罗费龙-A

Roferon-A说明

Roferon-A（干扰素α-2a，重组体）是一种无菌蛋白质产品，可注射使用。 Roferon-A是通过重组DNA技术制造的，该技术采用了一种基因工程化的大肠杆菌细菌，该细菌含有编码人类蛋白质的DNA。重组干扰素α-2a是一种高度纯化的蛋白质，含有165个氨基酸，分子量约为19,000道尔顿。在含有5 mg / L抗生素四环素盐酸盐的特定营养培养基中进行发酵。但是，在最终产品中无法检测到抗生素的存在。 Roferon-A装在预装的注射器中。每个玻璃注射器筒中装有0.5 mL的产品。此外，还有一根针，长度为½英寸。

一次性使用的预填充注射器

每个注射器3,000,000 IU（11.1 mcg / 0.5 mL）Roferon-A —该溶液无色，每0.5 mL包含3 MIU的干扰素alfa-2a，重组体，3.605 mg氯化钠，0.1 mg聚山梨酸酯80、5 mg苄醇防腐剂和0.385毫克醋酸铵。

每个注射器600万IU（22.2 mcg / 0.5 mL）Roferon-A —该溶液无色，每0.5 mL包含6 MIU的干扰素alfa-2a，重组体，3.605 mg氯化钠，0.1 mg聚山梨酯80、5 mg苄醇防腐剂和0.385毫克醋酸铵。

每个注射器900万IU（33.3 mcg / 0.5 mL）Roferon-A —该溶液无色，每0.5 mL包含9 MIU的干扰素alfa-2a，重组体，3.605 mg氯化钠，0.1 mg聚山梨酸酯80、5 mg苄醇防腐剂和0.385毫克醋酸铵。

施用途径是通过皮下注射。

Roferon-A-临床药理学

干扰素α-2a，重组体或任何其他干扰素发挥抗肿瘤或抗病毒活性的机制尚不清楚。然而，据信对肿瘤细胞的直接抗增殖作用，病毒复制的抑制和宿主免疫应答的调节在抗肿瘤和抗病毒活性中起重要作用。

重组干扰素α-2a的生物活性受到物种限制，即它们在除人类以外的非常少数物种中表达。结果，重组子干扰素α-2a的临床前评价涉及人细胞的体外实验和一些体内实验。 1在培养的人类细胞干扰素α-2a中，重组体具有抗增殖和免疫调节活性，与人白细胞产生的干扰素α亚型混合物非常相似。在体内，干扰素α-2a重组体已显示能抑制免疫受损（裸鼠）中生长的几种人类肿瘤的生长。由于其物种限制的活性，不可能在免疫完整的同系肿瘤模型系统中证明抗肿瘤活性，在该系统中可以观察到对宿主免疫系统的影响。但是，这种抗肿瘤活性已经在例如可移植的小鼠肿瘤系统中用小鼠干扰素-α反复证明。这些发现的临床意义尚不清楚。

一般而言，重组干扰素α-2a的代谢与α-干扰素的代谢相一致。 α-干扰素通过肾小球被完全过滤，并在肾小管重吸收过程中发生快速的蛋白水解降解，使完整的α-干扰素在体循环中的出现可忽略不计。少量放射性标记的干扰素α-2a重组体出现在离体大鼠肾脏的尿液中，表明重组干扰素α-2a几乎完全重吸收。肝代谢和随后的胆汁排泄被认为是消除α干扰素的次要途径。

重组人干扰素α-2a的血清浓度反映出健康志愿者和癌症患者的受试者间差异很大。

在健康人群中，重组干扰素alfa-2a的消除半衰期为3.7至8.5小时（平均5.1小时），稳态分布量为0.223至0.748 L / kg（平均0.400 L / kg），静脉输注36 MIU（2.2×10 8 pg）后，全身清除率达到2.14至3.62 mL / min / kg（平均2.79 mL / min / kg）。肌内和皮下给药36 MIU后，平均血清峰值浓度范围为1500至2580 pg / mL（平均2020 pg / mL），平均时间达到3.8小时的峰值，而从1250至2320 pg / mL（平均1730 pg / mL） ）分别平均达到7.3小时的峰值。肌内注射后所吸收剂量的表观分数大于80％。

