英文药名：JANUVIA(sitagliptin Tablets) 中文药名：磷酸西他列汀片 生产厂家：美国默克公司 药品简介 近日，美国食品药品管理局已批准磷酸西他列汀（sitagliptin phosphate）上市。用于治疗2型糖尿病的二肽基肽酶-4（DPP-4）抑制剂类药物。 该药具有新颖的不同于现已上市降血糖药物的作用机制，属二肽基肽酶-Ⅳ抑制剂，能通过抑制该酶活性而相对提高天然发生肠促胰岛素，包括胰高血糖素样肽-1和葡萄糖依赖性促胰岛素肽的水平，由此触发胰腺提高胰岛素生产并使肝脏停止葡萄糖生产、最终降低血糖浓度的临床效果。 临床试验中最常报告的副反应有鼻塞或流涕、咽喉痛、头痛、腹泻和关节痛等，但似无体重增加效应，其低血糖症发生率也类于安慰剂。 批准日期：2006年10月17日 公司：默克公司 JANUVIA（西他列汀[sitagliptin]）片剂 供口服使用 美国初步批准：2006年 最近的主要变化 警告和注意事项 大疱性天疱疮：01/2017 作用机制 西他列汀是一种DPP-4抑制剂，据信可通过减缓肠降血糖素激素的失活来发挥其对2型糖尿病患者的作用。活性完整激素的浓度由JANUVIA增加，从而增加和延长这些激素的作用。包括胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）在内的胰高血糖素激素全天释放，并且对膳食的反应水平升高。这些激素被酶DPP-4快速灭活。肠促胰岛素是参与葡萄糖体内平衡生理调节的内源性系统的一部分。当血糖浓度正常或升高时，GLP-1和GIP通过涉及环AMP的细胞内信号通路增加胰岛素合成和从胰β细胞释放。 GLP-1还降低胰腺α细胞的胰高血糖素分泌，导致肝葡萄糖产生减少。通过增加和延长活性肠降血糖素水平，JANUVIA以葡萄糖依赖的方式增加胰岛素释放并降低循环中的胰高血糖素水平。西他列汀显示对DPP-4的选择性，并且在体外接近治疗剂量的浓度时不抑制DPP-8或DPP-9活性。 适用范围及用途 JANUVIA是一种二肽基肽酶-4（DPP-4）抑制剂，表示为饮食和运动辅助，以改善2型糖尿病成人的血糖控制。 使用的重要限制： JANUVIA不应用于1型糖尿病患者或治疗糖尿病酮症酸中毒。 JANUVIA尚未在具有胰腺炎病史的患者中进行研究。 剂量和管理 JANUVIA的推荐剂量为每日100mg。 JANUVIA可以带或不带食物。 建议对中度或重度肾功能不全或终末期肾病患者进行剂量调整。 中度，严重和末期肾脏病患者的剂量调整（ESRD） 50毫克，每日一次25毫克，每日一次 中等 CrCl≥30至<50mL/min 〜血清Cr水平[mg/dL] 男子：>1.7-≤3.0; 女性：>1.5-≤2.5 严重和ESRD CrCl <30 mL / min 〜血清Cr水平[mg / dL] 男子：> 3.0; 女性：> 2.5; 或透析 剂量形式和强度 片剂：100mg，50mg和25mg 禁忌症 对西他列汀的严重超敏反应的历史，如过敏反应或血管性水肿 警告和注意事项 已经有急性胰腺炎的上市报告，包括致命和非致命性出血性或坏死性胰腺炎。如果怀疑胰腺炎，请及时停止JANUVIA。 已经有急性肾衰竭的上市报告，有时需要透析。在中度或重度肾功能不全患者和ESRD患者中推荐剂量调整。推荐JANUVIA之前评估肾功能，并在此之后定期进行。 当将JANUVIA加入到胰岛素促分泌素（例如磺酰脲）或胰岛素治疗中时，存在降低血糖的风险增加。考虑降低磺酰脲或胰岛素的剂量以降低低血糖的风险。 已经出现了用JANUVIA治疗的患者如过敏反应，血管性水肿和包括史蒂文森 - 约翰逊综合征在内的剥脱性皮肤病症的严重过敏和过敏反应的上市报告。在这种情况下，请及时停止JUVUVIA，评估其他潜在病因，进行适当的监测和治疗，并开始糖尿病的替代治疗。 已报道在服用DPP-4抑制剂的患者中严重和无力的关节痛。考虑作为严重关节疼痛的可能原因，并酌情停止使用药物。 已经出现了需要住院治疗DPP-4抑制剂的大疱性类天疱疮的上市后报告。告诉患者报告水泡或糜烂的发展。如果怀疑有大疱性类天疱疮，请停止JANUVIA。 没有临床研究确定JANUVIA或任何其他抗糖尿病药物的大血管风险降低的确凿证据。 不良反应 报道有≥5％用JANUVIA治疗的患者的不良反应比常规治疗安慰剂的患者有：上呼吸道感染，鼻咽炎和头痛。在加入磺酰脲和附加胰岛素研究中，与安慰剂相比，用JANUVIA治疗的患者中更常见的是低血糖。 在特定人口中使用 JANUVIA在18岁以下儿童的安全性和有效性尚未建立。 对孕妇没有足够的和良好对照的研究。在怀孕期间报告药物暴露呼叫1-800-986-8999。 包装规格/存储和处理 No.6737-片剂JANUVIA，25mg，粉红色，圆形，薄膜包衣片，一侧为“221”。它们提供如下： NDC 0006-0221-31单位使用瓶30 NDC 0006-0221-54单位使用瓶90 NDC 0006-0221-28单位剂量吸塑包装100。 No.6738 - 片剂JANUVIA，50毫克，是浅米色，圆形，薄膜包衣片，一面为“112”。它们提供如下： NDC 0006-0112-31单位使用瓶30 NDC 0006-0112-54瓶使用90瓶 NDC 0006-0112-28单位剂量吸塑包装100。 No.6739 - 片剂JANUVIA，100毫克，是一边为“277”的米色圆形，薄膜包衣片。它们提供如下： NDC 0006-0277-31单位使用瓶30 NDC 0006-0277-54单位使用瓶90 NDC 0006-0277-02单位使用的吸塑日历包30 NDC 0006-0277-33单位使用的吸塑日历包30 NDC 0006-0277-28单位剂量吸塑包装100 NDC 0006-0277-82瓶1000。 存储 储存于20-25°C（68-77°F），偏移允许在15-30°C（59-86°F）。 [见USP受控室温] https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f85a48d0-0407-4c50-b0fa-7673a160bf01 Merck ($MRK) intended its new weekly diabetes treatment, Marizev, to build on the success of its blockbuster DPP-4 inhibitor Januvia. But at least when it comes to safety, Marizev is lagging behind, a new report finds. Healthcare analytics firm Advera Health Analytics compared the drugs' head-to-head trial data and found that Marizev had more serious side effects than Januvia in two studies. Marizev, approved by Japanese regulators in September but not cleared for sale in the U.S., turned up higher rates of prostate cancer and cardiovascular and hepatobiliary issues, or problems with the liver, pancreas or digestive system. And Marizev did not reduce glycosylated hemoglobin, a key indicator of long-term diabetes, as well as Januvia did. The drug was also "less impressive" in improving fasting blood sugar levels, according to Advera's report. Merck is standing by Marizev, though. "Results of double-blind, randomized, placebo- and active-controlled studies have demonstrated an overall balance in adverse events (AEs), including serious adverse events, in patients taking (Marizev)," the company told FiercePharma in an email. "Merck believes that the labeling in Japan accurately reflects the overall benefit-risk profile of our once-weekly DPP-4 inhibitor." Last Friday, Merck said it did not plan to seek approval for Marizev in the U.S. or Europe, but will