Kombiglyze XR缓释剂是首个由二肽基肽酶-4抑制剂沙格列汀（Onglyza）和双胍类药物二甲双胍（metformin hydrochloride）缓释剂组成的复方制剂,本品将2种降血糖药物联合使用,通过互补作用提高对II型糖尿病患者血糖控制的作用。 近日，阿斯利康和百时美-施贵宝共同推出的新药Kombiglyze XR已获得FDA批准用于治疗2型糖尿病成人患者。 Kombiglyze XR每日用药一次，是一种复方制剂，同时含有缓释型甲福明二甲双胍和DPP-4抑制剂两种成分，可以控制血糖水平—包括糖化血蛋白水平（HbA1c）、空腹血糖水平和饭后血糖水平。 称Kombiglyze XR为“2型糖尿病缓释新药”，主要是由于它作为一种辅助药物，用于那些适合同时采用saxagliptin（商品名为Onglyza）和甲福明二甲双胍治疗的2型糖尿病患者，再结合饮食和运动帮助他们控制血糖水平。 这次获准的依据是该药在一系列临床实验中获取的数据，其中包括两项III期临床实验和一项生物等效性实验，后者从疗效和安全性对saxagliptin和甲福明二甲双胍IR两种单独药物合用和安慰剂+甲福明二甲双胍IR进行了检测。 Kombiglyze XR和saxagliptin+甲福明二甲双胍XR（两种单独药物联用）的生物等效性也在实验中得到了证实。 批准日期：2011年1月28日  公司：阿斯利康和百时美-施贵宝公司 KOMBIGLYZE XR（沙格列汀和盐酸二甲双胍[saxagliptin and metformin hydrochloride extended-release]）缓释片剂，口服使用 最初美国批准：2010 警告： 乳酸ACIDOSISSee完整处方完整黑框警告信息 •乳酸性酸中毒可由于二甲双胍积累发生。风险与如败血症，脱水，过量饮酒，肝功能不全，肾功能不全，急性充血性心脏衰竭的条件而增加。 •症状包括乏力，肌痛，呼吸窘迫，增加嗜睡和非特异性腹痛困扰。实验室检查异常包括低pH值，增加阴离子间隙，和血乳酸升高。 •如果酸中毒怀疑，停止KOMBIGLYZE XR并立即就医患者。 作用机理 KOMBIGLYZE XR KOMBIGLYZE XR结合作用的互补机制的两种抗高血糖药物，以改善血糖控制成人的2型糖尿病：沙格列汀，一个二肽基肽酶-4（DPP4）抑制剂，和盐酸二甲双胍，双胍。 沙格列汀 增加肠降血糖素激素的浓度，如胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）响应于膳食释放到血液中，从小肠。这些激素使从胰腺β细胞的葡萄糖依赖性胰岛素释放，但由分钟内DPP4酶被灭活。GLP-1还从胰腺α细胞中，降低肝葡萄糖生成降低胰高血糖素分泌。在例2型糖尿病，GLP-1的浓度降低，但胰岛素响应于GLP-1被保存下来。沙格列汀是竞争DPP4抑制剂减缓了肠促胰岛素激素的失活，从而增加他们的血液浓度和患者减少空腹和餐后葡萄糖浓度在葡萄糖依赖性2型糖尿病。 盐酸二甲双胍 二甲双胍改善患者的2型糖尿病患者的葡萄糖耐受性，降低基础和餐后血浆葡萄糖。二甲双胍降低肝葡萄糖生产，降低葡萄糖的肠吸收，并通过增加外周葡萄糖摄取和利用提高胰岛素的敏感性。与磺脲类药物，二甲双胍不例2型糖尿病患者或健康人发生低血糖除非在特殊情况下[见警告和注意事项]，并不会导致高胰岛素血症。与二甲双胍治疗，胰岛素的分泌，同时保持空腹胰岛素水平和一天的血浆胰岛素反应可能实际上会降低不变。 适应症和用法 KOMBIGLYZE XR是沙格列汀，一个二肽基肽-4（DPP4）抑制剂，和二甲双胍，双胍的组合，表示作为辅助饮食和锻炼，以改善血糖控制成人2型糖尿病时既沙格列汀和二甲双胍治疗是适当的。 使用限制： •不治疗1型糖尿病或糖尿病酮症酸中毒。 •尚未研究的患者胰腺炎病史。 用法用量 •用晚餐，每天一次辖。 •进行个性根据患者的当前治疗方案的起始剂量，然后调整基于有效性和耐受剂量。 •不要超过5毫克沙格列汀/2000毫克的盐酸二甲双胍缓释的日剂量。 •整片吞服。不要挤压，切割，或咀嚼。 •涨停沙格列汀剂量至2.5mg的患者也采取强有力的细胞色素P450 3A4/5抑制剂（例如，酮康唑）。 剂型和规格 片剂： •5毫克沙格列汀/500毫克的盐酸二甲双胍缓释 •5毫克沙格列汀/1000毫克的盐酸二甲双胍缓释 •2.5毫克沙格列汀/1000毫克的盐酸二甲双胍缓释 禁忌症 • 肾功能不全。 •过敏者盐酸二甲双胍。 •代谢性酸中毒，包括糖尿病酮症酸中毒。 •严重过敏反应史（如，过敏反应，血管神经性水肿，剥脱皮肤状况），以KOMBIGLYZE XR或沙格列汀。 警告和注意事项 •乳酸性酸中毒：警惕过量饮酒的患者。 KOMBIGLYZE XR在肝损害不推荐在肾功能不全禁忌。发起此后每年至少前确保正常的肾功能。暂时停止KOMBIGLYZE XR在经历与碘造影剂材料或迫使食物和液体摄入限制任何外科手术的血管内给药放射学检查的患者。 •急性胰腺炎（上市后报告）：如果胰腺炎被怀疑，立即停止KOMBIGLYZE XR。 •维生素B12缺乏：二甲双胍可降低维生素B 12的水平。每年测量血液参数。 •低血糖：在沙格列汀附加磺酰脲类，附加胰岛素，并添加二甲双胍加磺脲类药物的试验，证实了低血糖是与沙格列汀治疗的患者与安慰剂相比，报道更常见。当与胰岛素促分泌素（例如，磺酰脲）或胰岛素使用时，可能需要所述胰岛素促分泌或胰岛素的较低剂量，以尽量减少低血糖的风险。 •过敏相关事件（例如，荨麻疹，颜面浮肿）：用沙格列汀比用安慰剂治疗的患者治疗的患者多见;和严重的过敏反应的上市后报告，如过敏反应，血管性水肿，以及与沙格列汀治疗的患者剥脱皮肤状况。及时停止KOMBIGLYZE XR，评估其他潜在原因，制定适当的监测和治疗，并开始替代治疗糖尿病。 •大血管成果：大血管风险降低与KOMBIGLYZE XR或任何其他降糖药物没有确凿的证据。 不良反应 •在与二甲双胍缓释和更普遍比用安慰剂治疗的患者治疗的患者> 5％的人报告不良反应有：腹泻和恶心/呕吐。 报告中的与沙格列汀和比用安慰剂治疗的患者比较常用治疗患者≥5％•不良反应有：上呼吸道感染，泌尿道感染，和头痛。 •与合用沙格列汀和二甲双胍且高于单用二甲双胍治疗的患者治疗治疗过的患者的≥5％，报告的不良反应有：头痛，鼻咽炎。 药物相互作用 •合用强CYP3A4 / 5抑制剂（例如，酮康唑）显著增加沙格列汀的浓度。限制KOMBIGLYZE XR剂量为2.5mg / 1000毫克，每天一次。 •由肾小管分泌消除阳离子药物可降低二甲双胍消除：谨慎使用。 特殊人群中使用 •孕妇无足够和良好对照的研究。 