英文药名：Oseni(Alogliptin and Pioglitazone Tablets) 中文药名：阿格列汀/吡格列酮复方片剂 生产厂家：武田制药北美公司 药品介绍 经过数年来的反复审查和驳回，美国食品药品管理局(FDA)最终批准二肽基肽酶Ⅳ(DPP-4)抑制剂阿格列汀上市。 FDA批准了该药品的3种版本：单剂(Nesina)、含二甲双胍的复方制剂(Kazano)，以及含吡格列酮的复方制剂(Oseni)。这3种版本的阿格列汀的适应证均为，结合饮食与运动干预治疗2型糖尿病。 阿格列汀生产商武田制药表示，该药的作用机制是减缓肠促胰岛素GLP-1(胰高血糖素样肽-1)和GIP(葡萄糖依赖性促胰岛素多肽)的失活。 Oseni是首个在美国获准上市的包含DPP-4抑制剂和噻唑烷二酮的复方制剂 阿格列汀是第4种获得FDA批准的DPP-4抑制剂。默克的西格列汀(捷诺维)是首个获得批准的DPP-4抑制剂，之后依次为沙格列汀(安立泽，由阿斯利康和百时美-施贵宝销售)和利拉利汀(Tradjenta，由勃林格-殷格翰和礼来销售)。 武田制药早在2008年就提出了上市申请，但获准之路并不平坦。首先，2007年罗格列酮(文迪雅)与心肌梗死风险增加之间的关联引起了公众的担忧，FDA随即于2008年开始要求所有糖尿病治疗都必须具有心血管安全性。武田制药只好重新开展临床试验，以便纳入心血管终点指标。出于安全性考虑，该公司随后接到了2项提供更多信息的要求——其中一项针对阿格列汀单药治疗，另一项针对阿格列汀/吡格列酮联合治疗。 结果，FDA对每种药品的批准令都带有诸多附加条件，包括不同的警告和要求。 作为单剂，Nesina在至少14项试验中显示出了在26周内使糖化血红蛋白(HbA1c)水平降低0.4%~0.6%(与安慰剂相比)的效能。该药品将有6.25 mg、12.5 mg和25 mg三种片剂可供选用。但FDA要求针对阿格列汀单药治疗开展5项上市后研究：1项监测肝脏异常、严重胰腺炎和严重超敏反应的增强药物警戒计划；3项按照儿科研究公平法案(PREA)开展的儿科研究，包括1项剂量探索研究和2项安全性、有效性研究(分别采用Nesina单药治疗和Nesina+二甲双胍联合治疗)。 在4项临床试验中，与Nesina相比，包含二甲双胍的复方制剂Kazano可使HbA1c多降低1.1%，与二甲双胍单药治疗相比可使HbA1c多降低0.5%。Kazano有12.5 mg阿格列汀/500 mg二甲双胍和12.5 mg阿格列汀/1,000 mg二甲双胍两种规格可供选择。FDA要求针对Kazano开展2项上市后研究：1项监测肝脏异常、严重胰腺炎和严重超敏反应的计划；1项儿科安全性与有效性研究。Kazano将附带一则有关乳酸酸中毒的加框警告。 阿格列汀/吡格列酮复方制剂Oseni有6种规格可供选用：5 mg/15 mg、25 mg/30 mg、25 mg/45 mg、12.5 mg/15 mg、12.5 mg/30 mg和12.5 mg/45 mg。与阿格列汀单药治疗相比，该药可使HbA1c额外降低0.4%~0.9%，与吡格列酮单药治疗相比可额外降低0.4%~0.6%。武田制药将开展1项有关Oseni与肝脏异常、胰腺炎和超敏反应的上市后研究。该药将附带一则有关心力衰竭的加框警告。 Oseni和Nesina均已在日本获准上市，但除了美国和日本之外尚无其他国家批准这些药品。 Pharmacological Class: Dipeptidyl peptidase-4 (DPP-4) inhibitor + thiazolidinedione. Active Ingredient(s): Alogliptin, pioglitazone; 12.5mg/15mg, 12.5mg/30mg, 12.5mg/45mg, 25mg/15mg, 25mg/30mg, 25mg/45mg; tabs. Company Takeda Pharmaceuticals North America, Inc. Indication(s): As adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM) when treatment with both alogliptin and pioglitazone is appropriate. Limitations of use: not for treatment of type 1 diabetes or diabetic ketoacidosis. Pharmacology: Alogliptin acts by slowing the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner. Pioglitazone activates peroxisome proliferator-activated receptor-gamma, thereby improving insulin sensitivity in muscle and adipose tissue while inhibiting hepatic gluconeogenesis. Clinical Trials: The coadministration of alogliptin and pioglitazone has been studied in patients with T2DM inadequately controlled on either diet and exercise alone or on metformin alone. A total of 655 patients inadequately controlled on diet and exercise alone were evaluated in a 26-week, double-blind, active-controlled study. Patients were randomized to alogliptin 25mg alone, pioglitazone 30mg