近日，美国食品药品管理局（FDA）批准 Forxiga (dapaglifozin) 片结合饮食和锻炼，用于改善2型糖尿病患者的血糖控制。在美国，2型糖尿病影响着大约2400万人，占确诊糖尿病患者的90% 以上。随着时间的推移，高血糖水平能够增加严重并发症风险，包括心脏疾病、失明及神经和肾损伤。
FORXIGA是日服1次的药物，用于改善血糖控制，该药是一种选择性、可逆性钠-葡萄糖协同转运蛋白（SGLT2）抑制剂，独立于胰岛素发挥作用，在肾脏中选择性抑制SGLT2，可帮助患者从尿液中排出多余的葡萄糖。SGLT2是一类特异性分布在肾脏近曲小管S1段的葡萄糖转运体，其生理作用是促进葡萄糖在肾小球的重吸收。
批准日期：2014年1月8日  公司：阿斯利康制药（AstraZeneca）
FARXIGA（达格列嗪[dapagliflozin]）片剂，用于口服
美国最初批准：2014年
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
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。
适应症和用法
FARXIGA是一种钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂，可作为饮食和运动的辅助手段，用于改善2型糖尿病患者的血糖控制。
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
•在开始FARXIGA之前评估肾功能，之后定期评估。
•推荐的起始剂量为每天一次5毫克，早上服用，有或没有食物。
•对于需要额外血糖控制的FARXIGA患者，每日一次剂量可增加至10mg。
•当eGFR小于45mL/min/1.73m 2时，不建议使用FARXIGA。
剂量形式和强度
•片剂：5mg和10mg
禁忌症
•对FARXIGA的严重超敏反应史。
•严重肾功能损害，终末期肾病或透析。
警告和注意事项
•低血压：在开始FARXIGA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。如果怀疑，停止FARXIGA，立即评估和治疗。在启动FARXIGA之前，请考虑酮症酸中毒的风险因素。 FARXIGA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。
•急性肾损伤和肾功能损害：考虑在减少口服摄入量或液体流失的情况下暂时停止使用。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：评估尿路感染的体征和症状，并及时治疗，如果需要的话。
•低血糖：在服用胰岛素或胰岛素促分泌剂与FARXIGA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。
•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。 FARXIGA不应该用于患有活动性膀胱癌的患者，并且应该在有膀胱癌病史的患者中谨慎使用。
•宏观结果：没有临床研究确定FARXIGA可以降低大血管风险的确凿证据。
不良反应
•与FARXIGA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，鼻咽炎和尿路感染。
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。
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FARXIGA。
•老年病学：与血管内容量减少相关的不良反应发生率更高。
•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。
包装提供/存储和处理
如何提供
FARXIGA（dapagliflozin）片剂两面都有标记，有表15中列出的强度和包装。
5mg  瓶30 NDC：0310-6205-30
10mg 瓶30 NDC：0310-6210-30
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]。
完整说明书附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72ad22ae-efe6-4cd6-a302-98aaee423d69
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.