KOMBIGLYZE™ XR (Saxagliptin and Metformin HCl Extended-Release) Tablets Approved in the U.S. for the Treatment of Type 2 Diabetes Mellitus in Adults PRINCETON, N.J. & LONDON - (Business Wire) Bristol-Myers Squibb Company (NYSE: BMY) and AstraZeneca (NYSE: AZN) today announced that the U.S. Food and Drug Administration (FDA) approved KOMBIGLYZE™ XR for the treatment of type 2 diabetes in adults. KOMBIGLYZE XR is the first and only once-a-day metformin extended-release (XR) plus dipeptidyl peptidase-4 (DPP-4) inhibitor combination tablet offering strong glycemic control across glycosylated hemoglobin levels (HbA1c), fasting plasma glucose (FPG) and post-prandial glucose (PPG). KOMBIGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate. KOMBIGLYZE XR should not be used for patients with type 1 diabetes or diabetic ketoacidosis and has not been studied in combination with insulin. Consistent with the Prescribing Information (PI) for metformin alone, the PI for KOMBIGLYZE XR contains a boxed warning for lactic acidosis, a rare, but serious metabolic complication that can occur due to metformin accumulation during treatment with KOMBIGLYZE XR. Once-a-day KOMBIGLYZE XR combines saxagliptin (also known as ONGLYZA™), a DPP-4 inhibitor, and metformin XR, a biguanide, in one tablet for the treatment of type 2 diabetes. KOMBIGLYZE XR should generally be administered once a day with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin. The maximum daily recommended dose is 5 mg for saxagliptin and 2,000 mg for metformin extended-release. “Nearly half of adult patients remain uncontrolled on their current treatment regimen and may thus require additional medications,” said Elliott Sigal, M.D., Ph.D, executive vice president, chief scientific officer, and president, Research & Development, Bristol-Myers Squibb. “With our heritage of bringing metformin--the most widely prescribed oral antidiabetic medication--and more recently saxagliptin to patients in the U.S., we are committed to making KOMBIGLYZE XR the newest building block in our long-term commitment to helping adult patients with type 2 diabetes.” “Patients with type 2 diabetes in the United States can be taking four or five medications for various diseases and conditions, which can lead to complicated medication schedules,” said Howard Hutchinson, M.D., chief medical officer, AstraZeneca. “KOMBIGLYZE XR combines two effective diabetes medications in a simple once-a-day dose for adult patients who need A1c reductions.” The Centers for Disease Control and Prevention (CDC) estimate that approximately one in every 11 adults in the United States has diagnosed diabetes. Type 2 diabetes accounts for approximately 90 to 95% of all cases of diagnosed diabetes in adults. The co-administration of saxagliptin and metformin has been well-studied in adult patients with type 2 diabetes inadequately controlled on metformin alone and in treatment-naïve patients inadequately controlled on diet and exercise alone. There have been no clinical efficacy or safety studies conducted with KOMBIGLYZE XR. Relative bioavailability between KOMBIGLYZE XR and coadministered saxagliptin and metformin immediate-release (IR) tablets has not been conducted. The FDA approved once-a-day KOMBIGLYZE XR based on two Phase III clinical trials and bioequivalence studies. The two clinical studies evaluated the efficacy and safety of saxagliptin and metformin IR as separate tablets compared to placebo added to metformin IR. Bioequivalence was demonstrated in healthy adults between KOMBIGLYZE XR and saxagliptin plus metformin XR as separate tablets. KOMBIGLYZE XR is contraindicated