英文药名: Relenza (Zanamivir Dry Powder Diskhaler) 中文药名: 扎那米韦吸入粉雾剂 此药品需要处方 生产品牌药厂家: Glaxo Smith Kline 药品名称 【药物名称】扎那米韦 zanamivir 【药物别名】 Relenza 依乐韦(扎那米韦吸入粉雾剂) 【分子式成分】化学名为：5-乙酰氨基-4-［(氨基亚氨基甲基)-氨基］-2，6-氢-3，4，5-三去氧-D-丙三醇基-D-半乳糖-2-烯醇酸。分子式C12H20N4O7，相对分子质量332.3。本品为白色或灰白色粉末，20℃时水中的溶解度约为18 mg.ml-1。　　 制剂/规格 吸入粉雾剂：5mg, 20 doses 。 药品介绍 依乐韦(扎那米韦吸入粉雾剂)(zanamivir)是一个有效的流感病毒唾液酸抑制剂，通过抑制流感病毒的神经氨酸酶，从而改变了流感病毒在感染细胞内的聚集和释放，临床用于流感的治疗。扎那米韦由葛兰素公司(Glaxo Smith Kline)研制成功，于1999年5月首先在澳大利亚获准上市，同时得到欧盟所有成员国的批准，商品名为“Relenza”。美国FDA于1999年8月批准扎那米韦用于治疗A型和B型流感。 继批准“达菲”进口以后，国家食品药品监管局近日又批准一种抗流感药物“依乐韦”在国内上市。这意味着国际上公认的两种有效抗流感药物均已进入中国内地。　　 世界卫生组织认可的流感治疗药品主要有两种：一是罗氏公司研发的“达菲”，二是葛兰素史克公司研发的“乐感清”。而将在内地上市的“依乐韦”（扎那米韦吸入粉雾剂）就是此前已在香港地区上市的“乐感清”。　　 “依乐韦”是世界卫生组织推荐的能有效治疗甲型和乙型流感的药物。该药直接作用于呼吸道病毒感染部位，不良反应较少，且具有良好的耐受性，7岁以上儿童、老年患者或肾、肝功能不全的患者也无须调整剂量。 药理毒理 美国FDA于1999年8月批准用于治疗A型和B型流感。它是自1993年金刚乙胺获准上市后第一个获得许可的流感治疗药物，将由葛兰素威康公司推向市场。 　　 本品通过抑制流感病毒的神经氨酸酶，从而改变了流感病毒在感染细胞内的聚集和释放。体外试验时发现，当药物浓度不断增加时，仍有流感病毒对扎那米韦的敏感性下降。经分析，这与病毒突变引起神经氨酸酶及血细胞凝集素二者或其一的氨基酸发生改变有关。 药 动 学 口腔吸入本品10 mg后，1～2 h内4%～17%的药物被全身吸收，药物峰浓度范围17～142 ng.ml-1，药时曲线下面积为111～1364 ng.h.ml-1。本品的血浆蛋白结合率低于10%。药物以原形在24 h内由肾排出，尚未检测到其代谢物。血清半衰期为2.5～5.1 h不等。总清除率为2.5～10.9 L.h-1。　　 轻(中)度或重度肾功能不良的患者分别静脉输注扎那米韦4 mg或2 mg后，肾清除率明显下降：正常人总清除率平均为5.3 L.h-1，轻(中)度肾功能不良者为2.7 L.h-1，重度肾功能不良者为0.8 L.h-1。半衰期明显增加：正常人平均为3.1 h，轻(中)度肾功能不良者为4.7 h，重度肾功能不良者为18.5 h。 　　 适 应 症 成年患者和12岁以上的青少年患者，治疗由A型和B型流感病毒引起的流感。 不良反应 本品对哮喘或慢性阻滞性肺疾病患者治疗无效，甚至可能引起危险。文献报告使用本品后，轻度或中度哮喘患者可引起支气管痉挛，引起支气管痉挛的患者应停药并通知其主治医生。患有呼吸道疾病的患者服用扎那米韦时，身边应备有吸入型速效支气管扩张药。　　 服用此药的其它不良反应包括：头痛、腹泄、恶心、呕吐、眩晕等。发生率低于2%，多为轻度反应。　　 动物试验表明：扎那米韦不会致癌、致畸、致突变，未见生殖毒性。扎那米韦在动物试验中能通过胎盘屏障，胎儿血药浓度明显低于母体。目前缺乏充分有效的研究结果证实怀孕妇女体内药物动力学，使用时应权衡对胎儿的影响。哺乳大鼠的乳汁中测得扎那米韦存在。但是，人乳汁中药物是否存在尚不肯定，哺乳妇女使用此药应慎重。该药物对老人及12岁以下儿童的不良反应尚不确定。　　 体外研究未见本品有明显的药物相互作用，本品不影响肝脏微粒体酶，也不是P450酶的底物。 用法用量 本品经口吸入给药。使用前患者应在其主治医生的指导下学习吸入剂正确使用，可能的话应由医师示范使用方法。患者也要仔细阅读并遵守药品包装内的使用说明。　　 本品可用于成年患者和12岁以上的青少年患者，每日两次，间隔约12 h。每次10 mg，分两次吸入，或者一次5 mg，连用5 d。随后数日两次的服药时间应尽可能保持一致，剂量间隔12 h(如早晨或傍晚)。　　 患者即使感到症状好转也应完成5 d疗程，并应被告知服用扎那米韦不能减少流感传染的危险性。　　 服用本品时，使用1种呼吸驱动的塑料吸入装置Dishkhaler。此装置可装入1片Relenza Rotodisk，每片Rotodisk含有4个泡囊，每个泡囊含Relenza(5 mg)和乳糖(20 mg)的混合粉末。使用时，将Relenza Rotodisk放入该吸入装置，当患者通过嘴吸入时，泡囊被刺穿，药物随气流释放出来。　　 本品是否可预防流感尚不清楚。 任何疑问，请遵医嘱！   注意事项 对该药物处方中的任何成分过敏者禁用。 Relenza Relenza™ is GlaxoSmithKline's brand of zanamivir, a first in-class antiviral drug for the treatment and prevention of influenza.  Zanamivir was licensed to GlaxoSmithKline by Biota in 1990 and launched worldwide in 1999. Relenza is delivered directly to the primary site of infection on the lungs, using a Disk Inhaler™ device.  The drug works by destroying an enzyme, neuraminidase, on the surface of the virus, essential for the multiplication and spread of influenza.  Relenza is not a vaccine. Neuraminidase inhibitors Zanamivir was the first of a new generation of drugs known as neuraminidase inhibitors, capable of treating or preventing infection from the influenza virus. Neuraminidase is essential for the replication of all influenza viruses.  It is an enzyme which allows new viruses to be released from the infected lung cells, further extending the infection.  Neuraminidase inhibitors block this activity, preventing the release and spread of new viruses. Development and commercialisation Zanamivir was the result of research and development initiated by Biota in the 1980's and was discovered in 1989 by a joint team of scientists from the Commonwealth Scientific and Industrial Research Organisation (CSIRO) and the Victorian College of Pharmacy, using the technique of three dimensional structure based drug design. Regulatory approval Relenza is approved in over 50 countries for the treatment of influenza, including in the United States, the European Union, Japan and Australia. Relenza is also widely approved for use as a preventative (prophylactic) treatment against influenza. Stockpiling A number of national governments are stockpiling Relenza™,  as part of their pandemic planning strategy. GlaxoSmithKline (GSK) has indicated that its  production capacity is 90 million treatment packs per year. 神经氨酸酶抑制剂类抗流感病毒药扎那米韦 扎那米韦（zanamivir）1991年由澳大利亚Biota 科学管理有限公司的 von Itzstein等合成，1999年获得美国食品与药品管理局和欧洲药品管理局批准，并由Glaxo Wellcome公司推向市场，商品名为Relenza，用于A型和B型流感的预防及治疗。在1999年底的欧洲流感大爆发中，该药被广泛使用并表现出很好的效果。扎那米韦的化学名为4-胍基-2-脱氧-2，3-二脱氢-N-乙酰神经氨酸（图1），分子式为C12H20N4O7，分子量为333.2，为白色至类白色粉末，20℃时在水中的溶解度约为18mg／ml。 扎那米韦是自1993年金刚乙胺上市后第一个获得批准的流感治疗药，也是第一个神经氨酸酶抑制剂类流感病毒治疗药。它的研制成功，被专家们认为是治疗流感方面取得的较大进展。 作用机制 扎那米韦是根据病毒表面蛋白神经氨酸酶的结晶结构，通过计算机辅助设计、筛选得到的对病毒神经氨酸酶有特异性抑制作用的神经氨酸酶抑制剂。病毒神经氨酸酶具有帮助新合成的病毒颗粒与感染细胞脱离，并促使其通过黏液在呼吸道中扩散的作用。神经氨酸酶广泛存在于动物及微生物中，是一种苷水解酶，可将以苷键连接在糖蛋白和糖脂末端的唾液酸水解掉。许多含有神经氨酸酶的微生物都是致病的，这种酶在微生物的感染和传播中起重要作用。扎那米韦的4-位肥基与病毒神经氨酸酶活性部位的氨基酸残基有2个结合点，其胍基的2个氮末端分别与酶活性部位的Glu119和Glu227相结合，使得扎那米韦对流感病毒神经氨酸酶具有更强的亲和力和高选择性。扎那米韦对人类唾液酸酶的抑制作用（IC50为1mmol／L）不到对流感病毒的（IC50为0.07～0.7nmol／L）百万分之一。 药物动力学 口腔吸入扎那米韦后，吸入剂量的4％～17％被机体吸收。口腔吸入10mg后 1-2h达到血药峰浓度（17～142μg／L），血药半衰期为2.5～5.1h，药时曲线下面积为111～136μg·h／L。扎那米韦的血浆蛋白结合率低于10％，在人体内不代谢，全部以原药形式经肾排出。单次给药时，24h内完全排出，总清除率为2.5～10.9L/h。末吸收的药物随粪便排出。 肾功能障碍者的药物动力学研究采用静脉注射给药，对具有中度或重度肾功能障碍的志愿者，分别单次注射4或2mg，肾清除率明显降低（总清除率的平均值：健康者为5.3L／h，中度障碍者为2.7L/h，重度障碍者为0.8L/h），血药半衰期明显延长（半衰期的平均值：健康者为3.1h，中度障碍者为4.7h，重度障碍者为 18.5h）。 种群药物动力学分析表明，性别、年龄、种族及体重的变化对扎那米韦的血药浓度和其它药物动力学参数没有显著影响，感染指标不同时扎那米韦的药物动力学也无显著变化。 体外研究结果显示，扎那米韦与其他药物之间没有明显药物动力学的相互影响。扎那米韦既不是人类肝细胞色素P450（CYP）及其异构酶（CYP1A1／2、2A6、2C9、2C18，2D6，2E1和3A4等）的底物，也不影响上述各酶的功能。 有关12岁以下的儿童患者及65岁以上的老年患者的药物动力学尚缺少研究。 药效学 扎那米韦特异地抑制A、B型流感病毒的神经氨酸酶，阻止子代病毒从感染细胞表面释放，阻止病毒经呼吸道扩散，从而达到抑制流感病毒的作用。 　　 细胞培养法测定扎那米韦对病毒实验株和临床分离株的抑制活性，其抑制病毒的浓度与测试方法、实验病毒来源关系很大，半数抑制浓度（IC50）和90％抑制浓度（IC90）的范围分别是0.005～16.0μmol／L和0.05～100μmol／L。体外研究扎那米韦在MDCK细胞和人呼吸道上皮细胞中抑制A型流感病毒实验株的IC50为4～14nmol/L，显著强于金刚烷胺（1.1～7.3μmol/L）、金刚乙胺（＜0.27～0.62μmol／L）和利巴韦林（10.4-54μmol／L）。对B型流感病毒Victoria／102／85的IC50为5nmol／L。对临床分离病毒株的抑制作用如表1所示，受试病毒株不同，IC50变化范围较大，金刚烷胺和金刚乙胺对B型流感病毒无作用（活性），同样，和巴韦林的活性也不加扎那米韦。 扎那米韦与GS4071抑制流感病毒作用比较见表 2。对不同的病毒株，扎那米韦的IC50与GS4071相当或更低。GS4071是继扎那米韦后第二个获得美国食品与药品管理局批准并上市的神经氨酸酶抑制剂类流感治疗药物。两药对野生型和突变型病毒神经氨酸酶的敏感性实验结果显示，对凝集素蛋白突变株，扎那米韦和GS4071的活性没有明显变化；而对神经氨酸酶活性区突变株，扎那米韦的IC50较对野生型病毒升高约1000倍，GS4071的IC50较对野生型病毒升高3万倍以上，说明扎那米韦对突变的神经氨酸酶仍具有较强的抑制作用，而GS4071则只对野生型病毒神经氨酸酶有活性。从作用机制上说明了扎那米韦不易出现耐药性问题。 体内试验表明，感染A型流感病毒（A／Singa－ Pore／1／57）的小鼠，于感染前18、3h和感染后3h分别滴鼻，及第1～3d每天2次滴鼻扎那米韦0.4或0.01 mg/kg，共观察10d，结果如表3所示。对照组的平均死亡时间为4.4d 于第6天全部死亡。其中对照组每天剔出4只小鼠做肺匀浆中病毒滴度及肺实变测定，治疗组每天剧出4只小鼠做肺匀浆中病毒滴度测定。结果，0.4mg／kg治疗组能明显降低感染的致命性，10d的观察期内无一只死亡；肺匀浆中病毒滴度也明显降低（P＜0.001）。0.01mg/kg治疗组共有2只死亡（第5，第8天）（5.4％，P＜0.001）。2个剂量组在降低感染的致命性上无显著差别（P＜0.05）。感染B型流感病毒的小鼠，每次滴鼻扎那米韦≥0.4mg／kg，可降低肺匀浆中病毒滴度。雪貂试验表明，感染前或感染后24h内滴鼻给药，扎那米韦在降低鼻内A、B型流感病毒液度及发热程度方面是利巴韦林和金刚烷胺的100～1000倍。 临床疗效 临床研究表明，流感患者服用扎那米韦短期内能有效改善流感症状，患者症状初起2d内用药疗效更好。体温正常或者症状不明显的患者疗效不明显。 　　 在一项随机、双盲、安慰剂对照的Ⅱ期临床人工感染模型实验中，志愿者在H1N1滴鼻接种1d后，开始使用扎那米韦3.6～16mg滴鼻，共4d，与使用安慰剂的对照组相比，病毒的复制明显降低（表4）。从表中还可以看出，每日给药2次与每日给药6次的效果相当。治疗组的病毒转阴时间比对照组缩短3d，病毒滴度 AUC降低87％，滴度峰值降低99％（平均降低2个数量级）（P＜0.001）。也就是说，使用扎那米韦能迅速降低病毒滴度及峰值。 另外，在使用扎那米韦的患者中，发热频率降低 84％（P＜0.01），综合症状评分——鼻粘液重量、咳嗽和乙酰氨基酚使用的频率均降低40％～65％。接种病毒后第2天，志愿者开始发病时给药，病毒滴度很快下降。 在455名12岁以上受试者参加的Ⅲ期临床研究中，采用随机、双盲、和安慰剂对照方案，患者在感冒症状发作后36h内开始口腔吸入扎那米韦，每次10mg，每天2次，连续5d。扎那米韦组的主要流感症状缓解所需时间比安慰剂组缩短2.5d（从6.8～8d减少至4.5-5.5d），痊愈时间缩短1～5d，而不良反应发生率并不增加。另外，在整个治疗过程中，扎那米韦组更少出现严重流感症状，并发症的发生率减少70％，抗菌药的使用率也下降60％（表5）。   扎那米韦还具有明确的预防流感作用。根据Ⅱ 期临床研究结果，扎那米韦对人工感染的预防有效率为82％，发热症状的预防效果为95％（对安慰剂组P ＜0.01）。在另一项研究其预防作用的实验中，1107名健康成人（86％未接种抗流感疫苗）在流感爆发期间口腔吸收10mg扎那米韦或安慰剂，每日1次，连续生周。结果发现，在接种疫苗的受试者中吸入扎那米韦者的流感感染率为2％，而安慰剂组为6％。在对337个家庭进行流感预防作用的实验中，每个家庭成员为2 ～5人，其中至少已有一人证实患有流感。患有流感的受试者吸入10mg扎那米韦，每日2次，连续5d；其他成员吸入预防剂量的扎那米韦10mg，每日1次，连续 10d。