首个每日一次的口服JAK抑制剂XELJANZ XR(tofacitinib citrate extended-release)获美国FDA批准用于治疗中度至重度的类风湿关节炎 近日，美国FDA批准XELJANZ®XR (tofacitinib citrate，枸橼酸托法替尼)治疗类风湿关节炎(RA)。该药采用日服一次11mg片剂经过缓释治疗中度至重度类风湿关节炎(RA)，且前提是甲氨蝶呤(MTX)已对这些患者不起作用，或产生不耐受性。 批准日期：2016年2月24日报 公司：辉瑞公司 XELJANZ（托法替尼[tofacitinib]）片剂，用于口服使用 XELJANZ XR（托法替尼[tofacitinib extended release tablets]）缓释片，用于口服使用 美国初步批准：2012年 警告： 严重感染和恶性见完整的处方信息，提供完整的盒装警告。 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/XELJANZ XR直到感染受到控制。 在开始XELJANZ/XELJANZ XR之前，进行潜伏性结核病的测试;如果是阳性，在开始XELJANZ/XELJANZ XR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。 近期主要变化 剂量和管理：2/2016 警告和注意事项，严重感染：6/2015 警告和注意事项，一般：2/2016 作用机制 托法替尼是一种Janus激酶（JAK）抑制剂。 JAK是细胞内酶，其传输来自细胞膜上的细胞因子或生长因子 - 受体相互作用的信号，以影响造血和免疫细胞功能的细胞过程。在信号通路内，JAK磷酸化和激活信号转导和转录激活因子（STAT），其调节细胞内活性，包括基因表达。托法替尼调节JAKs点的信号通路，阻止STAT的磷酸化和激活。JAK酶通过JAK（例如，JAK1/JAK3，JAK1/JAK2，JAK1/TyK2，JAK2/JAK2）的配对来传递细胞因子信号传导。托法替尼抑制JAK1/JAK2，JAK1/JAK3和JAK2/JAK2组合的体外活性，IC50分别为406,56和1377nM。 然而，具体的JAK组合对治疗有效性的相关性是未知的。 适应症和用法 XELJANZ/XELJANZ XR是Janus激酶（JAK）的抑制剂，用于治疗患有中度至重度活动性类风湿性关节炎的成年患者，这些患者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。 使用限制：不建议将XELJANZ/XELJANZ XR与生物DMARD或强力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。 XELJANZ XR的推荐剂量为11mg，每日一次。 中重度肾损伤和中度肝损伤患者的推荐剂量为XELJANZ 5mg，每日一次。 不推荐在重度肝损伤患者中使用XELJANZ/XELJANZ XR。 剂量形式和强度 XELJANZ片剂：5mg XELJANZ XR片剂：11mg 禁忌症 没有 警告和注意事项 避免在活动严重感染期间使用XELJANZ / XELJANZ XR，包括本地化感染。 胃肠穿孔-在可能有增加风险的患者中谨慎使用。 实验室监测-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而推荐。 免疫接种-活疫苗：避免与XELJANZ / XELJANZ XR一起使用。 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）（例如酮康唑）的强效抑制剂： 推荐剂量为XELJANZ 5mg，每日一次。 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： 推荐剂量为XELJANZ 5mg，每日一次。 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。 如何供应/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： XELJANZ 瓶28：NDC 0069-1001-03 瓶60：NDC 0069-1001-01 瓶180：NDC 0069-1001-02 XELJANZ XR以11mg托法替尼（相当于17.77mg托泊替尼柠檬酸盐）片剂形式提供：粉末，椭圆形，延长释放片剂，在片剂带的一端具有钻孔，在片剂的一侧上印有“JKI 11” XELJANZ XR 瓶14：NDC 0069-0501-14 瓶30：NDC 0069-0501-30 存储和处理 将XELJANZ/XELJANZ XR存储在20°C至25°C（68°F至77°F）。[见USP控制室温]。 XELJANZ/XELJANZ XR不要重新包装。 完整资料附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cf74ba2f-afc5-4baa-8594-979c889a5831 Pfizer Announces FDA Approval of XELJANZ® XR (tofacitinib citrate) Extended-Release Tablets, the First and Only Once-Daily Oral JAK Inhibitor Treatment for Rheumatoid Arthritis U.S. Food and Drug Administration (FDA) has approved XELJANZ® XR (tofacitinib citrate) extended-release 11 mg tablets for the once-daily treatment of moderate to severe rheumatoid arthritis (RA) in patients who have had an inadequate response or intolerance to methotrexate (MTX). XELJANZ XR is the first and only once-daily oral RA treatment in its class, known as Janus kinase (JAK) inhibitors. “Pfizer continues to be an innovator in inflammation and immunology. The introduction of the first and only once-daily oral JAK inhibitor for RA, XELJANZ XR, builds upon Pfizer’s tradition of developing patient-centered therapies,” said Michael Corbo, Category Development Lead, Inflammation & Immunology, Pfizer Global Innovative Pharmaceuticals Business. “The availability of XELJANZ XR provides physicians with a new treatment option for people with RA who may prefer an oral once-daily treatment,” said Dr. Roy Fleischmann, clinical professor in the Department of Internal Medicine at the University of Texas Southwestern Medical Center and Co-Medical Director, Metroplex Clinical Research Center. About XELJANZ and XELJANZ XR XELJANZ®/XELJANZ XR® (tofacitinib citrate) is a prescription medicine called a Janus kinase (JAK) inhibitor. XELJANZ XR 11 mg is the first and only once-daily oral JAK inhibitor for the treatment of moderate to severe rheumatoid arthritis (RA). As the