白细胞介素-1是在炎症因子的刺激下所诱导产生的,它主要介导一些炎症和免疫反应中所发生的病理和生理学反应.白细胞介素-1受体拮抗剂是世界上第一个发现的、在人体内天然存在的受体拮抗剂。它主要通过与广泛存在与各种不同组织和器官中表达的白细胞介素-1受体结合，并对竞争性地拮抗白细胞介素-1的生物活性。 白细胞介素-1受体拮抗剂也叫Kineret Kineret（Anakinra）是一种重组的非糖基化的人IL-1受体的拮抗剂，由153个氨基酸组成，分子量为17.3 KD，由美国Amgen公司开发。Kineret与天然的人IL-1受体的拮抗剂区别是，在它的氨基端加了一蛋氨酸残基。2001年11月14日，Kineret获得美国FDA的批准上市，用于治疗对一种或多种DMARDs无效的中至重度的活动期成人RA患者，以减轻其症状。欧洲专利药评估署于2001年11月21日批准Kineret在欧洲上市，与MTX联用治疗对单用MTX疗效欠佳RA患者。目前，Kineret正在进行用于IBD、气喘和移植物排异的临床试验。   Amgen公司就与Kineret产品相关的技术专利申请了如下保护： （1）编码具有生理功能的白细胞介素-1抑制剂（IL-li）的DNA序列，包括——编码IL-li X，IL-li a，或IL-li b 的DNA；可与编码IL-li X，IL-li a，或IL-li b的DNA序列杂交的DNA序列；可与编码IL-li X，IL-li a，或IL-li b的DNA互补的序列杂交的序列。 （2）重组的DNA分子GT10-lLli-2A。 （3）采用重组DNA的方法生产白细胞介素-1抑制剂的方法。 （4）白细胞介素-1抑制剂（IL-1i)，包括具有白细胞介素-1抑制活性的糖基化与非糖基化的多肽，可以是——全长的白细胞介素-1抑制剂或具有以下氨基酸序列的多肽(U) (X) P S G R K S S K M Q A F R I W D V N Q K T F Y L R N N Q L V A G Y L Q G P N V N L E E K I D V V P I E P H A L F L G I H G G K M C L S C V K S G D E T R L Q L E A V N I T D L S E N R K Q D K R F A F I R S D S G P T T S F E S A A C P G W F L C T A M E A D Q P V S L T N M P D E G V M V T K F Y F Q E D E，其中 (U) 是 M 或缺失，(X)是 R 或 P；与a的氨基酸序列同源性达到90%的多肽。 是目前治疗风湿性关节炎病人最有效的药物之一。 国内初步的临床试验已经表明：与常规的激素药物治疗比较，白细胞介素-1受体拮抗剂具有疗效好、无明显毒副反应的特点. 部分中文Kineret处方资料（仅供参考） 药品说明 类风湿性关节炎治疗药阿那白滞素（anakinra） 商品名: Kineret 结构特点: 本品为重组、非糖基化的人白介素-1受体拮抗剂（IL-1Ra），与天然人IL-1Ra的不同之处在于其N-末端增加了一个蛋氨酸残基。本品由153个氨基酸组成，分子量为17.3kDa。本品采用大肠杆菌表达系统生产。 开发厂商: 美国安进公司研制开发，2001年11月首次在美国上市。 　 适应症: 适用于对1个或多个缓解病症的抗风湿性药物（DMARD）治疗无效的18岁及以上中重度活动性类风湿性关节炎（RA）患者，以减轻体征和症状。 药理: 本品竞争性地抑帛IL-1与IL-1Ⅰ型受体（IL-1Rl）相结合，从而阻滞在多个组织和器官中表达的IL-1的生物活性。 炎症刺激诱导IL-1产生，后者可调节各种生理反应包括炎症反应和免疫应答。IL-1具有广泛活性，包括通过诱导蛋白多糖书刊号衰减而降解软骨以及刺激骨吸收。类风湿性关节炎（RA）患者滑膜和滑液中天然产生的IL-1Ra水平不足以对抗局部产生的IL-1量的增加。 11例健康志愿者接受本品70mg，大剂量皮下注射，绝对生物利用度为95%。18例RA患者接受本品临床相关剂量（1-2mg/kg）皮下注射后3-7小时达血药峰值，终末t1-2为4-6小时。RA患者每日接受本品皮下注射，用药24周，未见药物蓄积。 341例患者一日接受本品30、75和150mg，皮下注射，用药24周，药动学分析显示本品的清除率随肌酐清除率升高和体重增加而升高，性别和年龄对平均血浆清除率无显著影响。在严重或末期肾病患者（肌酐清除率低于30ml/min）中，本品的平均血浆清除率下降70％-75％。 在大鼠中进行的毒理学和毒理动力学试验显示本品与甲氨蝶呤合用未见两药清除率或毒理学性质的改变。 临床评价: 在2932例患者中进行了随机双盲安慰剂对照临床研究，为期13周的研究结果显示，本品减轻了大多数患者的炎症和疼痛。 一项疗效研究中，501例患者在接受甲氨蝶呤的基础上随机加用本品或安慰剂治疗。6个月时，本品组达到美国风湿病学会评分中的20％改善（ACR20）的患者为38％，而安慰剂组为22%（P＜0.001）。 一项随机双盲多中心研究中472例患者随机静脉注射本品30、75、150mg或安慰剂，一日1次，连用6-24个月。24周时，本品组健康评价调查表评分下降0.24，安慰剂组下降0.03。在75％的基础骨侵蚀患者中，本品150mg，24周组，31％的患者的进行性关节损害停止，而安慰剂组为16%。研究结束时，本品组14%的患者能够工作和进行日常家务活动，而安慰剂组为6%。 在一项包括419例RA患者的双盲安慰剂对照Ⅱ期临床研究中，接受本品加上1mg/kg甲氨蝶呤皮下注射的患者临床有效率为46％，而单用甲氨蝶呤者为23%。 不良反应: 最常见的不良反应为注射部位反应，通常为轻至中度，表现为发红、肿胀和疼痛。 与安慰剂组相比，本品组严重感染的危险（2%对＜1%）增加。因此，如果患者发生严重感染，应停用本品。 其它不良反应（发生率≥5%且高于安慰剂组）有头痛、恶心、腹泻、鼻窦炎、流感样症状和腹痛。 注意事项: 对大肠杆菌衍生蛋白、本品及其制剂成分过敏者，发生感染的患者禁用。怀孕、哺乳期女、老年人、肾功能不全者慎用。 初步数据显示与单用相比，本品与依那西普（etanercept）合用引起的严重感染和中性粒细胞减少症的发生率较高（分别为7%和3%）。应尽量避免本品与肿瘤坏死因子（TNF）阻断剂合用。 本品可干扰患者对新的抗原如疫苗的正常免疫反应，因此使用本品时接种疫苗无效。 用法用量: 推荐剂量为100mg，一日1次，皮下注射时，在每天的同一时间给药。 可单用或除TNF阻断剂外的DMARD合用。 制剂: 每毫升含本品0.67ml（100mg）。   --------------------------------------------------------------- 原产地英文商品名: KINERET 100mg/0.67mL/SYRINGE 28DISP SYRINGES/box 原产地英文药品名: ANAKINRA 中文参考商品译名: KINERET 100毫克/0.67毫升/注射器 28注射器/盒 中文参考药品译名: 阿那白滞素 中文参考化合物名称: 白细胞介素-1的受体拮抗剂 生产厂家中文参考译名: 安进 生产厂家英文名: Amgen --------------------------------------------------------------- Kineret Company: Amgen Approval Status: Approved November 2001 Treatment for: Rheumatoid arthritis Areas: Musculoskeletal; Rheumatology ------------------------------------------------------------- DRUG DESCRIPTION Kineret® (anakinra) is a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). Kineret® differs from native human IL-1Ra in that it has the addition of a single methionine residue at its amino terminus. Kineret® consists of 153 amino acids and has a molecular weight of 17.3 kilodaltons. It is produced by recombinant DNA technology using an E colibacterial expression system. Kineret® is supplied in single use prefilled glass syringes with 27 gauge