首个每日一次的治疗类风湿关节炎新型口服制剂XELJANZ(TOFACITINIB CITRATE)TABLET ORAL获美国FDA批准上市 FDA的药物评价和研究中心肺，变态反应，和风湿病产品部主任Badrul Chowdhury，M.D.，Ph.D.说：“Xeljanz为对甲氨蝶呤反应不佳遭受令人衰弱已反应差的RA疾病的成年提供一种新的治疗选择。” 批准日期：2012年11月6日： 公司：辉瑞公司 XELJANZ（托法替尼[tofacitinib]）片剂  用于口服给药 美国初步批准：2012年 警告： 严重感染和恶性肿瘤完全包装警告的完整处方信息。 在接受XELJANZ的患者中发生了导致住院或死亡的严重感染，包括结核病和细菌，侵入性真菌，病毒和其他机会性感染。 如果严重感染发展，中断XELJANZ直到感染受到控制。 在开始XELJANZ之前，进行潜伏性结核病的测试;如果是阳性，在开始XELJANZ之前开始治疗结核病。 在治疗期间监测所有患者的活动性结核病，即使初始潜伏性结核试验为阴性。 在用XELJANZ治疗的患者中观察到淋巴瘤和其他恶性肿瘤。在用XELJANZ和伴随的免疫抑制药物治疗的肾移植患者中，已观察到Epstein Barr病毒相关的移植后淋巴增殖性疾病的增加。 作用机制 Tofacitinib是一种Janus激酶(JAK)抑制剂。JAKs是细胞内酶其传输信号发生来自细胞因子或生长因子-受体相互作用在细胞膜上影响造血和免疫细胞功能的细胞过程。在信号通路内，JAKs磷酸化和激活信号转导物和转录激活因子(STATs)调节细胞内的活性包括基因表达。Tofacitinib在JAKs点调控信号通路，预防STATs磷酸化和激活。JAK酶通过JAKs配对传输细胞因子信号(如，JAK1/JAK3，JAK1/JAK2，JAK1/TyK2，JAK2/JAK2)。Tofacitinib在体外抑制JAK1/JAK2，JAK1/JAK3，和JAK2/JAK2的活性联合有IC50分别为406，56,和1377nM。但是，不知道特异性JAK组合与治疗有效性的关联。 适应症和用法 XELJANZ，Janus激酶（JAK）的抑制剂，用于治疗患有中度至严重活动的类风湿性关节炎的成年患者，其对甲氨蝶呤具有不充分的反应或不耐受。它可以用作单一治疗或与甲氨蝶呤或其他非生物疾病缓解性抗风湿药（DMARD）组合使用。 XELJANZ不应与生物DMARD或强效免疫抑制剂如硫唑嘌呤和环孢霉素联合使用。 剂量和给药 类风湿关节炎 XELJANZ的推荐剂量为5mg，每日两次。 剂量形式和强度 片剂：5mg 禁忌症 没有 警告和注意事项 严重感染-在活动感染期间不要给予XELJANZ，包括局部感染。如果严重感染发展，中断XELJANZ直到感染受到控制。 已报道在用XELJANZ治疗的患者中的淋巴瘤和其他恶性肿瘤。 胃肠穿孔-在可能增加风险的患者中谨慎使用。 实验室监测-推荐由于淋巴细胞，嗜中性粒细胞，血红蛋白，肝酶和脂质的潜在变化。 免疫-活疫苗不应与XELJANZ同时给予。 严重肝损伤-不推荐。 不良反应 在受控临床试验中的最初3个月中最常报道的不良反应（发生在大于或等于2％的用XELJANZ单一疗法治疗或与DMARD组合的患者）是上呼吸道感染，头痛，腹泻和鼻咽炎。 药物相互作用 细胞色素P450 3A4（CYP3A4）的强效抑制剂（例如，酮康唑）：每天减少剂量至5mg。 一种或多种导致CYP3A4的中度抑制和对CYP2C19的有效抑制（例如，氟康唑）的伴随药物：每天减少剂量至5mg。 强效CYP诱导剂（例如，利福平）：可能导致临床反应的丧失或减少。 在特定人群中使用 中度和重度肾损伤和中度肝损伤：每天减少剂量至5毫克 供应/存储和处理 提供XELJANZ作为5mg托法替尼（相当于8mg托法替尼柠檬酸盐）片剂：白色圆形，速释薄膜包衣片剂，在一侧用“Pfizer”压制，在另一侧用“JKI 5”压制， 在： 瓶28：NDC 0069-1001-03 瓶60：NDC 0069-1001-01 瓶180：NDC 0069-1001-02 存储和处理 储存在20°C至25°C（68°F至77°F）。 [见USP控制室温]。 https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68e3d6b2-7838-4d2d-a417-09d919b43e13 XELJANZ®  XELJANZ (ZEL'jans) is the first approved RA treatment in a new class of medicines known as Janus kinase (JAK) inhibitors and the first new oral DMARD for RA in more than 10 years. XELJANZ is approved as a second-line medicine for RA, which means treatment with a biologic is not required before taking XELJANZ. “XELJANZ is an important new option that could potentially change the way rheumatologists treat this serious autoimmune disease,” said Ian Read, chairman and chief executive officer of Pfizer. “With its novel mechanism of action, the discovery and development of XELJANZ by Pfizer scientists reflects our commitment to R&D innovation and our dedication to bringing important and meaningful medicines to patients.” XELJANZ is specifically designed to inhibit the JAK pathways, which are signaling pathways inside the cell that play an important role in the inflammation involved in RA. With one of the largest clinical databases of any RA drug ever submitted to the FDA for review, the comprehensive, multi-study, global clinical development program evaluated approximately 5,000 patients who represent a broad cross-section of the RA patient population. “RA is a serious and disabling disease that affects people in their everyday lives, and many patients do not adequately respond or are intolerant to currently available therapies,” said study investigator Stanley