in patients with renal impairment, metabolic acidosis including diabetic ketoacidosis, and hypersensitivity to metformin. KOMBIGLYZE XR should be temporarily discontinued in patients undergoing radiologic studies with iodinated contrast materials. KOMBIGLYZE XR Delivered Strong Glycemic Control A total of 1,306 treatment-naïve adult patients with type 2 diabetes participated in a multicenter, randomized, double-blind, active-controlled, 24-week study to evaluate the efficacy and safety of KOMBIGLYZE XR in patients with inadequate glycemic control on diet and exercise alone. KOMBIGLYZE XR, administered as ONGLYZA (saxagliptin) 5 mg and metformin IR as separate tablets (n=306; baseline HbA1c 9.4%), delivered significant reductions in HbA1c of -2.5% compared to -2.0% with metformin IR plus placebo (n=313; baseline HbA1c 9.4%). In the study, KOMBIGLYZE XR delivered statistically significant reductions in FPG and PPG versus metformin IR plus placebo. The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 7.5% with ONGLYZA 5 mg plus metformin IR and 10.1% with metformin IR plus placebo. There was no increase of reported hypoglycemia in treatment-naïve patients treated with KOMBIGLYZE XR: incidence of 3.4% for saxagliptin 5 mg plus metformin IR versus 4.0% with metformin IR alone. The adverse reactions occurring in ≥5% of patients treated with saxagliptin 5 mg plus metformin IR and more commonly than in patients treated with metformin IR alone were headache (7.5% vs. 5.2%) and nasopharyngitis (6.9% vs. 4.0%). A 24-week, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of KOMBIGLYZE XR in 743 adult patients with type 2 diabetes inadequately controlled on metformin monotherapy. This study showed that patients taking KOMBIGLYZE XR, administered as ONGLYZA 5 mg (saxagliptin) and metformin IR as separate tablets (n=186; baseline HbA1c 8.1%), experienced significant reductions in HbA1c of -0.7% compared to an increase of +0.1% in patients taking metformin IR plus placebo (n=175; baseline HbA1c 8.1%). HbA1c reduction with ONGLYZA 2.5 mg plus metformin IR (n=186; baseline HbA1c 8.1%) was -0.6% versus metformin IR plus placebo. In the study, KOMBIGLYZE XR delivered statistically significant reductions in FPG and PPG versus metformin IR plus placebo. The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 15% in the ONGLYZA 2.5 mg add-on to metformin IR group, 13% in the ONGLYZA 5 mg add-on to metformin IR group and 27% in the placebo add-on to metformin IR group. The incidences of reported hypoglycemia in patients treated with KOMBIGLYZE XR who were inadequately controlled on metformin were 5.8% for saxagliptin 5 mg plus metformin IR and 7.8% for saxagliptin 2.5 mg plus metformin IR versus 5.0% with metformin IR alone. KOMBIGLYZE XR Combines Complementary Mechanisms of Action KOMBIGLYZE XR addresses three key defects in type 2 diabetes, by incorporating the mechanism of saxagliptin, a DPP-4 inhibitor, with metformin, a commonly used glucose lowering agent. With the two active components, saxagliptin and metformin, KOMBIGLYZE XR has a comprehensive mechanism of action that targets and addresses all three key defects in type 2 diabetes for improved glycemic control: increases insulin secretion in a glucose-dependent manner, decreases hepatic glucose production, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. “Type 2 diabetes is a chronic, progressive and multi-factorial disease, and over time, patients often require more than one medication to address the multiple defects associated with the disease,” said Matthew Mintz, M.D., FACP, The George Washington University School of Medicine. “KOMBIGLYZE XR now provides patients with the first once-a-day DPP-4 inhibitor and metformin XR combination tablet containing two complementary therapies that can improve key measures of glucose control including glycosylated hemoglobin levels, fasting plasma glucose and postprandial glucose, in a convenient once-a-day treatment regimen.” Insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia if used in combination with KOMBIGLYZE XR. Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, during concomitant use with other glucose-lowering agents (such as sulfonylureas or insulin), or with use of ethanol. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Impact on Body Weight and Gastrointestinal (GI) Adverse Events As clinicians select various medications to add to the treatment regimens of patients with uncontrolled type 2 diabetes, it is important to consider issues such as weight gain and gastrointestinal disturbances. Decrease in body weight in the treatment groups given KOMBIGLYZE XR was similar to that in the groups given metformin IR alone. In patients treated with KOMBIGLYZE XR, diarrhea was the only gastrointestinal-related event that occurred in greater than or equal to 5% in any treatment group. In patients treated with KOMBIGLYZE XR who were inadequately controlled on metformin alone, the incidence of diarrhea was 5.8% (saxagliptin 5 mg plus metformin IR), 9.9% (saxagliptin 2.5 mg plus metformin IR), and 11.2% (metformin IR alone); the incidence in treatment-naïve patients was 6.9% (saxagliptin 5 mg plus metformin IR) and 7.3% (metformin IR alone). Indication and Important Limitations of Use KOMBIGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate. KOMBIGLYZE XR should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. KOMBIGLYZE XR has not been studied in combination with insulin. Important Safety Information WARNING: LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, KOMBIGLYZE XR should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions] Contraindications •Renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance) •Hypersensitivity to metformin hydrochloride •Acute or chronic metabolic acidosis, including diabetic ketoacidosis •KOMBIGLYZE XR should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contract materials because use of such products may result in acute alteration of renal function. Warnings and Precautions •The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1000 patient-years). When it occurs, it is fatal in approximately 50% of cases. Reported cases of lactic acidosis have occurred primarily in diabetic patients with significant renal insufficiency. •Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. •Lactic acidosis risk increases with the degree of renal dysfunction and