needles as a sterile, clear, colorless-to-white, preservative-free solution for daily subcutaneous (SC) administration. Each prefilled glass syringe contains: 0.67 mL (100 mg) of anakinra in a solution (pH 6.5) containing sodium citrate (1.29 mg), sodium chloride (5.48 mg), disodium EDTA (0.12 mg), and polysorbate 80 (0.70 mg) in Water for Injection, USP. ------------------------------------------------------------- INDICATIONS Kineret® is indicated for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugs (DMARDs). Kineret® can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents (see WARNINGS). ------------------------------------------------------------- DOSAGE AND ADMINISTRATION The recommended dose of Kineret® for the treatment of patients with rheumatoid arthritis is 100 mg/day administered daily by subcutaneous injection. Higher doses did not result in a higher response. The dose should be administered at approximately the same time every day. Physicians should consider a dose of 100 mg of Kineret® administered every other day for RA patients who have severe renal insufficiency or end stage renal disease (defined as creatinine clearance < 30 mL/min, as estimated from serum creatinine levels). See CLINICAL PHARMACOLOGY, Pharmacokinetics: Patients with Renal Impairment. Instructions on appropriate use should be given by the healthcare provider to the patient or caregiver. Patients or caregivers should not be allowed to administer Kineret® until the patient or caregiver has demonstrated a thorough understanding of procedures and an ability to inject the product. After administration of Kineret®, it is essential to follow the proper procedure for disposal of syringes and needles. See the "Information for Patients" insert for detailed instructions on the handling and injection of Kineret®. Do not use Kineret® beyond the expiration date shown on the carton. Visually inspect the solution for particulate matter and discoloration before administration. If particulates or discoloration are observed, the prefilled syringe should not be used. Administer only one dose (the entire contents of one prefilled glass syringe) per day. Discard any unused portions. ------------------------------------------------------------- HOW SUPPLIED Kineret® is supplied in single-use preservative free, prefilled glass syringes with 27 gauge needles. Each prefilled glass syringe contains 0.67 mL (100 mg) of anakinra. Kineret® is dispensed in a 4 x 7 syringe dispensing pack containing 28 syringes (NDC 55513-177-28). Storage Kineret® should be stored in the refrigerator at 2° to 8° C (36° to 46° F). DO NOT FREEZE OR SHAKE. Protect from light. This product, its production, and/or its use may be covered by one or more U.S. Patents, including U.S. Patent Nos. 6,599,873 and 5,075,222 as well as other patents or patents pending. ------------------------------------------------------------- SIDE EFFECTS The most serious adverse reactions were: Serious Infections - see WARNINGS Neutropenia, particularly when used in combination with TNF blocking agents The most common adverse reaction with Kineret® is injection-site reactions. These reactions were the most common reason for withdrawing from studies. Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. The data described herein reflect exposure to Kineret® in 3025 patients, including 2124 exposed for at least 6 months and 884 exposed for at least one year. Studies 1 and 4 used the recommended dose of 100 mg per day. The patients studied were representative of the general population of patients with rheumatoid arthritis. Injection-site Reactions The most common and consistently reported treatment-related adverse event associated with Kineret® is injection-site reaction (ISR). The majority of ISRs were reported as mild. These typically lasted