Cohen, MD, clinical professor of rheumatology at the University of Texas Southwestern Medical School; co-director, Division of Rheumatology, Presbyterian Hospital Dallas; and co-medical director, Metroplex Clinical Research Center. “In clinical trials, XELJANZ significantly reduced the signs and symptoms of RA and improved physical function. As a physician, I am pleased that we have another choice for patients living with inadequately controlled, moderately to severely active RA.” “In clinical trials, XELJANZ demonstrated consistent efficacy across a broad range of clinical measures and patient types, including patients who inadequately responded to non-biologic DMARDs and anti-TNF agents, and it has a safety profile that is well-characterized to date,” said Geno Germano, president and general manager, Specialty Care and Oncology, Pfizer. “We are proud of the comprehensive data that support the use of XELJANZ, and we are excited to make it available to patients in the U.S. as a powerful oral option that can be taken as a second-line treatment with or without methotrexate.” Safety findings observed in the overall XELJANZ RA program include serious and other important infections, including tuberculosis and herpes zoster; malignancies, including lymphoma; gastrointestinal perforations; decreased neutrophil and lymphocyte counts; decreased hemoglobin; liver enzyme elevations; and lipid elevations. The most common serious adverse events were serious infections. The most commonly reported adverse events were upper respiratory tract infections, headache, diarrhea and nasopharyngitis. Regarding the potential for further assessment by the FDA of the inhibition of structural damage, Pfizer plans to immediately discuss with the FDA the submission of the results of the previously disclosed ORAL Start (A3921069) study, which demonstrated significant efficacy of XELJANZ taken as monotherapy versus methotrexate, including inhibiting structural damage. The ORAL Start study was ongoing at the time of the New Drug Application submission and was not included in the original application to the FDA. In the clinical trials, XELJANZ was studied in both a 5 mg and 10 mg twice-daily dosing regimen. The FDA has approved the 5 mg twice-daily dose in the second-line setting and has indicated that further data are required to assess the benefit: risk profile of the 10 mg twice-daily dose. Pfizer will continue to generate additional clinical data on the 10 mg twice-daily dose and work with the FDA to understand the additional data needed for further assessment of the 10 mg twice-daily dose. FDA has approved XELJANZ with a Risk Evaluation and Mitigation Strategy (REMS) designed to inform healthcare providers and patients about the serious risks associated with XELJANZ treatment. The approved REMS includes a Medication Guide for patients, a communication plan for healthcare providers and pharmacists, and periodic submissions of assessments of the REMS. Pfizer has agreed to conduct post-marketing clinical trials to evaulate that long-term safety of XELJANZ and to assess XELJANZ in the pediatric population with polyarticular juvenile ideopathic arthritis (JIA). For full prescribing information, including boxed warning and