结果，在吸人安慰剂的家庭中，10％的家庭一位或者一位以上的成员发展成为流感，与之相比，使用扎那米韦的169个家庭中仅有4％的家庭有成员发展成为流感，保护功效为79％。在感染初期即开始使用扎那米韦，保护效果增加到84％。 在与金刚烷胺盐酸盐、金刚乙胺盐酸盐的预防效果对照研究中，用药后1～3d接种流感病毒，金刚烷胺盐酸盐和金刚乙胺盐酸盐防止感染的效果是7％～ 55％（平均30％），预防发热的效果为61％～100％（平均82％），而扎那米韦的预防效果分别是82％和 95％，明显高于前两者。   用法和剂量 　　 扎那米韦口服吸收差、肾清除速度快、组织渗透性低，不宜全身给药，甚至在高血药浓度下，其渗入到呼吸道的量也很少。因此，只能局部给药，鼻腔滴液或口腔吸入。局部给药给临床使用增添不便，但减少了用量和降低了全身毒性。 扎那米韦采用口腔吸入，药粉被直接吸入到病毒的复制部位（呼吸道内）而发挥作用。市售Relenza 使用一种呼吸驱动塑料吸入装置Diskhaler。将含有 4 个泡囊的Relenza药片装人装置内，当患者用嘴吸入时，泡囊被刺穿，药物随气流释放出来。每次吸入只有一个泡囊刺破，适当操作后便可进行下次吸入。每个池囊含有Relenza 5mg和乳糖20mg的混合粉末。每日用药2次，每次5mg，连用5d。2次用药时间应尽可能保持一致，间隔12h（如早晨或傍晚）。既使感到症状好转也应完成5d的疗程。 不良反应 　　 扎那米声不需要进入细胞内即可在细胞外抑制病毒神经氨酸酶，病毒复制部位（呼吸道）局部给药有如下优点： （1）在不需要高血药浓度的情况下即可实现靶部位（呼吸道）中的高药物浓度，因此，全身毒性低； （2）细胞膜通透性弱，使其局部用药后进入体内的药物很少，而且，水溶性强，使吸收之少量药物很快经肾脏排出体外，半衰期很短。有关扎那米韦的毒性研究表明，扎那米韦无致癌、致畸、致突变性和未见生殖毒性。大鼠和小鼠分别口腔吸入扎那米韦，最多时每天分别吸入20～22次和23～25次，2年后的结果显示，与对照组相比，没有统计学意义的肿瘤形成增加。在致突变研究中，对体外鼠伤寒沙门氏菌和大肠埃希氏菌、鼠淋巴瘤、人类未消表皮血液淋巴染色体异常及体内小鼠骨髓微核的研究都表明扎那米韦没有致突变作用。 　　 生殖毒性研究中，雄鼠交配前10周开始静脉注射扎那米韦，并一直持续到交配期间、妊娠、哺乳甚至断奶后的一段时间；雌鼠于交配前3周开始静脉注射扎那米韦，妊娠期的19d、及分娩后21d中不间断，注射剂量为1、9和90mg／（kg·d）。结果显示，扎那米韦对雌性大鼠的交配及生殖无不良损伤，也不影响雄鼠的精液质量。扎那米韦对F1代生产的雌性大鼠的生殖性能没有影响。应该指出的是，大鼠静脉注射90mg／（kg·d）扎那米韦的亚急性毒性研究中，AUC为 0.142～0.199g·h／L，是人临床使用剂量的300倍以上。 　　 大鼠妊娠后第6天开始至第15天；兔从妊娠后第7天开始至第19天，分别静脉注射1、9和90mg／（kg·d）扎那米韦，没有致畸形、母体毒性、胚胎毒性发生。而且，在另外一项关于扎那米韦对出生前后大鼠发育情况的研究结果也没有发现任何不良作用。实验已经证明扎那米韦能透过大鼠和免的胎盘，但胎儿血中药物浓度明显低于母体。目前尚缺乏充分有效的研究结果证实扎那米韦对怀孕妇女的影响。哺乳大鼠的乳汁中测得了扎那米韦的存在，但人乳汁中药物是否存在尚不肯定，哺乳期妇女使用此药时应慎重。 扎那米韦对哮喘或慢性阻滞性肺病患者治疗无效，甚至可能引起危险。扎那米韦的主要不良反应包括头痛、恶心、呕吐、眩晕等，不良反应发生率为1.5％。临床安全性研究中，病人口腔吸入Relenza 10mg，每天2次；对照组吸入Relenza的辅剂乳糖10mg，每天2次，不良反应发生情况如表6所示。安慰剂组不良反应发生率与Relenza组几乎相当，所以，可以认为Relenza的一些不良反应是由辅剂引起的。扎那米韦对老人及12岁以下儿童的不良反应尚不确定。 综上所述，扎那米韦是一种高效、广谱、低毒的抗流感病毒药。扎那米韦分子极性强、水溶性大、组织渗透能力差，使得口服甚至静脉注射给药后到达靶部位呼吸道的药物都很少，即通过全身给药难以实现良好的治疗效果。口腔吸入或滴鼻给药法，将扎那米韦直接输送到病毒的复制部位，使得局部药物浓度很高，从而快速有效地抑制病毒的复制和扩散。口腔吸入或滴鼻法用药，给药物的使用带来一定的不便；但也因此大大降低了剂量和全身毒性，并赋予扎那米韦低成本，低毒性和高疗效的特性。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use relenza safely and effectively. See full prescribing information for relenza. relenza (zanamivir)  powder for respiratory (inhalation) use Initial U.S. Approval: 1999 INDICATIONS AND USAGE RELENZA, an influenza neuraminidase inhibitor, is indicated for: Treatment of influenza in patients 7 years of age and older who have been symptomatic for no more than 2 days. (1.1) Prophylaxis of influenza in patients 5 years of age and older. (1.2) Important Limitations on Use of RELENZA: Not recommended for treatment or prophylaxis of influenza in: Individuals with underlying airways disease. (5.1) Not proven effective for: Treatment in individuals with underlying airways disease. (1.3) Prophylaxis in nursing home residents. (1.3) Not a substitute for annual influenza vaccination. (1.3) DOSAGE AND ADMINISTRATION  Indication  Dose   Treatment of Influenza (2.2)  10 mg twice daily for 5 days   Prophylaxis: (2.3)   Household Setting  10 mg once daily for 10 days   Community Outbreaks  10 mg once daily for 28 days   Note: The 10 mg dose is provided by 2 inhalations (one 5 mg blister per inhalation). (2.1) DOSAGE FORMS AND STRENGTHS Four 5 mg blisters of powder on a ROTADISK for oral inhalation via DISKHALER. Packaged in carton containing 5 ROTADISKs (total of 10 doses) and 1 DISKHALER inhalation device. (3) CONTRAINDICATIONS Do not use in patients with history of allergic reaction to any ingredient of RELENZA, including lactose (which contains milk proteins). (4) WARNINGS AND PRECAUTIONS Bronchospasm: Serious, sometimes fatal, cases have occurred. Not recommended in individuals with underlying airways disease. Discontinue RELENZA if bronchospasm or decline in respiratory function develops. (5.1) Allergic Reactions: Discontinue RELENZA and initiate appropriate treatment if an allergic reaction occurs or is suspected. (5.2) High-risk underlying medical conditions: Safety and effectiveness have not been demonstrated in these patients. (5.3) ADVERSE REACTIONS The most common adverse events reported in >1.5% of patients treated with RELENZA and more commonly than in patients treated with placebo are: Treatment Studies – sinusitis, dizziness. Prophylaxis studies – fever and/or chills, arthralgia and articular rheumatism. (6.1) DRUG INTERACTIONS Live attenuated influenza vaccine, intranasal (7): Do not administer until 48 hours following cessation of RELENZA. Do not administer RELENZA until 2 weeks following administration of the live attenuated influenza vaccine, unless medically indicated. Revised: September 2007 RLZ:1PI See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling  Revised: 10/2007  1 INDICATIONS AND USAGE 1.1 Treatment of Influenza RELENZA is indicated for treatment of uncomplicated acute illness due to influenza A and B virus in adults and pediatric patients 7 years of age and older who have been symptomatic for no more than 2 days. 1.2 Prophylaxis of Influenza RELENZA is indicated for prophylaxis of influenza in adults and pediatric patients 5 years of age and older. 1.3 Important Limitations on Use of RELENZA RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease) due to risk of serious bronchospasm [see Warnings and Precautions (5.1)]. RELENZA has not been proven effective for treatment of influenza in individuals with underlying airways disease. RELENZA has not been proven effective for prophylaxis of influenza in the nursing home setting. RELENZA is not a substitute for early influenza vaccination on an annual basis as recommended by the Centers for Disease Control's Immunization Practices Advisory Committee. There is no evidence for efficacy of zanamivir in any illness caused by agents other than influenza virus A and B. Patients should be advised that the use of RELENZA for treatment of influenza has not been shown to reduce the risk of transmission of influenza to others. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Considerations RELENZA is for administration to the respiratory tract by oral inhalation only, using the DISKHALER device provided. The 10 mg dose is provided by 2 inhalations (one 5 mg blister per inhalation). Patients should be instructed in the use of the delivery system. Instructions should include a demonstration whenever possible. If RELENZA is prescribed for children, it should be used only under adult supervision and instruction, and the supervising adult should first be instructed by a healthcare professional [see Patient Counseling Information (17.3)]. Patients scheduled to use an inhaled bronchodilator at the same time as RELENZA should use their bronchodilator before taking RELENZA [see Patient Counseling Information (17.2)]. 2.2 Treatment of Influenza The recommended dose of RELENZA for treatment of influenza in adults and pediatric patients ages 7 years of age and older is 10 mg twice daily (approximately 12 hours apart) for 5 days. Two doses should be taken on the first day of treatment whenever possible provided there is at least 2 hours between doses. On subsequent days, doses should be about 12 hours apart (e.g., morning and evening) at approximately the same time each day. The safety and efficacy of repeated treatment courses have not been studied. 