for 14 to 28 days and were characterized by 1 or more of the following: erythema, ecchymosis, inflammation, and pain. In studies 1 and 4, 71% of patients developed an ISR, which was typically reported within the first 4 weeks of therapy. The development of ISRs in patients who had not previously experienced ISRs was uncommon after the first month of therapy. Infections In studies 1 and 4 combined, the incidence of infection was 39% in the Kineret®-treated patients and 37% in placebo-treated patients during the first 6 months of blinded treatment. The incidence of serious infections in studies 1 and 4 was 2% in Kineret®-treated patients and 1% in patients receiving placebo over 6 months. The incidence of serious infection over 1 year was 3% in Kineret®-treated patients and 2% in patients receiving placebo. These infections consisted primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections, rather than unusual, opportunistic, fungal, or viral infections. Patients with asthma appeared to be at higher risk of developing serious infections when treated with Kineret® (8 of 177 patients, 4.5%) compared to placebo (0 of 50 patients, 0%). Most patients continued on study drug after the infection resolved. In open-label extension studies, the overall rate of serious infections was stable over time and comparable to that observed in controlled trials. In clinical studies and postmarketing experience, rare cases of opportunistic infections have been observed and included fungal, mycobacterial and bacterial pathogens. Infections have been noted in all organ systems and have been reported in patients receiving Kineret® alone or in combination with immunosuppressive agents. In patients who received both Kineret® and etanercept for up to 24 weeks, the incidence of serious infections was 7%. The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure. Malignancies Among 5300 RA patients treated with Kineret® in clinical trials for a mean of 15 months (approximately 6400 patient years of treatment),8 lymphomas were observed for a rate of 0.12 cases/100 patient years. This is 3.6 fold higher than the rate of lymphomas expected in the general population, based on the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database.9 An increased rate of lymphoma, up to several fold, has been reported in the RA population, and may be further increased in patients with more severe disease activity. Thirty-seven malignancies other than lymphoma were observed. Of these, the most common were breast, respiratory system, and digestive system. There were 3 melanomas observed in study 4 and its long-term open-label extension, greater than the 1 expected case. The significance of this finding is not known. While patients with RA, particularly those with highly active disease, may be at a higher risk (up to several fold) for the development of lymphoma, the role of IL-1 blockers in the development of malignancy is not known. Hematologic Events In placebo-controlled studies with Kineret®, treatment was associated with small reductions in the mean values for total white blood count, platelets, and absolute neutrophil count (ANC), and a small increase in the mean eosinophil differential percentage. In all placebo-controlled studies, 8% of patients receiving Kineret® had decreases in ANC of at least 1 WHO toxicity grade, compared with 2% of placebo patients. Nine Kineret®-treated patients (0.4%) developed neutropenia (ANC < 1 x 109/L). Two percent of patients treated concurrently with Kineret® and etanercept developed neutropenia (ANC < 1 x 109/L). While neutropenic, one patient developed cellulitis which recovered with antibiotic therapy. Immunogenicity In studies 1 and 4, from which data is available for up to 36 months, 49% of patients tested positively at one or more timepoints for