肌注单次肌注后对已扩散的癌症患者进行重组的干扰素α-2a的药代动力学与健康志愿者相似。单剂量至198 MIU后观察到剂量呈比例增加的血清浓度。每天28次（0.5至36 MIU），每天一次（1至54 MIU）或每周3次（1至136 MIU）给药方案（最多28次）进行重组，干扰素alfa-2a的分布或消除没有变化天的剂量。多次肌内注射干扰素α-2a重组产生的累积量是单剂血清浓度的2至4倍。慢性丙型肝炎，毛细胞白血病和慢性粒细胞性白血病患者没有药代动力学信息。

在接受Roferon-A的所有患者中，大约有25％检测到血清中和活性，这是通过高灵敏度酶免疫测定和中和生物测定确定的。 2从未接受过外源性干扰素的患者，在某些临床情况（癌症，系统性红斑狼疮，带状疱疹）中，人白细胞干扰素的抗体可能会自发出现。 3出现血清中和活性的意义尚不清楚。

临床研究

研究表明，Roferon-A可以使慢性丙型肝炎患者的血清ALT正常化，改善肝脏组织学并降低病毒载量。其他研究表明，Roferon-A可以在毛细胞白血病患者中产生具有临床意义的肿瘤消退或疾病稳定作用。 4,5在Ph阳性慢性粒细胞性白血病中，与单独接受化疗的患者相比，补充有间歇性化疗的Roferon-A可延长总生存期并延缓疾病进展。 6此外，已证明Roferon-A在慢性期的一小部分CML患者中产生持续的完整细胞遗传学应答。 Roferon-A在Ph阴性CML中的活性尚未确定。

对慢性丙型肝炎的影响

Roferon-A的安全性和有效性在多项临床试验中进行了评估，该试验涉及2000多名18岁以上18岁以上肝炎，有或没有肝硬化，血清丙氨酸氨基转移酶（ALT）水平升高且丙型肝炎抗体呈阳性的患者通过各种剂量方案，包括剂量递增和递减方案，通过皮下注射（SC）或肌内注射（IM）每周给予Roferon-A 3次。在所有研究中，血清ALT的正常化定义为相距至少21天的两个连续的正常血清ALT值。持续反应（SR）定义为在治疗结束和至少6个月的无治疗随访结束时ALT正常化。

在给予Roferon-A 6个月的试验中，直接比较了6 MIU，3 MIU和1 MIU。六个MIU与更高的SR率相关，但毒性更大（请参阅“不良反应” ）。在使用相同剂量的Roferon-A进行6或12个月的研究中，持续时间较长与较高的SR率相关，并且在接下来的6个月中，不良事件的发生率没有比最初6个月中严重或频繁。根据这些数据，推荐的治疗方案为12个月3 MIU或前3个月6 MIU，随后9个月3 MIU（请参阅表1和剂量和用法）。这两种方案没有直接比较。

与年龄大于35岁或肝活检肝硬化的患者相比，年轻患者（例如，小于35岁）和肝活检无肝硬化的患者更有可能完全对Roferon-A做出反应。

在两项每周12次，每周3次皮下注射Roferon-A的研究中，有20/173（12％）的患者对治疗产生持续的反应（见表1）。在这些患者中，有15/173（9％）在持续随访长达四年的时间内保持了这种持续反应。 ALT正常化但在初始治疗后未能持续缓解的患者可受益于高剂量Roferon-A的再治疗（参见剂量和用法）。