2.3 Prophylaxis of Influenza Household Setting The recommended dose of RELENZA for prophylaxis of influenza in adults and pediatric patients 5 years of age and older in a household setting is 10 mg once daily for 10 days. The dose should be administered at approximately the same time each day. There are no data on the effectiveness of prophylaxis with RELENZA in a household setting when initiated more than 1.5 days after the onset of signs or symptoms in the index case. Community Outbreaks The recommended dose of RELENZA for prophylaxis of influenza in adults and adolescents in a community setting is 10 mg once daily for 28 days. The dose should be administered at approximately the same time each day. There are no data on the effectiveness of prophylaxis with RELENZA in a community outbreak when initiated more than 5 days after the outbreak was identified in the community. The safety and effectiveness of prophylaxis with RELENZA have not been evaluated for longer than 28 days’ duration. 3 DOSAGE FORMS AND STRENGTHS Four 5 mg blisters of powder on a ROTADISK® for oral inhalation via DISKHALER. Packaged in carton containing 5 ROTADISKs (total of 10 doses) and 1 DISKHALER inhalation device [see How Supplied/Storage and Handling (16)]. 4 CONTRAINDICATIONS Do not use in patients with history of allergic reaction to any ingredient of RELENZA including lactose (which contains milk proteins) [see Warnings and Precautions (5.2), Description (11)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bronchospasm RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease). Serious cases of bronchospasm, including fatalities, have been reported during treatment with RELENZA in patients with and without underlying airways disease. Many of these cases were reported during postmarketing and causality was difficult to assess. RELENZA should be discontinued in any patient who develops bronchospasm or decline in respiratory function; immediate treatment and hospitalization may be required. Some patients without prior pulmonary disease may also have respiratory abnormalities from acute respiratory infection that could resemble adverse drug reactions or increase patient vulnerability to adverse drug reactions. Bronchospasm was documented following administration of zanamivir in 1 of 13 patients with mild or moderate asthma (but without acute influenza-like illness) in a Phase 1 study. In a Phase III study in patients with acute influenza-like illness superimposed on underlying asthma or chronic obstructive pulmonary disease, 10% (24 of 244) of patients on zanamivir and 9% (22 of 237) on placebo experienced a greater than 20% decline in FEV1 following treatment for 5 days. If use of RELENZA is considered for a patient with underlying airways disease, the potential risks and benefits should be carefully weighed. If a decision is made to prescribe RELENZA for such a patient, this should be done only under conditions of careful monitoring of respiratory function, close observation, and appropriate supportive care including availability of fast-acting bronchodilators. 5.2 Allergic Reactions Allergic-like reactions, including oropharyngeal edema, serious skin rashes, and anaphylaxis have been reported in post-marketing experience with RELENZA. RELENZA should be stopped and appropriate treatment instituted if an allergic reaction occurs or is suspected. 5.3 Limitations of Populations Studied Safety and efficacy have not been demonstrated in patients with high-risk underlying medical conditions. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring inpatient management. 5.4 Bacterial Infections Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. RELENZA has not been shown to prevent such complications. 5.5 Importance of Proper Use of DISKHALER Effective and safe use of RELENZA requires proper use of the DISKHALER to inhale the drug. Prescribers should carefully evaluate the ability of young children to use the delivery system if use of RELENZA is considered [see Use in Specific Populations (8.4)]. 6 ADVERSE REACTIONS See Warnings and Precautions for information about risk of serious adverse events such as bronchospasm (5.1) and allergic-like reactions (5.2), and for safety information in patients with underlying airways disease (5.1). 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The placebo used in clinical studies consisted of inhaled lactose powder, which is also the vehicle for the active drug; therefore, some adverse events occurring at similar frequencies in different treatment groups could be related to lactose vehicle inhalation. Treatment of Influenza Clinical Trials in Adults and Adolescents Adverse events that occurred with an incidence ≥1.5% in treatment studies are listed in Table 1. This table shows adverse events occurring in patients≥12 years of age receiving RELENZA 10 mg inhaled twice daily, RELENZA in all inhalation regimens, and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA). Table 1. Summary of Adverse Events ≥1.5% Incidence During Treatment in Adults and Adolescents RELENZA Adverse Event 10 mg b.i.d. Inhaled (n = 1,132) All Dosing Regimens* (n = 2,289) Placebo (Lactose Vehicle) (n = 1,520) Body as a whole Headaches 2% 2% 3% Digestive Diarrhea 3% 3% 4% Nausea 3% 3% 3% Vomiting 1% 1% 2% Respiratory Nasal signs and symptoms 2% 3% 3% Bronchitis 2% 2% 3% Cough 2% 2% 3% Sinusitis 3% 2% 2% Ear, nose, and throat infections 2% 1% 2% Nervous system Dizziness 2% 1% <1% * Includes studies where RELENZA was administered intranasally (6.4 mg 2 to 4 times per day in addition to inhaled preparation) and/or inhaled more frequently (q.i.d.) than the currently recommended dose. Additional adverse reactions occurring in less than 1.5% of patients receiving RELENZA included malaise, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria. The most frequent laboratory abnormalities in Phase III treatment studies included elevations of liver enzymes and CPK, lymphopenia, and neutropenia. These were reported in similar proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness. Clinical Trials in Pediatric Patients Adverse events that occurred with an incidence ≥1.5% in children receiving treatment doses of RELENZA in 2 Phase III studies are listed in Table 2. This table shows adverse events occurring in pediatric patients 5 to 12 years old receiving RELENZA 10 mg inhaled twice daily and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA). Table 2. Summary of Adverse Events ≥1.5% Incidence During Treatment in Pediatric Patients* Adverse Event RELENZA 10 mg b.i.d. Inhaled (n = 291) Placebo (Lactose Vehicle) (n = 318) Respiratory Ear, nose, and throat infections 5% 5% Ear, nose, and throat hemorrhage <1% 2% Asthma <1% 2% Cough <1% 2% Digestive Vomiting 2% 3% Diarrhea 2% 2% Nausea <1% 2% * Includes a subset of patients receiving RELENZA for treatment of influenza in a prophylaxis study. In 1 of the 2 studies described in Table 2, some additional information is available from children (5 to 12 years old) without acute influenza-like illness who received an investigational prophylaxis regimen of RELENZA; 132 children received RELENZA and 145 children received placebo. Among these children, nasal signs and symptoms (zanamivir 20%, placebo 9%), cough (zanamivir 16%, placebo 8%), and throat/tonsil discomfort and pain (zanamivir 11%, placebo 6%) were reported more frequently with RELENZA than placebo. In a subset with chronic pulmonary disease, lower respiratory adverse events (described as asthma, cough, or viral respiratory infections which could include influenza-like symptoms) were reported in 7 of 7 zanamivir recipients and 5 of 12 placebo recipients. Prophylaxis