anti-anakinra antibodies in a highly sensitive, anakinra-binding biosensor assay. Of the 1615 patients with available data at Week 12 or later, 30 (2%) were seropositive in a cell-based bioassay for antibodies capable of neutralizing the biologic effects of Kineret®. Of the 13 patients with available follow-up data, 5 patients remained positive for neutralizing antibodies at the end of the studies. No correlation between antibody development and adverse events was observed. Antibody assay results are highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Kineret® with the incidence of antibodies to other products may be misleading. ------------------------------------------------------------- DRUG INTERACTIONS No drug-drug interaction studies in human subjects have been conducted. Toxicologic and toxicokinetic studies in rats did not demonstrate any alterations in the clearance or toxicologic profile of either methotrexate or Kineret® when the two agents were administered together. TNF Blocking Agents: A higher rate of serious infections has been observed in patients treated with concurrent Kineret® and etanercept therapy than in patients treated with etanercept alone (see also WARNINGS: Use with TNF Blocking Agents). Two percent of patients treated concurrently with Kineret® and etanercept developed neutropenia (ANC < 1 x 109/L). Use of Kineret® in combination with TNF blocking agents is not recommended. ------------------------------------------------------------- WARNINGS Serious Infections Kineret® HAS BEEN ASSOCIATED WITH AN INCREASED INCIDENCE OF SERIOUS INFECTIONS (2%) VS. PLACEBO ( < 1%). ADMINISTRATION OF Kineret® SHOULD BE DISCONTINUED IF A PATIENT DEVELOPS A SERIOUS INFECTION. TREATMENT WITH Kineret® SHOULD NOT BE INITIATED IN PATIENTS WITH ACTIVE INFECTIONS. THE SAFETY AND EFFICACY OF Kineret® IN IMMUNOSUPPRESSED PATIENTS OR IN PATIENTS WITH CHRONIC INFECTIONS HAVE NOT BEEN EVALUATED. Use With TNF Blocking Agents IN A 24-WEEK STUDY OF CONCURRENT Kineret® AND ETANERCEPT THERAPY, THE RATE OF SERIOUS INFECTIONS IN THE COMBINATION ARM (7%) WAS HIGHER THAN WITH ETANERCEPT ALONE (0%). THE COMBINATION OF Kineret® AND ETANERCEPT DID NOT RESULT IN HIGHER ACR RESPONSE RATES COMPARED TO ETANERCEPT ALONE (see Clinical Studies). USE OF Kineret® IN COMBINATION WITH TNF BLOCKING AGENTS IS NOT RECOMMENDED. ------------------------------------------------------------- PRECAUTIONS General Hypersensitivity reactions associated with Kineret® administration are rare. If a severe hypersensitivity reaction occurs, administration of Kineret® should be discontinued and appropriate therapy initiated. The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex. Immunosuppression The impact of treatment with Kineret® on active and/or chronic infections and the development of malignancies is not known (see WARNINGS and ADVERSE REACTIONS: Infections and Malignancies). Immunizations In a placebo-controlled clinical trial (n = 126), no difference was detected in anti-tetanus antibody response between the Kineret® and placebo treatment groups when the tetanus/diphtheria toxoids vaccine was administered concurrently with Kineret®. No data are available on the effects of vaccination with other inactivated antigens in patients receiving Kineret®. No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving Kineret® (see PRECAUTIONS: Immunosuppression). Therefore, live vaccines should not be given concurrently with Kineret®. Information for Patients If a physician has determined that a patient can safely and effectively receive Kineret® at home, patients and their caregivers should be instructed on the proper dosage and administration of Kineret®. All patients should be provided with the "Information for Patients" insert. While this "Information for Patients" insert provides