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【药品名称】


通用名称：重组人干扰素α2b注射液
商品名称：甘乐能INTRON A 
英文名称：Interferon alfa-2b Injection  
 


【成份】


主要成份：重组人干扰素α2b
辅料：磷酸氢二钠、磷酸二氢钠、依地酸二钠、氯化钠、间-甲苯酚、聚山梨醇80和注射用水。


【性状】


本品为无色澄明的无菌水针剂。


【规格】


18MIU/1.2mL/支


【适应症】


　　全身给药 慢性乙型肝炎 ：用于治疗成人和儿童（≥ (greater than or equal to) 1岁）代偿性肝病患者，患者的血清HBsAg阳性至少达6个月，同时存在乙肝病毒（HBV）复制（血清HBeAg阳性）和血清ALT升高。
　　在开始用本品治疗前，建议先进行肝组织活检，以便确诊慢性肝炎及肝损伤的程度。
　　在本品治疗慢性乙肝的大量临床研究中采用了下列标准，慢性乙肝患者使用本品治疗前可作为参考指标 ：
　　无肝性脑病、静脉曲张出血、腹水史及其他临床失代偿的表现。
　　胆红素正常。
　　白蛋白稳定在正常范围内。
　　凝血酶原时间 ：成人延长<3秒钟 ； 儿童延长≤ (smaller than or equal to) 2秒钟。
　　白细胞≥ (greater than or equal to) 4000/mm3。
　　血小板 ：成人≥ (greater than or equal to) 10万/ mm3；儿童≥ (greater than or equal to) 15万/ mm3。
　　慢性丙型肝炎 ：本品单独给药或与病毒唑（利巴韦林）合用，对于肝酶升高而无肝脏失代偿的慢性丙肝成人患者，可缓解疾病的活动程度。在这些患者身上进行的许多研究表明，本品可使血清ALT转为正常，血清HCV-RNA被清除，肝组织学病变改善。
　　到目前为止的临床经验表明 ：持续使用本品12-18个月的患者在长期用药后取得的疗效较用药6个月后停药者为持久。
　　为确诊慢性肝炎应进行肝组织活检。
　　在本品治疗的慢性丙肝的大量临床研究中采用了下列标准，慢性丙肝患者采用本品治疗前可考虑作为参考 ：
　　胆红素≤ (smaller than or equal to) 2 mg/dl。
　　白蛋白稳定在正常范围内。
　　凝血酶原时间延长<3秒钟。白细胞≥ (greater than or equal to) 3000/ mm3。
　　血小板≥ (greater than or equal to) 7万/mm3。
　　血清肌酐正常或接近正常。
　　慢性丁型肝炎 ：治疗慢性丁肝患者。
　　喉乳头状瘤 ：治疗喉乳头状瘤的儿童或成人患者。
　　毛细胞白血病 ：治疗毛细胞白血病患者。
　　慢性髓细胞性白血病（CML） ：本品单独给药或与阿糖胞苷（Ara-C）合用，治疗慢性髓细胞性白血病患者。
　　与慢性髓细胞性白血病（CML）有关的血小板增多症 ：血小板增多症常与CML有关。本品在治疗与CML有关的血小板增多症方面已有疗效。
　　多发性骨髓瘤 ：对于采用诱导疗法取得实质性缓解的患者和复发患者，本品可作为维持疗法。
　　非何杰金淋巴瘤 ：结合适当的化疗方案，如环磷酰胺-羟基柔红霉素-长春新碱-泼尼松（CHOP）化疗方案，本品可治疗III或IV期高肿瘤负荷（high tumor burden）滤泡性淋巴瘤。
　　艾滋病有关的卡波氏肉瘤 ：治疗与艾滋病有关的卡波氏肉瘤患者，患者无机会性感染病史，同时CD4>250/mm3。
　　肾细胞癌 ：治疗晚期肾癌患者。
　　转移性类癌瘤（胰腺内分泌肿瘤） ：治疗转移性类癌瘤患者。
恶性黑素瘤 ：作为手术后无病变但处于高度复发危险的成人黑素瘤患者的辅助治疗。


 


【用法用量】


　　用于维持治疗的皮下注射方案中，患者可遵医嘱自行注射。
　　对于血小板<5万/mm3的患者，应采用皮下注射代替肌注。
　　在本品用于任何适应症时，如果发生不良反应，则应调整剂量（减量50％）或暂时停药，直至不良反应消退。如果在调整剂量后不良反应持续出现或复发，或者疾病发生进展，则应停用本品治疗。
　　慢性乙型肝炎 标准给药方案-成人：推荐剂量为每周总量30-35 MIU，皮下注射，每天5 MIU，连续7天，或每周3次，每次10 MIU（隔日1次），共16-24周 ；儿童（1-17岁）：推荐剂量为第1周皮下注射3次（隔日1次），每次3 MIU/m2，以后剂量升高至每周3次，每次6 MIU/m2（最大可达每次10 MIU/m2），共给药16-24周。
　　对于白细胞、粒细胞或血小板计数减少的患者，在临床试验中曾采用下列剂量调整方案 ：
　　以下情况减量50％ ：
　　成人和儿童白细胞计数<1500/mm3；粒细胞计数成人<750/mm3，儿童<1000/mm3；血小板计数成人<5万/mm3，儿童<10万/mm3。
　　以下情况停药 ：
　　成人和儿童白细胞计数<1200/mm3；粒细胞计数成人<500/mm3，儿童<750/mm3；血小板计数成人<3万/mm3，儿童<7万/mm3。
　　当白细胞、粒细胞和（或）血小板计数恢复至正常或基础值时，本品剂量可恢复至初始量。
　　部分国家认可的另一种给药方案 ：本品的最低有效剂量为每周3次皮下注射，每次3 MIU。HBV-DNA基础水平较低（即<100 pcg/mL）的患者对本品的应答最强，大多数患者在1个月内HBV-DNA下降达50％。高危病人（HBV-DNA>100 pcg/mL）或在1月内无应答的患者，可用本品每周3次，每次5 MIU治疗或剂量增至每天5 MIU。剂量可随病人对本品的耐受情况调整。若病人有应答，该选择方案应维持4个月，除非病人发生严重的不耐受反应（见上述粒细胞和血小板计数下降的指导原则）。
　　慢性丙型肝炎 ：单独治疗：推荐剂量为3 MIU皮下注射，每周3次（隔日1次）。产生疗效的多数患者在12-16周内ATL水平有所改善。经16周治疗ALT达正常水平的病人，本品治疗应延长至18-24月（72-96周），以提高持续应答率。经16周治疗后ALT未能达到正常水平的患者，应考虑终止本品治疗。
　　对于停用本品后复发的患者，可重新使用本品治疗时，可采用患者以前奏效的相同给药剂量。
　　与病毒唑合用 ：若本品与病毒唑合用治疗慢性丙肝患者，另请参考病毒唑的说明书中关于治疗剂量方案、注意事项及禁忌症。
　　慢性丁型肝炎 ：本品初始剂量为5 MIU/m2，皮下注射，每周3次，至少3-4个月，亦可使用更长时间。可按患者对药物的耐受情况而调整剂量。
　　喉乳头状瘤 ：本品的推荐剂量为皮下注射每周3次（隔日1次），每次3 MIU/m2，于外科（激光）切除肿瘤组织后开始给药。可根据病人对本品的耐受程度调整剂量。治疗应答需要6个月以上的治疗。
　　毛细胞白血病 ：本品的推荐剂量为2 MIU/m2皮下注射或肌注，每周3次（隔日1次）。可按患者对药物的耐受情况而调整剂量。
　　脾脏未切除患者的疗效与脾脏切除者相似，均可减少输血。
　　通常血液学指标在用药2个月内开始出现1个或数个恢复正常。所有3项血液学指标（粒细胞计数、血小板计数和血红蛋白水平）均达到改善的时间可能需要6个月以上。在开始给药前，应进行实验室检查以测定外周血红蛋白、血小板、粒细胞和毛细胞以及骨髓毛细胞数量。在用药期间应定期监测这些指标以确定是否产生疗效。如有效，则应继续给药直至病情达到最大改善，以及实验室指标稳定约3个月。如果给药6个月而无疗效，则应停药。如果未见疾病迅速进展或严重不良反应，则应维持上述治疗方案。
　　对本品治疗中断者，90％以上的患者在重新使用本品治疗时有效。
　　慢性髓细胞性白血病 ：单独治疗 ：本品的推荐剂量为每日皮下注射4-5 MIU/m2。为持续控制白细胞计数，每日的剂量范围可能需要0.5-10 MIU/m2。当白细胞计数得以控制时，为维持血液学指标改善，应给予最大耐受量（每日4－10 MIU/m2）。如果用药8-12周后仍未见部分血液指标缓解或有临床意义的血液学细胞减少，则应考虑停药。
　　与阿糖胞苷合用（Ara-C） ：当与阿糖胞苷合用时，先用本品每天皮下注射5 MIU/m2，2周后加用阿糖胞苷（Ara-C）皮下注射每天20 mg/m2，每月连续用药10日（最大剂量可达每天40 mg）。8-12周后如果未取得血液指标部分改善或有临床意义的血液学细胞减少，应停用本品。
　　临床研究已表明，对于疾病处于慢性阶段的患者，使用本品治疗有效的可能性很大。诊断明确后应尽可能早地开始给药，需持续至血液指标完全改善或至少用药达18个月。有效的患者一般在用药2-3个月内显示血液指标改善。这些患者应继续用药，直到血液指标达到完全改善，即白细胞计数达3.0-4.0x109/L。血液指标完全改善的患者均应继续用药以期产生细胞遗传学改善，有些患者在用药两年后才达到这种改善。
　　对于在诊断时白细胞计数多于50x109/L的患者，医师在开始治疗阶段可使用标准剂量的羟基脲，待白细胞数低于50x109/L时，则可改用本品。
　　对于新近诊断为Ph－阳性的慢性髓细胞性白血病患者，亦可合用本品和羟基脲进行治疗。本品的起始剂量范围为每日6-10 MIU，皮下注射 ；如果开始治疗时白细胞数高于10x109/L，则可加用羟基脲，剂量为1.0-1.5 g，每日2次，持续用药至白细胞数低于10x109/L。此后停用羟基脲，并调整本品剂量以使中性细胞（多形核细胞）维持在1.0-5.0x109/L以上，血小板在75x109/L以上。
　　与慢性髓细胞性白血病（CML）有关的血小板增多症 ：治疗与CML有关的血小板增多症的推荐剂量与上述治疗CML相同。控制白细胞计数的剂量调整应同时对控制血小板计数有效。
　　基于目前所积累的临床经验，约?的CML患者（26％）伴发血小板增多症，血小板的基础水平>500×109/L。通过2个月的治疗所有的病人的血小板计数都得到控制。在治疗中没有患者血小板计数<80×109/L。
　　多发性骨髓瘤 ：维持治疗 ：对于经诱导化疗后处于稳定期的患者，可单用本品皮下注射，剂量为3－5 MIU/m2，每周3次（隔天用药）。
　　复发治疗或顽固性疾病治疗 ：对于化疗后复发或对化疗无效的患者，可单用本品治疗，剂量为3－5 MIU/m2，每周3次。
　　非何杰金淋巴瘤 ：与化疗结合，用本品皮下注射每周3次，每次5 MIU（隔日1次）。
　　艾滋病有关的卡波氏肉瘤 ：最佳的剂量尚不明确。
　　已证明，采用本品皮下或肌注给药，在30 MIU/m2，每周3-5次的剂量下有效，亦有用较低剂量（每日10-12 MIU/m2）而未明显减低疗效。
　　当病情稳定或药物起效时，应继续给药直至肿瘤消失，除非因严重机会性感染或不良反应而需停药。
　　与齐多夫定（AZT）联合用药 ：在临床研究中，已联合使用本品与齐多夫定治疗伴发卡波氏肉瘤的艾滋病患者。多数病人能很好地耐受下列给药方案：本品剂量为每日5-10 MIU/m2；齐多夫定为每4小时100 mg。剂量受限制的主要毒性反应为中性粒细胞减少症。
　　本品的初始剂量为每日3-5 MIU，用药2-4周后，可根据患者对药物的耐受情况将剂量增至每日5-10 MIU/m2；齐多夫定的剂量可增至每4小时200 mg。
　　应按照患者对药物的疗效和耐受情况而调整剂量。
　　肾细胞癌 ：单用本品治疗时 ：尚未确定最佳的剂量及给药方案。本品皮下注射或静注剂量3-30 MIU/m2，方案有每周3次、每周5天或每天。在皮下注射，每周3次，每次3-10 MIU的剂量下，应答率最高。
　　与其它药物合用，如白介素-2：尚未确定最佳剂量。与白介素-2合用，本品皮下注射剂量有3-20 MIU/ m2。报道本品皮下注射6MIU/ m2，1周3次取得最高总体应答率 ；治疗期间可按需要调整剂量。
　　转移性类癌瘤（胰腺内分泌肿瘤） ：皮下注射本品每天3-4 MIU/ m2或隔天注射，已证明本品对转移性类癌瘤及类癌瘤综合征患者的治疗作用，起始剂量为皮下注射每周3次，每次2 MIU/m2，每隔两周根据耐受性增加剂量至3、5、7和10 MIU。
　　尽管未取得肿瘤实质性消退指标，20％的病人24小时尿中的5-羟基吲哚乙酸（5-HIAA）水平下降50％。病人使用本品6个月（最初3天每天皮给药2 MIU/m2，随后增加至5 MIU/ m2，每周3次），取得约50％的客观有效率。
　　患有恶性类癌瘤的患者在本品治疗期间可能发生自身免疫性疾病，尤其是当存在自身抗体时，应密切监测病人在治疗期间的自身免疫性症状体征。
　　恶性黑色素瘤 ：作为诱导治疗，可采用本品静脉给药，剂量为每日20MIU/m2，每周5次，共4周，然后维持治疗皮下给药，剂量为10 MIU/m2，每周3次（隔日1次）共用药48周。
　　若使用本品发生严重不良反应，尤其当粒细胞下降至<500/mm3，或ALT/AST升至正常值上限的5倍以上，应暂时停止治疗直至不良反应消退。重新开始本品治疗应从起始剂量的50％开始。若经剂量调整后不良反应再次发生或粒细胞减少至<250/mm3，或ALT/AST升至正常值上限的10倍以上，应终止使用本品。
虽然尚未确定最佳（最小的）剂量，为取得充分疗效，应按推荐剂量给药，根据耐受情况进行如上剂量调整。


 


