部分中文派罗欣处方资料（仅供参考） 【药品名称】 通用名：聚乙二醇干扰素α-2a注射液 商品名：Pegasys® 英文名：Peginterferon alfa-2a Solution for Injection 本品主要组成成分：聚乙二醇干扰素α-2a 【性状】 无菌小瓶装液体制剂，供皮下注射用。 每小瓶含180μg（1.0ml）的聚乙二醇干扰素α-2a； 赋形剂：氯化钠、吐温80、苯甲醇、乙酸钠、乙酸、注射用水 溶液为透明无色至淡黄色液体 【药理毒理】 药理作用 聚乙二醇干扰素α-2a是聚乙二醇（PEG）与重组干扰素α-2a结合形成的长效干扰素。干扰素与细胞表面的特异性受体结合，触发细胞内复杂的信号传递途径并迅速激活基因转录，调节多种生物效应，包括抑制感染细胞内的病毒复制，抑制细胞增殖，并具有免疫调节作用。 健康人单次皮下注射PEG干扰素α-2a 180μg后3-6小时，血清2, 5-寡腺苷酸合成酶（2, 5-OAS，抗病毒活性指标）活性迅速升高。PEG干扰素α-2a所引起的2, 5-OAS血清活性可维持1周以上，且比单次皮下注射300万单位和1800万单位干扰素的活性高。与年轻人比较，62岁以上的老年人单次皮下注射PEG干扰素α-2a 180μg，所产生的血清2, 5-OAS活性强度和持续时间有所减低。 毒理研究 生殖毒性 动物试验提示，与其他干扰素相同，雌猴给予PEG干扰素α-2a后出现月经周期延长，并伴随17β-雌二醇和黄体激素峰的减低和延迟。停药后，月经恢复正常；雄猴给予干扰素α-2a 25×106IU/kg/天，连续5个月，未见其对生育力的影响。恒河猴给予干扰素α-2a后，流产率显著升高，未见畸胎。 【药代动力学】 在健康志愿者中和丙型肝炎病毒感染病人中进行了本品的药代动力学的研究。 *吸收 在健康受试者人群中，180μg单次皮下注射后，血清浓度可在3-6小时内检测到。在24-48小时内，可达到血清浓度峰值的80%。注射后可维持血清浓度达72-96小时。其绝对生物利用度是84%，与干扰素α-2a相似。 *分布 本品主要分布在血液和细胞外液中。静脉注射后稳态分布容积（Vss）为6-14升。已在大鼠进行了本品的物质平衡、组织学分布和机体自动放射发光图谱研究，结果显示本品除了血液中浓度较高外，还分布在肝脏、肾脏和骨髓中。本品经放射标记后，单次静脉给药脑组织中未检出。 *代射 代谢是清除本品的主要机制。代谢的全貌尚未完全了解。但是在大鼠中进行的研究显示，肾脏是排泌的放射标记物和代谢产物的主要脏器。 *清除 人体内对本品的系统清除率大约是100ml/h，较普通干扰素α-2a低100倍。静脉给药后，半衰期大约是60小时，而普通干扰素一般仅3-4小时。皮下注射给药后，其半衰期更长（约80小时，大部分病人在50-140小时之间）。皮下注射后的半衰期可能不能反应该化合物的清除相，但可以反应持续吸收。健康受试者和慢性丙型肝炎患者每周一次使用后的血药浓度随给药剂量的增加而增加。 在慢性丙型肝炎病人中，每周给药一次，连续5-8周后，本品产生蓄积，其血清浓度可达单次给药的2-3倍。但8周后无进一步蓄积。使用48周后的峰谷比约为1.5-2.0。其血清浓度可在整个一周内维持在一个较稳定的水平。 特殊人群药效学和药代动力学特性 *肾功能异常病人 对23例肌酐清除率在高于100ml/min（肾功能正常）到20ml/min（肾功能显著异常）的病人在研究显示，本品的药代动力学与肌酐清除率无显著相关性。在严重肾功能损害的病人中本品诱导的寡腺苷酸合成酶（OAS）活性较肾功能正常者有明显减低。但肾功能异常对本品的药代动力学影响非常小。 单次皮下注射90μg，肾功能异常受试者与健康受试者对本品的耐受性及不良事件的发生率是相似的，肾功能异常受试者发生频率仅轻度增加。研究中出现的不良事件和实验室检查异常与使用普通干扰素出现的相似。（见注意事项）。 *性别 男性和女性健康受试者单次皮下注射的药代动力学参数具有可比性。 *老年患者 62岁以上的老年受试者在给予单次皮下注射180μg后对本品的吸收较健康受试者延迟，但仍呈持续性。两者达峰时间分别为115小时和82小时；AUC中度增加（分别为1663和1295ng.h/ml）；但峰浓度相似（分别为9.1和10.3ng/ml）。根据药物分布、药效学应答和药物耐受性特点，老年病人不需要调整剂量。（具体见用法用量章节） *无肝硬化和伴肝硬化患者 本品在健康受试者中和在慢性丙型肝炎患者中的药代动力学特点是相似的。代偿期肝硬化患者和无肝硬化患者的药物分布和药代动力参数具有可比性。 【适应症】 用于治疗以下慢性丙型肝炎患者： －无肝硬化病人 －肝硬化代偿期病人 【用法用量】 *常规剂量 推荐剂量为180μg每周一次皮下注射使用，共48周。 *特殊剂量指导 对于中度和重度不良反应（包括临床表现和/或实验室指标异常）的患者应给予调整剂量，初始剂量一般减至135μg，但有些病例需要将剂量减至90μg或45μg。随着不良反应的减轻，可以考虑逐渐增加或恢复至常规使用剂量（见警告、注意事项及不反应章节）。 *血液学指标 当中性粒细胞计数（ANC）小于750个/mm3时，应考虑减量；当中性粒细胞计数（ANC）小于500个/mm3时，应考虑暂时停药，直到ANC恢复至大于1000个/mm3时，可再恢复治疗。重新治疗开始应使用90μg，并应监测中性粒细胞计数。 当血小板计数小于50,000个/mm3时，应将派罗欣®剂量减低至90μg；当血小板计数低于25,000个/mm3时，应考虑停药。 *肝脏功能 慢性丙型肝炎患者，肝功能经常出现波动。与其它α干扰素相同，使用本品治疗后，也会发生ALT升高，包括有病毒应答的患者。当出现ALT的持续升高时，应考虑将剂量减至90μg。减量后，如ALT仍持续升高，或发生胆红素升高或肝功能失代偿时，应考虑停药。 特殊说明 *应用和处置 作为皮下注射药物，使用前必须肉眼观察注射剂中有无颗粒和颜色变化。 在家中使用时，应向病人提供可以用来丢弃用过的注射器和针头的抗穿刺容器；应向病人说明正确处理用过的注射器和针的重要性，绝对不能重复使用针和注射器；整个空容器应依据医生的要求处理。 *不相容性 不应将本品与其它产品混合。 *特殊人群 *肾功能异常 肾功能异常患者无需调整剂量。尚未在血液透析患者中进行过有关的研究（详见注意事项）。 *肝功能异常 根据药代动力学、临床耐受性和安全性资料，Child分类为A级的肝硬化病人无需调整剂量。 尚未在肝功能失代偿的患者中进行过有关研究（见警告）。 【不良反应】 使用本品时的不良反应与应用其它α-干扰素类似。 *临床试验中发现的不良反应 本品最常见的不良反应的频率和严重性与干扰素α-2a相似。 使用本品180μg治疗最常出现的不良反应大多数属轻至中度，一般无需调整用药剂量或停止治疗。 在国外临床试验中，因不良反应和实验室检查异常退出试验的发生率，在干扰素α-2a和本品治疗组中均为10%。仅有2%的病人由于实验室指标异常需要中止治疗。伴有肝硬化的病人退出试验的比例与整个治疗组的比例相似。 在临床试验中，有超过1000例的病人接受了本品的治疗。 使用本品后，不良反应发生率≥2%，但<10%的有：乏力、嗜睡、胸痛、流感样症状、不适、潮热、颤抖、记忆力减退、感觉异常、味觉障碍、虚弱、感觉迟钝、震颤、肌肉痉挛、颈痛、皮炎、多汗、皮疹、皮肤干燥、盗汗、光过敏反应、口干、牙龈出血、口腔溃疡、焦虑、情绪改变、性欲减退、神经过敏、攻击意识、体重减轻、咳嗽、呼吸困难、咽痛、鼻咽炎、视觉模糊、眼炎、甲状腺功能减退、心悸和潮红。 与其它干扰素相同，发生在本品临床试验期间孤立的不良事件包括：肝功能异常、脂肪肝、胆管炎、心律不齐、行为异常（包括自杀动机、自杀行为）、糖尿病、自身免疫现象、周围神经疾病、消化性溃疡、胃肠道出血、可逆的胰腺炎反应（淀粉酶/胰肪酶升高，伴或不伴腹痛）、角膜溃疡、感染、心内膜炎、肺炎、致死性间质性肺炎、肺栓塞、昏迷、药物过量。另外，已有使用本品发生肌炎和脑出血的报告。 实验室指标 *血液学 与其它干扰素相同，血象降低与使用本品180μg治疗有关，血象在调整使用剂量后可逐渐提高，停止治疗后4-8周内血象可恢复至治疗前水平（详见注意事项、实验室检查、用法用量诸章节）。 *血红蛋白和红细胞容积 虽然使用本品180μg治疗可以引起血红蛋白和红细胞容积逐渐降低，但包括伴有肝硬化的患者仅有少于1%的病人因贫血需要调整使用剂量。 *血白细胞 使用本品治疗可引起白细胞和绝对中性粒细胞计数减少。大约4%的病人在治疗期间出现短暂的中性粒细胞计数低于500个/mm3。 *血小板计数 本品可引起血小板降低。在临床试验中，大约5%的病人在治疗期间出现血小板计数低于50,000个/mm3，其中大部分是伴有肝硬化和参加本试前血小板计数低于的75,000个/mm3的那些患者。 *甲状腺功能 使用派罗欣®治疗有可能导致有关甲状腺功能检查指标的显著异常并需要药物干预治疗，其发生机会与其它干扰素相似。 【禁忌】 禁用于已知对α-干扰素、大肠杆菌产物、聚乙烯二醇或本品任何成分过敏的患者；禁用于自身免疫性肝炎患者。 【注意事项】 已有使用α干扰素治疗导致自身免疫性疾病加重的报道。对伴有自身免疫性疾病的患者应慎用本品。 与其它干扰素一样，已观察到使用本品导致的低血糖症和高血糖症。 使用α-干扰素可引起牛皮癣的加重。伴有牛皮癣的患者应慎用，如果使用中出现牛皮癣复发和恶化征象，应考虑停药。