一部分患者在用Roferon-A治疗之前和之后均进行了肝活检。通常观察到通过Knodell组织学活性指数评估的肝组织学改善。

一项来自两项研究的317例患者的回顾性亚组分析表明，通过聚合酶链反应（PCR）测得的肝组织学改善，血清ALT持久应答率与病毒载量降低之间存在相关性。

对Ph阳性慢性粒细胞白血病（CML）的影响

在两项慢性CML期患者的试验中评估了Roferon-A。 DM84-38研究是在MD安德森癌症中心进行的一项单中心II期研究，招募了91名患者，其中81％曾接受过治疗，82％呈Ph阳性，63％的患者在诊断后1年内接受了Roferon-A治疗。 MI400研究是意大利合作研究小组（CML）在意大利对335例患者进行的一项多中心随机III期研究； 226 Roferon-A和109化疗。患有Ph阳性，新诊断或未接受最低限度治疗的CML患者被随机分配（比率2：1）接受Roferon-A或采用羟基脲或白消安的常规化疗。在研究DM84-38中，患者以9 MIU /天的剂量开始使用Roferon-A，而在研究MI400中，它在第一个月从3 MIU /天逐步提高到9 MIU /天。在这两项试验中，均允许因血液学反应不足而增加剂量，并因毒性作用而使剂量减少或中断。在研究MI400的化疗组中未提供剂量减量的正式指南。此外，在Roferon-A组中，MI400方案允许添加间歇性单药化疗，以防止仅对Roferon-A的血液学反应不足。在该试验中，在研究期间的某些时间，接受Roferon-A治疗的患者中有44％还接受了间歇性单药化疗。

根据统一反应标准对这两项研究进行了分析。对于血液学反应：完全反应（WBC <9×10 9 / L，外周血中未成熟形态的差异正常化，脾肿大消失），部分反应（从WBC基线下降> 50％至<20％× 10 9 / L）。对于细胞遗传学应答：完全应答（Ph阳性中期为0％），部分应答（Ph阳性中期为1％至34％）。

在研究DM84-38中，启动Roferon-A的中位生存期为47个月。在研究MI400中，干扰素臂患者的中位生存期为69个月，明显好于化疗对照组中的55个月（研究MI400中的48位患者行了BMT，而研究DM84-38中的15位患者前往BMT）。 Roferon-A治疗可显着延缓疾病发展至成骨期，化学疗法可使疾病进展的中位时间为69个月至46个月。

通过对参与随机研究的全部335例患者的预后因素进行多变量分析，采用Roferon-A（有或没有间歇性补充化疗； p = 0.006），Sokal指数7 （p = 0.006）和WBC（p = 0.023）进行治疗是与生存改善相关的三个变量，与其他基线特征无关（卡诺夫斯基的机能状态和血红蛋白是输入模型的其他因素）。

在研究MI400中，在大约60％接受Roferon-A治疗的患者中观察到总体血液学反应[完全缓解（CR）和部分缓解（PR）]（40％CR，20％PR），而70％接受化疗（CR为30％，PR为40％）。 Roferon-A组达到完全血液学应答的中位时间为5个月，化疗组为4个月。根据意图治疗原则，接受Roferon-A的患者的总体细胞遗传学应答率（CR + PR）在研究MI400和DM84-38中分别为10％和12％。相反，在研究MI400的化疗分支中，只有2％的患者实现了细胞遗传学应答（无完全应答）。仅在完全血液学反应的患者中观察到细胞遗传学反应。在研究DM84-38中，与开始使用Roferon-A治疗的亚组相比，在诊断后1年内接受Roferon-A治疗的患者亚组的血液学和细胞遗传学应答率更高（分别为76％和17％）。从诊断得出（分别为29％和4％）。在一项探索性分析中，达到细胞遗传学应答的患者比未存活的患者活得更长。

在研究DM84-38和MI400中，分别有66％和31％的患者观察到严重不良事件。经常需要减少剂量和暂时停止治疗。在研究DM84-38和MI400中，分别由于15％和23％的患者需要永久性停用Roferon-A（请参阅“不良反应” ）。

关于Roferon-A在Ph阳性，成人型CML儿童中的使用的可用数据有限。已发表的有关15例CML儿童的报告表明，其安全性与成人CML相似。还观察到了临床反应8 （参见剂量和用法）。

对毛细胞白血病的影响

美国一项多中心II期研究（N2752）招募了218例患者；在初步分析中，有75位患者的疗效可以评估； 218名患者的安全性可评估。患者将接受高达6 MIU / m 2 /天的Roferon-A起始剂量，诱导期为4到6个月。有反应的患者将接受12个月的维持治疗。