【 不良反应】


　　全身给药 最常见的不良反应为发热、疲乏、头痛和肌痛。发热和疲乏在终止给药后72小时内恢复正常，这两种反应与剂量有关。
　　常见的不良反应包括寒战、食欲不振及恶心。
　　不太常见的不良反应包括呕吐、腹泻、关节痛、无力、嗜睡、眩晕、口干、脱发、流感样症状（非特异性）、背痛、抑郁、自杀意图、不适、疼痛、盗汗、味觉改变、易激惹、易怒、失眠、意识模糊、注意力受损及低血压。
　　偶见报道的不良反应包括腹痛、右上腹痛、皮疹、神经过敏、注射局部反应、感觉异常、单纯疱疹、瘙痒、眼痛、焦虑、情绪不稳、精神疾病（包括幻觉、攻击性行为）、鼻衄、咳嗽、咽炎、肺浸润、肺炎、局限性肺炎、意识障碍、体重减轻、面部水肿、呼吸困难、消化不良、心动过速、高血压、食欲增加、性欲减退、月经不调（包括闭经或月经过多）、感觉减退、味觉反常、稀便、牙龈出血、小腿痛性痉挛、神经病变和多发性神经病变、横纹肌溶解（有时较严重）、听觉障碍、眩晕、肾功能不全。甲状腺功能亢进或减退亦偶见报道。偶见肝毒性包括致命性肝毒性。
　　使用α干扰素的患者，包括使用本品（重组α-2b干扰素），偶见报道视网膜出血、棉絮状渗出点、视网膜动脉或静脉梗塞。
　　本品上市后罕见报道肾病综合征、肾功能不全、糖尿病加重、糖尿病、高血糖、胰腺炎、心脏缺血和心肌梗塞。
　　心血管不良反应尤其是心律失常，大多与原先存在的心血管疾病以及应用有心脏毒性的药物有关。原先并无心脏病证据的患者偶见报道一过性可逆性心肌病变。
　　具有临床意义的实验室检查异常，最常见于每日剂量超过10 MIU时，包括粒细胞和白细胞减少，血红蛋和血小板减少，以及碱性磷酸酶、乳酸脱氢酶、血清肌酐、血尿素氮和促甲状腺素升高。在某些非肝炎患者可异常地发生血清ALT/AST (SGPT/SGOT)增高，这种情况亦见于清除病毒DNA聚合酶的某些慢性乙肝患者。
　　本品单独使用或与病毒唑（利巴韦林）合用时，可能发生的罕见不良反应为再生障碍性贫血。
　　儿童 小儿慢性乙肝患者所发生的不良反应与成人患者类似。最常见的不良反应为流感样症状和胃肠道障碍（如呕吐和腹痛）。同样，有报道中性白细胞减少和血小板减少。正如对这一年龄组可预见的，出现易怒较常见。不良反应均未达危及生命的严重程度，主要是中度和轻重度反应，减药或停药后可消除。
　　使用本品的儿童（1-17岁）可发现暂时性的生长延缓，停药后可恢复。
儿童患者的实验室检查异常情况与成人患者相似。


 


【禁忌】


对重组干扰素α－2b及其所含组份有过敏史的患者禁用。


【 注意事项】


　　实验室检查 ：所有患者在使用本品前和用药期间应定期进行血常规检查和血液化学检查（全血细胞计数和分类、血小板计数、电解质、肝酶包括血清ALT、血清胆红素和白蛋白、血清蛋白及血清肌酐）。在用药前促甲状腺素（TSH）水平必须在正常值内。在用药期间，任何发生甲状腺功能障碍症状的任何患者应评定其甲状腺功能。
　　对于肝炎患者，建议在给药第1、2、4、8、12、16周进行检查，以后每隔1个月检查一次直至治疗结束。如果在用药期间ALT升高（≥ (greater than or equal to)基础水平的2倍），可继续使用本品，除非发现肝功能不全的症状或体征。在ALT升高期间，应每隔2周检查一次肝功能，包括凝血酶原时间、ALT、碱性磷酸酶、白蛋白和胆红素水平。
　　对于恶性黑素瘤患者，在治疗的诱导期间，应每周检查1次肝功能和白细胞计数及其分类，在治疗的维持期间，应每月检查一次。
　　本品含稳定剂间－甲苯酚，某些患者对此可发生过敏反应。
　　在用本品治疗时，很少见有急性、严重的过敏反应（如荨麻疹、血管神经性水肿、支气管痉挛、过敏性休克）。如果发生以上任一反应，应停药并立即给予适当医治。一过性皮疹不需终止给药。
　　对于虚弱患者如肺部疾患（慢性阻塞性肺病）或有酮症酸中毒倾向的糖尿病患者应慎用本品。对凝血障碍患者（如血栓性静脉炎、肺栓塞）或严重骨髓抑制患者亦应慎用。
　　本品与某些化疗药物联合应用时可导致毒性（严重程度和持续时间）增加的危险，某结果可能导致危及生命甚至致死。报道最多的可危及生命或致死性的不良反应包括粘膜炎、腹泻、中性白细胞减少、肾功能不全及电解质紊乱。由于联合用药可致毒性增加的危险，故需慎重调整本品和合用化疗药物的剂量。虽然在用干扰素时常报道伴有流感样综合征的发热，但应排除其他可导致持续发热的病因。
　　下列患者不应使用本品 ：有肝脏失代偿症状的慢性肝炎患者，自身免疫性肝炎或有自身免疫性疾病史的患者，以及用过免疫抑制药接受移植的患者。因本品可使这些患者的肝病恶化。
　　偶见致死性肝脏毒性反应，故对于使用本品期间发生肝功能异常的患者应严密监测，如果症状和体征有所发展，则应停药。
　　对于肝脏代偿失调的患者不应使用本品。对于肝脏合成功能减退的乙肝患者（如白蛋白减少或凝血酶原时间延长）但仍符合用药标准的患者，如果在用药期间转氨酶突然升高，则发生临床肝脏失代偿的危险性增加（见实验室检查项）。在考虑对这些患者是否使用本品治疗时，必须充分权衡其临床效益及其潜在的危险性。
　　有初步资料表明，使用α干扰素可提高排异反应的发生率（肝和肾移植）。
　　由于某些患者在使用本品时可见与失水有关的低血压，故用药病人应保持充足的水分，必要时补液。
　　曾有充血性心力衰竭病史、心肌梗死和（或）以前或现在有心律失常或有艾滋病有关的卡波氏肉瘤的患者，如需使用本品治疗，应严密监护。艾滋病相关的卡波氏肉瘤患者，在使用本品时，罕见一过性可逆的心肌病变报道。对于原有心脏病史和（或）晚期癌症的患者，在用药前和用药期间应作心电图检查。罕见发生心律失常（主要是室上性），并似与其原有心脏疾病或治疗前用过的心脏毒性药物有关。常规疗法往往有效，但可能需考虑调整剂量或停用本品。
　　肺浸润、局限性肺炎和肺炎偶见于用α干扰素包括本品治疗的患者，甚至危及生命。发病机制尚未明确。对于有发热、咳嗽、呼吸困难或其他呼吸系统症状的患者应作胸部X线检查。如果胸部X光检查显示肺浸润或存在肺功能受损的证据，则应严密监护，必要时停药。虽然上述情况往往见于用α干扰素治疗的慢性丙肝患者，但亦见报道发生于用α干扰素治疗的肿瘤患者。立即停用α干扰素并用皮质激素治疗似可使肺部不良反应消失。此外，有报道当α干扰素与中药小柴胡汤联合使用时，上述症状更易发生。
　　对于原有精神疾病特别是抑郁症或曾有严重精神病史患者，不应使用本品。
　　如果发现严重中枢神经系统反应尤其是抑郁症，则应停用本品。某些患者可发生抑郁、意识模糊和其它的精神状态改变等反应。偶见自杀想法或企图自杀。上述不良反应发生于使用本品推荐剂量或较高剂量的患者。老年患者药物剂量较大时，甚至可见较为明显的感觉迟钝和昏迷。虽然这些不良反应一般是可逆的，但少数患者需历时3周才能恢复。使用大剂量本品可发生癫痫发作，但这种情况十分罕见。
　　由于使用α干扰素病人偶见眼科异常，如患者偶见视网膜出血、棉絮状渗出点、视网膜动脉或静脉梗塞（见不良反应），所有病人应在用药前作眼科检查。如果病人有眼科主诉，包括视觉模糊或视野改变，应立即作眼科检查。由于上述眼科主诉有可能与其他状态并存，对于一些可能发生视网膜病变的病人如糖尿病和高血压病人在使用本品时，建议作定期眼科检查。
　　对于甲状腺功能障碍患者，只有当通过治疗使促甲状腺素（TSH）保持在正常范围内时，才可开始或继续使用本品。停用本品并不能逆转用药期间发生的甲状腺功能障碍。
　　据报道，本品可加重原有的牛皮癣病变，故对于牛皮癣患者只有在利大于弊时可采用本品。
　　对于艾滋病有关的卡波氏肉瘤患者，当出现快速进行性内脏病变时不应使用本品。除了齐多夫定，尚无安全性资料说明本品可与逆转录酶抑制药联合使用。本品与齐多夫定合用时，中性粒细胞减少症的发生率较单用齐多夫定时为高。尚未知本品与其他治疗艾滋病的药品合用的疗效。
　　在使用各种α干扰素期间，有报道产生不同的自体抗体。在使用干扰素治疗期间，自体免疫性疾病的临床表现更易发生在有自身免疫性疾病倾向的患者。
　　在公司监测的临床试验中，对接受本品的患者血清样本进行干扰素中和因子的测定。干扰素中和因子为中和干扰素抗病毒活性的抗体。在全身给药时，癌症患者出现中和作用的临床发生率约为3％，慢性肝炎患者为6.2％，因中和抗体滴度低,治疗应答率未下降。几乎所有患者的中和抗体检出滴度均低，尚未发现与临床降低或自身免疫现象有关。
慢性乙肝儿童患者在用本品6 MIU/m2，每周3次治疗时约9％检出血清干扰素中和抗体。检出滴度较低，未见血清抗干扰素中和活性影响本品的安全性或疗效。


 


【 孕妇及哺乳期妇女用药】


　　在恒河猴中的研究中表明，本品剂量为肌肉或皮下注射推荐剂量（2 MIU/m2）的90-180倍时有堕胎作用。虽然各剂量组（7.5 MIU，15 MIU和30 MIU/kg)均出现流产，但与对照组相比，仅在中剂量和高剂量组（相当于肌肉或皮下注射推荐量2 MIU/m2的90-180倍）具有统计学意义。已知高剂量的其它类型的干扰素α或β可使恒河猴产生剂量相关的排卵停止和流产。目前尚未对孕妇进行充分及严格对照的临床研究，只有确实认为本品潜在临床利益大于对胎儿潜在危险性，孕妇才可以使用本品。孕妇不能进行本品膀胱内给药。
　　目前尚不清楚本品是否可以从人乳汁中分泌。由于本品对哺乳期婴儿产生不良反应，因此，应考虑本品对授乳母亲的重要性，决定停止哺乳或停止用药。
　　若本品合用病毒唑治疗慢性丙肝，请参阅病毒唑使用说明书。
　　目前尚不清楚本品是否可以从人乳汁中分泌。由于本品对哺乳期婴儿产生不良反应，因此，应考虑本品对授乳母亲的重要性，决定停止哺乳或停止用药。
若本品合用病毒唑治疗慢性丙肝，请参阅病毒唑使用说明书。


 


【 儿童用药】


对于1岁以上的慢性活动性乙肝患儿，高达10 MIU/m2的剂量是安全的。


【 药物相互作用】


　　应用对乙酰氨基酚（扑热息痛）可成功地缓解应用本品所致的发热和头痛症状。
　　推荐的对乙酰氨基酚剂量为500 mg-1 g，在使用本品前30分钟服用。对乙酰氨基酚的最大剂量为每次1 g，每日4次。
　　本品与麻醉药、催眠药或镇静药合用时应谨慎。
　　尚未有充分数据可评价本品与其他药品之间的相互作用。本品在与其他潜在的骨髓抑制药联合应用时应谨慎。
本品与齐多夫定合用时，可协同增强对白细胞的不良反应，同时接受这两种药物的患者，产生剂量依赖性中性粒细胞减少症的发生率高于单用齐多夫定。


【 药物过量】


　　尚未见过量使用本品的报道，但如同其它具药理活性的化合物一样，当发生药物过量时应对症处理并密切监护生命征象。 


【 用药须知】


　　与其他注射用药一样，本品使用前需肉眼检查是否澄清透明。本品应为无色、澄明液体。
　　本品可用多次剂量笔给药方式进行皮下注射，多次剂量笔是利用简单的刻度原理，将预先灌注的注射液以固定剂量进行多次注射。
　　包装中的针头为多次剂量笔专用，每次注射更换一支新针头。
　　每支注射液、每支多次剂量笔只供一个病人使用。
　　给药前30分钟将多剂量笔从冰箱中取出，以使注射液达到室温（15-25°C）。
　　每支多次剂量笔最多使用4周后必须丢弃。每次注射必须更换新针头。每次给药后，针头应丢弃于安全处，并将多次剂量笔立即放回冰箱中。如果不慎将多次剂量笔遗忘于室温（15-25°C）环境中，4周使用期内于室温下的总放置时间最多为2天（48小时）。
　　本品及多次剂量笔在2-8°C能稳定保存。


 


【 药理作用】


　　临床前细胞培养系统和动物异种肿瘤移植试验结果显示，重组人干扰素α-2b具有抗肿瘤增殖作用，在体外具有明显的免疫调节作用。体外研究还表明，重组干扰素α-2b可抑制病毒复制。
　　干扰素通过与细胞表面的特异性膜受体相结合而产生上述作用。多项研究提示，干扰素一旦与细胞膜受体结合，便可以启动一系列复杂的细胞内过程，其中包括对某些酶的诱导。据认为，这一过程至少在某种程度上导致了干扰素的各种细胞反应，包括抑制病毒感染细胞中病毒的复制、抑制细胞增殖及一系列免疫调节作用，如增强巨噬细胞的吞噬作用和淋巴细胞对靶细胞的特异性细胞毒作用。干扰素的治疗作用涉及以上某种或全部作用机制。
　　在体外抗病毒试验中，α干扰素可抑制人肝胚细胞瘤细胞系（HB611）的乙肝病毒DNA，并能消除持续存在于人胚（肺）成纤维细胞中的甲肝感染。
　　已知干扰素具有种属特异性。 


 


【 毒理研究】


　　干扰素可能损伤生育力。在灵长类动物研究中观察到，使用干扰素的动物月经周期出现异常。据报道，用人白细胞干扰素进行治疗的妇女血清雌二醇和黄体酮的浓度降低。因此除非在用药期间使用有效的避孕措施，育龄妇女不应使用本品。育龄男性应慎用本品。
　　在恒河猴中的研究中表明，本品剂量为肌肉或皮下注射推荐剂量（2 MIU/m2）的90-180倍时有堕胎作用。虽然各剂量组（7.5 MIU,15 MIU和30 MIU/kg)均出现流产，但与对照组相比，仅在中剂量和高剂量组（相当于肌肉或皮下注射推荐量2 MIU/m2的90-180倍）具有统计学意义。已知高剂量的其它类型的干扰素α或β可使恒河猴产生剂量相关的排卵停止和流产。目前尚未对孕妇进行充分及严格对照的临床研究，只有确实认为本品潜在临床利益大于对胎儿潜在危险性，孕妇才可以使用本品。孕妇不能进行本品膀胱内给药。
　　目前尚不清楚本品是否可以从人乳汁中分泌。由于本品对哺乳期婴儿产生不良反应，因此，应考虑本品对授乳母亲的重要性，决定停止哺乳或停止用药。 


 


【 药代动力学】


对健康志愿者进行单次皮下注射Intron A500万IU/m2和1000万IU/m2、肌肉注射500万IU/m2后的药代动力学研究，皮下和肌内注射后的平均血清干扰素浓度可比。
清除滴注干扰素后，滴注时的血清干扰素浓度达峰值，然后迅速下降，滴注后4小时不能测出血清浓度；浓度下降速度比皮下或肌肉注射的快，清除半衰期为2小时左右。
三种给药途径的尿内干扰素浓度都低于检测下限。


【 贮藏】


本品应在2-8°C保存，不宜冷冻。


【 包装】


1支/盒。注射液灌装在一个1.5ml的Ⅰ型燧石玻璃的注射药筒内，一端用带有溴丁基橡胶衬垫的铝帽封口，另一端用溴丁基橡胶塞封口。


【 有效期】


在2-8°C下，可稳定保存15个月。


【 生产企业】


Schering-Plough(Brinny) Co.经美国先灵葆雅公司授权生产

INTRON® A
(interferon alfa-2b, recombinant) for Injection

WARNING

Alpha interferons, including INTRON® A, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping INTRON A therapy. See WARNINGS and ADVERSE REACTIONS.

