近日,　阿斯利康的糖尿病复方新药Xigduo XR（dapagliflozin/缓释二甲双胍）获FDA批准，作为一种辅助药物，结合运动和饮食，用于适合dapagliflozin和二甲双胍联合治疗的2型糖尿病成人患者。
Xigduo XR为每日1次的复方单片，由固定剂量的dapagliflozin（达帕格列净，商品名：Forxiga）和缓释型盐酸二甲双胍组成，这2种成分具有互补性的作用机制，能够帮助改善血糖控制。
批准日期：2014年10月30日  公司：阿斯利康
XIGDUO XR（达帕格列净/盐酸二甲双胍[dapagliflozin and metformin HCl]）缓释片剂，用于口服
美国最初批准：2014年
警告：
LACTIC ACIDOSIS查看完整的BOXED警告的完整预定信息。
•二甲双胍相关乳酸性酸中毒的上市后病例导致死亡，体温过低，低血压和耐药性缓慢性心律失常。症状包括不适，肌痛，呼吸窘迫，嗜睡和腹痛。实验室异常包括血乳酸水平升高，阴离子间隙酸中毒，乳酸/丙酮酸比率增加;和二甲双胍血浆水​​平一般> 5mcg/mL。
•风险因素包括肾功能损害，同时使用某些药物，年龄>65岁，对比放射学研究，手术和其他程序，缺氧状态，过量饮酒和肝功能损害。完整处方信息中提供了降低这些高风险组中二甲双胍相关乳酸酸中毒风险的步骤。
•如果怀疑乳酸性酸中毒，停止使用XIGDUO XR并在医院环境中采取一般支持措施。建议立即进行血液透析。
最近的重大变化
剂量和用法：02/2019
警告和注意事项：02/2019
警告和注意事项：10/2018
作用机制
XIGDUO XR
XIGDUO XR结合了两种具有互补作用机制的抗高血糖药物，以改善2型糖尿病患者的血糖控制：dapagliflozin，一种钠 - 葡萄糖协同转运蛋白2（SGLT2）抑制剂和二甲双胍盐酸盐，一种双胍。
达格列
在近端肾小管中表达的钠 - 葡萄糖协同转运蛋白2（SGLT2）负责从管腔中过滤葡萄糖的大部分再吸收。 Dapagliflozin是SGLT2的抑制剂。通过抑制SGLT2，达格列嗪减少过滤葡萄糖的重吸收并降低葡萄糖的肾阈值，从而增加尿葡萄糖排泄。
盐酸二甲双胍
二甲双胍改善2型糖尿病患者的葡萄糖耐量，降低基础和餐后血浆葡萄糖。二甲双胍通过增加外周葡萄糖摄取和利用来降低肝葡萄糖产生，减少肠道对葡萄糖的吸收，并改善胰岛素敏感性。二甲双胍不会在2型糖尿病患者或健康受试者中产生低血糖，除非在特殊情况下[见警告和预防措施]，并且不会引起高胰岛素血症。使用二甲双胍治疗，胰岛素分泌保持不变，而空腹胰岛素水平和一天的血浆胰岛素反应可能实际上降低。
适应症和用法
XIGDUO XR是dapagliflozin，一种钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂和二甲双胍（一种双胍类）的组合，用作饮食和运动的辅助手段，用于改善2型糖尿病患者用dapagliflozin和dapagliflozin治疗时的血糖控制二甲双胍是合适的。
使用限制：
•不适用于治疗1型糖尿病或糖尿病酮症酸中毒。
剂量和给药
•开始前评估肾功能。如果eGFR低于45mL/min/1.73m2，请勿启动或继续。
•根据患者目前的治疗方法个性化起始剂量。
•每天早上每天食用一次食物。
•吞下整个。永远不要压碎，切割或咀嚼。
•对于尚未服用达格列嗪的患者，达帕格列净的推荐起始剂量为每日一次5毫克。
•对于需要剂量为5mg达格列嗪和2000mg盐酸二甲双胍缓释剂的患者，使用2.5mg/1000mg二甲双胍缓释片中的两种。
•不要超过10mg达格列嗪/2000mg盐酸二甲双胍缓释剂的日剂量。
•eGFR大于或等于45mL/min/1.73m 2的患者未进行剂量调整。
•XIGDUO XR可能需要在碘化造影成像程序之前或之前停用。
剂量形式和强度
•2.5mg dapagliflozin/1000 mg二甲双胍HCl延长释放
•5mg dapagliflozin/500mg二甲双胍HCl延长释放
•5mg dapagliflozin/1000mg二甲双胍HCl延长释放
•10mg dapagliflozin/500mg二甲双胍HCl延长释放
•10mg dapagliflozin/1000mg二甲双胍HCl延长释放
禁忌症
•严重肾功能损害：（eGFR低于30mL/min/1.73m2），终末期肾病或透析。
•对达格列嗪严重过敏或对盐酸二甲双胍过敏的病史。
•代谢性酸中毒，包括糖尿病酮症酸中毒。
警告和注意事项
•乳酸性酸中毒：见框警告。
•低血压：在开始XIGDUO XR之前，评估老年人，肾功能不全或收缩压低的患者以及利尿剂患者的体积状况和纠正血容量不足。在治疗期间监测体征和症状。
•酮症酸中毒：评估出现酮症酸中毒代谢性酸中毒症状和体征的患者，无论血糖水平如何。如有疑问，请停止XIGDUO XR，及时评估和治疗。在启动XIGDUO XR之前，请考虑酮症酸中毒的风险因素。XIGDUO XR患者可能需要在已知易患酮症酸中毒的临床情况下监测并暂时停止治疗。
•急性肾脏损伤和肾功能损害：考虑在口服摄入量减少或体液流失的情况下暂时停药。如果发生急性肾损伤，请停药并及时治疗。在治疗期间监测肾功能。
•尿脓毒症和肾盂肾炎：评估患者尿路感染的体征和症状，并及时治疗，如果有需要的话。
•低血糖：在服用胰岛素或使用XIGDUO XR的胰岛素促分泌剂的患者中，考虑使用较低剂量的胰岛素或胰岛素促分泌剂来降低低血糖的风险。