在毛细胞白血病患者治疗的头1到2个月内，造血功能可能会明显下降。随后，循环血细胞计数得到改善。在治疗至少16周后可评估疗效的75例患者中，有46例（61％）达到了完全或部分缓解。 21例患者（28％）轻度缓解，8例（11％）保持稳定，无一例病情恶化。所有达到完全或部分反应的患者的所有外周血成分（包括血红蛋白水平，白细胞，中性粒细胞，单核细胞和血小板计数）全部或部分正常，同时外周血和骨髓毛细胞减少。有反应的患者还表现出红血球和血小板输注需求的显着降低，感染发作的减少以及运动状态的改善。与历史对照组（75％）相比，接受Roferon-A的患者2年生存率（94％）在统计学上有所增加。

Roferon-A的适应症和用法

Roferon-A适用于治疗18岁或18岁以上的慢性丙型肝炎和毛细胞白血病。此外，对于慢性期，费城染色体（Ph）阳性的慢性骨髓性白血病（CML）患者，需进行最低限度的预处理（诊断1年之内）。

对于慢性丙型肝炎患者

Roferon-A适用于通过HCV抗体诊断出患有慢性丙型肝炎的患者和/或有补偿性肝病且年龄在18岁以上的丙型肝炎暴露史。应进行肝活检和血清检测是否存在HCV抗体，以诊断慢性丙型肝炎。在用Roferon-A治疗之前，应排除包括乙型肝炎在内的其他肝炎原因。

禁忌症

Roferon-A禁用于以下患者：

• 对Roferon-A或其任何成分过敏
• 自身免疫性肝炎
• 治疗前或治疗中肝功能失代偿（Child-Pugh B级和C级）

Roferon-A在新生儿和婴儿中禁忌使用，因为它含有苯甲醇。苯甲醇与新生儿和婴儿的神经系统疾病和其他并发症的发生率增加相关，有时是致命的。

警告事项

Roferon-A应在合格医师的指导下进行给药（参见剂量和管理）。仅当有足够的可用设备时，才可能对治疗及其并发症进行适当的管理。

神经精神疾病

在患有或未患有先前精神病的患者中，已经报道了与自杀倾向有关的抑郁和自杀行为，自杀尝试和自杀与阿尔法干扰素（包括Roferon-A）治疗相关。报告患有抑郁症的患者应格外小心使用Roferon-A。应告知患者抑郁和自杀意念可能是治疗的副作用，并应建议立即将这些副作用报告给处方医生。接受Roferon-A治疗的患者应密切监测抑郁症状的发生。患有抑郁症的患者应考虑进行精神科干预和/或停止治疗。尽管减少剂量或停止治疗可能会导致抑郁症状的缓解，但退出治疗后抑郁可能会持续存在并且自杀已发生（请参阅注意事项和不良反应）。

已有许多患者报道中枢神经系统不良反应。这些反应包括精神状态下降，头晕，记忆力减退，躁动，躁狂行为和精神病反应。很少观察到更严重的肥胖和昏迷。在减少剂量或停用Roferon-A治疗后的几天至3周内，这些异常大多数为轻度且可逆。建议对所有患者进行仔细的定期神经精神病学监测。癫痫发作和/或中枢神经系统功能受损的患者应谨慎使用Roferon-A。

心血管疾病

对于患有心脏病或有心脏病史的患者，应谨慎使用Roferon-A。经常与Roferon-A给药相关的急性，自限毒性（例如，发烧，发冷）可能会加剧先前存在的心脏疾病。接受Roferon-A的患者很少发生心肌梗塞。在接受α干扰素治疗的患者中，很少见到心肌病病例。

脑血管疾病

在使用基于干扰素阿尔法的疗法（包括Roferon-A）治疗的患者中观察到缺血性和出血性脑血管事件。事件发生在很少或没有报道中风危险因素的患者中，包括小于45岁的患者。由于这些是自发报告，因此无法估算频率，并且难以确定基于干扰素α的疗法与这些事件之间的因果关系。

过敏症

在α-干扰素治疗期间，包括干扰素α-2a，很少见到严重的急性超敏反应（例如荨麻疹，血管性水肿，支气管收缩和过敏反应）以及皮疹。如果在用Roferon-A治疗期间发生严重反应，请停止治疗并立即进行适当的医学治疗。短暂性皮疹无需中断治疗。