与其它α-干扰素一样，已有用药期间出现肺部症状的报道，包括呼吸困难、肺浸润、肺炎、局限性肺炎包括死亡。如果肺浸润持续存在或出现原因不明的肺功能异常，应停用。目前已有个别使用α干扰素导致眼科疾患的报道，包括视网膜出血、盲点、视网膜静脉或动脉阴塞。任何使用派罗欣®的患如出现视力下降或视野缺失必须进行眼科检查。 *实验室检查 在使用本品治疗前，建议所有病人进行血常规检查和生化检查。在开始治疗以后，病人应在第2周进行血常规检查和在第4周进行生化检查。治疗期间应定期进行上述检查。 用于临床研究的病例入选标准可以用来作为判断病人能否使用本品治疗的标准，包括： ※血小板计数≥90,000个/mm3（伴有肝硬化患者或向肝硬化转变患者为75,000个/mm3）， ※中性粒细胞计数（ANC）≥1,500个/mm3， ※血肌酐<正常上限的1.5倍， ※TSH和T4在正常范围内或甲状腺疾病可以完全控制。 一般在开始使用本品治疗的二周内，有可能出现白细胞（WBC）计数和中性粒细胞计数（ANC）减少（见不良反应章节）。在临床研究中，WBC和ANC的进行性减少较少见。当ANC减少至低于750个/mm3时，建议减少使用剂量（详见用法用量章节）。当ANC减少至低于500个/mm3时，应暂时停药直至ANC恢复至高于1000个/mm3。在临床研究中，减量或停药后，ANC的减少是可逆的。由于使用干扰素导致的流感样症状所伴有的发热是非常常见的，但在使用本品治疗过程中，应排除其它原因导致的发热，尤其是有中性粒细胞减少的病人。 本品有可能导致血小板减少，但在治疗结果后的随访期内可恢复至治疗前水平（见不良反应章节）。当血小板计数小于50,000个/mm3时，应减少使用剂量；当血小板计数小于25,000个/mm3时，应予以停药（见用法用量章节）。 目前已有使用干扰素（包括本品）导致的甲状腺功能异常或以前存在的甲状腺疾病恶化的报道。对于甲状腺功能异常不能完全控制的病人应考虑停药。 *甘油三酯 与其它干扰素一样，在本品治疗期间，一些病人出现血清甘油三酯的明显升高。根据病人空腹甘油三脂水平，应在调整剂量前，首先采取饮食调节或降脂治疗措施。在停药后，血清甘油三酯可以很快恢复正常。 **警告 本品应在合格的内科医生指导下使用。使用本品治疗有可能导致不良反应的出现，以至需要药物减量、临时停药或停止治疗。 使用干扰素治疗，包括使用本品，有可能出现严重的精神方面的不良反应。不论以往是否有精神疾病，使用者都有可能出现抑郁、自杀心态和自杀企图。有抑郁史的患者应慎用本品。医生应对所有出现抑郁征象的患者进行监控。在使用本品治疗前，医生应告知病人有可能出现抑郁现象，病人应随时向医生报告抑郁的征兆或症状。如有上述精神症状出现、应给予心理治疗干预，并根据情况考虑是否停止治疗（见不良反应章节）。 心血管事件，如高血压、室上性心律失常、胸痛和心肌梗塞，与干扰素治疗有关。因此，既往有心脏疾病的患者应慎用本品。 尚未有肝功能失代偿的患者中进行本品的疗效和安全性的研究。因此，不推荐肝功能失代偿的患者使用。对使用本品治疗过程中出现肝功能失代偿的患者，应给予停药。与其它干扰素一样，在使用本品治疗过程中也能观察到ALT升高，包括出现病毒应答的病人。尽管减低本品剂量后，如果ALT仍持续升高或伴胆红素升高，应给予停药（详见用法用量章节）。 与其它干扰素一样，当与其它有骨髓抑制作用的药物同时使用时，应谨慎。 中性粒细胞计数<1500个/mm3和血小板计数<75,000个/mm3或血红蛋白<10g/dl病人要慎用（参见用法用量章节）。 使用本品后可能出现过敏样反应。如果出现过敏样反应，应停药，并立即给予适当的治疗。 本品不适用于婴幼儿，因此不能用于此年龄的患者。目前很少有过量使用苯甲醇导致婴幼儿死亡的报告。有可能导致婴幼儿中毒和不良反应的苯甲醇的剂量目前尚未确定（参见儿童用药章节）。 *对驾驶交通工具和操作机器的影响 同于使用本品出现头晕、意识模糊、嗜睡和疲劳，应注意不要驾驶交通工具和操作机器。 【孕妇及哺乳期妇女用药】 目前尚未进行本品对生育影响的研究。动物试验中对雌性猴的研究表明，与其它干扰素相同，在使用聚乙二醇干扰素α-2a后，出现月经周期的延长并伴随17β-雌二醇和黄体激素峰的减低和延迟。在停药后，月经周期恢复正常。 目前尚未进行本品对男性生育影响的研究。但是，对雄性恒河猴使用剂量高达25╳106单位/公斤体重/天、用药时间长达5个月的干扰素α-2a时，其生育能力未受影响。 目前尚未进行本品致畸作用的研究。使用干扰素α-2a可导致恒河猴的流产可能性显著升高。在足月分娩的后代中未见致畸作用。但是，与其它α干扰素相同，建议在使用本品治疗期间育龄妇女应采取有效避孕措施。 目前尚无本品在妊娠期的安全性资料。只有经综合判断认为使用本品的可能益处大于可能对胎儿产生的危险时，才可以在妊娠期间使用。 目前尚不清楚本品及其组成成分是否经人乳排泌。但鉴于许多药物可以在人乳中排泌，因此哺乳期妇女应慎用。对哺乳期婴儿的影响尚未进行研究。 【儿童用药】 尚无18岁以下病人用药安全性和疗效的资料。另外因为本品注射溶液中含苯甲醇，所以不能用于新生儿和婴幼儿（见注意事项）。 【老年患者用药】 根据药代动力学、药效学和临床耐受性及安全性资料，老年病人无需调整剂量。 【药物相互作用】 在正在进行的本品与利巴韦林联合应用的临床试验中，尚未发现两者药代动力学有交叉反应。 α-干扰素可以通过降低肝微粒体细胞色素P450酶的活性而影响机体的氧化代谢过程。但是，在健康男性中皮下注射派罗欣®180μg每周1次共4周后，未显示对美芬妥英、氨苯砜、异喹胍和甲磺丁脲等药物的药代动力学有影响。本品对细胸包素P450 3A4、2C9、2C19和2D6等同功酶的体内代谢活性也没有影响。 在同一研究中，发现茶碱的AUC（表示细胞色素P450 1A2活性的指标）出现了25%的升高。本品可中度抑制细胞色素P450 1A2活性。如果同时使用本品和茶碱，应监测茶碱血清浓度并适当调整茶碱用量。 【药物过量】 已有连续每天给药的报告，最少为连续2天每日注射本品一次（而不是间隔一周注射），最大为连续一周每天注射、总剂量达1260μg/周。这些病人未出现特殊的、严重的、或与治疗相关的不良事件。已分别进行了使用450μg/周和630μg/周治疗肾细胞癌和慢性粒细胞白血病的临床试验。与剂量相关的毒性反应包括疲劳、转氨酶升高和中性粒细胞减少。 【贮藏】 避光，贮存于2～8℃的冰箱内，请勿冷冻或摇晃。药品应存放于小孩接触不到处。 Pegasys (Peginterferon alfa-2a) Indications And Usage Pegasys (Peginterferon alfa-2a) , peginterferon alfa-2a, alone or in combination with COPEGUS, is indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Efficacy has been demonstrated in subjects with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and in adult subjects with clinically stable HIV disease and CD4 count greater than 100 cells/mm. The following points should be considered when initiating therapy with Pegasys (Peginterferon alfa-2a) and COPEGUS: Pegasys (Peginterferon alfa-2a) Dosage And Administration Pegasys (Peginterferon alfa-2a) is administered by subcutaneous injection in the abdomen or thigh. See COPEGUS Package Insert for all instructions regarding COPEGUS dosing and administration. In patients with CrCL less than 30 mL/min, including patients with end-stage renal disease requiring hemodialysis, dose reduction to 135 mcg Pegasys (Peginterferon alfa-2a) is recommended. Signs and symptoms of interferon toxicity should be closely monitored. If severe adverse reactions or laboratory abnormalities develop, the dose of Pegasys (Peginterferon alfa-2a) may be reduced to 90 mcg until the adverse reactions