continue to sell the drug in Japan. The company said it's shifting its diabetes development focus and Marizev no longer fits the bill. It didn't drop the drug for efficacy or safety reasons, Merck's statement said. But that's not to say that Marizev is riskier on the whole, Advera's chief product officer, Bob Kyle, told FiercePharma. Januvia already has a long-term cardiovascular study demonstrating its heart safety, Kyle said. Results from Marizev's long-term cardiovascular safety study haven't been reported out yet, so it's hard to tell how the drug will shape up, Kyle added. Nor is Marizev without its advantages, Kyle said. It is a weekly treatment, while Januvia is taken once a day. "That's a major benefit that might outweigh some of the potential risks that show up with Marizev," he said. Merck is quick to tak up both meds' safety. Results of a Phase III head-to-head study that pitted once-a-week Marizev against once-a-day Januvia showed that "the incidences of serious adverse events, drug-related adverse events and discontinuations were similar across both treatment groups," company spokeswoman Kristen Drake told FiercePharma in an email. The company reported the results at the EASD Annual Meeting in September. The company's decision to drop Marizev in the U.S. and Europe "did not result from concerns about the efficacy or safety" of the drug, Merck said in a statement last week. The company has instead "decided to focus its development resources on a promising pipeline of late-stage compounds and, in early development, new approaches to diabetes control, while continuing to emphasize its existing portfolio," which includes Januvia, it said. Merck "remains committed" to marketing Marizev in Japan, the company said.  Marizev competes in a crowded DPP-4 class that includes AstraZeneca's ($AZN) Onglyza and metformin combo drug Kombiglyze; Eli Lilly ($LLY) and Boehringer Ingelheim's Tradjenta and related combo meds Glyxambi and Jentadueto; and Takeda's Nesina and two combo pills, Kazano and Oseni. Plus, the class faces a laundry list of safety issues. DPP-4 meds come with warnings about the risk of pancreatitis and allergic reactions, not to mention hypoglycemia when used in combination with other diabetes meds. In August, the FDA issued a serious warning that the drugs might cause "severe and disabling joint pain," delivering another blow to the class. Last week, the agency flagged increased risks of heart failure with Onglyza and Nesina. Onglyza had already come under fire for its links to heart issues in patients. Merck has fared better with Januvia in terms of safety. Last year, the company enjoyed a bright point after study results showed that the drug did not come with an increased risk of heart failure. "It's reassuring to be able to present data from a large study over a number of years that provides more information about the safety profile," Peter Stein, Merck's VP of clinical research in diabetes and endocrinology and a member of the executive committee for the TECOS trial, told FiercePharma at the time. " ... I think that's very important in helping (physicians) to feel comfortable about the tools they're using to get their patients to glycemic goals." That information is also important in helping Merck keep patients on Januvia and away from SGLT2 meds like Lilly and Boehringer Ingelheim's Jardiance. Last year, Jardiance became the first diabetes treatment to show that it could lower the risk of heart attack, stroke and death from cardiovascular issues. Even though "DPP-4s are generally well-tolerated, neutral on weight and have for the most part been viewed as safe," overall they've "failed to demonstrate a CV outcomes benefit," Evercore ISI analyst Mark Schoenebaum said in a note to investors last year after the TECOS trial data was released. That, combined with Jardiance's cardiovascular benefits, could mean that "doctors will be more eager to prescribe SGLT2s in front of DPP-4s," Schoenebaum said.