肝病

在慢性丙型肝炎中，已报道开始使用包括Roferon-A在内的α-干扰素治疗可引起短暂性肝异常，这在肝病补偿能力差的患者中可能导致腹水增加，肝衰竭或死亡。

胃肠道疾病

很少有严重或致命的胃肠道出血与α-干扰素治疗相关的报道。

在开始α干扰素治疗后12周内观察到溃疡性和出血性/缺血性结肠炎，有时甚至致命。腹痛，血性腹泻和发烧是结肠炎的典型表现。如果出现这些症状，应立即停用Roferon-A。结肠炎通常在中断α干扰素后1-3周内消退。

传染病

尽管发烧可能与干扰素治疗期间普遍报告的流感样综合征有关，但必须排除高发或持续发烧的其他原因，特别是在中性粒细胞减少症患者中。据报道，在使用包括Roferon-A在内的α干扰素治疗期间，出现了严重和严重的感染（细菌，病毒，真菌）感染，有些致命。应立即开始适当的抗感染治疗，并应考虑终止治疗。

骨髓毒性

α-干扰素会抑制骨髓功能，并可能导致严重的血细胞减少和贫血，包括再生障碍性贫血的罕见情况。甲状腺机能减退（例如白细胞减少症，血小板减少症）会导致感染或出血的风险增加。建议在治疗前获得全血细胞计数（CBC）并进行常规监测。如果中性粒细胞严重减少（<0.5×10 9 / L）或血小板计数严重下降（<25×10 9 / L）的患者应停止α干扰素治疗。

当将Roferon-A给予患有骨髓抑制的患者或当Roferon-A与已知引起骨髓抑制的其他药物联合使用时，应谨慎行事。当Roferon-A与齐多夫定（AZT）组合使用时，已观察到协同毒性。 9

内分泌失调

Roferon-A引起或加重甲状腺功能减退和甲亢。在用Roferon-A治疗的患者中观察到高血糖症。有症状的患者应测量血糖并进行相应的随访。糖尿病患者可能需要调整其抗糖尿病方案。

肺部疾病

α干扰素治疗可能诱发或加重呼吸困难，肺部浸润，肺炎，闭塞性细支气管炎，间质性肺炎和结节病，其中一些会导致呼吸衰竭和/或患者死亡。出现持续性或无法解释的肺浸润或肺功能损害的患者应停止使用Roferon-A治疗。

眼科疾病

干扰素α-2a或其他α干扰素治疗可引起或加重视力下降或丧失，视网膜病变（包括黄斑水肿，视网膜动脉或静脉血栓形成），视网膜出血和棉絮斑，视神经炎和乳头水肿。所有患者均应在基线时接受眼睛检查。患有先前存在的眼科疾病（例如糖尿病性或高血压性视网膜病）的患者应在α干扰素治疗期间接受定期的眼科检查。任何出现眼部症状的患者均应立即进行彻底的眼科检查。发生新的或恶化的眼科疾病的患者应停止干扰素α-2a治疗。

胰腺炎

在接受α干扰素治疗的患者中，包括那些甘油三酯明显升高的患者，均已观察到胰腺炎。在某些情况下，已经观察到死亡。尽管尚未确定与Roferon-A的因果关系，但甘油三酸酯明显升高是胰腺炎发展的危险因素。如果观察到提示胰腺炎的症状或体征，应暂停使用Roferon-A。在诊断为胰腺炎的患者中，应考虑停用Roferon-A治疗。

预防措施

一般

在考虑使用Roferon-A进行化学疗法的所有情况下，医生必须针对不良反应的风险评估药物的需求和有效性。如果及早发现，大多数不良反应是可逆的。如果发生严重反应，应减少剂量或停药，并应根据医师的临床判断采取适当的纠正措施。再次使用Roferon-A疗法时应格外谨慎，并应充分考虑对该药的进一步需求，并警惕可能再次发生毒性反应。 Roferon-A治疗毛细胞白血病和慢性粒细胞白血病的最低有效剂量尚未确定。