of Influenza Family/Household Prophylaxis Studies Adverse events that occurred with an incidence of ≥1.5% in the 2 prophylaxis studies are listed in Table 3. This table shows adverse events occurring in patients≥5 years of age receiving RELENZA 10 mg inhaled once daily for 10 days. Table 3. Summary of Adverse Events ≥1.5% Incidence During 10-Day Prophylaxis Studies in Adults, Adolescents, and Children* Adverse Event Contact Cases RELENZA (n = 1,068) Placebo (n = 1,059) Lower respiratory Viral respiratory infections 13% 19% Cough 7% 9% Neurologic Headaches 13% 14% Ear, nose, and throat Nasal signs and symptoms 12% 12% Throat and tonsil discomfort and pain 8% 9% Nasal inflammation 1% 2% Musculoskeletal Muscle pain 3% 3% Endocrine and metabolic Feeding problems (decreased or increased appetite and anorexia) 2% 2% Gastrointestinal Nausea and vomiting 1% 2% Non-site specific Malaise and fatigue 5% 5% Temperature regulation disturbances (fever and/or chills) 5% 4% * In prophylaxis studies symptoms associated with influenza-like illness were captured as adverse events; subjects were enrolled during a winter respiratory season during which time any symptoms that occurred were captured as adverse events. Community Prophylaxis Studies Adverse events that occurred with an incidence of ≥1.5% in 2 prophylaxis studies are listed in Table 4. This table shows adverse events occurring in patients≥5 years of age receiving RELENZA 10 mg inhaled once daily for 28 days. Table 4. Summary of Adverse Events ≥1.5% Incidence During 28-Day Prophylaxis Studies in Adults, Adolescents, and Children* Adverse Event RELENZA (n = 2,231) Placebo (n = 2,239) Neurologic Headaches 24% 26% Ear, nose, and throat Throat and tonsil discomfort and pain 19% 20% Nasal signs and symptoms 12% 13% Ear, nose, and throat infections 2% 2% Lower respiratory Cough 17% 18% Viral respiratory infections 3% 4% Musculoskeletal Muscle pain 8% 8% Musculoskeletal pain 6% 6% Arthralgia and articular rheumatism 2% <1% Endocrine and metabolic Feeding problems (decreased or increased appetite and anorexia) 4% 4% Gastrointestinal Nausea and vomiting 2% 3% Diarrhea 2% 2% Non-site specific Temperature regulation disturbances (fever and/or chills) 9% 10% Malaise& fatigue 8% 8% * In prophylaxis studies symptoms associated with influenza-like illness were captured as adverse events; subjects were enrolled during a winter respiratory season during which time any symptoms that occurred were captured as adverse events. 6.2 Postmarketing Experience In addition to adverse events reported from clinical trials, the following events have been identified during post-marketing use of zanamivir (RELENZA). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to zanamivir (RELENZA). Allergic Reactions Allergic or allergic-like reaction, including oropharyngeal edema [see Warnings and Precautions (5.2)]. Cardiac Arrhythmias, syncope. Neurologic Seizures. Respiratory Bronchospasm, dyspnea [see Warnings and Precautions (5.1)]. Skin Facial edema; rash, including serious cutaneous reactions; urticaria [see Warnings and Precautions (5.2)]. 7 DRUG INTERACTIONS Zanamivir is not a substrate nor does it affect cytochrome P450 (CYP) isoenzymes (CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) in human liver microsomes. No clinically significant pharmacokinetic drug interactions are predicted based on data from in vitro studies. The concurrent use of RELENZA with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of potential interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of RELENZA, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of RELENZA [see Clinical Pharmacology (12.4)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. There are no adequate and well-controlled studies of zanamivir in pregnant women. Zanamivir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Embryo/fetal development studies were conducted in rats (dosed from days 6 to 15 of pregnancy) and rabbits (dosed from days 7 to 19 of pregnancy) using the same IV doses (1, 9, and 90 mg/kg/day). Pre- and post-natal developmental studies were performed in rats (dosed from day 16 of pregnancy until litter day 21 to 23). No malformations, maternal toxicity, or embryotoxicity were observed in pregnant rats or rabbits and their fetuses. Because of insufficient blood sampling timepoints in rat and rabbit reproductive toxicity studies, AUC values were not available. In a subchronic study in rats at the 90 mg/kg/day IV dose, the AUC values were greater than 300 times the human exposure at the proposed clinical dose. An additional embryo/fetal study, in a different strain of rat, was conducted using subcutaneous administration of zanamivir, 3 times daily, at doses of 1, 9, or 80 mg/kg during days 7 to 17 of pregnancy. There was an increase in the incidence rates of a variety of minor skeleton alterations and variants in the exposed offspring in this study. Based on AUC measurements, the 80 mg/kg dose produced an exposure greater than 1,000 times the human exposure at the proposed clinical dose. However, in most instances, the individual incidence rate of each skeletal alteration or variant remained within the background rates of the historical occurrence in the strain studied. Zanamivir has been shown to cross the placenta in rats and rabbits. In these animals, fetal blood concentrations of zanamivir were significantly lower than zanamivir concentrations in the maternal blood. 8.3 Nursing Mothers Studies in rats have demonstrated that zanamivir is excreted in milk. However, nursing mothers should be instructed that it is not known whether zanamivir is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RELENZA is administered to a nursing mother. 8.4 Pediatric Use Treatment of Influenza Safety and effectiveness of RELENZA for treatment of influenza have not been assessed in pediatric patients less than 7 years of age, but were studied in a Phase III treatment study in pediatric patients, where 471 children 5 to 12 years of age received zanamivir or placebo [see Clinical Studies 14.1)]. Adolescents were included in the three principal Phase 3 adult treatment studies. In these studies, 67 patients were 12 to 16 years of age. No definite differences in safety and efficacy were observed between these adolescent patients and young adults. In a Phase I study of 16 children ages 6 to 12 years with signs and symptoms of respiratory disease, 4 did not produce a measurable peak inspiratory flow rate (PIFR) through the DISKHALER (3 with no adequate inhalation on request, 1 with missing data), 9 had measurable PIFR on each of2 inhalations, and 3 achieved measurable PIFR on only 1 of 2 inhalations. Neither of two 6-year-olds and one of two 7-year-olds produced measurable PIFR. Overall, 8 of the 16 children (including all those under 8 years old) either did not produce measurable inspiratory flow through the DISKHALER or produced peak inspiratory flow rates below the 60 L/min considered optimal for the device under standardized in vitro testing; lack of measurable flow rate was related to low or undetectable serum concentrations [see Clinical Pharmacology (12.3), Clinical Studies (14.1)]. Prescribers should carefully evaluate the ability of young children to use the delivery system if prescription of RELENZA is considered. Prophylaxis of Influenza The safety and effectiveness of RELENZA for prophylaxis of influenza have been studied in four Phase III studies where 273 children 5 to 11 years of age and 239 adolescents 12 to 16 years of age received RELENZA. No differences in safety and effectiveness were observed between pediatric and adult subjects [see Clinical Studies(14.2)]. 