DESCRIPTION

INTRON® A (Interferon alfa-2b) for intramuscular, subcutaneous, intralesional, or intravenous Injection is a purified sterile recombinant interferon product.

INTRON A recombinant for Injection has been classified as an alpha interferon and is a water-soluble protein with a molecular weight of 19,271 daltons produced by recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid containing an interferon alfa2b gene from human leukocytes. The fermentation is carried out in a defined nutrient medium containing the antibiotic tetracycline hydrochloride at a concentration of 5 to 10 mg/L; the presence of this antibiotic is not detectable in the final product. The specific activity of interferon alfa-2b, recombinant is approximately 2.6 x 108 IU/mg protein as measured by the HPLC assay.

Powder for Injection

Prior to administration, the INTRON A Powder for Injection is to be reconstituted with the provided Diluent for INTRON A (Sterile Water for Injection USP) (see DOSAGE AND ADMINISTRATION). INTRON A Powder for Injection is a white to cream-colored powder.

Solution Vials for Injection

These packages do not require reconstitution prior to administration (see DOSAGE AND ADMINISTRATION). INTRON A Solution for Injection is a clear, colorless solution.

Indications

INDICATIONSHairy Cell Leukemia

INTRON® A is indicated for the treatment of patients 18 years of age or older with hairy cell leukemia.

Malignant Melanoma

INTRON A is indicated as adjuvant to surgical treatment in patients 18 years of age or older with malignant melanoma who are free of disease but at high risk for systemic recurrence, within 56 days of surgery.

Follicular Lymphoma

INTRON A is indicated for the initial treatment of clinically aggressive (see CLINICAL PHARMACOLOGY) follicular Non-Hodgkin's Lymphoma in conjunction with anthracycline-containing combination chemotherapy in patients 18 years of age or older. Efficacy of INTRON A therapy in patients with low-grade, lowtumor burden follicular Non-Hodgkin's Lymphoma has not been demonstrated.

Condylomata Acuminata

INTRON A is indicated for intralesional treatment of selected patients 18 years of age or older with condylomata acuminata involving external surfaces of the genital and perianal areas (see DOSAGE AND ADMINISTRATION).

The use of this product in adolescents has not been studied.

AIDS-Related Kaposi's Sarcoma

INTRON A is indicated for the treatment of selected patients 18 years of age or older with AIDS-Related Kaposi's Sarcoma. The likelihood of response to INTRON A therapy is greater in patients who are without systemic symptoms, who have limited lymphadenopathy and who have a relatively intact immune system as indicated by total CD4 count.

Chronic Hepatitis C

INTRON A is indicated for the treatment of chronic hepatitis C in patients 18 years of age or older with compensated liver disease who have a history of blood or blood-product exposure and/or are HCV antibody positive. Studies in these patients demonstrated that INTRON A therapy can produce clinically meaningful effects on this disease, manifested by normalization of serum alanine aminotransferase (ALT) and reduction in liver necrosis and degeneration.

A liver biopsy should be performed to establish the diagnosis of chronic hepatitis. Patients should be tested for the presence of antibody to HCV. Patients with other causes of chronic hepatitis, including autoimmune hepatitis, should be excluded. Prior to initiation of INTRON A therapy, the physician should establish that the patient has compensated liver disease. The following patient entrance criteria for compensated liver disease were used in the clinical studies and should be considered before INTRON A treatment of patients with chronic hepatitis C:

· No history of hepatic encephalopathy, variceal bleeding, ascites, or other clinical signs of decompensation

· Bilirubin Less than or equal to 2 mg/dL

· Albumin Stable and within normal limits

· Prothrombin Time Less than 3 seconds prolonged

· WBC Greater than or equal to 3000/mm³

· Platelets Greater than or equal to 70,000/mm³

Serum creatinine should be normal or near normal.

Prior to initiation of INTRON A therapy, CBC and platelet counts should be evaluated in order to establish baselines for monitoring potential toxicity. These tests should be repeated at Weeks 1 and 2 following initiation of INTRON A therapy, and monthly thereafter. Serum ALT should be evaluated at approximately 3-month intervals to assess response to treatment (see DOSAGE AND ADMINISTRATION).

Patients with preexisting thyroid abnormalities may be treated if thyroidstimulating hormone (TSH) levels can be maintained in the normal range by medication. TSH levels must be within normal limits upon initiation of INTRON A treatment and TSH testing should be repeated at 3 and 6 months (see PRECAUTIONS, Laboratory Tests).

INTRON A in combination with REBETOL® is indicated for the treatment of chronic hepatitis C in patients 3 years of age and older with compensated liver disease previously untreated with alpha interferon therapy and in patients 18 years of age and older who have relapsed following alpha interferon therapy. See REBETOL prescribing information for additional information.

Chronic Hepatitis B

INTRON A is indicated for the treatment of chronic hepatitis B in patients 1 year of age or older with compensated liver disease. Patients who have been serum HBsAg positive for at least 6 months and have evidence of HBV replication (serum HBeAg positive) with elevated serum ALT are candidates for treatment. Studies in these patients demonstrated that INTRON A therapy can produce virologic remission of this disease (loss of serum HBeAg) and normalization of serum aminotransferases. INTRON A therapy resulted in the loss of serum HBsAg in some responding patients.

Prior to initiation of INTRON A therapy, it is recommended that a liver biopsy be performed to establish the presence of chronic hepatitis and the extent of liver damage. The physician should establish that the patient has compensated liver disease. The following patient entrance criteria for compensated liver disease were used in the clinical studies and should be considered before INTRON A treatment of patients with chronic hepatitis B:

· No history of hepatic encephalopathy, variceal bleeding, ascites, or other signs of clinical decompensation

· Bilirubin Normal

· Albumin Stable and within normal limits

· Prothrombin Time Adults less than 3 seconds prolonged
Pediatrics less than or equal to 2 seconds prolonged

· WBC Greater than or equal to 4000/mm³

· Platelets Adults greater than or equal to 100,000/mm³
Pediatrics greater than or equal to 150,000/mm³

Patients with causes of chronic hepatitis other than chronic hepatitis B or chronic hepatitis C should not be treated with INTRON A. CBC and platelet counts should be evaluated prior to initiation of INTRON A therapy in order to establish baselines for monitoring potential toxicity. These tests should be repeated at treatment Weeks 1, 2, 4, 8, 12, and 16. Liver function tests, including serum ALT, albumin, and bilirubin, should be evaluated at treatment Weeks 1, 2, 4, 8, 12, and 16. HBeAg, HBsAg, and ALT should be evaluated at the end of therapy, as well as 3- and 6-months posttherapy, since patients may become virologic responders during the 6-month period following the end of treatment. In clinical studies in adults, 39% (15/38) of responding patients lost HBeAg 1 to 6 months following the end of INTRON A therapy. Of responding patients who lost HBsAg, 58% (7/12) did so 1 to 6 months post-treatment.

A transient increase in ALT greater than or equal to 2 times baseline value (flare) can occur during INTRON A therapy for chronic hepatitis B. In clinical trials in adults and pediatrics, this flare generally occurred 8 to 12 weeks after initiation of therapy and was more frequent in responders (adults 63%, 24/38; pediatrics 59%, 10/17) than in nonresponders (adults 27%, 13/48; pediatrics 35%, 19/55). However, in adults and pediatrics, elevations in bilirubin greater than or equal to 3 mg/dL (greater than or equal to 2 times ULN) occurred infrequently (adults 2%, 2/86; pediatrics 3%, 2/72) during therapy. When ALT flare occurs, in general, INTRON A therapy should be continued unless signs and symptoms of liver failure are observed. During ALT flare, clinical symptomatology and liver function tests including ALT, prothrombin time, alkaline phosphatase, albumin, and bilirubin, should be monitored at approximately 2-week intervals (see WARNINGS).

Dosage

DOSAGE AND ADMINISTRATIONGeneralIMPORTANT

INTRON® A is supplied as 1) Powder for Injection/Reconstitution; 2) Solution for Injection in Vials. Not all dosage forms and strengths are appropriate for some indications. It is important that you carefully read the instructions below for the indication you are treating to ensure you are using an appropriate dosage form and strength.

To enhance the tolerability of INTRON A, injections should be administered in the evening when possible.

To reduce the incidence of certain adverse reactions, acetaminophen may be administered at the time of injection.

The solution should be allowed to come to room temperature before using.

Hairy Cell Leukemia

(see General)

Dose

The recommended dose for the treatment of hairy cell leukemia is 2 million IU/m² administered intramuscularly or subcutaneously 3 times a week for up to 6 months. Patients with platelet counts of less than 50,000/mm³ should not be administered INTRON A intramuscularly, but instead by subcutaneous administration. Patients who are responding to therapy may benefit from continued treatment.

Dosage Forms For This Indication

NOTE: INTRON A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

Dose Adjustment

· If severe adverse reactions develop, the dosage should be modified (50% reduction) or therapy should be temporarily withheld until the adverse reactions abate and then resume at 50% (1 MIU/m² TIW).

· If severe adverse reactions persist or recur following dosage adjustment, INTRON A should be permanently discontinued.

· INTRON A should be discontinued for progressive disease or failure to respond after six months of treatment.

Malignant Melanoma

(see DOSAGE AND ADMINISTRATION, General)

INTRON A adjuvant treatment of malignant melanoma is given in two phases, induction and maintenance.

Induction Recommended Dose

The recommended daily dose of INTRON A in induction is 20 million IU/m² as an intravenous infusion, over 20 minutes, 5 consecutive days per week, for 4 weeks (see Dose Adjustment below).

Dosage Forms for This Indication

NOTE: INTRON A Solution for Injection in vials is NOT recommended for intravenous administration and should not be used for the induction phase of malignant melanoma.

NOTE: INTRON A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

Dose Adjustment

NOTE: Regular laboratory testing should be performed to monitor laboratory abnormalities for the purpose of dose modifications (see PRECAUTIONS, Laboratory Tests).

· INTRON A should be withheld for severe adverse reactions, including granulocyte counts greater than 250/mm³ but less than 500/mm³ or SGPT/SGOT greater than 5- 10x upper limit of normal, until adverse reactions abate. INTRON A treatment should be restarted at 50% of the previous dose.

· INTRON A should be permanently discontinued for:

o Toxicity that does not abate after withholding INTRON A

o Severe adverse reactions which recur in patients receiving reduced doses of INTRON A

o Granulocyte count less than 250/mm³ or SGPT/SGOT of greater than 10x upper limit of normal

Maintenance Recommended Dose

The recommended dose of INTRON A for maintenance is 10 million IU/m² as a subcutaneous injection three times per week for 48 weeks (see Dose Adjustment below).

Dosage Forms for This Indication

NOTE: INTRON A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose. Dose Adjustment: NOTE: Regular laboratory testing should be performed to monitor laboratory abnormalities for the purpose of dose modifications (see PRECAUTIONS, Laboratory Tests).

· INTRON A should be withheld for severe adverse reactions, including granulocyte counts greater than 250/mm³ but less than 500/mm³ or SGPT/SGOT greater than 5- 10x upper limit of normal, until adverse reactions abate. INTRON A treatment should be restarted at 50% of the previous dose.

· INTRON A should be permanently discontinued for:

o Toxicity that does not abate after withholding INTRON A

o Severe adverse reactions which recur in patients receiving reduced doses of INTRON A

o Granulocyte count less than 250/mm³ or SGPT/SGOT of greater than 10x upper limit of normal

Follicular Lymphoma

(see General)

Dose

The recommended dose of INTRON A for the treatment of follicular lymphoma is 5 million IU subcutaneously three times per week for up to 18 months in conjunction with anthracycline-containing chemotherapy regimen and following completion of the chemotherapy regimen.

Dosage Forms for This Indication

NOTE: INTRON A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

Dose Adjustment

· Doses of myelosuppressive drugs were reduced by 25% from a full-dose CHOP regimen, and cycle length increased by 33% (e.g., from 21 to 28 days) when alpha interferon was added to the regimen.

· Delay chemotherapy cycle if neutrophil count was less than 1500/mm³ or platelet count was less than 75,000/mm³.

· INTRON A should be permanently discontinued if SGOT exceeds greater than 5x the upper limit of normal or serum creatinine greater than 2.0 mg/dL (see WARNINGS).

· Administration of INTRON A therapy should be withheld for a neutrophil count less than 1000/mm³, or a platelet count less than 50,000/mm³.

· INTRON A dose should be reduced by 50% (2.5 MIU TIW) for a neutrophil count greater than 1000/mm³, but less than 1500/mm³. The INTRON A dose may be reescalated to the starting dose (5 million IU TIW) after resolution of hematologic toxicity (ANC greater than 1500/mm³).

Condylomata Acuminata

(see General)

Dose

The recommended dose is 1.0 million IU per lesion in a maximum of 5 lesions in a single course. The lesions should be injected three times weekly on alternate days for 3 weeks. An additional course may be administered at 12 to 16 weeks.