alone, alogliptin 12.5mg + pioglitazone 30mg, or alogliptin 25mg + pioglitazone 30mg once daily. Coadministration of alogliptin 25mg + pioglitazone 30mg resulted in statistically significant improvements from baseline in A1C (−1.7%) and fasting blood glucose (FPG; −50mg/dL) compared to either alogliptin 25mg (−1% and −26mg/dL, respectively) or pioglitazone 30mg (−1.2% and −37mg/dL, respectively; P<0.01 compared to individual component regimens) alone at Week 26. For information on all other studies conducted: see full labeling. Legal Classification: Rx Adults: Swallow whole; do not split tabs. Take once daily with or without food. Inadequately controlled on diet/exercise, or on metformin or alogliptin monotherapy: initially 25mg/15mg or 25mg/30mg daily. Previously on pioglitazone alone: initially 25mg/15mg, 25mg/30mg, or 25mg/45mg daily. Switching from alogliptin with pioglitazone: start at dose based on current therapy. NYHA Class I or II HF: initially 25mg/15mg. All: max 25mg/45mg daily. Renal impairment: moderate (CrCl ≥30–<60mL/min): 12.5mg/15mg, 12.5mg/30mg, or 12.5mg/45mg daily; severe or ESRD: not recommended. Concomitant gemfibrozil or other strong CYP2C8 inhibitors: max pioglitazone 15mg daily. Children: Not recommended. Contraindication(s): NYHA Class III or IV heart failure. Warnings/Precautions: Symptomatic HF: not recommended. Risk of CHF; monitor after initiation and dose increases; consider discontinuation or reduce pioglitazone dose if occurs. Monitor for pancreatitis or serious hypersensitivity reaction; discontinue if suspected. History of angioedema with other DPP-4 inhibitors. Renal impairment; monitor prior to starting therapy and periodically thereafter. Hepatic impairment; obtain LFTs before starting therapy; interrupt and evaluate if liver enzymes elevated; do not restart if liver injury is confirmed and no other etiology can be found. Active bladder cancer: do not use. Do regular eye exams. Resumption of premenopausal ovulation in anovulatory women may occur (may result in unintended pregnancy). Pregnancy (Category C); use adequate contraception. Nursing mothers: not recommended. Interaction(s) Concomitant insulin may cause fluid retention. Potentiated by strong CYP2C8 inhibitors (eg, gemfibrozil). Antagonized by CYP2C8 inducers (eg, rifampin). Concomitant sulfonylurea or insulin: may need lower dose of sulfonylurea or insulin to reduce risk of hypoglycemia. Adverse Reaction(s) Nasopharyngitis, back pain, upper respiratory tract infection; edema, fractures (esp. females), macular edema. How Supplied: Tabs—30, 90, 500 LAST UPDATED: 8/16/2013