8.5 Geriatric Use Of the total number of patients in 6 clinical studies of RELENZA for treatment of influenza, 59 patients were 65 years of age and older, while 24 patients were 75 years of age and older. Of the total number of patients in 4 clinical studies of RELENZA for prophylaxis of influenza in households and community settings, 954 patients were 65 years of age and older, while 347 patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients may need assistance with use of the device. In 2 additional studies of RELENZA for prophylaxis of influenza in the nursing home setting, efficacy was not demonstrated [see Indications and Usage (1.3)]. 10 OVERDOSAGE There have been no reports of overdosage from administration of RELENZA. 11 DESCRIPTION The active component of RELENZA is zanamivir. The chemical name of zanamivir is 5-(acetylamino)-4-[(aminoiminomethyl)-amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid. It has a molecular formula of C12H20N4O7 and a molecular weight of 332.3. It has thefollowing structural formula: Zanamivir is a white to off-white powder for oral inhalation with a solubility of approximately 18 mg/mL in water at 20°C. RELENZA is for administration to the respiratory tract by oral inhalation only. Each RELENZA ROTADISK contains 4 regularly spaced double-foil blisters with each blister containing a powder mixture of 5 mg of zanamivir and 20 mg of lactose (which contains milk proteins). The contents of each blister are inhaled using a specially designed breath-activated plastic device for inhaling powder called the DISKHALER. After a RELENZA ROTADISK is loaded into the DISKHALER, a blister that contains medication is pierced and the zanamivir is dispersed into the air stream created when the patient inhales through the mouthpiece. The amount of drug delivered to the respiratory tract will depend on patient factors such as inspiratory flow. Under standardized in vitro testing, RELENZA ROTADISK delivers 4 mg of zanamivir from the DISKHALER device when tested at a pressure drop of 3 kPa (corresponding to a flow rate of about 62 to 65 L/min) for 3 seconds. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Zanamivir is an antiviral drug [see Clinical Pharmacology (12.4)]. 12.3 Pharmacokinetics Absorption and Bioavailability Pharmacokinetic studies of orally inhaled zanamivir indicate that approximately 4% to 17% of the inhaled dose is systemically absorbed. The peak serum concentrations ranged from 17 to 142 ng/mL within 1 to 2 hours following a 10 mg dose. The area under the serum concentration versus time curve (AUC∞) ranged from 111 to 1,364 ng•hr/mL. Distribution Zanamivir has limited plasma protein binding (<10%). Metabolism Zanamivir is renally excreted as unchanged drug. No metabolites have been detected in humans. Elimination The serum half-life of zanamivir following administration by oral inhalation ranges from 2.5 to 5.1 hours. It is excreted unchanged in the urine with excretion of a single dose completed within 24 hours. Total clearance ranges from 2.5 to 10.9 L/hr. Unabsorbed drug is excreted in the feces. Impaired Hepatic Function The pharmacokinetics of zanamivir have not been studied in patients with impaired hepatic function. Impaired Renal Function After a single intravenous dose of 4 mg or 2 mg of zanamivir in volunteers with mild/moderate or severe renal impairment, respectively, significant decreases in renal clearance (and hence total clearance: normals 5.3 L/hr, mild/moderate 2.7 L/hr, and severe 0.8 L/hr; median values) and significant increases in half-life (normals 3.1 hr, mild/moderate 4.7 hr, and severe 18.5 hr; median values) and systemic exposure were observed. Safety and efficacy have not been documented in the presence of severe renal insufficiency. Due to the low systemic bioavailability of zanamivir following oral inhalation, no dosage adjustments are necessary in patients with renal impairment. However, the potential for drug accumulation should be considered. Pediatric Patients The pharmacokinetics of zanamivir were evaluated in pediatric patients with signs and symptoms of respiratory illness. Sixteen patients, 6 to 12 years of age, received a single dose of 10 mg zanamivir dry powder via DISKHALER. Five patients had either undetectable zanamivir serum concentrations or had low drug concentrations (8.32 to 10.38 ng/mL) that were not detectable after 1.5 hours. Eleven patients had Cmax median values of 43 ng/mL (range 15 to 74) and AUC∞ median values of 167 ng•hr/mL (range 58 to 279). Low or undetectable serum concentrations were related to lack of measurable PIFR in individual patients [see Use in Specific Populations (8.4), Clinical Studies (14.1)]. Geriatric Patients The pharmacokinetics of zanamivir have not been studied in patients over 65 years of age [see Use in Specific Populations (8.5)]. Gender, Race, and Weight In a population pharmacokinetic analysis in patient studies, no clinically significant differences in serum concentrations and/or pharmacokinetic parameters (V/F, CL/F, ka, AUC0-3, Cmax, Tmax, CLr, and % excreted in urine) were observed when demographic variables (gender, age, race, and weight) and indices of infection (laboratory evidence of infection, overall symptoms, symptoms of upper respiratory illness, and viral titers) were considered. There were no significant correlations between measures of systemic exposure and safety parameters. 12.4 Microbiology Mechanism of Action Zanamivir is an inhibitor of influenza virus neuraminidase affecting release of viral particles. Antiviral Activity The antiviral activity of zanamivir against laboratory and clinical isolates of influenza virus was determined in cell culture assays. The concentrations of zanamivir required for inhibition of influenza virus were highly variable depending on the assay method used and virus isolate tested. The 50% and 90% effective concentrations (EC50 and EC90) of zanamivir were in the range of 0.005 to 16.0 μM and 0.05 to >100 μM, respectively (1 μM = 0.33 mcg/mL). The relationship between the cell culture inhibition of influenza virus by zanamivir and the inhibition of influenza virus replication in humans has not been established. Resistance Influenza viruses with reduced susceptibility to zanamivir have been selected in cell culture by multiple passages of the virus in the presence of increasing concentrations of the drug. Genetic analysis of these viruses showed that the reduced susceptibility in cell culture to zanamivir is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. Resistance mutations selected in cell culture which result in neuraminidase amino acid substitutions include E119G/A/D and R292K. Mutations selected in cell culture in hemagglutinin include: K68R, G75E, E114K, N145S, S165N, S186F, N199S, and K222T. In an immunocompromised patient infected with influenza B virus, a variant virus emerged after treatment with an investigational nebulized solution of zanamivir for 2 weeks. Analysis of this variant showed a hemagglutinin substitution (T198I) which resulted in a reduced affinity for human cell receptors, and a substitution