abate. If intolerance persists after dose adjustment, Pegasys (Peginterferon alfa-2a) /COPEGUS therapy should be discontinued. Renal function should be evaluated in all patients on COPEGUS. The dose of COPEGUS should be reduced for patients with creatinine clearance less than or equal to 50 mL/min No data are available for pediatric subjects with renal impairment. Discontinuation of therapy should be considered if the patient has failed to demonstrate at least a 2 log reduction from baseline in HCV RNA titer by 12 weeks of therapy or undetectable HCV RNA after 24 weeks of therapy . During treatment, patients' clinical status and hepatic function should be closely monitored, and Pegasys (Peginterferon alfa-2a) treatment should be immediately discontinued if decompensation is observed . Patients should be monitored for serious adverse reactions, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should have their therapy withdrawn . A patient should self-inject Pegasys (Peginterferon alfa-2a) only if the physician determines that it is appropriate and the patient agrees to medical follow-up as necessary and has been trained in proper injection technique Pegasys (Peginterferon alfa-2a) should be inspected visually for particulate matter and discoloration before administration, and not used if particulate matter is visible or product is discolored. Vials, prefilled syringes, and disposable autoinjectors with particulate matter or discoloration should be returned to the pharmacist. Discard the unused portion of Pegasys (Peginterferon alfa-2a) in single-use vials or prefilled syringes in excess of the labeled volume. Use only one vial or prefilled syringe or disposable autoinjector per dose. Pegasys (Peginterferon alfa-2a) Contraindications Pegasys (Peginterferon alfa-2a) is contraindicated in patients with: Pegasys (Peginterferon alfa-2a) is contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurologic and other complications which are sometimes fatal in neonates and infants. Pegasys (Peginterferon alfa-2a) /COPEGUS combination therapy is additionally contraindicated in: Pegasys (Peginterferon alfa-2a) Warnings And Precautions Patients should be monitored for the following serious conditions, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should have their therapy withdrawn . Life-threatening or fatal neuropsychiatric reactions may manifest in all patients receiving therapy with Pegasys (Peginterferon alfa-2a) and include suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug overdose. These reactions may occur in patients with and without previous psychiatric illness. Pegasys (Peginterferon alfa-2a) should be used with extreme caution in all patients who report a history of depression. Neuropsychiatric adverse events observed with alpha interferon treatment include aggressive behavior, psychoses, hallucinations, bipolar disorders, and mania. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. Patients should be advised to report any sign or symptom of depression or suicidal ideation to their prescribing physicians. In severe cases, therapy should be stopped immediately and psychiatric intervention instituted . Pegasys (Peginterferon alfa-2a) suppresses bone marrow function and may result in severe cytopenias. Ribavirin may potentiate the neutropenia and lymphopenia induced by alpha interferons including Pegasys (Peginterferon alfa-2a) . Very rarely, alpha interferons may be associated with aplastic anemia. It is advised that complete blood counts (CBC) be obtained pre-treatment and monitored routinely during therapy . Pegasys (Peginterferon alfa-2a) /COPEGUS should be used with caution in patients with baseline neutrophil counts less than 1,500 cells/mm, with baseline platelet counts less than 90,000 cells/mm or baseline hemoglobin less than 10 g/dL. Pegasys (Peginterferon alfa-2a) therapy should be discontinued, at least temporarily, in patients who develop severe decreases in neutrophil and/or platelet counts . Severe neutropenia and thrombocytopenia occur with a greater incidence in HIV coinfected patients than monoinfected patients and may result in serious infections or bleeding . Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Pegasys (Peginterferon alfa-2a) , COPEGUS, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine . Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including Pegasys (Peginterferon alfa-2a) . Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study 6 , among 129 CHC/HIV cirrhotic subjects receiving HAART, 14 (11%) of these subjects across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 subjects were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs for the associated risk. Exacerbations of hepatitis during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT. Chronic hepatitis B subjects experienced transient acute exacerbations (flares) of hepatitis B (ALT elevation greater than 10-fold higher than the upper limit of normal) during Pegasys (Peginterferon alfa-2a) treatment (12% and 18%) and post-treatment (7% and 12%) in HBeAg negative and HBeAg positive subjects, respectively. Marked transaminase flares while on Pegasys (Peginterferon alfa-2a) therapy have been accompanied by other liver test abnormalities. Patients experiencing ALT flares should receive more frequent monitoring of liver function. Pegasys (Peginterferon alfa-2a) dose reduction should be considered in patients experiencing transaminase flares. If ALT increases are progressive despite reduction of Pegasys (Peginterferon alfa-2a) dose or are accompanied by increased bilirubin or evidence of hepatic decompensation, Pegasys (Peginterferon alfa-2a) should be immediately discontinued . Pediatric subjects treated with Pegasys (Peginterferon alfa-2a) plus COPEGUS combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Both weight and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative growth curve percentiles for weight and height (mean weight for age percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of subjects experienced a weight percentile decrease of 15 percentiles or more, and 25% experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-treatment, 16% of subjects remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve. Before beginning Pegasys (Peginterferon alfa-2a) or Pegasys (Peginterferon alfa-2a) /COPEGUS combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with Pegasys (Peginterferon alfa-2a) /COPEGUS. After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In adult clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. The entrance criteria used for the clinical studies of Pegasys (Peginterferon alfa-2a) may be considered as a guideline to acceptable baseline values for initiation of treatment: Pegasys (Peginterferon alfa-2a) Adverse Reactions In clinical trials, a broad variety of serious adverse reactions were observed in 1,010 subjects who received Pegasys (Peginterferon alfa-2a) at doses of 180 mcg for 48 weeks, alone or in combination with COPEGUS . The most common life-threatening or fatal events induced or aggravated by Pegasys (Peginterferon alfa-2a) and COPEGUS include depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) of CHC/HIV subjects . The following adverse reactions have been identified and reported during post-approval use of Pegasys (Peginterferon alfa-2a) therapy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Ear and labyrinth disorders: Metabolism and nutrition disorders: Skin and subcutaneous tissue disorders: Neurological: Pegasys (Peginterferon alfa-2a) Drug Interactions There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4. Treatment with Pegasys (Peginterferon alfa-2a) once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC. In a PK study of HCV subjects concomitantly receiving methadone, treatment with Pegasys (Peginterferon alfa-2a) once