Dosage Forms for This Indication

NOTE: INTRON A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

NOTE: Do not use the following formulations for this indication:

the 18 million or 50 million IU Powder for Injection

the 18 million IU multidose INTRON A Solution for Injection

Dose Adjustment

None

Technique For Injection

The injection should be administered intralesionally using a Tuberculin or similar syringe and a 25- to 30-gauge needle. The needle should be directed at the center of the base of the wart and at an angle almost parallel to the plane of the skin (approximately that in the commonly used PPD test). This will deliver the interferon to the dermal core of the lesion, infiltrating the lesion and causing a small wheal. Care should be taken not to go beneath the lesion too deeply; subcutaneous injection should be avoided, since this area is below the base of the lesion. Do not inject too superficially since this will result in possible leakage, infiltrating only the keratinized layer and not the dermal core.

AIDS-Related Kaposi’s Sarcoma

(see General)

Dose

The recommended dose of INTRON A for Kaposi's Sarcoma is 30 million IU/m²/dose administered subcutaneously or intramuscularly three times a week until disease progression or maximal response has been achieved after 16 weeks of treatment. Dose reduction is frequently required (see Dose Adjustment below).

Dosage Forms for This Indication

NOTE: INTRON A Solution for Injection in vials should NOT be used for AIDSRelated Kaposi’s Sarcoma.

NOTE: INTRON A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

Dose Adjustment

· INTRON A dose should be reduced by 50% or withheld for severe adverse reactions.

· INTRON A may be resumed at a reduced dose if severe adverse reactions abate with interruption of dosing.

· INTRON A should be permanently discontinued if severe adverse reactions persist or if they recur in patients receiving a reduced dose.

Chronic Hepatitis C

(see General)

Dose

The recommended dose of INTRON A for the treatment of chronic hepatitis C is 3 million IU three times a week (TIW) administered subcutaneously or intramuscularly. In patients tolerating therapy with normalization of ALT at 16 weeks of treatment, INTRON A therapy should be extended to 18 to 24 months (72 to 96 weeks) at 3 million IU TIW to improve the sustained response rate (see CLINICAL PHARMACOLOGY, Chronic Hepatitis C). Patients who do not normalize their ALTs or have persistently high levels of HCV RNA after 16 weeks of therapy rarely achieve a sustained response with extension of treatment. Consideration should be given to discontinuing these patients from therapy.

When INTRON A is administered in combination with REBETOL®, patients with impaired renal function and/or those over the age of 50 should be carefully monitored with respect to the development of anemia. See REBETOL prescribing information for dosing when used in combination with REBETOL for adults and pediatric patients.

Dosage Forms for This Indication

Dose Adjustment

If severe adverse reactions develop during INTRON A treatment, the dose should be modified (50% reduction) or therapy should be temporarily discontinued until the adverse reactions abate. If intolerance persists after dose adjustment, INTRON A therapy should be discontinued.

Chronic Hepatitis B

Adults

(see DOSAGE AND ADMINISTRATION, General)

Dose

The recommended dose of INTRON A for the treatment of chronic hepatitis B is 30 to 35 million IU per week, administered subcutaneously or intramuscularly, either as 5 million IU daily (QD) or as 10 million IU three times a week (TIW) for 16 weeks.

Dosage Forms for This Indication

NOTE: INTRON A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

Adults – HCV/HBV co-infection

The safety and efficacy of Intron A alone or in combination with boceprevir or ribavirin for the treatment of chronic hepatitis C genotype 1 infection in patients co-infected with hepatitis B virus(HBV) and HCV have not been studied.

Chronic Hepatitis B

Pediatrics

(see General)

Dose

The recommended dose of INTRON A for the treatment of chronic hepatitis B is 3 million IU/m² three times a week (TIW) for the first week of therapy followed by dose escalation to 6 million IU/m² TIW (maximum of 10 million IU TIW) administered subcutaneously for a total duration of 16 to 24 weeks.

Dosage Forms for This Indication

NOTE: INTRON A Powder for Injection does not contain a preservative. The vial must be discarded after reconstitution and withdrawal of a single dose.

Dose Adjustment

If severe adverse reactions or laboratory abnormalities develop during INTRON A therapy, the dose should be modified (50% reduction) or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, INTRON A therapy should be discontinued.

For patients with decreases in white blood cell, granulocyte or platelet counts, the following guidelines for dose modification should be followed:

INTRON A therapy was resumed at up to 100% of the initial dose when white blood cell, granulocyte, and/or platelet counts returned to normal or baseline values.

Preparation And AdministrationReconstitution Of INTRON® A Powder For Injection

Reconstitute INTRON A Powder for Injection with 1 mL of Sterile Water for Injection, USP. The Sterile Water for Injection supplied contains 5 mL and is intended for single use. Discard the unused portion. The reconstituted solution is clear and colorless to light yellow. The INTRON A powder reconstituted with Sterile Water for Injection USP is a single-use vial and does not contain a preservative. DO NOT REENTER VIAL AFTER WITHDRAWING THE DOSE. DISCARD UNUSED PORTION. Once the dose from the single-dose vial has been withdrawn, the sterility of any remaining product can no longer be guaranteed. Pooling of unused portions of some medications has been linked to bacterial contamination and morbidity.

Intramuscular, Subcutaneous, Or Intralesional Administration

Inject 1 mL Diluent (Sterile Water for Injection USP) for INTRON A into the INTRON A vial. Swirl gently to hasten complete dissolution of the powder. The appropriate INTRON A dose should then be withdrawn and injected intramuscularly, subcutaneously, or intralesionally (see Medication Guide and Instructions for Use for detailed instructions).

Please refer to the MEDICATION GUIDE and Instructions for Use for detailed, step-by-step instructions on how to inject the INTRON A dose. After preparation and administration of the INTRON A injection, it is essential to follow the procedure for proper disposal of syringes and needles (see Medication Guide and Instructions for Use for detailed instructions).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Intravenous Infusion

The infusion solution should be prepared immediately prior to use. Based on the desired dose, the appropriate vial strength(s) of INTRON A should be reconstituted with the diluent provided. Inject 1 mL Diluent (Sterile Water for Injection USP) for INTRON A into the INTRON A vial. Swirl gently to hasten complete dissolution of the powder. The appropriate INTRON A dose should then be withdrawn and injected into a 100-mL bag of 0.9% Sodium Chloride Injection USP. The final concentration of INTRON A should not be less than 10 million IU/100 mL.

INTRON A Solution For Injection In Vials

INTRON A Solution for Injection is supplied in two multidose vials. The solutions for injection do not require reconstitution prior to administration; the solution is clear and colorless.

The appropriate dose should be withdrawn from the vial and injected intramuscularly, subcutaneously, or intralesionally.

INTRON A Solution for Injection is not recommended for intravenous administration.

Please refer to the MEDICATION GUIDE and Instructions for Use for detailed, step-by-step instructions on how to inject the INTRON A dose. After preparation and administration of INTRON A, it is essential to follow the procedure for proper disposal of syringes and needles.

HOW SUPPLIEDINTRON® A Powder For Injection

INTRON A Powder for Injection, 10 million IU per vial and Diluent for INTRON A (Sterile Water for Injection USP) 5 mL per vial; boxes containing 1 INTRON A vial and 1 vial of INTRON A Diluent (NDC0085-4350-01).

INTRON A Powder for Injection, 18 million IU per vial and Diluent for INTRON A (Sterile Water for Injection USP) 5 mL per vial; boxes containing 1 vial of INTRON A and 1 vial of INTRON A Diluent (NDC0085-4351-01).

INTRON A Powder for Injection, 50 million IU per vial and Diluent for INTRON A (Sterile Water for Injection USP) 5 mL per vial; boxes containing 1 INTRON A vial and 1 vial of INTRON A Diluent (NDC0085-4352-01).

INTRON A Solution For Injection In Vials

INTRON A Solution for Injection, 18 million IU multidose vial (22.8 million IU per 3.8 mL per vial); boxes containing 1 vial of INTRON A Solution for Injection (NDC 0085- 1168-01).

INTRON A Solution for Injection, 25 million IU multidose vial (32 million IU per 3.2 mL per vial); boxes containing 1 vial of INTRON A Solution for Injection (NDC 0085- 1133-01).

StorageINTRON A Powder For Injection/Reconstitution

INTRON A Powder for Injection should be stored in the refrigerator at 2° to 8°C (36°- 46°F). After reconstitution, the solution should be used immediately, but may be stored up to 24 hours at 2° to 8°C (36°-46°F). Throw away any medicine left in the vial after you withdraw 1 dose.

INTRON A Solution For Injection In Vials

INTRON A Solution for Injection in vials should be stored in the refrigerator at 2° to 8°C (36°-46°F).

INTRON A Solution for Injection should not be frozen and should be kept away from heat. Throw away any unused INTRON A Solution for Injection remaining in the vial after one month.

REFERENCES

4. Schiller J, et al. J Biol Response Mod. 1989;8:252-261.

11. Kauppila A, et al. Int J Cancer. 1982;29:291-294.

Manufactured by: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. Revised: May 2018

Side Effects & Drug Interactions

SIDE EFFECTSGeneral

The adverse experiences listed below were reported to be possibly or probably related to INTRON® A therapy during clinical trials. Most of these adverse reactions were mild to moderate in severity and were manageable. Some were transient and most diminished with continued therapy.

The most frequently reported adverse reactions were “flu-like” symptoms, particularly fever, headache, chills, myalgia, and fatigue. More severe toxicities are observed generally at higher doses and may be difficult for patients to tolerate.

TREATMENT-RELATED ADVERSE EXPERIENCES BY INDICATION

Hairy Cell Leukemia

The adverse reactions most frequently reported during clinical trials in 145 patients with hairy cell leukemia were the “flu-like” symptoms of fever (68%), fatigue (61%), and chills (46%).

Malignant Melanoma

The INTRON A dose was modified because of adverse events in 65% (n=93) of the patients. INTRON A therapy was discontinued because of adverse events in 8% of the patients during induction and 18% of the patients during maintenance. The most frequently reported adverse reaction was fatigue, which was observed in 96% of patients. Other adverse reactions that were recorded in greater than 20% of INTRON A-treated patients included neutropenia (92%), fever (81%), myalgia (75%), anorexia(69%), vomiting/nausea (66%), increased SGOT (63%), headache (62%), chills (54%), depression (40%), diarrhea (35%), alopecia (29%), altered taste sensation (24%), dizziness/vertigo (23%), and anemia (22%).

Adverse reactions classified as severe or life threatening (ECOG Toxicity Criteria grade 3 or 4) were recorded in 66% and 14% of INTRON A-treated patients, respectively. Severe adverse reactions recorded in greater than 10% of INTRON Atreated patients included neutropenia/leukopenia (26%), fatigue (23%), fever (18%), myalgia (17%), headache (17%), chills (16%), and increased SGOT (14%). Grade 4 fatigue was recorded in 4% and grade 4 depression was recorded in 2% of INTRON Atreated patients. No other grade 4 AE was reported in more than 2 INTRON A-treated patients. Lethalhepatotoxicity occurred in 2 INTRON A-treated patients early in the clinical trial. No subsequent lethal hepatotoxicities were observed with adequate monitoring of liver function tests (see PRECAUTIONS, Laboratory Tests).

Follicular Lymphoma

Ninety-six percent of patients treated with CHVP plus INTRON A therapy and 91% of patients treated with CHVP alone reported an adverse event of any severity. Asthenia, fever, neutropenia, increased hepatic enzymes, alopecia, headache, anorexia, “flu-like” symptoms, myalgia, dyspnea, thrombocytopenia, paresthesia, and polyuria occurred more frequently in the CHVP plus INTRON A-treated patients than in patients treated with CHVP alone. Adverse reactions classified as severe or life threatening (World Health Organization grade 3 or 4) recorded in greater than 5% of CHVP plus INTRON A-treated patients included neutropenia (34%), asthenia (10%), and vomiting (10%). The incidence of neutropenic infection was 6% in CHVP plus INTRON A versus 2% in CHVP alone. One patient in each treatment group required hospitalization.

Twenty-eight percent of CHVP plus INTRON A-treated patients had a temporary modification/interruption of their INTRON A therapy, but only 13 patients (10%) permanently stopped INTRON A therapy because of toxicity. There were four deaths on study; two patients committed suicide in the CHVP plus INTRON A arm and two patients in the CHVP arm had unwitnessed sudden death. Three patients with hepatitis B (one of whom also had alcoholic cirrhosis) developed hepatotoxicity leading to discontinuation of INTRON A. Other reasons for discontinuation included intolerable asthenia (5/135), severe flu symptoms (2/135), and one patient each with exacerbation of ankylosing spondylitis, psychosis, and decreased ejection fraction.

Condylomata Acuminata

Eighty-eight percent (311/352) of patients treated with INTRON A for condylomata acuminata who were evaluable for safety reported an adverse reaction during treatment. The incidence of the adverse reactions reported increased when the number of treated lesions increased from one to five. All 40 patients who had five warts treated reported some type of adverse reaction during treatment.

Adverse reactions and abnormal laboratory test values reported by patients who were re-treated were qualitatively and quantitatively similar to those reported during the initial INTRON A treatment period.

AIDS-Related Kaposi's Sarcoma

In patients with AIDS-Related Kaposi's Sarcoma, some type of adverse reaction occurred in 100% of the 74 patients treated with 30 million IU/m² three times a week and in 97% of the 29 patients treated with 35 million IU per day.

Of these adverse reactions, those classified as severe (World Health Organization grade 3 or 4) were reported in 27% to 55% of patients. Severe adverse reactions in the 30 million IU/m² TIW study included: fatigue (20%), influenza-like symptoms (15%), anorexia (12%), dry mouth (4%), headache (4%), confusion (3%), fever (3%), myalgia (3%), and nausea and vomiting (1% each). Severe adverse reactions for patients who received the 35 million IU QD included: fever (24%), fatigue (17%), influenza-like symptoms (14%), dyspnea (14%), headache (10%), pharyngitis (7%), and ataxia, confusion, dysphagia, GI hemorrhage, abnormal hepatic function, increased SGOT, myalgia, cardiomyopathy, face edema, depression, emotional lability, suicide attempt, chest pain, and coughing (1 patient each). Overall, the incidence of severe toxicity was higher among patients who received the 35 million IU per day dose.

Chronic Hepatitis C

Adults

Two studies of extended treatment (18-24 months) with INTRON A show that approximately 95% of all patients treated experience some type of adverse event and that patients treated for extended duration continue to experience adverse events throughout treatment. Most adverse events reported are mild to moderate in severity. However, 29/152 (19%) of patients treated for 18 to 24 months experienced a serious adverse event compared to 11/163 (7%) of those treated for 6 months. Adverse events which occur or persist during extended treatment are similar in type and severity to those occurring during short-course therapy.

Of the patients achieving a complete response after 6 months of therapy, 12/79 (15%) subsequently discontinued INTRON A treatment during extended therapy because of adverse events, and 23/79 (29%) experienced severe adverse events (WHO grade 3 or 4) during extended therapy.

In patients using combination treatment with INTRON A and REBETOL, the primary toxicity observed was hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of therapy. Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients treated with INTRON A/REBETOL therapy. See REBETOL prescribing information for additional information.

