译名: 百时美施贵宝 生产厂家英文名: BRISTOL MYERS SQUIBB ---------------------------------------------------- 产地国家：美国 原产地英文商品名: ONGLYZA 5mg/tab 30tabs/bottle 原产地英文药品名: SAXAGLIPTIN HYDROCHLORIDE 中文参考商品译名: ONGLYZA  5毫克/片 30片/瓶 中文参考药品译名: 盐酸沙格列汀 生产厂家中文参考译名: 百时美施贵宝 生产厂家英文名: BRISTOL MYERS SQUIBB