weekly for 4 weeks was associated with methadone levels that were 10% to 15% higher than at baseline. The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of methadone toxicity. The pharmacokinetics of concomitant administration of methadone and Pegasys (Peginterferon alfa-2a) were evaluated in 24 Pegasys (Peginterferon alfa-2a) naïve chronic hepatitis C (CHC) subjects (15 male, 9 female) who received 180 mcg Pegasys (Peginterferon alfa-2a) subcutaneously weekly. All subjects were on stable methadone maintenance therapy (median dose 95 mg, range 30 mg to 150 mg) prior to receiving Pegasys (Peginterferon alfa-2a) . Mean methadone PK parameters were 10% to 15% higher after 4 weeks of Pegasys (Peginterferon alfa-2a) treatment as compared to baseline. Methadone did not significantly alter the PK of Pegasys (Peginterferon alfa-2a) as compared to a PK study of 6 chronic hepatitis C subjects not receiving methadone. In vitro Pegasys (Peginterferon alfa-2a) Use In Specific Populations The safety and effectiveness of Pegasys (Peginterferon alfa-2a) , alone or in combination with COPEGUS in patients below the age of 5 years have not been established. Pegasys (Peginterferon alfa-2a) contains benzyl alcohol. In neonates and infants, benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications which are sometimes fatal in neonates and infants . Renal function should be evaluated in all patients prior to initiation of Pegasys (Peginterferon alfa-2a) by estimating the patient's creatinine clearance. A clinical trial evaluated treatment with Pegasys (Peginterferon alfa-2a) and COPEGUS in 50 CHC subjects with moderate (creatinine clearance 30 – 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). In 18 subjects with ESRD receiving chronic HD, Pegasys (Peginterferon alfa-2a) was administered at a dose of 135 mcg once weekly. Dose reductions and temporary interruptions of Pegasys (Peginterferon alfa-2a) (due to Pegasys (Peginterferon alfa-2a) -related adverse reactions, mainly anemia) were observed in up to 22% ESRD/HD subjects during treatment; and 17% of these subjects discontinued Pegasys (Peginterferon alfa-2a) due to Pegasys (Peginterferon alfa-2a) -related adverse reactions. Only one-third of ESRD/HD subjects received Pegasys (Peginterferon alfa-2a) for 48 weeks. Subjects with severe (n=14) or moderate (n=17) renal impairment received Pegasys (Peginterferon alfa-2a) 180 mcg once weekly. Pegasys (Peginterferon alfa-2a) discontinuation rates were 36% and 0% in subjects with severe and moderate renal impairment, respectively, compared to 0% discontinuation rate in subjects with normal renal function. Based on the pharmacokinetic and safety results from this trial, patients with creatinine clearance less than 30 mL/min should receive a reduced dose of Pegasys (Peginterferon alfa-2a) , and patients with creatinine clearance less than or equal to 50 mL/min should receive a reduced dose of COPEGUS. In addition, patients with any degree of renal impairment should be carefully monitored for laboratory abnormalities (especially decreased hemoglobin) and adverse reactions, and should undergo careful monitoring of creatinine clearance. Patients with clinically significant laboratory abnormalities or adverse reactions which are persistently severe or worsening should have therapy withdrawn . Pegasys (Peginterferon alfa-2a) Overdosage There is limited experience with overdosage. The maximum dose received by any patient was 7 times the intended dose of Pegasys (Peginterferon alfa-2a) (180 mcg/day for 7 days). There were no serious reactions attributed to overdosages. Weekly doses of up to 630 mcg have been administered to patients with cancer. Dose-limiting toxicities were fatigue, elevated liver enzymes, neutropenia, and thrombocytopenia. There is no specific antidote for Pegasys (Peginterferon alfa-2a) . Hemodialysis and peritoneal dialysis are not effective. Pegasys (Peginterferon