Chronic Hepatitis C

Pediatrics

In pediatric patients with chronic hepatitis C treated with INTRON A 3 MIU/m² three times weekly and REBETOL 15 mg/kg per day, all subjects (n=118) had at least one adverse event during 24-48 weeks of treatment, of which 80% were considered to be mild or moderate in severity. Six percent discontinued therapy due to adverse reactions and dose modifications were required in 30% of subjects, most commonly for anemia and neutropenia. Adverse events occurring in more than 50% of subjects included headache, fever, fatigue and anorexia. Adverse events occurring in 20-50% of subjects included influenza-like symptoms, abdominal pain, vomiting, nausea, myalgia, pharyngitis, diarrhea, viral infection, rigors, weight decrease, musculoskeletal pain, alopecia and dizziness. The most common laboratory test abnormalities were neutropenia (34%) and anemia (27%). Depression was reported in 13% (n=15) of children. Three of these subjects had suicidal ideation, and one attempted suicide. Weight loss and slowed growth are common in pediatric patients during combination therapy with INTRON A and REBETOL. Following treatment, rebound growth and weight gain occurred in most subjects. Long-term follow-up data in pediatric subjects, however, indicates that INTRON A in combination with REBETOL may induce a growth inhibition that results in reduced adult height in some patients (see PRECAUTIONS, Pediatric Use).

Chronic Hepatitis B

Adults

In patients with chronic hepatitis B, some type of adverse reaction occurred in 98% of the 101 patients treated at 5 million IU QD and 90% of the 78 patients treated at 10 million IU TIW. Most of these adverse reactions were mild to moderate in severity, were manageable, and were reversible following the end of therapy.

Adverse reactions classified as severe (causing a significant interference with normal daily activities or clinical state) were reported in 21% to 44% of patients. The severe adverse reactions reported most frequently were the “flu-like” symptoms of fever (28%), fatigue (15%), headache (5%), myalgia (4%), rigors (4%), and other severe “flulike” symptoms, which occurred in 1% to 3% of patients. Other severe adverse reactions occurring in more than one patient were alopecia (8%), anorexia (6%), depression (3%), nausea (3%), and vomiting (2%).

To manage side effects, the dose was reduced, or INTRON A therapy was interrupted in 25% to 38% of patients. Five percent of patients discontinued treatment due to adverse experiences.

Chronic Hepatitis B

Pediatrics

In pediatric patients with chronic hepatitis B (n=72) during 16-24 weeks of treatment, the most frequently reported adverse events were those commonly associated with interferon treatment: flu-like symptoms (100%), gastrointestinal system disorders (46%), and nausea and vomiting (40%). Neutropenia (13%) and thrombocytopenia (3%) were also reported. None of the adverse events was life threatening and most were moderate to severe and resolved upon dose reduction or drug discontinuation.

ABNORMAL LABORATORY TEST VALUES BY INDICATION

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of INTRON A alone or in combination with REBETOL. 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

pancytopenia (concurrent anemia, leukopenia, thrombocytopenia), aplastic anemia, pure red cell aplasia, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura

Cardiac Disorders

pericarditis

Ear and Labyrinth Disorders

hearing loss

Endocrine Disorders

hypopituitarism

Eye Disorders

Vogt-Koyanagi-Harada syndrome, serous retinal detachment

Gastrointestinal Disorders

pancreatitis, tongue pigmentation

General Disorders and Administration Site Conditions

asthenic conditions (including asthenia, malaise, fatigue)

Immune System Disorders

cases of acute hypersensitivity reactions, including anaphylaxis and angioedema, systemic lupus erythematosus, sarcoidosis or exacerbation of sarcoidosis

Infections and Infestations

hepatitis B virus reactivation in HCV/HBV co-infected patients

Musculoskeletal and Connective Tissue Disorders

myositis

Nervous System Disorders

peripheral neuropathy

Psychiatric Disorders

homicidal ideation, psychosis including hallucinations

Renal and Urinary Disorders

renal failure, renal insufficiency, nephrotic syndrome

Respiratory, Thoracic, and Mediastinal Disorders

pulmonary hypertension, pulmonary fibrosis

Skin and Subcutaneous Tissue Disorders

injection site necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, urticaria

DRUG INTERACTIONS

Interactions between INTRON A and other drugs have not been fully evaluated. Caution should be exercised when administering INTRON A therapy in combination with other potentially myelosuppressive agents such as zidovudine. Concomitant use of alpha interferon and theophylline decreases theophylline clearance, resulting in a 100% increase in serum theophylline levels.

Warnings

WARNINGSGeneral

Moderate to severe adverse experiences may require modification of the patient's dosage regimen, or in some cases termination of INTRON® A therapy. Because of the fever and other “flu-like” symptoms associated with INTRON A administration, it should be used cautiously in patients with debilitating medical conditions, such as those with a history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone to ketoacidosis. Caution should also be observed in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Cardiovascular Disorders

INTRON A therapy should be used cautiously in patients with a history of cardiovascular disease. Those patients with a history of myocardial infarction and/or previous or current arrhythmic disorder who require INTRON A therapy should be closely monitored (see PRECAUTIONS, Laboratory Tests). Cardiovascular adverse experiences, which include hypotension, arrhythmia, or tachycardia of 150 beats per minute or greater, and rarely, cardiomyopathy and myocardial infarction have been observed in some INTRON A-treated patients. Some patients with these adverse events had no history of cardiovascular disease. Transient cardiomyopathy was reported in approximately 2% of the AIDS-Related Kaposi's Sarcoma patients treated with INTRON A. Hypotension may occur during INTRON A administration, or up to 2 days post-therapy, and may require supportive therapy including fluid replacement to maintain intravascular volume.

Supraventricular arrhythmias occurred rarely and appeared to be correlated with preexisting conditions and prior therapy with cardiotoxic agents. These adverse experiences were controlled by modifying the dose or discontinuing treatment, but may require specific additional therapy.

Cerebrovascular Disorders

Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alpha-based therapies, including INTRON A. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and a causal relationship between interferon alpha-based therapies and these events is difficult to establish.

Neuropsychiatric Disorders

DEPRESSION AND SUICIDAL BEHAVIOR INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND COMPLETED SUICIDES, HOMICIDAL IDEATION, AND AGGRESSIVE BEHAVIOR SOMETIMES DIRECTED TOWARDS OTHERS, HAVE BEEN REPORTED IN ASSOCIATION WITH TREATMENT WITH ALPHA INTERFERONS, INCLUDING INTRON A THERAPY. If patients develop psychiatric problems, including clinical depression, it is recommended that the patients be carefully monitored during treatment and in the 6-month follow-up period.

INTRON A should be used with caution in patients with a history of psychiatric disorders. INTRON A therapy should be discontinued for any patient developing severe psychiatric disorder during treatment. Obtundation and coma have also been observed in some patients, usually elderly, treated at higher doses. While these effects are usually rapidly reversible upon discontinuation of therapy, full resolution of symptoms has taken up to 3 weeks in a few severe episodes. If psychiatric symptoms persist or worsen, or suicidal or homicidal ideation or aggressive behavior towards others is identified, discontinue treatment with INTRON A and follow the patient closely, with psychiatric intervention as appropriate. Narcotics, hypnotics, or sedatives may be used concurrently with caution and patients should be closely monitored until the adverse effects have resolved. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up. Cases of encephalopathy have also been observed in some patients, usually elderly, treated with higher doses of INTRON A.

Treatment with interferons may be associated with exacerbated symptoms of psychiatric disorders in patients with co-occurring psychiatric and substance use disorders. If treatment with interferons is initiated in patients with prior history or existence of psychiatric condition or with a history of substance use disorders, treatment considerations should include the need for drug screening and periodic health evaluation, including psychiatric symptom monitoring. Early intervention for reemergence or development of neuropsychiatric symptoms and substance use is recommended.

Bone Marrow Toxicity

INTRON A therapy suppresses bone marrow function and may result in severe cytopenias including aplastic anemia. It is advised that complete blood counts (CBC) be obtained pretreatment and monitored routinely during therapy (see PRECAUTIONS, Laboratory Tests). INTRON A therapy should be discontinued in patients who develop severe decreases in neutrophil (less than 0.5 x 109/L) or platelet counts (less than 25 x 109/L) (see DOSAGE AND ADMINISTRATION, Guidelines for Dose Modification).

Ophthalmologic Disorders

Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots; optic neuritis, papilledema, and serous retinal detachment may be induced or aggravated by treatment with interferon alfa-2b or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocularsymptoms should receive a prompt and complete eye examination. Interferon alfa-2b treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Endocrine Disorders

Infrequently, patients receiving INTRON A therapy developed thyroid abnormalities, either hypothyroid or hyperthyroid. The mechanism by which INTRON A may alter thyroid status is unknown. Patients with preexisting thyroid abnormalities whose thyroid function cannot be maintained in the normal range by medication should not be treated with INTRON A. Prior to initiation of INTRON A therapy, serum TSH should be evaluated. Patients developing symptoms consistent with possible thyroid dysfunction during the course of INTRON A therapy should have their thyroid function evaluated and appropriate treatment instituted. Therapy should be discontinued for patients developing thyroid abnormalities during treatment whose thyroid function cannot be normalized by medication. Discontinuation of INTRON A therapy has not always reversed thyroid dysfunction occurring during treatment. Diabetes mellitus has been observed in patients treated with alpha interferons. Patients with these conditions who cannot be effectively treated by medication should not begin INTRON A therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should not continue INTRON A therapy.

Gastrointestinal Disorders

Hepatotoxicity, including fatality, has been observed in interferon alpha-treated patients, including those treated with INTRON A. INTRON A increases the risk of hepatic decompensation and death in patients with cirrhosis. Any patient developing liver function abnormalities during treatment should be monitored closely and if appropriate, treatment should be discontinued.

Pulmonary Disorders

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by INTRON A or other alpha interferons. Recurrence of respiratory failure has been observed with interferon rechallenge. The etiologic explanation for these pulmonary findings has yet to be established. Any patient developing fever, cough, dyspnea, or other respiratory symptoms should have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient should be closely monitored, and, if appropriate, interferon alpha treatment should be discontinued. While this has been reported more often in patients with chronic hepatitis C treated with interferon alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha.

Autoimmune Disorders

Rare cases of autoimmune diseases including thrombocytopenia, vasculitis, Raynaud's phenomenon, rheumatoid arthritis, lupus erythematosus, and rhabdomyolysis have been observed in patients treated with alpha interferons, including patients treated with INTRON A. In very rare cases the event resulted in fatality. The mechanism by which these events developed and their relationship to interferon alpha therapy is not clear. Any patient developing an autoimmune disorder during treatment should be closely monitored and, if appropriate, treatment should be discontinued.

Human Albumin

The powder formulations of this product contain albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

AIDS-Related Kaposi's Sarcoma

INTRON A therapy should not be used for patients with rapidly progressive visceral disease (see CLINICAL PHARMACOLOGY). Also of note, there may be synergistic adverse effects between INTRON A and zidovudine. Patients receiving concomitant zidovudine have had a higher incidence of neutropenia than that expected with zidovudine alone. Careful monitoring of the WBC count is indicated in all patients who are myelosuppressed and in all patients receiving other myelosuppressive medications. The effects of INTRON A when combined with other drugs used in the treatment of AIDS-related disease are unknown.

Chronic Hepatitis C And Chronic Hepatitis B

Patients with decompensated liver disease, autoimmune hepatitis or a history of autoimmune disease, and patients who are immunosuppressed transplant recipients should not be treated with INTRON A. There are reports of worsening liver disease, including jaundice, hepatic encephalopathy, hepatic failure, and death following INTRON A therapy in such patients. Therapy should be discontinued for any patient developing signs and symptoms of liver failure.

Chronic hepatitis B patients with evidence of decreasing hepatic synthetic functions, such as decreasing albumin levels or prolongation of prothrombin time, who nevertheless meet the entry criteria to start therapy, may be at increased risk of clinical decompensation if a flare of aminotransferases occurs during INTRON A treatment. In such patients, if increases in ALT occur during INTRON A therapy for chronic hepatitis B, they should be followed carefully, including close monitoring of clinical symptomatology and liver function tests including ALT, prothrombin time, alkaline phosphatase, albumin, and bilirubin. In considering these patients for INTRON A therapy, the potential risks must be evaluated against the potential benefits of treatment.

Peripheral Neuropathy

Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and pegylated interferon alfa-2a as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated.

Use With Ribavirin

(see also REBETOL® prescribing information)

REBETOL may cause birth defects and/or death of the unborn child. REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least two forms of contraception and have monthly pregnancy tests (see CONTRAINDICATIONS and PATIENT INFORMATION).

Combination treatment with INTRON A and REBETOL was associated with hemolytic anemia. Hemoglobin less than 10 g/dL was observed in approximately 10% of adult and pediatric patients in clinical trials. Anemia occurred within 1 to 2 weeks of initiation of ribavirin therapy. Combination treatment with INTRON A and REBETOL should not be used in patients with creatinine clearance less than 50 mL/min. See REBETOL prescribing information for additional information.

Precautions

PRECAUTIONSGeneral

Acute serious hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed rarely in INTRON® A-treated patients; if such an acute reaction develops, the drug should be discontinued immediately and appropriate medical therapy instituted. Transient rashes have occurred in some patients following injection, but have not necessitated treatment interruption.

While fever may be related to the flu-like syndrome reported commonly in patients treated with interferon, other causes of persistent fever should be ruled out.

There have been reports of interferon, including INTRON A, exacerbating preexisting psoriasis and sarcoidosis as well as development of new sarcoidosis. Therefore, INTRON A therapy should be used in these patients only if the potential benefit justifies the potential risk.

Variations in dosage, routes of administration, and adverse reactions exist among different brands of interferon. Therefore, do not use different brands of interferon in any single treatment regimen.

Triglycerides

Elevated triglyceride levels have been observed in patients treated with interferons, including INTRON A therapy. Elevated triglyceride levels should be managed as clinically appropriate. Hypertriglyceridemia may result in pancreatitis. Discontinuation of INTRON A therapy should be considered for patients with persistently elevated triglycerides (e.g., triglycerides greater than 1000 mg/dL) associated with symptoms of potential pancreatitis, such as abdominal pain, nausea, orvomiting.

Information For Patients

Patients receiving INTRON A alone or in combination with REBETOL® should be informed of the risks and benefits associated with treatment and should be instructed on proper use of the product. To supplement your discussion with a patient, you may wish to provide patients with a copy of theMEDICATION GUIDE.

Patients should be informed of, and advised to seek medical attention for, symptoms indicative of serious adverse reactions associated with this product. Such adverse reactions may include depression (suicidal ideation), cardiovascular (chest pain), ophthalmologic toxicity (decrease in/or loss of vision), pancreatitis or colitis (severe abdominal pain), and cytopenias (high persistent fevers, bruising, dyspnea). Patients should be advised that some side effects such as fatigue and decreased concentration might interfere with the ability to perform certain tasks. Patients who are taking INTRON A in combination with REBETOL must be thoroughly informed of the risks to a fetus. Female patients and female partners of male patients must be told to use two forms of birth control during treatment and for six months after therapy is discontinued (see MEDICATION GUIDE).