in the neuraminidase active site (R152K) which reduced the enzyme’s activity to zanamivir by 1,000-fold. Insufficient information is available to characterize the risk of emergence of zanamivir resistance in clinical use. Cross-Resistance Cross-resistance has been observed between some zanamivir-resistant and some oseltamivir-resistant influenza virus mutants generated in cell culture. However, some of the in cell culture zanamivir-induced resistance mutations, E119G/A/D and R292K, occurred at the same neuraminidase amino acid positions as in the clinical isolates resistant to oseltamivir, E119V and R292K. No studies have been performed to assess risk of emergence of cross-resistance during clinical use. Influenza Vaccine Interaction Study An interaction study (n = 138) was conducted to evaluate the effects of zanamivir (10 mg once daily) on the serological response to a single dose of trivalent inactivated influenza vaccine, as measured by hemagglutination inhibition titers. There was no difference in hemagglutination inhibition antibody titers at 2 weeks and 4 weeks after vaccine administration between zanamivir and placebo recipients. Influenza Challenge Studies Antiviral activity of zanamivir was supported for infection with influenza A virus, and to a more limited extent for infection with influenza B virus, by Phase I studies in volunteers who received intranasal inoculations of challenge strains of influenza virus, and received an intranasal formulation of zanamivir or placebo starting before or shortly after viral inoculation. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In 2-year carcinogenicity studies conducted in rats and mice using a powder formulation administered through inhalation, zanamivir induced no statistically significant increases in tumors over controls. The maximum daily exposures in rats and mice were approximately 23 to 25 and 20 to 22 times, respectively, greater than those in humans at the proposed clinical dose based on AUC comparisons. Mutagenesis Zanamivir was not mutagenic in in vitro and in vivo genotoxicity assays which included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in mouse lymphoma, chromosomal aberration assays in human peripheral blood lymphocytes, and the in vivo mouse bone marrow micronucleus assay. Impairment of Fertility The effects of zanamivir on fertility and general reproductive performance were investigated in male (dosed for 10 weeks prior to mating, and throughout mating, gestation/lactation, and shortly after weaning) and female rats (dosed for 3 weeks prior to mating through day 19 of pregnancy, or day 21 post partum) at IV doses 1, 9, and 90 mg/kg/day. Zanamivir did not impair mating or fertility of male or female rats, and did not affect the sperm of treated male rats. The reproductive performance of the F1 generation born to female rats given zanamivir was not affected. Based on a subchronic study in rats at a 90 mg/kg/day IV dose, AUC values ranged between 142 and 199 mcg•hr/mL (>300 times the human exposure at the proposed clinical dose). 14 CLINICAL STUDIES 14.1 Treatment of Influenza Adults and Adolescents The efficacy of RELENZA 10 mg inhaled twice daily for 5 days in the treatment of influenza has been evaluated in placebo-controlled studies conducted in North America, the Southern Hemisphere, and Europe during their respective influenza seasons. The magnitude of treatment effect varied between studies, with possible relationships to population-related factors including amount of symptomatic relief medication used. Populations Studied The principal Phase III studies enrolled 1,588 patients ages 12 years and older (median age 34 years, 49% male, 91% Caucasian), with uncomplicated influenza-like illness within 2 days of symptom onset. Influenza was confirmed by culture, hemagglutination inhibition antibodies, or investigational direct tests. Of 1,164 patients with confirmed influenza, 89% had influenza A and 11% had influenza B. These studies served as the principal basis for efficacy evaluation, with more limited Phase II studies providing supporting information where necessary. Following randomization to either zanamivir or placebo (inhaled lactose vehicle), all patients received instruction and supervision by a healthcare professional for the initial dose. Principal Results The definition of time to improvement in major symptoms of influenza included no fever and self-assessment of “none” or “mild” for headache, myalgia, cough, and sore throat. A Phase II and a Phase III study conducted in North America (total of over 600 influenza-positive patients) suggested up to one day of shortening of median time to this defined improvement in symptoms in patients receiving zanamivir compared with placebo, although statistical significance was not reached in either of these studies. In a study conducted in the Southern Hemisphere (321 influenza-positive patients), a 1.5-day difference in median time to symptom improvement was observed. Additional evidence of efficacy was provided by the European study. Other Findings There was no consistent difference in treatment effect in patients with influenza A compared with influenza B; however, these trials enrolled smaller numbers of patients with influenza B and thus provided less evidence in support of efficacy in influenza B. In general, patients with lower temperature (e.g., 38.2°C or less) or investigator-rated as having less severe symptoms at entry derived less benefit from therapy. No consistent treatment effect was demonstrated in patients with underlying chronic medical conditions, including respiratory or cardiovascular disease [see Warnings and Precautions (5.3)]. No consistent differences in rate of development of complications were observed between treatment groups. Some fluctuation of symptoms was observed after the primary study endpoint in both treatment groups. Pediatric Patients The efficacy of RELENZA 10 mg inhaled twice daily for 5 days in the treatment of influenza in pediatric patients has been evaluated in a placebo-controlled study conducted in North America and Europe, enrolling 471 patients, ages 5 to 12 years (55% male, 90% Caucasian), within 36 hours of symptom onset. Of 346 patients with confirmed influenza, 65% had influenza A and 35% had influenza B. The definition of time to improvement included no fever and parental assessment of no or mild cough and absent/minimal muscle and joint aches or pains, sore throat, chills/feverishness, and headache. Median time to symptom improvement was one day shorter in patients receiving zanamivir compared with placebo. No consistent differences in rate of development of complications were observed between treatment groups. Some fluctuation of symptoms was observed after the primary study endpoint in both treatment groups. Although this study was designed to enroll children ages 5 to 12 years, the product is indicated only for children 7 years of age and older. This evaluation is based on the combination of lower estimates of treatment effect in 5- and 6-year-olds compared with the overall study population, and evidence of inadequate inhalation through the DISKHALER in a pharmacokinetic study [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3)]. 