alfa-2a) Description Pegasys (Peginterferon alfa-2a) , peginterferon alfa-2a, is a covalent conjugate of recombinant alfa-2a interferon (approximate molecular weight [MW] 20,000 daltons) with a single branched bis-monomethoxy polyethylene glycol (PEG) chain (approximate MW 40,000 daltons). The PEG moiety is linked at a single site to the interferon alfa moiety via a stable amide bond to lysine. Peginterferon alfa-2a has an approximate molecular weight of 60,000 daltons. Interferon alfa-2a is produced using recombinant DNA technology in which a cloned human leukocyte interferon gene is inserted into and expressed in . Pegasys (Peginterferon alfa-2a) is a sterile, preservative-free, colorless to light yellow injectable solution administered subcutaneously. Each vial of 180 mcg/mL peginterferon alfa-2a (expressed as the amount of interferon alfa-2a) also contains acetic acid (0.05 mg), benzyl alcohol (10 mg), polysorbate 80 (0.05 mg), sodium acetate trihydrate (2.62 mg), and sodium chloride (8 mg) at pH 6 ± 0.5. Each prefilled syringe of 180 mcg/0.5 mL peginterferon alfa-2a (expressed as the amount of interferon alfa-2a) also contains acetic acid (0.0231 mg), benzyl alcohol (5 mg), polysorbate 80 (0.025 mg), sodium acetate trihydrate (1.3085 mg), and sodium chloride (4 mg) at pH 6 ± 0.5. Each Autoinjector containing 180 mcg/0.5 mL peginteferon alfa-2a (expressed as the amount of interferon alfa-2a), also contains acetic acid (0.0231 mg), benzyl alcohol (5 mg), polysorbate 80 (0.025 mg), sodium acetate trihydrate (1.3085 mg), and sodium chloride (4 mg) at pH 6 ± 0.5. Each Autoinjector containing 135 mcg/0.5 mL peginteferon alfa-2a (expressed as the amount of interferon alfa-2a), also contains acetic acid (0.0231 mg), benzyl alcohol (5 mg), polysorbate 80 (0.025 mg), sodium acetate trihydrate (1.3085 mg), and sodium chloride (4 mg) at pH 6 ± 0.5. Because the autoinjectors are designed to deliver the full content, autoinjectors should only be used for patients who need the full dose (180 or 135 mcg). If the required dose is not available in an autoinjector, prefilled syringes, or vials should be used to administer the required dose. The autoinjector is for subcutaneous administration only. Pegasys (Peginterferon alfa-2a) Clinical Pharmacology Maximal serum concentrations (C) and AUC increased in a nonlinear dose related manner following administration of 90 to 270 mcg of Pegasys (Peginterferon alfa-2a) . Maximal serum concentrations (C) occur between 72 to 96 hours post-dose. Week 48 mean trough concentrations (16 ng/mL; range 4 to 28) at 168 hours post-dose are approximately 2-fold higher than week 1 mean trough concentrations (9 ng/mL; range 0 to 15). Steady-state serum levels are reached within 5 to 8 weeks of once weekly dosing. The peak to trough ratio at week 48 is approximately 2. The mean systemic clearance in healthy subjects given Pegasys (Peginterferon alfa-2a) was 94 mL/h, which is approximately 100-fold lower than that for interferon alfa-2a (ROFERON-A). The mean terminal half-life after subcutaneous dosing in subjects with chronic hepatitis C was 160 hours (range 84 to 353 hours) compared to 5 hours (range 3.7 to 8.5 hours) for ROFERON-A. Pegasys (Peginterferon alfa-2a) Clinical Studies The safety and effectiveness of Pegasys (Peginterferon alfa-2a) for the treatment of hepatitis C virus infection were assessed in three randomized, open-label, active-controlled clinical studies. All subjects were adults, had compensated liver disease, detectable hepatitis C virus (HCV), liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. All subjects received therapy by subcutaneous injection for 48 weeks, and were followed for an additional 24 weeks to assess the durability of response. In studies 1 and 2, approximately 20% of subjects had cirrhosis or bridging fibrosis. Study 3 enrolled subjects with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%). In Study 1 (n=630), subjects received either ROFERON-A (interferon alfa-2a) 3 MIU three times a week, Pegasys (Peginterferon alfa-2a) 135 mcg once weekly or Pegasys (Peginterferon alfa-2a) 180 mcg once weekly. In Study 2 (n=526), subjects received either ROFERON-A 6 MIU three times a week for 12 weeks followed by 3 MIU three times a week for 36 weeks or Pegasys (Peginterferon alfa-2a) 180 mcg once weekly. In Study 3 (n=269), subjects received ROFERON-A 3 MIU three times a week, Pegasys (Peginterferon alfa-2a) 90 mcg once weekly or Pegasys (Peginterferon alfa-2a) 180 mcg once each week. In all three studies, treatment with Pegasys (Peginterferon alfa-2a) 180 mcg resulted in significantly more subjects who experienced a sustained response (defined as undetectable HCV RNA [less than 50 IU/mL] using the COBAS AMPLICORHCV Test, version 2 and normalization of ALT on or after study week 68) compared to treatment with ROFERON-A. In Study 1, response to Pegasys (Peginterferon alfa-2a) 135 mcg was not different from response to 180 mcg. In Study 3, response to Pegasys (Peginterferon alfa-2a) 90 mcg was intermediate between Pegasys (Peginterferon alfa-2a) 180 mcg and ROFERON-A. Matched pre- and post-treatment liver biopsies were obtained in approximately 70% of subjects. Similar modest reductions in inflammation compared to baseline were observed in all treatment groups. Of the subjects who did not demonstrate either undetectable HCV RNA or at least a 2 log drop in HCV RNA titer from baseline by 12 weeks of Pegasys (Peginterferon alfa-2a) 180 mcg therapy, 2% (3/156) achieved a sustained virologic response . Averaged over Study 1, Study 2, and Study 3, response rates to Pegasys (Peginterferon alfa-2a) were 23% among subjects with viral genotype 1 and 48% among subjects with other viral genotypes. The treatment response rates were similar in men and women. In Study 7, subjects with CHC/HIV were randomized to receive either Pegasys (Peginterferon alfa-2a) 180 mcg subcutaneous once weekly plus an oral placebo, Pegasys (Peginterferon alfa-2a) 180 mcg once weekly plus COPEGUS 800 mg by mouth daily or ROFERON-A (interferon alfa-2a), 3 MIU subcutaneous three times a week plus COPEGUS 800 mg by mouth daily. All subjects received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded in the Pegasys (Peginterferon alfa-2a) treatment arms. All subjects were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Subjects also had CD4+ cell count greater than or equal to 200 cells/mmor CD4+ cell count greater than or equal to 100 cells/mm but less than 200 cells/mmand HIV-1 RNA less than 5,000 cells/mm, and stable status of HIV. Approximately 15% of subjects in the study had cirrhosis. Results are shown in Treatment response rates are lower in CHC/HIV subjects with poor prognostic factors (including HCV genotype 1, HCV RNA greater than 800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy. Geographic region is not a prognostic factor for response. However, poor prognostic factors occur more frequently in the US population than in the non-US population. Of the subjects who did not demonstrate either undetectable HCV RNA or at least a 2 log reduction from baseline in HCV RNA titer by 12 weeks of Pegasys (Peginterferon alfa-2a) and COPEGUS combination therapy, 2% (2/85) achieved an SVR. In CHC subjects with HIV coinfection who received 48 weeks of Pegasys (Peginterferon alfa-2a) alone or in combination with COPEGUS treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post-treatment. The safety and effectiveness of Pegasys (Peginterferon alfa-2a) for the treatment of chronic hepatitis B were assessed in controlled clinical trials in HBeAg positive (Study 8) and HBeAg negative (Study 9) subjects with chronic hepatitis B. Subjects were randomized to Pegasys (Peginterferon alfa-2a) 180 mcg subcutaneous once weekly, Pegasys (Peginterferon alfa-2a) 180 mcg subcutaneous once weekly combined with lamivudine 