Patients should be advised to remain well hydrated during the initial stages of treatment and that use of an antipyretic may ameliorate some of the flu-like symptoms.

If a decision is made to allow a patient to self-administer INTRON A, they should be instructed, based on their treatment, if they should inject a dose of INTRON® A subcutaneously or intramuscularly. If it is too difficult for them to inject themselves, they should be instructed to ask someone who has been trained to give the injection to them. Patients should be instructed on the importance of site selection for self-administering the injection, as well as the importance on rotating the injection sites. A puncture resistant container for the disposal of needles and syringes should be supplied. Patients self-administering INTRON A should be instructed on the proper disposal of needles and syringes and cautioned against reuse.

Patients should be instructed that the Sterile Water for Injection vial supplied with Intron A Powder for Injection contains an excess amount of diluent (5 mL) and only 1 mL should be withdrawn to reconstitute Intron A Powder for Injection. The vial of Sterile Water for Injection is intended for single use only. Discard the unused portion of sterile water. Do not save or reuse.

Dental And Periodontal Disorders

Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucousmembranes of the mouth during long-term treatment with the combination of REBETOL and interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition, some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.

Laboratory Tests

In addition to those tests normally required for monitoring patients, the following laboratory tests are recommended for all patients on INTRON A therapy, prior to beginning treatment and then periodically thereafter.

· Standard hematologic tests — including hemoglobin, complete and differential white blood cell counts, and platelet count.

· Blood chemistries — electrolytes, liver function tests, and TSH.

· Monitor hepatic function with serum bilirubin, ALT (alanine transaminase), AST (aspartate aminotransferase), alkaline phosphatase, and LDH (lactate dehydrogenase) at 2, 8 and 12 weeks following initiation of INTRON A, then every 6 months while receiving INTRON A. Permanently discontinue INTRON A for evidence of severe (Grade 3) hepatic injury or hepatic decompensation  (Child-Pugh score >6 [class B and C]).

Those patients who have preexisting cardiac abnormalities and/or are in advanced stages of cancershould have electrocardiograms taken prior to and during the course of treatment.  

Mild-to-moderate leukopenia and elevated serum liver enzyme (SGOT) levels have been reported with intralesional administration of INTRON A (see ADVERSE REACTIONS); therefore, the monitoring of these laboratory parameters should be considered.  

Baseline chest X-rays are suggested and should be repeated if clinically indicated.

For malignant melanoma patients, differential WBC count and liver function tests should be monitored weekly during the induction phase of therapy and monthly during the maintenance phase of therapy.

For specific recommendations in chronic hepatitis C and chronic hepatitis B, see INDICATIONS AND USAGE.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Studies with INTRON A have not been performed to determine carcinogenicity.

Interferon may impair fertility. In studies of interferon administration in nonhuman primates, menstrual cycle abnormalities have been observed. Decreases in serum estradiol and progesteroneconcentrations have been reported in women treated with human leukocyte interferon.12 Therefore,fertile women should not receive INTRON A therapy unless they are using effective contraception during the therapy period. INTRON A therapy should be used with caution in fertile men.

Mutagenicity studies have demonstrated that INTRON A is not mutagenic.

Studies in mice (0.1, 1.0 million IU/day), rats (4, 20, 100 million IU/kg/day), and cynomolgus monkeys (1.1 million IU/kg/day; 0.25, 0.75, 2.5 million IU/kg/day) injected with INTRON A for up to 9 days, 3 months, and 1 month, respectively, have revealed no evidence of toxicity. However, in cynomolgus monkeys (4, 20, 100 million IU/kg/day) injected daily for 3 months with INTRON A, toxicity was observed at the mid and high doses and mortality was observed at the high dose.

However, due to the known species-specificity of interferon, the effects in animals are unlikely to be predictive of those in man.

INTRON A in combination with REBETOL should be used with caution in fertile men. See the REBETOL prescribing information for additional information.

Pregnancy Category C

INTRON A has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60-kg adult). There are no adequate and well-controlled studies in pregnantwomen. INTRON A therapy should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Category X

applies to combination treatment with INTRON A and REBETOL (see CONTRAINDICATIONS). See REBETOL prescribing information for additional information. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. REBETOL therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. See CONTRAINDICATIONS and the REBETOL prescribing information.

Ribavirin Pregnancy Registry: A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.

Nursing Mothers

It is not known whether this drug is excreted in human milk. However, studies in mice have shown that mouse interferons are excreted into the milk. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or to discontinue INTRON A therapy, taking into account the importance of the drug to the mother.

Pediatric UseGeneral

Safety and effectiveness in pediatric patients have not been established for indications other than chronic hepatitis B and chronic hepatitis C. Chronic Hepatitis B Safety and effectiveness in pediatric patients ranging in age from 1 to 17 years have been established based upon one controlled clinical trial (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION, Chronic Hepatitis B Pediatrics).

Chronic Hepatitis C

Safety and effectiveness in pediatric patients ranging in age from 3 to 16 years have been established based upon clinical studies in 118 patients. See REBETOL prescribing information for additional information. Suicidal ideation or attempts occurred more frequently among pediatric patients compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up (see WARNINGS, Neuropsychiatric Disorders). During a 48-week course of therapy there was a decrease in the rate of linear growth (mean percentile assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 9%). A general reversal of these trends was noted during the 24-week post-treatment period.

Long-term data in a limited number of patients suggests that combination therapy may induce a growth inhibition that results in reduced final adult height in some patients (see ADVERSE REACTIONS, Chronic Hepatitis C Pediatrics).

Geriatric Use

In all clinical studies of INTRON A, including studies as monotherapy and in combination with REBETOL (ribavirin USP) Capsules, only a small percentage of the subjects were aged 65 and over. These numbers were too few to determine if they respond differently from younger subjects except for the clinical trials of INTRON A in combination with REBETOL, where elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%).

In a database consisting of clinical study and postmarketing reports for various indications, cardiovascular adverse events and confusion were reported more frequently in elderly patients receiving INTRON A therapy compared to younger patients.

In general, INTRON A therapy should be administered to elderly patients cautiously, reflecting the greater frequency of decreased hepatic, renal, bone marrow, and/or cardiac function and concomitant disease or other drug therapy. INTRON A is known to be substantially excreted by the kidney, and the risk of adverse reactions to INTRON A may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, patients should be carefully monitored during treatment, and dose adjustments made based on symptoms and/or laboratory abnormalities (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Overdosage & Contraindications

OVERDOSE

There is limited experience with overdosage. Postmarketing surveillance includes reports of patients receiving a single dose as great as 10 times the recommended dose. In general, the primary effects of an overdose are consistent with the effects seen with therapeutic doses of interferon alfa-2b. Hepatic enzyme abnormalities, renal failure,  hemorrhage, and myocardial infarction have been reported with single administration overdoses and/or with longer durations of treatment than prescribed (see ADVERSE REACTIONS). Toxic effects after ingestion of interferon alfa-2b are not expected because interferons are poorly absorbed orally. Consultation with a poison center is recommended.

Treatment

There is no specific antidote for interferon alfa-2b. Hemodialysis and peritoneal dialysis are not considered effective for treatment of overdose.

CONTRAINDICATIONS

INTRON® A is contraindicated in patients with:

· Hypersensitivity to interferon alpha or any component of the product

· Autoimmune hepatitis

· Decompensated liver disease

INTRON A and REBETOL® combination therapy is additionally contraindicated in:

· Patients with hypersensitivity to ribavirin or any other component of the product

· Women who are pregnant

· Men whose female partners are pregnant

· Patients with hemoglobinopathies (e.g., thalassemia major, sickle cell anemia)

· Patients with creatinine clearance less than 50 mL/min.

See REBETOL prescribing information for additional information.

Clinical Pharmacology

CLINICAL PHARMACOLOGYGeneral

The interferons are a family of naturally occurring small proteins and glycoproteins with molecular weights of approximately 15,000 to 27,600 daltons produced and secreted by cells in response to viral infections and to synthetic or biological inducers.

Preclinical Pharmacology

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Once bound to the cell membrane, interferons initiate a complex sequence of intracellular events. In vitro studies demonstrated that these include the induction of certain enzymes, suppression of cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus-infected cells.

In a study using human hepatoblastoma cell line HB 611, the in vitro antiviral activity of alpha interferon was demonstrated by its inhibition of hepatitis B virus (HBV) replication.

The correlation between these in vitro data and the clinical results is unknown. Any of these activities might contribute to interferon's therapeutic effects.

Pharmacokinetics

The pharmacokinetics of INTRON® A were studied in 12 healthy male volunteers following single doses of 5 million IU/m² administered intramuscularly, subcutaneously, and as a 30-minute intravenous infusion in a crossover design.

The mean serum INTRON A concentrations following intramuscular and subcutaneous injections were comparable. The maximum serum concentrations obtained via these routes were approximately 18 to 116 IU/mL and occurred 3 to 12 hours after administration. The elimination half-life of INTRON A following both intramuscular and subcutaneous injections was approximately 2 to 3 hours. Serum concentrations were undetectable by 16 hours after the injections.

After intravenous administration, serum INTRON A concentrations peaked (135- 273 IU/mL) by the end of the 30-minute infusion, then declined at a slightly more rapid rate than after intramuscular or subcutaneous drug administration, becoming undetectable 4 hours after the infusion. The elimination half-life was approximately 2 hours.

Urine INTRON A concentrations following a single dose (5 million IU/m²) were not detectable after any of the parenteral routes of administration. This result was expected since preliminary studies with isolated and perfused rabbit kidneys have shown that the kidney may be the main site of interferon catabolism.

There are no pharmacokinetic data available for the intralesional route of administration.

Serum Neutralizing Antibodies

In INTRON A-treated patients tested for antibody activity in clinical trials, serum anti-interferon neutralizing antibodies were detected in 0% (0/90) of patients with hairy cell leukemia, 0.8% (2/260) of patients treated intralesionally for condylomata acuminata, and 4% (1/24) of patients with AIDS-Related Kaposi's Sarcoma. Serum neutralizing antibodies have been detected in less than 3% of patients treated with higher INTRON A doses in malignancies other than hairy cell leukemia or AIDS-Related Kaposi's Sarcoma. The clinical significance of the appearance of serum anti-interferon neutralizing activity in these indications is not known.

Serum anti-interferon neutralizing antibodies were detected in 7% (12/168) of patients either during treatment or after completing 12 to 48 weeks of treatment with 3 million IU TIW of INTRON A therapy for chronic hepatitis C and in 13% (6/48) of patients who received INTRON A therapy for chronic hepatitis B at 5 million IU QD for 4 months, and in 3% (1/33) of patients treated at 10 million IU TIW. Serum anti-interferon neutralizing antibodies were detected in 9% (5/53) of pediatric patients who received INTRON A therapy for chronic hepatitis B at 6 million IU/m² TIW. Among all chronic hepatitis B or C patients, pediatrics and adults with detectable serum neutralizing antibodies, the titers detected were low (22/24 with titers less than or equal to 1:40 and 2/24 with titers less than or equal to 1:160). The appearance of serum anti-interferon neutralizing activity did not appear to affect safety or efficacy.

Hairy Cell Leukemia

In clinical trials in patients with hairy cell leukemia, there was depression of hematopoiesis during the first 1 to 2 months of INTRON A treatment, resulting in reduced numbers of circulating red and white blood cells, and platelets. Subsequently, both splenectomized and nonsplenectomized patients achieved substantial and sustained improvements in granulocytes, platelets, and hemoglobin levels in 75% of treated patients and at least some improvement (minor responses) occurred in 90%. INTRON A treatment resulted in a decrease in bone marrow hypercellularity and hairy cell infiltrates. The hairy cell index (HCI), which represents the percent of bone marrow cellularity times the percent of hairy cell infiltrate, was greater than or equal to 50% at the beginning of the study in 87% of patients. The percentage of patients with such an HCI decreased to 25% after 6 months and to 14% after 1 year. These results indicate that even though hematologic improvement had occurred earlier, prolonged INTRON A treatment may be required to obtain maximal reduction in tumor cell infiltrates in the bone marrow.

The percentage of patients with hairy cell leukemia who required red blood cell or platelet transfusions decreased significantly during treatment and the percentage of patients with confirmed and serious infections declined as granulocyte counts improved. Reversal of splenomegaly and of clinically significant hypersplenism was demonstrated in some patients.

A study was conducted to assess the effects of extended INTRON A treatment on duration of response for patients who responded to initial therapy. In this study, 126 responding patients were randomized to receive additional INTRON A treatment for 6 months or observation for a comparable period, after 12 months of initial INTRON A therapy. During this 6-month period, 3% (2/66) of INTRON A-treated patients relapsed compared with 18% (11/60) who were not treated. This represents a significant difference in time to relapse in favor of continued INTRON A treatment (P=0.006/0.01, Log Rank/Wilcoxon). Since a small proportion of the total population had relapsed, median time to relapse could not be estimated in either group. A similar pattern in relapses was seen when all randomized treatment, including that beyond 6 months, and available follow-up data were assessed. The 15% (10/66) relapses among INTRON A patients occurred over a significantly longer period of time than the 40% (24/60) with observation (P=0.0002/0.0001, Log Rank/Wilcoxon). Median time to relapse was estimated, using the Kaplan-Meier method, to be 6.8 months in the observation group but could not be estimated in the INTRON A group.

Subsequent follow-up with a median time of approximately 40 months demonstrated an overall survival of 87.8%. In a comparable historical control group followed for 24 months, overall median survival was approximately 40%.

Malignant Melanoma

The safety and efficacy of INTRON A was evaluated as adjuvant to surgical treatment in patients with melanoma who were free of disease (post surgery) but at high risk for systemic recurrence. These included patients with lesions of Breslow thickness greater than 4 mm, or patients with lesions of any Breslow thickness with primary or recurrent nodal involvement. In a randomized, controlled trial in 280 patients, 143 patients received INTRON A therapy at 20 million IU/m² intravenously five times per week for 4 weeks (induction phase) followed by 10 million IU/m² subcutaneously three times per week for 48 weeks (maintenance phase). In the clinical trial, the median daily INTRON A dose administered to patients was 19.1 million IU/m² during the induction phase and 9.1 million IU/m² during the maintenance phase. INTRON A therapy was begun less than or equal to 56 days after surgical resection. The remaining 137 patients were observed.