Medication Guide, please visit www.XELJANZ.com. About XELJANZ XELJANZ is a prescription medicine called a Janus kinase (JAK) selective inhibitor. XELJANZ is used to treat adults with moderately to severely active rheumatoid arthritis in which methotrexate did not work well. It is not known if XELJANZ is safe and effective in people with hepatitis B or C. XELJANZ is not for people with severe liver problems. It is not known if XELJANZ is safe and effective in children. Important Safety Information XELJANZ can lower the ability of the immune system to fight infections. Some people have serious infections while taking XELJANZ, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections. Healthcare providers should test patients for TB before starting XELJANZ and monitor them closely for signs and symptoms of TB and other infections during treatment. XELJANZ may increase the risk of certain cancers by changing the way the immune system works. Lymphoma and other cancer can happen in patients taking XELJANZ. Some people taking XELJANZ get tears in their stomach or intestines. Patients should tell their healthcare provider right away if they have fever and stomach-area pain that does not go away or a change in bowel habits. XELJANZ can cause changes in certain lab test results including low blood cell counts, increases in certain liver tests and increases in cholesterol levels. Normal cholesterol levels are important to good heart health. Healthcare providers may stop XELJANZ treatment because of changes in blood cell counts or liver test results. Patients should tell their healthcare providers if they plan to become pregnant or are pregnant It is not known if XELJANZ will harm an unborn baby. Patients should tell their healthcare providers if they plan to breastfeed or are breastfeeding. Patients and their healthcare provider should decide if they will take XELJANZ or breastfeed. They should not do both. In carriers of the hepatitis B or C virus (viruses that affect the liver), the virus may become active while using XELJANZ. Healthcare providers may do blood tests for hepatitis before and during treatment with XELJANZ. Common side effects include upper respiratory tract infections (common cold, sinus infections), headache, diarrhea, nasal congestion, sore throat, and runny nose (nasopharyngitis). About Rheumatoid Arthritis Rheumatoid arthritis is a chronic inflammatory autoimmune disease that typically affects the hands and feet, although any joint lined by a synovial membrane may be affected. RA affects approximately 1.6 million Americans1,2 and 23.7 million people worldwide.3 Although multiple treatments are available, many patients do not adequately respond. Specifically, up to one-third of patients do not adequately respond, and about half stop responding to any particular DMARD within five years.4,5,6,7,8,9 As a result, there remains a need for additional options. Generic Name and Formulations: Tofacitinib 5mg tabs. Company: Pfizer Inc. Indications for XELJANZ: Treatment of adults with moderately-to-severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX); may be used as monotherapy or in combination with MTX or other nonbiologic disease-modifying anti-rheumatic drugs (DMARDs). Do not use