100 mg once daily by mouth or lamivudine 100 mg once daily by mouth. All subjects received 48 weeks of their assigned therapy followed by 24 weeks of treatment-free follow-up. Assignment to receipt of Pegasys (Peginterferon alfa-2a) or no Pegasys (Peginterferon alfa-2a) was not masked. All subjects were adults with compensated liver disease, had chronic hepatitis B virus (HBV) infection, and evidence of HBV replication (serum HBV greater than 500,000 copies/mL for Study 8 and greater than 100,000 copies/mL for Study 8) as measured by PCR (COBAS AMPLICOR HBV Assay). All subjects had serum alanine aminotransferase (ALT) between 1 and 10 times the upper limit of normal (ULN) and liver biopsy findings compatible with the diagnosis of chronic hepatitis. The results observed in the Pegasys (Peginterferon alfa-2a) and lamivudine monotherapy groups are shown in . Pegasys (Peginterferon alfa-2a) co-administered with lamivudine did not result in any additional sustained response when compared to Pegasys (Peginterferon alfa-2a) monotherapy. Conclusions regarding comparative efficacy of Pegasys (Peginterferon alfa-2a) and lamivudine treatment based upon the end of follow-up results are limited by the different mechanisms of action of the two compounds. Most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn. Pegasys (Peginterferon alfa-2a) How Supplied/storage And Handling Storage and Handling Store in the refrigerator at 2°C to 8°C (36°F to 46°F). Do not leave Pegasys (Peginterferon alfa-2a) out of the refrigerator for more than 24 hours. Do not freeze or shake. Protect from light. Vials, prefilled syringes and autoinjectors are for single use only. Discard any unused portion remaining in the vial, prefilled syringe. Disposal Instructions If home use is prescribed, a puncture-resistant container for the disposal of used needles, syringes and autoinjectors should be supplied to the patients. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of any needles, syringes and autoinjectors. The full container should be disposed of according to the directions provided by the physician . Pegasys (Peginterferon alfa-2a) Patient Counseling Information Dosing Instructions Patients should be advised to take their prescribed dose of Pegasys (Peginterferon alfa-2a) on the same day and approximately same time each week. Patients should also be advised that if they miss a dose, but remember within 2 days, to take their missed dose as soon as they remember and then to take their next dose on the day they normally do. If they remember when more than 2 days have passed, patients should be advised to consult their healthcare provider. Patients should also be advised to consult their healthcare provider if the full dose is not received (e.g., leakage around the injection site). Patients must be instructed on the use of aseptic techniques when administering Pegasys (Peginterferon alfa-2a) . Appropriate training for preparation using the vial, prefilled syringe or autoinjector must be given by a healthcare provider, including a careful review of the Pegasys (Peginterferon alfa-2a) Medication Guide and Instructions for Use for the vial, prefilled syringe and autoinjector. Patients should be instructed to allow the vial, prefilled syringe or autoinjector to come to room temperature and for condensation on the outside of the prefilled syringe or autoinjector to disappear before use. The following instructions should be given: Patients should be advised not to shake the vial, prefilled syringe or autoinjector as foaming may occur. Patients should be advised to choose a different place on either the thigh or abdomen each time an injection is made. 附件: 201231118595737.PDF     200952604241330.pdf ------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: PEGASYS 180MCG/0.5 ML/SYRINGE 原产地英文药品名: PEGINTERFERON ALFA-2A 中文参考商品译名: 派罗欣 180微克/0.5毫升/注射器 中文参考药品译名: 聚乙二醇干扰素α-2a 生产厂家中文参考译名: 罗氏 生产厂家英文名: HOFFMAN-LA ROCHE