14.2 Prophylaxis of Influenza The efficacy of RELENZA in preventing naturally occurring influenza illness has been demonstrated in 2 post-exposure prophylaxis studies in households and 2 seasonal prophylaxis studies during community outbreaks of influenza. The primary efficacy endpoint in these studies was the incidence of symptomatic, laboratory-confirmed influenza, defined as the presence of 2 or more of the following symptoms: oral temperature ≥100°F/37.8°C or feverishness, cough, headache, sore throat, and myalgia; and laboratory confirmation of influenza A or B by culture, PCR, or seroconversion (defined as a 4-fold increase in convalescent antibody titer from baseline). Household Prophylaxis Studies Two studies assessed post-exposure prophylaxis in household contacts of an index case. Within 1.5 days of onset of symptoms in an index case, each household (including all family members ≥5 years of age) was randomized to RELENZA 10 mg inhaled once daily or placebo inhaled once daily for 10 days. In the first study only, each index case was randomized to RELENZA 10 mg inhaled twice daily for 5 days or inhaled placebo twice daily for 5 days. In this study, the proportion of households with at least 1 new case of symptomatic laboratory-confirmed influenza was reduced from 19.0% (32 of 168 households) for the placebo group to 4.1% (7 of 169 households) for the group receiving RELENZA. In the second study, index cases were not treated. The incidence of symptomatic laboratory-confirmed influenza was reduced from 19.0% (46 of 242 households) for the placebo group to 4.1% (10 of 245 households) for the group receiving RELENZA. Seasonal Prophylaxis Studies Two seasonal prophylaxis studies assessed RELENZA 10 mg inhaled once daily versus placebo inhaled once daily for 28 days during community outbreaks. The first study enrolled subjects 18 years of age or greater (mean age 29 years) from 2 university communities. The majority of subjects were unvaccinated (86%). In this study, the incidence of symptomatic laboratory-confirmed influenza was reduced from 6.1% (34 of 554) for the placebo group to 2.0% (11 of 553) for the group receiving RELENZA. The second seasonal prophylaxis study enrolled subjects 12 to 94 years of age (mean age 60 years) with 56% of them older than 65 years of age. Sixty-seven percent of the subjects were vaccinated. In this study, the incidence of symptomatic laboratory-confirmed influenza was reduced from 1.4% (23 of 1,685) for the placebo group to 0.2% (4 of 1,678) for the group receiving RELENZA. 16 HOW SUPPLIED/STORAGE AND HANDLING RELENZA is supplied in a circular double-foil pack (a ROTADISK) containing 4 blisters of the drug. Five ROTADISKS are packaged in a white polypropylene tube. The tube is packaged in a carton with 1 blue and gray DISKHALER inhalation device (NDC 0173-0681-01). Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Keep out of reach of children. Do not puncture any RELENZA ROTADISK blister until taking a dose using the DISKHALER. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.5). 17.1 Bronchospasm Patients should be advised of the risk of bronchospasm, especially in the setting of underlying airways disease, and should stop RELENZA and contact their physician if they experience increased respiratory symptoms during treatment such as worsening wheezing, shortness of breath, or other signs or symptoms of bronchospasm [see Warnings and Precautions (5.1)]. If a decision is made to prescribe RELENZA for a patient with asthma or chronic obstructive pulmonary disease, the patient should be made aware of the risks and should have a fast-acting bronchodilator available. 17.2 Concomitant Bronchodilator Use Patients scheduled to take inhaled bronchodilators at the same time as RELENZA should be advised to use their bronchodilators before taking RELENZA. 17.3 Instructions for Use Patients should be instructed in use of the delivery system. Instructions should include a demonstration whenever possible. For the proper use of RELENZA, the patient should read and follow carefully the accompanying Patient Instructions for Use. If RELENZA is prescribed for children, it should be used only under adult supervision and instruction, and the supervising adult should first be instructed by a healthcare professional [see Dosage and Administration (2.1)]. 17.4 Risk of Influenza Transmission to Others Patients should be advised that the use of RELENZA for treatment of influenza has not been shown to reduce the risk of transmission of influenza to others. 17.5 FDA-Approved PatientLabeling and Instructions for Use See separate leaflet. GlaxoSmithKline Research Triangle Park, NC 27709 ©2007, GlaxoSmithKline. All rights reserved. Patient Labeling RELENZA® (zanamivir) Inhalation Powder This leaflet contains important patient information about RELENZA (zanamivir) inhalation powder, and should be read completely before beginning treatment. It does not, however, take the place of discussions with your healthcare provider about your medical condition or your treatment. This summary does not list all benefits and risks of RELENZA. The medication described here can only be prescribed and dispensed by a licensed healthcare provider, who has information about your medical condition and more information about the drug, including how to take it, what to expect, and potential side effects. If you have any questions about RELENZA, talk with your healthcare provider. What is RELENZA? RELENZA (ruh-LENS-uh) is a medicine for the treatment of influenza (flu, infection caused by influenza virus) and for reducing the chance of getting the flu in community and household settings. It belongs to a group of medicines called neuraminidase inhibitors. These medications attack the influenza virus and prevent it from spreading inside your body. RELENZA treats the cause of influenza at its source, rather than simply masking the symptoms. Important Safety Information About RELENZA Some patients have had bronchospasm (wheezing) or serious breathing problems when they used RELENZA. Many but not all of these patients had previous asthma or chronic obstructive pulmonary disease. RELENZA has not been shown to shorten the duration of influenza in people with these diseases. Because of the risk of side effects and because it has not been shown to help them, RELENZA is not recommended for people with chronic respiratory disease such as asthma or chronic obstructive pulmonary disease. If you develop worsening respiratory symptoms such as wheezing or shortness of breath, stop using RELENZA and contact your healthcare provider right away. If you have chronic respiratory disease such as asthma and chronic obstructive pulmonary disease and your healthcare provider has prescribed RELENZA, you should have a fast-acting, inhaled bronchodilator available for your use. If you are scheduled to use an inhaled bronchodilator at the same time as RELENZA, use the inhaled bronchodilator before using RELENZA. Read the rest of this leaflet for more information about side effects and risks. Other kinds of infections can appear like influenza or occur along with influenza, and need different kinds of treatment. Contact your healthcare provider if you feel worse or develop new symptoms during or after treatment, or if your influenza symptoms do not start to get better. Who should not take RELENZA? RELENZA is not recommended for people who have chronic lung disease such as asthma or chronic obstructive pulmonary disease. RELENZA has not been shown to shorten the duration of