INTRON A therapy produced a significant increase in relapse-free and overall survival. Median time to relapse for the INTRON A-treated patients versus observation patients was 1.72 years versus 0.98 years (P<0.01, stratified Log Rank). The estimated 5-year relapse-free survival rate, using the Kaplan-Meier method, was 37% for INTRON A-treated patients versus 26% for observation patients. Median overall survival time for INTRON A-treated patients versus observation patients was 3.82 years versus 2.78 years (P=0.047, stratified Log Rank). The estimated 5-year overall survival rate, using the Kaplan-Meier method, was 46% for INTRON A-treated patients versus 37% for observation patients.

In a second study of 642 resected high-risk melanoma patients, subjects were randomized equally to one of three groups: high-dose INTRON A therapy for 1 year (same schedule as above), low-dose INTRON A therapy for 2 years (3 MU/d TIW SC), and observation. Consistent with the earlier trial, high-dose INTRON A therapy demonstrated an improvement in relapse-free survival (3-year estimated RFS 48% versus 41%; median RFS 2.4 versus 1.6 years, P=not significant). Relapse-free survival in the low-dose INTRON A arm was similar to that seen in the observation arm. Neither high-dose nor low-dose INTRON A therapy showed a benefit in overall survival as compared to observation in this study.

Follicular Lymphoma

The safety and efficacy of INTRON A in conjunction with CHVP, a combination chemotherapy regimen, was evaluated as initial treatment in patients with clinically aggressive, large tumor burden, Stage III/IV follicular Non-Hodgkin's Lymphoma. Large tumor burden was defined by the presence of any one of the following: a nodal or extranodal tumor mass with a diameter of greater than 7 cm; involvement of at least three nodal sites (each with a diameter of greater than 3 cm); systemic symptoms; splenomegaly; serous effusion, orbital or epidural involvement; ureteral compression; or leukemia.

In a randomized, controlled trial, 130 patients received CHVP therapy and 135 patients received CHVP therapy plus INTRON A therapy at 5 million IU subcutaneously three times weekly for the duration of 18 months. CHVP chemotherapy consisted of cyclophosphamide 600 mg/m², doxorubicin 25 mg/m², and teniposide (VM- 26) 60 mg/m², administered intravenously on Day 1 and prednisone at a daily dose of 40 mg/m² given orally on Days 1 to 5. Treatment consisted of six CHVP cycles administered monthly, followed by an additional six cycles administered every 2 months for 1 year. Patients in both treatment groups received a total of 12 CHVP cycles over 18 months.

The group receiving the combination of INTRON A therapy plus CHVP had a significantly longer progression-free survival (2.9 years versus 1.5 years, P=0.0001, Log Rank test). After a median follow-up of 6.1 years, the median survival for patients treated with CHVP alone was 5.5 years while median survival for patients treated with CHVP plus INTRON A therapy had not been reached (P=0.004, Log Rank test). In three additional published, randomized, controlled studies of the addition of interferon alpha to anthracycline-containing combination chemotherapy regimens,1-3 the addition of interferon alpha was associated with significantly prolonged progression-free survival. Differences in overall survival were not consistently observed.

Condylomata Acuminata

Condylomata acuminata (venereal or genital warts) are associated with infections of the human papilloma virus (HPV). The safety and efficacy of INTRON A in the treatment of condylomata acuminata were evaluated in three controlled double-blind clinical trials. In these studies, INTRON A doses of 1 million IU per lesion were administered intralesionally three times a week (TIW), in less than or equal to 5 lesions per patient for 3 weeks. The patients were observed for up to 16 weeks after completion of the full treatment course.

INTRON A treatment of condylomata was significantly more effective than placebo, as measured by disappearance of lesions, decreases in lesion size, and by an overall change in disease status. Of 192 INTRON A-treated patients and 206 placebotreated patients who were evaluable for efficacy at the time of best response during the course of the study, 42% of INTRON A patients versus 17% of placebo patients experienced clearing of all treated lesions. Likewise, 24% of INTRON A patients versus 8% of placebo patients experienced marked (75% to less than 100%) reduction in lesion size, 18% versus 9% experienced moderate (50% to 75%) reduction in lesion size, 10% versus 42% had a slight (less than 50%) reduction in lesion size, 5% versus 24% had no change in lesion size, and 0% versus 1% experienced exacerbation (P<0.001).

In one of these studies, 43% (54/125) of patients in whom multiple (less than or equal to 3) lesions were treated experienced complete clearing of all treated lesions during the course of the study. Of these patients, 81% remained cleared 16 weeks after treatment was initiated.

Patients who did not achieve total clearing of all their treated lesions had these same lesions treated with a second course of therapy. During this second course of treatment, 38% to 67% of patients had clearing of all treated lesions. The overall percentage of patients who had cleared all their treated lesions after two courses of treatment ranged from 57% to 85%.

INTRON A-treated lesions showed improvement within 2 to 4 weeks after the start of treatment in the above study; maximal response to INTRON A therapy was noted 4 to 8 weeks after initiation of treatment.

The response to INTRON A therapy was better in patients who had condylomata for shorter durations than in patients with lesions for a longer duration.

Another study involved 97 patients in whom three lesions were treated with either an intralesional injection of 1.5 million IU of INTRON A per lesion followed by a topical application of 25% podophyllin, or a topical application of 25% podophyllin alone. Treatment was given once a week for 3 weeks. The combined treatment of INTRON A and podophyllin was shown to be significantly more effective than podophyllin alone, as determined by the number of patients whose lesions cleared. This significant difference in response was evident after the second treatment (Week 3) and continued through 8 weeks post-treatment. At the time of the patient's best response, 67% (33/49) of the INTRON A- and podophyllin-treated patients had all three treated lesions clear while 42% (20/48) of the podophyllin-treated patients had all three clear (P=0.003).

AIDS-Related Kaposi's Sarcoma

The safety and efficacy of INTRON A in the treatment of Kaposi's Sarcoma (KS), a common manifestation of the Acquired Immune Deficiency Syndrome (AIDS), were evaluated in clinical trials in 144 patients.

In one study, INTRON A doses of 30 million IU/m² were administered subcutaneously three times per week (TIW) to patients with AIDS-Related KS. Doses were adjusted for patient tolerance. The average weekly dose delivered in the first 4 weeks was 150 million IU; at the end of 12 weeks this averaged 110 million IU/week; and by 24 weeks averaged 75 million IU/week.

Forty-four percent of asymptomatic patients responded versus 7% of symptomatic patients. The median time to response was approximately 2 months and 1 month, respectively, for asymptomatic and symptomatic patients. The median duration of response was approximately 3 months and 1 month, respectively, for the asymptomatic and symptomatic patients. Baseline T4/T8 ratios were 0.46 for responders versus 0.33 for nonresponders.

In another study, INTRON A doses of 35 million IU were administered subcutaneously, daily (QD), for 12 weeks. Maintenance treatment, with every other day dosing (QOD), was continued for up to 1 year in patients achieving antitumor and antiviral responses. The median time to response was 2 months and the median duration of response was 5 months in the asymptomatic patients.

In all studies, the likelihood of response was greatest in patients with relatively intact immune systems as assessed by baseline CD4 counts (interchangeable with T4 counts). Results at doses of 30 million IU/m² TIW and 35 million IU/QD were subcutaneously similar and are provided together in TABLE 1. This table demonstrates the relationship of response to baseline CD4 count in both asymptomatic and symptomatic patients in the 30 million IU/m² TIW and the 35 million IU/QD treatment groups.

In the 30 million IU study group, 7% (5/72) of patients were complete responders and 22% (16/72) of the patients were partial responders. The 35 million IU study had 13% (3/23 patients) complete responders and 17% (4/23) partial responders.

For patients who received 30 million IU TIW, the median survival time was longer in patients with CD4 greater than 200 (30.7 months) than in patients with CD4 less than or equal to 200 (8.9 months). Among responders, the median survival time was 22.6 months versus 9.7 months in nonresponders.

Chronic Hepatitis C

The safety and efficacy of INTRON A in the treatment of chronic hepatitis C was evaluated in 5 randomized clinical studies in which an INTRON A dose of 3 million IU three times a week (TIW) was assessed. The initial three studies were placebo-controlled trials that evaluated a 6-month (24-week) course of therapy. In each of the three studies, INTRON A therapy resulted in a reduction in serum alanine aminotransferase (ALT) in a greater proportion of patients versus control patients at the end of 6 months of dosing. During the 6 months of follow-up, approximately 50% of the patients who responded maintained their ALT response. A combined analysis comparing pretreatment and post-treatment liver biopsies revealed histological improvement in a statistically significantly greater proportion of INTRON A-treated patients compared to controls.

Two additional studies have investigated longer treatment durations (up to 24 months).5,6 Patients in the two studies to evaluate longer duration of treatment had hepatitis with or without cirrhosis in the absence of decompensated liver disease. Complete response to treatment was defined as normalization of the final two serum ALT levels during the treatment period. A sustained response was defined as a complete response at the end of the treatment period, with sustained normal ALT values lasting at least 6 months following discontinuation of therapy.

In Study 1, all patients were initially treated with INTRON A 3 million IU TIW subcutaneously for 24 weeks (run-in-period). Patients who completed the initial 24-week treatment period were then randomly assigned to receive no further treatment, or to receive 3 million IU TIW for an additional 48 weeks. In Study 2, patients who met the entry criteria were randomly assigned to receive INTRON A 3 million IU TIW subcutaneously for 24 weeks or to receive INTRON A 3 million IU TIW subcutaneously for 96 weeks. In both studies, patient follow-up was variable and some data collection was retrospective.

Results show that longer durations of INTRON A therapy improved the sustained response rate (see TABLE 2). In patients with complete responses (CR) to INTRON A therapy after 6 months of treatment (149/352 [42%]), responses were less often sustained if drug was discontinued (21/70 [30%]) than if it was continued for 18 to 24 months (44/79 [56%]). Of all patients randomized, the sustained response rate in the patients receiving 18 or 24 months of therapy was 22% and 26%, respectively, in the two trials. In patients who did not have a CR by 6 months, additional therapy did not result in significantly more responses, since almost all patients who responded to therapy did so within the first 16 weeks of treatment.

A subset (less than 50%) of patients from the combined extended dosing studies had liver biopsies performed both before and after INTRON A treatment. Improvement in necroinflammatory activity as assessed retrospectively by the Knodell (Study 1) and Scheuer (Study 2) Histology Activity Indices was observed in both studies. A higher number of patients (58%, 45/78) improved with extended therapy than with shorter (6 months) therapy (38%, 34/89) in this subset.

Combination treatment with INTRON A and REBETOL® (ribavirin USP) provided a significant reduction in virologic load and improved histologic response in adult patients with compensated liver disease who were treatment-naïve or had relapsed following therapy with alpha interferon alone; pediatric patients previously untreated with alpha interferon experienced a sustained virologic response. See REBETOL prescribing information for additional information.

Chronic Hepatitis BAdults

The safety and efficacy of INTRON A in the treatment of chronic hepatitis B were evaluated in three clinical trials in which INTRON A doses of 30 to 35 million IU per week were administered subcutaneously (SC), as either 5 million IU daily (QD), or 10 million IU three times a week (TIW) for 16 weeks versus no treatment. All patients were 18 years of age or older with compensated liver disease, and had chronic hepatitis B virus (HBV) infection (serum HBsAg positive for at least 6 months) and HBV replication (serum HBeAg positive). Patients were also serum HBV-DNA positive, an additional indicator of HBV replication, as measured by a research assay.7,8 All patients had elevated serum alanine aminotransferase (ALT) and liver biopsy findings compatible with the diagnosis of chronic hepatitis. Patients with the presence of antibody to human immunodeficiency virus (anti-HIV) or antibody to hepatitis delta virus (anti-HDV) in the serum were excluded from the studies.

Virologic response to treatment was defined in these studies as a loss of serum markers of HBV replication (HBeAg and HBV DNA). Secondary parameters of response included loss of serum HBsAg, decreases in serum ALT, and improvement in liver histology.

In each of two randomized controlled studies, a significantly greater proportion of INTRON A-treated patients exhibited a virologic response compared with untreated control patients (see TABLE 3). In a third study without a concurrent control group, a similar response rate to INTRON A therapy was observed. Pretreatment with prednisone, evaluated in two of the studies, did not improve the response rate and provided no additional benefit.

The response to INTRON A therapy was durable. No patient responding to INTRON A therapy at a dose of 5 million IU QD or 10 million IU TIW relapsed during the follow-up period, which ranged from 2 to 6 months after treatment ended. The loss of serum HBeAg and HBV DNA was maintained in 100% of 19 responding patients followed for 3.5 to 36 months after the end of therapy.

In a proportion of responding patients, loss of HBeAg was followed by the loss of HBsAg. HBsAg was lost in 27% (4/15) of patients who responded to INTRON A therapy at a dose of 5 million IU QD, and 35% (8/23) of patients who responded to 10 million IU TIW. No untreated control patient lost HBsAg in these studies.

In an ongoing study to assess the long-term durability of virologic response, 64 patients responding to INTRON A therapy have been followed for 1.1 to 6.6 years after treatment; 95% (61/64) remain serum HBeAg negative, and 49% (30/61) lost serum HBsAg.

INTRON A therapy resulted in normalization of serum ALT in a significantly greater proportion of treated patients compared to untreated patients in each of two controlled studies (see TABLE 4). In a third study without a concurrent control group, normalization of serum ALT was observed in 50% (12/24) of patients receiving INTRON A therapy.

Virologic response was associated with a reduction in serum ALT to normal or near normal (less than or equal to 1.5 x the upper limit of normal) in 87% (13/15) of patients responding to INTRON A therapy at 5 million IU QD, and 100% (23/23) of patients responding to 10 million IU TIW.

Improvement in liver histology was evaluated in Studies 1 and 3 by comparison of pretreatment and 6-month post-treatment liver biopsies using the semiquantitative Knodell Histology Activity Index.9No statistically significant difference in liver histology was observed in treated patients compared to control patients in Study 1. Although statistically significant histological improvement from baseline was observed in treated patients in Study 3 (P≤0.01), there was no control group for comparison. Of those patients exhibiting a virologic response following treatment with 5 million IU QD or 10 million IU TIW, histological improvement was observed in 85% (17/20) compared to 36% (9/25) of patients who were not virologic responders. The histological improvement was due primarily to decreases in severity of necrosis, degeneration, and inflammation in the periportal, lobular, and portal regions of the liver (Knodell Categories I + II + III). Continued histological improvement was observed in four responding patients who lost serum HBsAg and were followed 2 to 4 years after the end of INTRON A therapy.10

Pediatrics

The safety and efficacy of INTRON A in the treatment of chronic hepatitis B was evaluated in one randomized controlled trial of 149 patients ranging from 1 year to 17 years of age. Seventy-two patients were treated with 3 million IU/m² of INTRON A therapy administered subcutaneously three times a week (TIW) for 1 week; the dose was then escalated to 6 million IU/m² TIW for a minimum of 16 weeks up to 24 weeks. The maximum weekly dosage was 10 million IU TIW. Seventy-seven patients were untreated controls. Study entry and response criteria were identical to those described in the adult patient population.