patient age. The risk may be significantly decreased by use of minimum effective dose of metformin and regular monitoring of renal function. Careful renal monitoring is particularly important in the elderly. KOMBIGLYZE XR should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced. •Withhold KOMBIGLYZE XR in the presence of any condition associated with hypoxemia, dehydration, or sepsis. •Before initiation of KOMBIGLYZE XR, and at least annually thereafter, renal function should be assessed and verified as normal. •KOMBIGLYZE XR is not recommended in patients with hepatic impairment. •Metformin may lower vitamin B12 levels. Measure hematological parameters annually. •Warn patients against excessive alcohol intake. •KOMBIGLYZE XR should be suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids), and should not be restarted until patient's oral intake has resumed and renal function is normal. •Use of saxagliptin or metformin with medications known to cause hypoglycemia - Saxagliptin: Insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia if used in combination with KOMBIGLYZE XR. - Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, during concomitant use with other glucose-lowering agents (such as sulfonylureas or insulin), or with use of ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. •Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. KOMBIGLYZE XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours after the procedure and reinstituted only after renal function is normal. •There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR or any other anti-diabetic drug. Adverse Reactions •Adverse reactions reported in >5% of patients treated with metformin extended-release and more commonly than in patients treated with placebo were: diarrhea (9.6% vs 2.6%) and nausea/vomiting (6.5% vs 1.5%). •Adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (7.7% vs 7.6%), urinary tract infection (6.8% vs 6.1%), and headache (6.5% vs 5.9%). •Adverse reactions reported in ≥5% of treatment-naive patients treated with coadministered saxagliptin and metformin immediate-release (IR) and more commonly than in patients treated with metformin IR alone were: headache (7.5% vs 5.2%) and nasopharyngitis (6.9% vs 4.0%). Drug Interactions: Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin exposure, limit KOMBIGLYZE XR to 2.5 mg/1000 mg once daily when coadministered with a strong CYP3A4/5 inhibitor (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). Use in Specific Populations •Pregnant and Nursing Women: There are no adequate and well-controlled studies in pregnant women. KOMBIGLYZE XR should be used during pregnancy only if clearly needed. It is not known whether saxagliptin or metformin are secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when KOMBIGLYZE XR is administered to a nursing woman. •Pediatric Patients: Safety and effectiveness of KOMBIGLYZE XR in pediatric patients have not been established. Please click here for US Full Prescribing Information for KOMBIGLYZE XR (5/500•5/1000•2.5/1000 mg tablets), including Boxed WARNING about lactic acidosis https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c1ac4f63-695c-6bd6-4a7f-ecb97e03569e