information about the product and its use, it is not intended to take the place of regular discussions between the patient and healthcare provider. Patients should be informed of the signs and symptoms of allergic and other adverse drug reactions and advised of appropriate actions. The patient should be informed that the needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex), which should not be handled by persons sensitive to latex. Patients and their caregivers should be thoroughly instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, and drug product. A puncture-resistant container for the disposal of used syringes should be available to the patient. The full container should be disposed of according to the directions provided by the healthcare provider. Laboratory Tests Patients receiving Kineret® may experience a decrease in neutrophil counts. In the placebo-controlled studies, 8% of patients receiving Kineret® had decreases in neutrophil counts of at least 1 World Health Organization (WHO) toxicity grade compared with 2% in the placebo control group. Nine Kineret®-treated patients (0.4%) experienced neutropenia (ANC < 1 x 109/L). This is discussed in more detail in the ADVERSE REACTIONS: Hematologic Events section. Neutrophil counts should be assessed prior to initiating Kineret® treatment, and while receiving Kineret®, monthly for 3 months, and thereafter quarterly for a period up to 1 year . Carcinogenesis, Mutagenesis, and Impairment of Fertility Kineret® has not been evaluated for its carcinogenic potential in animals. Using a standard in vivo and in vitro battery of mutagenesis assays, Kineret® did not induce gene mutations in either bacteria or mammalian cells. In rats and rabbits, Kineret® at doses of up to 100-fold greater than the human dose had no adverse effects on male or female fertility. Pregnancy Category B Reproductive studies have been conducted with Kineret® on rats and rabbits at doses up to 100 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Kineret® should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether Kineret® is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised if Kineret® is administered to nursing women. Pediatric Use Kineret® was studied in a single randomized, blinded multi-center trial in 86 patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA; ages 2-17 years) receiving a dose of 1 mg/kg subcutaneously daily, up to a maximum dose of 100 mg. The 50 patients who achieved a clinical response after a 12-week open-label run-in were randomized to Kineret® (25 patients) or placebo (25 patients), administered daily for an additional 16 weeks. A subset of these patients continued open label treatment with Kineret® for up to 1 year in a companion extension study. An adverse event profile similar to that seen in adult RA patients was observed in these studies. Pediatric use of Kineret® is not recommended because the prefilled syringes do not permit accurate dosing lower than 100 mg and efficacy could not be demonstrated due to low trial enrollment. Geriatric Use A total of 752 patients ≥ 65 years of age, including 163 patients ≥ 75 years of age, were studied in clinical trials. No differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. ------------------------------------------------------------- OVERDOSE There have been no cases of overdose reported with Kineret® in clinical trials of RA. In sepsis trials no serious toxicities attributed to Kineret® were seen when administered at mean calculated doses of up to 35 times those given patients with RA over a 72-hour treatment period. ------------------------------------------------------------- CONTRAINDICATIONS Kineret® is contraindicated in patients with known hypersensitivity to E coli-derived proteins, Kineret®, or any components of the product.