Patients treated with INTRON A therapy had a better response (loss of HBV DNA and HBeAg at 24 weeks of follow-up) compared to the untreated controls (24% [17/72] versus 10% [8/77] P=0.05). Sixteen of the 17 responders treated with INTRON A therapy remained HBV DNA and HBeAg negative and had a normal serum ALT 12 to 24 months after completion of treatment. Serum HBsAg became negative in 7 out of 17 patients who responded to INTRON A therapy. None of the control patients who had an HBV DNA and HBeAg response became HBsAg negative. At 24 weeks of follow-up, normalization of serum ALT was similar in patients treated with INTRON A therapy (17%, 12/72) and in untreated control patients (16%, 12/77). Patients with a baseline HBV DNA less than 100 pg/mL were more likely to respond to INTRON A therapy than were patients with a baseline HBV DNA greater than 100 pg/mL (35% versus 9%, respectively). Patients who contracted hepatitis B through maternal vertical transmission had lower response rates than those who contracted the disease by other means (5% versus 31%, respectively). There was no evidence that the effects on HBV DNA and HBeAg were limited to specific subpopulations based on age, gender, or race.

TABLE 1: RESPONSE BY BASELINE CD4 COUNT* IN AIDS-RELATED KS PATIENTS

TABLE 2: SUSTAINED ALT RESPONSE RATE VERSUS DURATION OF THERAPY IN CHRONIC HEPATITIS C PATIENTS INTRON A 3 Million IU TIW

TABLE 3: VIROLOGIC RESPONSE* IN CHRONIC HEPATITIS B PATIENTS

TABLE 4: ALT RESPONSES* IN CHRONIC HEPATITIS B PATIENTS

REFERENCES

1. Smalley R, et al. N Engl J Med. 1992;327:1336-1341.

2. Aviles A, et al. Leukemia and Lymphoma. 1996;20:495-499.

3. Unterhalt M, et al. Blood. 1996;88(10 Suppl 1):1744A.

5. Poynard T, et al. N Engl J Med. 1995;332(22)1457-1462.

6. Lin R, et al. J Hepatol. 1995;23:487-496.

7. Perrillo R, et al. N Engl J Med. 1990;323:295-301.

8. Perez V, et al. J Hepatol. 1990;11:S113-S117.

9. Knodell R, et al. Hepatology. 1981;1:431-435.

10. Perrillo R, et al. Ann Intern Med. 1991;115:113-115.

Medication Guide

PATIENT INFORMATION

INTRON® A 
(In-tron-aye)
(Interferon alfa-2b, recombinant)

If you are taking INTRON A with REBETOL, also read the Medication Guide for REBETOL® (ribavirin) Capsules and Oral Solution.

INTRON A alone is a treatment for certain types of cancers and hepatitis B virus. INTRON A by itself or with REBETOL is a treatment for some people infected with hepatitis C virus.

What is the most important information I should know about INTRON A?

INTRON A can cause serious side effects that may cause death or worsen certain serious conditions that you may already have.

Tell your healthcare provider right away if you have any of the symptoms listed below while taking INTRON A. If symptoms get worse, or become severe and continue, your healthcare provider may tell you to stop taking INTRON A permanently. In many, but not all people, these symptoms go away after they stop taking INTRON A.

Heart problems. Some people who take INTRON A may develop heart problems, including:

· low blood pressure

· fast heart rate or abnormal heart beats

· trouble breathing or chest pain

· heart attacks or heart muscle problems (cardiomyopathy)

Stroke or symptoms of a stroke. Symptoms may include weakness, loss of coordination, and numbness. Stroke or symptoms of a stroke may happen in people who have some risk factors or no known risk factors for a stroke.

Mental health problems, including suicide. INTRON A may cause you to develop mood or behavior problems that may get worse during treatment with INTRON A or after your last dose, including:

· irritability (getting upset easily)

· depression (feeling low, feeling bad about yourself, or feeling hopeless)

· acting aggressive, being angry or violent

· thoughts of hurting yourself or others, or suicide

· former drug addicts may fall back into drug addiction or overdose

If you have these symptoms, your healthcare provider should carefully monitor you during treatment with INTRON A and for 6 months after your last dose.

New or worsening autoimmune disease. Some people taking INTRON A develop autoimmune diseases (a condition where the body's immune cells attack other cells or organs in the body), including rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, and psoriasis. In some people who already have an autoimmune disease, the disease may get worse while on INTRON A.

Infections. Some people who take INTRON A may get an infection. Symptoms may include:

· fever

· chills

· bloody diarrhea

· burning or pain with urination

· urinating often

· coughing up mucus (phlegm) that is colored (for example yellow or pink)

During treatment with INTRON A, you should see a healthcare provider regularly for check-ups and blood tests to make sure that your treatment is working, and to check for side effects.

What is INTRON A?

INTRON A is a prescription medicine that is used:

· to treat adults with a blood cancer called hairy cell leukemia

· to treat certain adults with a type of skin cancer called malignant melanoma

· to treat adults with some types of Follicular Non-Hodgkin's Lymphoma along with certain chemotherapy medicines

· to treat certain adults with genital warts (condylomata acuminata), by injecting the medicine directly into the warts

· to treat certain adults with a type of cancer caused by AIDS, called AIDS-related Kaposi's Sarcoma

· alone to treat adults with chronic (lasting a long time) hepatitis C infection with stable liverproblems

· with REBETOL to treat chronic (lasting a long time) hepatitis C infection in people 3 years and older with stable liver problems

· to treat chronic (lasting a long time) hepatitis B infection in people 1 year and older with stable liver problems

Who should not take INTRON A?

Do not take INTRON A if you:

· had a serious allergic reaction to another alpha interferon product or are allergic to any of the ingredients in INTRON A. See the end of this Medication Guide for a complete list of ingredients. Ask your healthcare provider if you are not sure.

· have certain types of hepatitis (autoimmune hepatitis)

· have certain other liver problems

Talk to your healthcare provider before taking INTRON A if you have any of these conditions.

What should I tell my healthcare provider before taking INTRON A?

Before you take INTRON A, tell your healthcare provider about all of your health problems, including if you:

· See “What is the most important information I should know about INTRON A?”

· have or ever had any problems with your heart, including heart attack or have high blood pressure

· have or ever had bleeding problems or blood clots

· are being treated for a mental illness or had treatment in the past for any mental illness, including depression and thoughts of hurting yourself or others

· have any kind of autoimmune disease (where the body's immune system attacks the body's own cells), such as psoriasis, systemic lupus erythematosus, rheumatoid arthritis

· have or ever had low blood cell counts

· have ever been addicted to drugs or alcohol

· have cirrhosis or other liver problems (other than hepatitis B or C)

· have or had lung problems, such as chronic obstructive pulmonary disease (COPD)

· have diabetes

· have colitis (inflammation of your intestine)

· have a condition that suppresses your immune system, such as cancer

· have hepatitis B or C infection

· have HIV infection (the virus that causes AIDS)

· have kidney problems

· have high blood triglyceride levels (fat in your blood)

· have an organ transplant and are taking medicine that keeps your body from rejecting your transplant (suppresses your immune system)

· have any other medical conditions

· are pregnant or plan to become pregnant. It is not known if INTRON A will harm your unborn baby. You should use effective birth control during treatment with INTRON A. Talk to your healthcare provider about birth control choices for you during treatment with INTRON A. Tell your healthcare provider if you become pregnant during treatment with INTRON A.

· are breast-feeding or plan to breast-feed. It is not known if INTRON A passes into your breast milk. You and your healthcare provider should decide if you will use INTRON A or breast-feed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. INTRON A and certain other medicines may affect each other and cause side effects.

Especially tell your healthcare provider if you take:

· the anti-hepatitis B medicine telbivudine (Tyzeka)

· the anti-HIV medicine zidovudine (Retrovir)

· theophylline (Theo-24, Elixophyllin, Uniphyl, Theolair). Your healthcare provider may need to monitor the amount of theophylline in your body and make changes to your theophylline dose.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take INTRON A?

· See the attached Instructions for Use for detailed instructions for preparing and injecting a dose of INTRON A.

· INTRON A comes as:

o a powder for injection in a vial that is used only 1 time (single-use vial). The powder must be mixed with water for injection (a diluent) before you inject it.

o a solution for injection in a multi-dose vial.

· INTRON A is given as an injection under the skin (subcutaneous) or into a muscle (intramuscular), into genital lesions, or as an injection into a vein (intravenous), depending on the condition that is being treated.

· Your healthcare provider will decide your dose of INTRON A and how often you will take it.

· If your healthcare provider decides that you can inject INTRON A for your condition, inject it exactly as prescribed, under your skin (subcutaneous injection) or into your muscle (intramuscular injection). Do not change your dose or how you inject INTRON A unless your healthcare provider tells you to.

· Do not take more than your prescribed dose.

· Your healthcare provider should show you how to prepare and measure your dose of INTRON A and how to inject yourself before you use INTRON A for the first time.

· You should not inject INTRON A until your healthcare provider has shown you how to use INTRON A the right way.

· If you miss a dose of INTRON A, take the missed dose as soon as possible during the same day or the next day, then continue on your regular dosing schedule. If several days go by after you miss a dose, check with your healthcare provider to see what to do.

· Do not inject more than 1 dose or take more than your prescribed dose without talking to your healthcare provider.

· If you take too much INTRON A, call your healthcare provider right away. Your healthcare provider may examine you more closely, and do blood tests.

· Your healthcare provider should do blood tests before you start INTRON A, and regularly during your treatment to see how well the treatment is working and to check for side effects.

What are the possible side effects of INTRON A?

INTRON A may cause serious side effects including:

· See “What is the most important information I should know about INTRON A?”

· Blood problems. INTRON A can affect your bone marrow and cause low white blood cell and platelet counts. In some people, these blood counts may fall to dangerously low levels. If your blood cell counts become very low, you can get infections or have bleeding problems.

· Serious eye problems. INTRON A may cause eye problems that may lead to vision loss or blindness. You should have an eye exam before you start taking INTRON A. If you have eye problems or have had them in the past, you may need eye exams while taking INTRON A. Tell your healthcare provider or eye doctor right away if you have any vision changes while taking INTRON A.

· Thyroid problems. Some people develop changes in the function of their thyroid. Symptoms of thyroid problems include:

o problems concentrating

o feeling cold or hot all the time

o changes in your weight

o skin changes

· Blood sugar problems. Some people may develop high blood sugar or diabetes. If you have high blood sugar or diabetes before starting INTRON A, talk to your healthcare provider before you take INTRON A. If you develop high blood sugar or diabetes while taking INTRON A, your healthcare provider may tell you to stop INTRON A and prescribe a different medicine for you. Symptoms of high blood sugar or diabetes may include:

o increased thirst

o tiredness

o urinating more often than normal

o increased appetite

o weight loss

o your breath smells like fruit

· Lung problems including:

o trouble breathing

o inflammation of lung tissue

o pneumonia

o new or worse high blood pressure of the lungs (pulmonary hypertension). This can be severe and may lead to death.

You may need to have a chest X-ray or other tests if you develop fever, cough, shortness of breath, or other symptoms of a lung problem during treatment with INTRON A.

· Severe liver problems, or worsening of liver problems including liver failure and death. Symptoms may include:

o nausea

o bleeding more easily than normal

o loss of appetite

o swelling of your stomach area (abdomen)

o tiredness

o confusion

o diarrhea

o sleepiness

o yellowing of your skin or the white o you cannot be awakened (coma) part of your eyes

· Serious allergic reactions and skin reactions. Symptoms may include:

o itching

o chest pain

o swelling of your face, eyes, lips,

o feeling faint tongue, or throat

o skin rash, hives, sores in your mouth, or your skin blisters

o trouble breathing and peels

o anxiousness

· Swelling of your pancreas (pancreatitis) and intestines (colitis). Symptoms may include:

o severe stomach area (abdomen)

o nausea

o pain

o vomiting

o severe back pain

o fever

· New or worsening autoimmune disease. Some people taking INTRON A develop autoimmune diseases (a condition where the body's immune cells attack other cells or organs in the body), including rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, and psoriasis. In some people who already have an autoimmune disease, the disease may worsen while on INTRON A.

· Nerve problems. People who take INTRON A or other alpha interferon products with telbivudine (Tyzeka) can develop nerve problems such as continuing numbness, tingling, or burning sensation in the arms or legs (peripheral neuropathy). Call your healthcare provider if you have any of these symptoms.

· Growth problems in children. Weight loss and slowed growth are common in children during combination treatment with INTRON A and REBETOL. Most children will go through a growth spurt and gain weight after treatment stops. Some children may not reach the height that they were expected to have before treatment. Talk to your healthcare provider if you are concerned about your child's growth during treatment with INTRON A and REBETOL.

· Dental and gum problems.

Tell your healthcare provider right away if you have any of the symptoms listed above.

The most common side effects of INTRON A include:

· Flu-like symptoms. Symptoms may include: headache, muscle aches, tiredness, and fever. Some of these symptoms may be decreased by injecting your INTRON A dose in the evening. Talk to your healthcare provider about which over-the-counter medicines you can take to help prevent or decrease some of the symptoms.

· Tiredness. Many people become very tired during treatment with INTRON A.

· Appetite problems. Nausea, loss of appetite, and weight loss can happen with INTRON A.

· Skin reactions. Redness, swelling, and itching are common at the injection site.

· Hair thinning.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the side effects of INTRON A. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1–800–FDA–1088.

How should I store INTRON A?

INTRON A Solution for Injection:

· Store in the refrigerator between 36°F to 46°F (2°C to 8°C).

· INTRON A Solution for Injection in Multidose vials for injection may be used to give more than 1 injection of medicine.

· Do not freeze.

· Throw away any unused INTRON A Solution for Injection remaining in the vial after one month.

INTRON A Powder for Injection:

Before mixing, store in the refrigerator between 36°F to 46°F (2°C to 8°C).

· After mixing the INTRON A Powder for Injection, use the solution right away or store the solution in the refrigerator for up to 24 hours between 36°F to 46°F (2°C to 8°C).

· Throw away any medicine left in the vial after you withdraw 1 dose.

· Do not freeze.

Keep INTRON A and all medicines out of the reach of children.

General Information about the safe and effective use of INTRON A

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use INTRON A for a condition for which it was not prescribed. Do not give INTRON A to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about INTRON A. If you would like more information, ask your healthcare provider. You can ask your healthcare provider or pharmacist for information about INTRON A that was written for health care professionals.

What are the ingredients in INTRON A?

Active ingredient: interferon alfa-2b

Inactive ingredients:

· Powder for injection contains: glycine, sodium phosphate dibasic, sodium phosphate monobasic, human albumin. Sterile water for injection is provided as a diluent.

· Solution Multidose vials for injection contain: sodium chloride, sodium phosphate dibasic, sodium phosphate monobasic, edetate disodium, polysorbate 80, and m-cresol as a preservative.