developer of XELJANZ/XELJANZ XR, Pfizer is a leader in JAK innovation. XELJANZ/XELJANZ XR do not require injections or infusions. XELJANZ/XELJANZ XR can be taken with or without methotrexate. XELJANZ is approved in more than 45 countries around the world for the treatment of moderate to severe RA as a second-line therapy after failure of one or more disease-modifying antirheumatic drugs (DMARDs). Pfizer is committed to advancing the science of JAK inhibition and enhancing understanding of XELJANZ through a robust clinical development program. The efficacy and safety profile of XELJANZ has been studied in approximately 6,200 patients with moderate to severe RA, amounting to more than 19,400 patient-years of drug exposure in the global clinical development program. XELJANZ is the only JAK inhibitor included in the 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. XELJANZ/XELJANZ XR U.S. Label Information XELJANZ/XELJANZ XR is a prescription medicine called a Janus kinase (JAK) inhibitor. XELJANZ/XELJANZ XR is used to treat adults with moderately to severely active rheumatoid arthritis in which methotrexate did not work well. XELJANZ/XELJANZ XR may be used as a single agent or in combination with methotrexate (MTX) or other non-biologic disease-modifying antirheumatic drugs (DMARDs). Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants, such as azathioprine and cyclosporine is not recommended. It is not known if XELJANZ/XELJANZ XR is safe and effective in people with hepatitis B or C. XELJANZ/XELJANZ XR is not for people with severe liver problems. It is not known if XELJANZ/XELJANZ XR is safe and effective in children. Important Safety Information XELJANZ/XELJANZ XR can lower the ability of the immune system to fight infections. Some people can have serious infections while taking XELJANZ/XELJANZ XR, 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/XELJANZ XR, and monitor them closely for signs and symptoms of TB and other infections during treatment. People should not start taking XELJANZ/XELJANZ XR if they have any kind of infection unless their healthcare provider tells them it is okay. People may be at a higher risk of developing shingles. XELJANZ/XELJANZ XR may increase the risk of certain cancers by changing the way the immune system works. Lymphoma and other cancers, including skin cancers, can happen in patients taking XELJANZ/XELJANZ XR. The risks and benefits of treatment should be considered prior to initiating XELJANZ/XELJANZ XR in patients with chronic or recurrent infection; who have been exposed to tuberculosis; with a history of a serious or an opportunistic infection; who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection. Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), was observed in clinical studies with XELJANZ. Use of live vaccines should be avoided concurrently with XELJANZ/XELJANZ XR. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy. Some people who have taken XELJANZ with certain other medicines to prevent kidney transplant rejection have had a problem with certain white blood cells growing out of control (Epstein Barr virus-associated post-transplant lymphoproliferative disorder). Some people taking XELJANZ/XELJANZ XR can get tears in their stomach or intestines. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis), or who have a narrowing within their digestive track. 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/XELJANZ XR can cause changes in certain lab test results including low blood cell counts, increases in certain liver tests, and increases in cholesterol levels. Healthcare providers should do blood tests before starting patients on XELJANZ/XELJANZ XR and while they are taking XELJANZ/XELJANZ XR, to check for these side effects. Normal cholesterol levels are important to good heart health. Healthcare providers may stop XELJANZ/XELJANZ XR treatment because of changes in blood cell counts or liver test results. Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. Patients should tell their healthcare providers if they plan to become pregnant or are pregnant. It is not known if XELJANZ/XELJANZ XR will harm an unborn baby. To monitor the outcomes of pregnant women exposed to XELJANZ/XELJANZ XR, a registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972. 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/XELJANZ XR 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/XELJANZ XR. Healthcare providers may do blood tests before and during treatment with XELJANZ/XELJANZ XR. Common side effects include upper respiratory tract infections (common cold, sinus infections), headache, diarrhea, and nasal congestion, sore throat, and runny nose (nasopharyngitis). About Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease that causes a range of symptoms, including pain and swelling in the joints,2,3 particularly those in the hands, feet and knees.3 Although the exact cause of RA is unknown,3 it is considered to be an autoimmune disease, because the immune system in people with RA mistakes the body’s healthy tissues for a threat and attacks them.3 Some people are at increased risk of developing RA, including people with a family history of RA, smokers and women.4 Three times as many women are affected by RA compared to men.3 RA affects approximately 23.7 million people worldwide5 and 1.6 million people in the United States.6,7 It can develop at any time during adulthood, but it usually occurs between 40 and 70 years of age.3 XELJANZ XR Generic Name and Formulations: Tofacitinib 11mg; ext-rel tabs. Company: Pfizer Inc. Select therapeutic use: Arthritis/rheumatic disorders Indications for XELJANZ XR: Moderately-to-severely active rheumatoid arthritis (RA) in adults 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). Adult: Swallow whole; do not crush, split, or chew. 11mg once daily. Concomitant potent CYP3A4 inducers: not recommended. Dose adjustments: see full labeling. Children: Not established. Warnings/Precautions: Increased risk of serious or fatal infections (eg, TB, bacterial, viral, invasive fungal, or other opportunistic pathogens). Active, serious, or localized infections: do not initiate therapy. Chronic or history of recurring or opportunistic 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, active TB (even if initial latent test is negative), or reactivation of herpes virus occurs; interrupt treatment if serious or opportunistic infection, or sepsis develops. Known malignancy. History of GI perforations. Specifically XR tabs: pre-existing severe GI narrowing. Monitor lymphocytes at baseline, then every 3 months; neutrophils and hemoglobin at baseline, after 4–8 weeks, then every 3 months thereafter. 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. Perform periodic skin exam in those with skin cancer risk. Diabetes. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Concomitant live vaccines, biologic DMARDs or potent immunosuppressants (eg, azathioprine, cyclosporine): 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); see Adults. See Also: XELJANZ Pharmacological Class: Janus kinase (JAK) inhibitor. Adverse Reactions: Upper respiratory tract infections, headache, diarrhea, nasopharyngitis; serious or opportunistic infections, TB, malignancies (eg, lymphoma), cytopenias, liver enzyme or lipid elevations, non-melanoma skin cancer. Metabolism: Hepatic (CYP3A4, 2C19). Elimination: Renal. Generic Availability: NO How Supplied: Tabs—28, 60, 180; XR tabs—14, 30