in combination with biologic DMARDs or potent immunosuppressants (eg, azathioprine, cyclosporine). Adult Dose for XELJANZ: 5mg twice daily. Moderate-to-severe renal impairment or moderate hepatic impairment; concomitant potent CYP3A4 inhibitors, or drugs that result in both moderate CYP3A4 and potent CYP2C19 inhibition: 5mg once daily. Dose adjustments: see full labeling. Children's Dose for XELJANZ: Not established. Pharmacological Class: Janus kinase (JAK) inhibitor. Rems: YES Warnings/Precautions: Increased risk of serious or fatal infections (eg, TB, bacterial, viral, invasive fungal, or other opportunistic pathogens). Active infections: do not initiate therapy. Chronic or history of recurring infections. Travel to, or residence in, areas with endemic TB or mycoses. Conditions that predispose to infection. Test/treat latent TB infection prior to initiating therapy. Monitor closely if new infection, or active TB (even if initial latent test is negative) occurs; interrupt treatment if serious or opportunistic infection, or sepsis develops. Known malignancy. History of GI perforations. Monitor lymphocytes, neutrophils, hemoglobin at baseline and during treatment; do not initiate therapy if lymphocytes <500cells/mm3, ANC <1000cells/mm3, or hemoglobin <9g/dL. Severe hepatic impairment: not recommended. Routinely monitor liver enzymes; interrupt therapy if drug-induced liver injury suspected. Monitor lipids 4–8 weeks following initiation. Elderly. Pregnancy (Cat. C). Nursing mothers: not recommended. Interactions: Concomitant live vaccines: not recommended. Potentiated by potent CYP3A4 inhibitors (eg, ketoconazole), or drugs that result in both moderate CYP3A4 and potent CYP2C19 (eg, fluconazole) inhibition. Antagonized by potent CYP3A4 inducers (eg, rifampin). Concomitant immunosuppressants (eg, azathioprine, tacrolimus, cyclosporine) or corticosteroids may increase risk of infections. Adverse Reactions: Upper respiratory tract infections, headache, diarrhea, nasopharyngitis; serious or opportunistic infections, TB, malignancies (eg, lymphoma). Metabolism: Hepatic (CYP3A4, 2C19). Elimination: Renal. Generic Availability: NO How Supplied: Tabs—28, 60, 180 托法替布（Tofacitinib，CP-690550）是辉瑞公司研发的一种新型口服JAK通路抑制剂。与当前多数其他RA治疗药物主要作用于细胞外靶点不同的是，托法替尼以细胞内信号转导通路为靶点，作用于细胞因子网络的核心部分。托法替布（tofacitinib）对JAK3的抑制强度是对JAK1及JAK2的5~100倍。托法替布是开发用于类风湿性关节炎治疗的首创药物（first-in-class drug），FDA于2012年11月6日批准了JAK抑制剂tofacitinib用于治疗成人活动期及对甲氨蝶呤（MTX）反应不佳的中至重度类风湿关节炎（RA）患者. FDA表示，中到重度的类风湿性关节炎病人，无法从常规口服治疗药物甲氨蝶呤（methotrexate）中获益或无法耐受治疗时，可使用辉瑞的新药Xeljanz(托法替尼)。托法替尼可单用，也可与甲氨蝶呤及其他特定的标准治疗药物合用。FDA批准Xeljanz一天两次、每次5毫克的使用剂量。但是同时指出，辉瑞还需提供更深入的数据支持一天两次、每次10毫克剂量的安全性。 -------------------------------------------- 产地国家: 美国 原产地英文商品名: XELJANZ 5MG/TABLET 28Tablets 原产地英文药品名: TOFACITINIB CITRATE 中文参考商品译名: XELJANZ 5毫克/片 28片/瓶 中文参考药品译名: 托法替尼 生产厂家中文参考译名: 辉瑞 生产厂家英文名: Pfizer -------------------------------------------- 产地国家: 美国 原产地英文商品名: XELJANZ 5MG/TABLET 60Tablets 原产地英文药品名: TOFACITINIB CITRATE 中文参考商品译名: XELJANZ 5毫克/片 60片/瓶 中文参考药品译名: 托法替尼 生产厂家中文参考译名: 辉瑞 生产厂家英文名: Pfizer ---------------------------------------------- 产地国家: 美国 原产地英文商品名: XELJANZ 5MG/TABLET 180Tablets 原产地英文药品名: TOFACITINIB CITRATE 中文参考商品译名: XELJANZ 5毫克/片 180片/瓶 中文参考药品译名: 托法替尼 生产厂家中文参考译名: 辉瑞 生产厂家英文名: Pfizer