•会阴部坏死性筋膜炎（Fournier's Gangrene）：女性和男性都发生严重的危及生命的病例。评估患有生殖器或会阴部疼痛或压痛，红斑或肿胀的患者，以及发烧或不适。如果怀疑，立即治疗。
•维生素B12缺乏症：二甲双胍可降低维生素B12水平。每年测量血液学参数。
•生殖器真菌感染：如果需要，监测和治疗。
•LDL-C增加：按照标准护理监测和治疗。
•膀胱癌：在临床试验中观察到膀胱癌的不平衡。Dapagliflozin不应用于活动性膀胱癌患者，对于既往有膀胱癌病史的患者应谨慎使用。
•宏观血管结果：目前还没有临床研究确定XIGDUO XR可以减少大血管风险的确凿证据。
不良反应
•与XIGDUO XR相关的最常见不良反应（发病率为5％或更高）是女性生殖器真菌感染，鼻咽炎，尿路感染，腹泻和头痛。
•接受二甲双胍延长释放治疗的患者中有不良反应报告的不良反应比使用安慰剂治疗的患者更常见：腹泻和恶心/呕吐。
要报告疑似不良反应，请致电1-800-236-9933联系AstraZeneca或1-800-FDA-1088WWW.FDA.GOV/MEDWATCH联系FDA。
药物相互作用
•碳酸酐酶抑制剂可能会增加乳酸性酸中毒的风险。考虑更频繁的监控。
•减少二甲双胍清除的药物（如雷诺嗪，vandetanib，dolutegravir和西咪替丁）可能会增加二甲双胍的积累。考虑同时使用的好处和风险。
•酒精可以增强二甲双胍对乳酸代谢的影响。警告患者饮酒过量。
用于特定人群
•怀孕：告知女性胎儿的潜在风险，特别是在孕中期和孕晚期。
•哺乳期：母乳喂养时不建议使用XIGDUO XR。
•生育潜能的女性和男性：告知绝经前女性可能意外怀孕。
•老年病学：与血管内容量减少相关的不良反应发生率更高。更频繁地评估肾功能。
•肾功能损害：与血管内容量和肾功能降低相关的不良反应发生率较高。
•肝功能损害：避免用于肝功能损害患者。
包装提供/存储和处理
提供
XIGDUO®XR（dapagliflozin和二甲双胍盐酸盐缓释）片剂的一面有标记，背面为平面，有表16中列出的强度和包装。
2.5/1000mg            瓶60  NDC：0310-6225-60
5/500mg               瓶30  NDC：0310-6250-30
                      瓶30  NDC：0310-6250-50
5/1000mg              瓶30  NDC：0310-6260-30
                      瓶60  NDC：0310-6260-60
                      瓶90  NDC：0310-6260-90
                      瓶400 NDC：0310-6260-40
10/500mg              瓶30  NDC：0310-6270-30
                      瓶500 NDC：0310-6270-50
10/1000mg             瓶30  NDC：0310-6280-30
                      瓶90  NDC：0310-6280-90
                      瓶400 NDC：0310-6280-40
存储和处理
储存在20°C至25°C（68°F至77°F）;允许的偏差在15°C至30°C（59°F至86°F）之间[见USP受控室温]。
完整说明资料附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac8a0f7b-9f69-4495-abbc-3a47cd75a859
US FDA Approves Expanded FARXIGA and XIGDUO XR Labels for Use in Patients with Type 2 Diabetes and Moderate Renal Impairment
Updated label confirms the well-established efficacy and safety profile for FARXIGA and XIGDUO XR
US Food and Drug Administration (FDA) has approved a label update for FARXIGA® (dapagliflozin) and XIGDUO® XR (dapagliflozin and metformin HCl extended-release) expanding use in patients with type 2 diabetes (T2D) and moderate renal impairment (chronic kidney disease with an estimated glomerular filtration rate [eGFR] of 45-59 mL/min/1.73 m2). FARXIGA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. XIGDUO 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 dapagliflozin and metformin is appropriate.