不同品牌的干扰素之间存在剂量和不良反应的差异。因此，请勿在单一治疗方案中使用不同品牌的干扰素。

在器官移植患者中尚未确定Roferon-A的安全性和有效性。

肾功能不全

限剂量的肾脏毒性异常。很少有单独或与IL-2联合使用α-干扰素治疗的严重肾毒性，有时需要进行肾透析的报道。对于肾功能受损的患者，应密切监测干扰素毒性的体征和症状。肌酐清除率<50 mL / min的患者应谨慎使用Roferon-A。

自身免疫病

在α干扰素治疗的患者中，已观察到自身免疫疾病的发展或加剧，包括特发性血小板减少性紫癜，血管炎，雷诺现象，类风湿性关节炎，牛皮癣，间质性肾炎，甲状腺炎，红斑狼疮，肝炎，肌炎和横纹肌溶解。任何在治疗过程中发生自身免疫性疾病的患者都应受到密切监测，如果合适，应停止治疗。

给患者的信息

应警告患者，未经医疗咨询不得更改干扰素品牌，因为可能会导致剂量变化。应告知患者使用Roferon-A可能带来的好处和风险。如果医师确定家庭使用是合乎需要的，则应给出有关适当使用的说明，包括阅读随附的《用药指南》中的内容。患者应保持充足的水分，尤其是在治疗初期。

应彻底指导患者正确处置程序的重要性，并告诫不要重复使用注射器和针头。如果规定要在家中使用，则应向患者提供用于处理用过的注射器和针头的防刺容器。完整的容器应按照医师提供的说明进行处置（请参阅《用药指南》 ）。

应建议患者在开始治疗之前及之后定期进行实验室评估（请参阅实验室测试）。

应警告接受高剂量α-干扰素的患者不要执行需要完全精神警觉的任务，例如操作机器或驾驶汽车。应告知将要接受Roferon-A治疗的患者，抑郁和自杀意念可能是治疗的副作用，并应建议立即将这些副作用报告给处方医生。

实验室测试

白细胞减少症和肝酶升高频繁发生，但很少受到剂量限制。血小板减少症的发生频率较低。也很少见到蛋白尿和尿沉渣中细胞增多。

在开始Roferon-A治疗之前以及治疗期间的适当时间，应进行全血细胞计数，血小板计数差异和临床化学测试。中性粒细胞计数<1500 / mm 3 ，血小板计数<75,000 / mm 3 ，血红蛋白<10 g / dL和肌酐> 1.5 mg / dL的患者被排除在几项主要的慢性丙型肝炎研究之外；如果使用Roferon-A治疗，应对这些实验室异常患者进行仔细监测。由于开始治疗后的1到3个月通常没有观察到毛细胞白血病，慢性丙型肝炎和慢性粒细胞性白血病的反应，因此在治疗的初始阶段应非常仔细地监测严重的血细胞计数下降。

那些患有先前存在的心脏异常和/或处于癌症晚期的患者应在治疗前和治疗过程中进行心电图检查。

对于正在接受慢性丙型肝炎治疗的患者，应在治疗前评估血清ALT以建立基线，并在开始治疗后的第2周和此后每月重复监测临床反应。在Roferon-A治疗期间出现肝功能异常的患者应受到密切监测，必要时应停止治疗。很少使用α-干扰素与严重的肝功能不全和肝功能衰竭相关。

如果可以通过药物维持正常的甲状腺刺激激素（TSH）水平，则可以治疗已有甲状腺功能异常的患者。建议在基线时和开始治疗后每3个月对这些患者的TSH水平进行测试。

在包括Roferon-A治疗在内的干扰素治疗的患者中，甘油三酯水平升高。治疗期间应定期监测甘油三酸酯水平，并应在临床上适当控制升高的水平。高甘油三酯血症可能导致胰腺炎。对于甘油三酸酯持续升高（例如，甘油三酸酯> 1000 mg / dL）并伴有潜在胰腺炎症状（如腹痛，恶心或呕吐）的患者，应考虑停用Roferon-A治疗。

药物相互作用

据报道，Roferon-A可降低茶碱的清除率。 10,11这种相互作用的临床相关性目前未知。与其他潜在的骨髓抑制药物联合使用Roferon-A时应谨慎。当Roferon-A与齐多夫定（AZT）组合使用时，观察到协同毒性（请参阅警告：骨髓毒性）。

In transplant recipients, therapeutic immunosuppression may be weakened because interferons also exert an immunostimulatory action.

