FDA批准两药复方制剂Janumet缓释片用于治疗2型糖尿病

ST LOUIS (MD Consult) - On February 2, 2012, Merck announced that the US Food and Drug Administration (FDA) has approved Janumet XR (sitagliptin and metformin extended-release) tablets for the treatment for type 2 diabetes. Janumet 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 sitagliptin and extended-release metformin is appropriate.

Janumet XR targets 3 key defects of diabetes: insulin deficiency from pancreatic beta cells, insulin resistance, and overproduction of glucose by the liver.

The FDA approved Janumet XR on the basis of results from a clinical bioequivalence study that demonstrated that administration of Janumet XR was equivalent to coadministration of corresponding doses of the 2 individual medications, sitagliptin and metformin extended-release. Extended-release metformin was as effective as immediate-release metformin.

According to Merck, the combination of sitagliptin and metformin provides greater hemoglobin A_1C goal attainment compared with sitagliptin or metformin alone. In a randomized, double-blind, placebo-controlled factorial study in 1091 patients with type 2 diabetes who experienced inadequate glycemic control with diet and exercise, the coadministration of metformin immediate-release and sitagliptin twice-daily resulted in a reduction of hemoglobin A_1C relative to placebo at 24 weeks. Mean placebo adjusted reduction was 2.1% with initial therapy combining sitagliptin 100 mg daily and metformin immediate-release 2000 mg daily (n = 178) from a mean baseline hemoglobin A_1C of 8.8 percent (P < .001). The mean placebo-adjusted hemoglobin A_1C reductions in the other arms of the study were 1.6% with sitagliptin 100 mg daily and metformin immediate-release 1000 mg daily (n = 183); 1.3% with metformin immediate-release 2000 mg daily (n = 177); 1.0% with metformin immediate-release 1000 mg daily (n = 178); and 0.8% with sitagliptin (n =175) (P < .001 for all treatment groups versus placebo). At 24 weeks, 66% of patients treated with the initial combination of sitagliptin 100 mg daily and metformin immediate-release 2000 mg daily achieved the American Diabetes Association (ADA) goal hemoglobin A_1C level of < 7%, compared with 38% of patients treated with metformin immediate-release 2000 mg daily alone. In the other arms of the study, 43% of patients treated with sitagliptin 100 mg daily and metformin immediate-release 1000 mg daily, 23% of patients treated with metformin immediate-release 1000 mg daily, and 20% of patients treated with sitagliptin achieved the ADA goal hemoglobin A_1C level of < 7 percent.

The labeling for Janumet XR contains a boxed warning for lactic acidosis. The drug is contraindicated in patients with renal impairment.

Postmarketing reports have been received of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with Janumet and at least annually thereafter, renal function should be assessed and verified as normal.

Postmarketing reports have also been received concerning the occurrence of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After initiation of Janumet XR, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, Janumet XR should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the occurrence of pancreatitis while receiving Janumet XR.

Janumet XR is available in tablets of 100 mg sitagliptin/1000 mg metformin extended-release, 50 mg sitagliptin/500 mg metformin extended-release, and 50 mg sitagliptin/1000 mg metformin extended-release. Janumet XR should be given once daily with a meal preferably in the evening. Patients should be informed that Janumet XR tablets must not be split, broken, crushed, or chewed before swallowing.

The dose of Janumet XR should be individualized on the basis of the patient's current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider. In patients already treated with metformin, the recommended total daily starting dose of Janumet XR is 100 mg sitagliptin and the previously prescribed dose of metformin.