influenza in people with these diseases, and some people have had serious side effects of bronchospasm and worsening lung function. (See the section of this Patient Information entitled “Important Safety Information About RELENZA.”) You should not take RELENZA if you are allergic to zanamivir or any other ingredient of RELENZA. Also tell your healthcare provider if you have any type of chronic condition including lung or heart disease, if you are allergic to any other medicines or food products, or if you are pregnant. RELENZA was not effective in reducing the chance of getting the flu in 2 studies in nursing home patients. RELENZA does not treat flu-like illness that is not caused by influenza virus. Who should consider taking RELENZA? Adult and pediatric patients at least 7 years of age who have influenza symptoms that appeared within the previous day or two. Typical symptoms of influenza include sudden onset of fever, cough, headache, fatigue, muscular weakness, and sore throat. RELENZA can also help reduce the chance of getting the flu in adults and children at least 5 years of age who have a higher chance of getting the flu because they spend time with someone who has the flu. RELENZA can also reduce the chance of getting the flu if there is a flu outbreak in the community. The use of RELENZA for the treatment of flu has not been shown to reduce the risk of spreading the virus to others. Can I take other medications with RELENZA? RELENZA has been shown to have an acceptable safety profile when used as labeled, with minimal risk of drug interactions. Your healthcare provider may recommend taking other medications, including over-the-counter medications, to reduce fever or other symptoms while you are taking RELENZA. Before starting treatment, make sure that your healthcare provider knows if you are taking other medicines. If you are scheduled to use an inhaled bronchodilator at the same time as RELENZA, you should use the inhaled bronchodilator before using RELENZA. Before taking RELENZA, please let your healthcare provider know if you received live attenuated influenza vaccine (FLUMIST® ) intranasal in the past 2 weeks. How and when should I take RELENZA? RELENZA is packaged in medicine disks called ROTADISKS® and is inhaled by mouth using a delivery device called a DISKHALER®. Each ROTADISK contains 4 blisters. Each blister contains 5 mg of active drug and 20 mg of lactose powder (which contains milk proteins). You should receive a demonstration on how to use RELENZA in the DISKHALER from a healthcare provider. Before taking RELENZA, read the “Patient Instructions for Use.” Make sure that you understand these instructions and talk to your healthcare provider if you have any questions. Children who use RELENZA should always be supervised by an adult who understands how to use RELENZA. Proper use of the DISKHALER to inhale the drug is necessary for safe and effective use of RELENZA. If you have the flu the usual dose for treatment is 2 inhalations of RELENZA (1 blister per inhalation) twice daily (in the morning and evening) for 5 days. It is important that you begin your treatment with RELENZA as soon as possible from the first appearance of your flu symptoms. Take 2 doses on the first day of treatment whenever possible if there are at least 2 hours between doses. To reduce the chance of getting the flu, the usual dose is 2 inhalations of RELENZA (1 blister per inhalation) once daily for 10 or 28 days as prescribed by your healthcare provider. Never share RELENZA with anyone, even if they have the same symptoms. If you feel worse or develop new symptoms during treatment with RELENZA, or if your flu symptoms do not start to get better, stop using the medicine and contact your healthcare provider. What if I miss a dose? If you forget to take your medicine at any time, take the missed dose as soon as you remember, except if it is near the next dose (within 2 hours). Then continue to take RELENZA at the usual times. You do not need to take a double dose. If you have missed several doses, inform your healthcare provider and follow the advice given to you. What are important or common possible side effects of taking RELENZA? Some patients have had breathing problems while taking RELENZA. This can be very serious and need treatment right away. Most of the patients who had this problem had asthma or chronic obstructive pulmonary disease, but some did not. If you have trouble breathing or have wheezing after your dose of RELENZA, stop taking RELENZA and get medical attention. In studies, the most common side effects with RELENZA have been headaches; diarrhea; nausea; vomiting; nasal irritation; bronchitis; cough; sinusitis; ear, nose, and throat infections; and dizziness. Other side effects that have been reported, but were not as common, include rashes and allergic reactions, some of which were severe. This list of side effects is not complete. Your healthcare provider or pharmacist can discuss with you a more complete list of possible side effects with RELENZA. Talk to your healthcare provider promptly about any side effects you have. Please refer to the section entitled "Important Safety Information About RELENZA" for additional information. Should I get a flu shot? RELENZA is not a substitute for a flu shot. You should receive an annual flu shot according to guidelines on immunization practices that your healthcare provider can share with you. What if I am pregnant or nursing? If you are pregnant or planning to become pregnant while taking RELENZA, talk to your healthcare provider before taking this medication. RELENZA is normally not recommended for use during pregnancy or nursing, as the effects on the unborn child or nursing infant are unknown. How and where should I store RELENZA? RELENZA should be stored at room temperature below 77°F (25°C). RELENZA is not in a childproof container. Keep RELENZA out of the reach of children. Discard the DISKHALER after finishing your treatment. PATIENT INSTRUCTIONS FOR USE IMPORTANT: Read Step-by-Step Instructions before using the DISKHALER®. Be sure to take the dose your healthcare provider has prescribed. BEFORE YOU START: Please read the entire Patient Information for important information about the effects of RELENZA including the section “Important Safety Information About RELENZA” for information about the risk of breathing difficulties. If RELENZA is prescribed for a child, dosing should be supervised by an adult who understands how to use RELENZA and has been instructed in its use by a healthcare provider. Step-by-step instructions for using the DISKHALER® Step A: Load the medicine into the DISKHALER Start by pulling off the blue cover. Always check inside the mouthpiece to make sure it is clear before each use. If foreign objects are in the mouthpiece, they could be inhaled and cause serious harm. Pull the white mouthpiece by the edges to extend the white tray all the way. Once the white tray is extended all the way, find the raised ridges on each side of it. Press in these ridges, both sides at the same time, and pull the whole white tray out of theDISKHALER body. Place one silver medicine disk onto the dark brown wheel, flat side up. The four silver blisters on the underside of the medicine disk will drop neatly into the four holes in the wheel. Push in the white tray as far as it will go. Now the DISKHALER is loaded with medicine.