The updated labels lower the eGFR threshold to 45 mL/min/1.73 m2 from 60 mL/min/1.73 m2, expanding the potential population of patients with T2D and impaired renal function who may benefit from the medicine. FARXIGA and XIGDUO XR are not recommended when the eGFR is less than 45 mL/min/1.73 m2 and remains contraindicated in patients with severe renal impairment (eGFR <30mL/min/1.73 m2), end-stage renal disease, or in patients on dialysis.
The updates were based on the results of DERIVE, a Phase 3 study of patients with inadequately controlled T2D (HbA1c 7.0%-11.0%) and an eGFR of 45 to 59 mL/min/1.73 m2 who received either FARXIGA (dapagliflozin 10 mg) or placebo over 24 weeks. At Week 24, FARXIGA (dapagliflozin 10 mg) provided statistically significant reductions in HbA1c compared with placebo. The safety profile following a treatment duration of 24 weeks was similar to that seen in the overall FARXIGA (dapagliflozin) clinical trial program.
Jim McDermott, PhD., Vice President, US Medical Affairs, Diabetes at AstraZeneca, said: “The DERIVE study, which further confirmed the well-established efficacy and safety profile for FARXIGA and XIGDUO XR, has resulted in important label changes for patients with type 2 diabetes that enable a broader population with impaired renal function to potentially benefit from these important treatment options.”
According to the Centers for Disease Control and Prevention, 30.3 million people in the US have diabetes, and T2D accounts for 90% to 95% of all diabetes cases. Diabetes is the leading cause of kidney disease, and approximately 1 in 4 adults with diabetes has kidney disease.
Indication and Limitations of Use for FARXIGA® (dapagliflozin)
FARXIGA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Important Safety Information for FARXIGA® (dapagliflozin)
Contraindications
Prior serious hypersensitivity reaction to FARXIGA
Severe renal impairment (eGFR <30 mL/min/1.73 m2), end-stage renal disease, or patients on dialysis
Warnings and Precautions
Hypotension: FARXIGA causes intravascular volume contraction, and symptomatic hypotension can occur. Assess and correct volume status before initiating FARXIGA in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for hypotension
Ketoacidosis has been reported in patients with type 1 and type 2 diabetes receiving FARXIGA. Some cases were fatal. Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue FARXIGA, eva luate and treat promptly. Before initiating FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA may require monitoring and temporary discontinuation in situations known to predispose to ketoacidosis
Acute Kidney Injury and Impairment in Renal Function: FARXIGA causes intravascular volume contraction and renal impairment, with reports of acute kidney injury requiring hospitalization and dialysis. Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat.
FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating FARXIGA, eva luate renal function and monitor periodically. FARXIGA is not recommended when the eGFR is<45mL/min/1.73 m2
Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the risk for urinary tract infections [UTIs] and serious UTIs have been reported with FARXIGA. eva luate for signs and symptoms of UTIs and treat promptly
Hypoglycemia: FARXIGA can increase the risk of hypoglycemia when coadministered with insulin and insulin secretagogues. Consider lowering the dose of these agents when coadministered with FARXIGA
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Rare but serious, life-threatening cases have been reported in patients receiving SGLT2 inhibitors including FARXIGA. Cases have been reported in females and males. Serious outcomes have included hospitalization, surgeries, and death. Assess patients presenting with pain or tenderness, erythema, swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment and discontinue FARXIGA.
Genital Mycotic Infections: FARXIGA increases the risk of genital mycotic infections, particularly in patients with prior genital mycotic infections. Monitor and treat appropriately
Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur with FARXIGA. Monitor LDL-C and treat per standard of care
Bladder cancer: An imbalance in bladder cancers was observed in clinical trials. There were too few cases to determine whether the emergence of these events is related to FARXIGA, and insufficient data to determine whether FARXIGA has an effect on pre-existing bladder tumors. FARXIGA should not be used in patients with active bladder cancer. Use with caution in patients with a history of bladder cancer
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA
Adverse Reactions
In a pool of 12 placebo-controlled studies, the most common adverse reactions (≥5%) associated with FARXIGA 5 mg, 10 mg, and placebo respectively were female genital mycotic infections (8.4% vs 6.9% vs 1.5%), nasopharyngitis (6.6% vs 6.3% vs 6.2%), and urinary tract infections (5.7% vs 4.3% vs 3.7%).
Use in Specific Populations
Pregnancy: Advise females of potential risk to a fetus especially during the second and third trimesters.
Lactation: FARXIGA is not recommended when breastfeeding.
Please see accompanying US Full Prescribing Information and Medication Guide for FARXIGA.
Indication and Limitations of Use for XIGDUO® XR (dapagliflozin and metformin HCl extended-release)
XIGDUO 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 dapagliflozin and metformin is appropriate.
XIGDUO XR is not recommended for patients with type 1 diabetes mellitus or diabetic ketoacidosis.
Important Safety Information for XIGDUO® XR (dapagliflozin and metformin HCl extended-release)
WARNING: LACTIC ACIDOSIS
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.
Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information.