圣路易斯(MD Consult)——2012年2月2日，默克公司宣布美国食品药品管理局(FDA)已经批准Janumet XR(西他列汀/二甲双胍缓释片)用于治疗2型糖尿病。Janumet XR适合作为饮食和运动疗法的辅助用药，用于同时适宜采用西他列汀和缓释型二甲双胍治疗的2型糖尿病患者，以改善其血糖控制。

Janumet XR以糖尿病的3个重要缺陷为靶点：胰岛β细胞引起的胰岛素缺乏、胰岛素抵抗以及肝脏葡萄糖生成过量。

FDA批准Janumet XR是基于一项临床生物等效性研究的结果，该研究显示应用Janumet XR与相应剂量的这两种药物——西他列汀和缓释二甲双胍联用的效果相当。缓释二甲双胍与速释二甲双胍等效。

据默克公司称，西他列汀与二甲双胍联合用药所能使血红蛋白A_1c(HbA_1c)水平降低的程度大于西他列汀或二甲双胍单独用药。在一项对1,091例通过饮食和运动疗法未能充分控制血糖的2型糖尿病患者进行的随机、双盲、安慰剂对照的析因研究中，在24周时，速释型二甲双胍与西他列汀联合用药、每日2次治疗组的HbA_1c水平相对于安慰剂对照组降低。西他列汀100 mg、每日1次+速释型二甲双胍2000 mg、每日1次治疗组(n=178)基线时的平均HbA_1c水平为8.8%，安慰剂调整的平均降幅为2.1%(P<0.001)。该研究的其他小组安慰剂调整的平均HbA_1c降幅分别为1.6%(西他列汀100 mg、每日1次+速释型二甲双胍1000 mg、每日1次治疗组，n=183)、1.3%(速释型二甲双胍2000 mg、每日1次治疗组，n=177)，1.0%(速释型二甲双胍1000 mg、每日1次治疗组，n=178)及0.8%(西他列汀治疗组，n=175)(所有治疗组vs. 安慰剂组：P<0.001)。在24周时，初始治疗方案为西他列汀100 mg、每日1次+速释型二甲双胍2000 mg、每日1次的患者中有66%达到美国糖尿病学会(ADA)设定的目标血红蛋白A_1c水平<7%，而采用速释型二甲双胍2000 mg、每日1次单药治疗组中有38%的患者达到此目标。在该研究的其他小组中，西他列汀100 mg、每日1次+速释型二甲双胍1000 mg、每日1次联合治疗组有43%、速释型二甲双胍1000 mg、每日1次治疗组有23%、西他列汀治疗组有20%的患者达到了ADA设定的血红蛋白A_1c<7%的目标水平。

Janumet XR的说明书中包含一个有关乳酸酸中毒的黑框警告，该药禁用于有肾功能损害的患者。

目前已收到有关服用西他列汀联合(或不联合)二甲双胍的患者发生肾功能恶化的上市后报告，其中包括急性肾衰竭，有时甚至需要透析治疗。在开始Janumet治疗前及此后至少每年应进行一次肾功能评估，以确认其正常。

此外，上市后报告还涉及急性胰腺炎，其中包括服用西他列汀联合(或不联合)二甲双胍的患者发生致死性和非致死性出血性或坏死性胰腺炎。在开始Janumet XR治疗后，应该对患者密切监测胰腺炎的症状和体征。若疑似胰腺炎，则应立即停用Jamumet XR，并开始适当的处置。有胰腺炎病史的患者在接受Janumet XR治疗的过程中发生胰腺炎的风险是否会增加，尚不清楚。

市售的Janumet XR有100 mg西他列汀/1000 mg二甲双胍缓释片、50 mg西他列汀/500 mg二甲双胍缓释片以及50 mg西他列汀/1000 mg二甲双胍缓释片。Janumet XR的用法为每日1次，最好在晚餐后服用。应告知患者Janumet XR片在吞服前不得切割、压碎或咀嚼。

Janumet XR的剂量应根据患者当前的治疗方案、有效性和耐受性采取个体化原则，同时不要超过西他列汀和二甲双胍的每日最大推荐剂量(分别为100 mg和2000 mg)。初始联合治疗或联合治疗的维持用药也应采取个体化原则，并由医务人员判断决定。对于已经开始二甲双胍治疗的患者，Janumet XR的每日总推荐开始剂量为西他列汀100 mg，二甲双胍仍遵循之前的处方剂量。

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