Alpha-interferons may affect the oxidative metabolic process by reducing the activity of hepatic microsomal cytochrome enzymes in the P450 group. Although the clinical relevance is still unclear, this should be taken into account when prescribing concomitant therapy with drugs metabolized by this route.

The neurotoxic, hematotoxic or cardiotoxic effects of previously or concurrently administered drugs may be increased by interferons. Interactions could occur following concurrent administration of centrally acting drugs. Use of Roferon-A in conjunction with interleukin-2 may potentiate risks of renal failure.

致癌，诱变，生育力受损

Roferon-A has not been tested for its carcinogenic potential.

A. Internal Studies — Ames tests using six different tester strains, with and without metabolic activation, were performed with Roferon-A up to a concentration of 1920 µg/plate. There was no evidence of mutagenicity.

Human lymphocyte cultures were treated in vitro with Roferon-A at noncytotoxic concentrations. No increase in the incidence of chromosomal damage was noted.

B. Published Studies — There are no published studies on the mutagenic potential of Roferon-A. However, a number of studies on the genotoxicity of human leukocyte interferon have been reported.

A chromosomal defect following the addition of human leukocyte interferon to lymphocyte cultures from a patient suffering from a lymphoproliferative disorder has been reported.

In contrast, other studies have failed to detect chromosomal abnormalities following treatment of lymphocyte cultures from healthy volunteers with human leukocyte interferon.

It has also been shown that human leukocyte interferon protects primary chick embryo fibroblasts from chromosomal aberrations produced by gamma rays.

Roferon-A has been studied for its effect on fertility in Macaca mulatta (rhesus monkeys). Nonpregnant rhesus females treated with Roferon-A at doses of 5 and 25 MIU/kg/day have shown menstrual cycle irregularities, including prolonged or shortened menstrual periods and erratic bleeding; these cycles were considered to be anovulatory on the basis that reduced progesterone levels were noted and that expected increases in preovulatory estrogen and luteinizing hormones were not observed. These monkeys returned to a normal menstrual rhythm following discontinuation of treatment.

怀孕

Roferon-A has been associated with statistically significant, dose-related increases in abortions in pregnant rhesus monkeys treated with 1, 5, or 25 MIU/kg/day (approximately 20 to 500 times the human weekly dose, when scaled by body surface area) during the early to midfetal period of organogenesis (gestation day 22 to 70). Abortifacient activity was also observed in 2/6 pregnant rhesus monkeys treated with 25 MIU/kg/day Roferon-A (500 times the human dose) during the period of late fetal development (days 79 to 100 of gestation). No teratogenic effects were seen in either study. However, the validity of extrapolating doses used in animal studies to human doses is not established. Therefore, no direct comparison of the doses that induced fetal death in monkeys to dose levels of Roferon-A used clinically can be made. There are no adequate and well-controlled studies of Roferon-A in pregnant women. Roferon-A is to be used during pregnancy only if the potential benefit to the woman justifies the potential risk to the fetus. Roferon-A is recommended for use in women of childbearing potential and in men only when they are using effectivecontraception during therapy.

The injectable solution contains benzyl alcohol. The excipient benzyl alcohol can be transmitted via the placenta. The possibility of toxicity should be taken into account in premature infants after the administration of Roferon-A solution for injection immediately prior to birth or Cesarean section.

Male fertility and teratologic evaluations have yielded no significant adverse effects to date.

护理母亲

尚不清楚该药物是否从人乳中排泄。 Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Roferon-A, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

儿科用

Use of Roferon-A in children with Ph-positive adult-type CML is supported by evidence from adequate and well-controlled studies of Roferon-A in adults with additional data from the literature on the use of alfa interferon in children with CML. A published report on 15 children with Ph-positive adult-type CML suggests a safety profile similar to that seen in adult CML; clinical responses were also observed 8 (see DOSAGE AND ADMINISTRATION ).

For all other indications, safety and effectiveness have not been established in patients below the age of 18 years.

The injectable solutions are not indicated for use in neonates or infants and should not be used by patients in that age group. There have been rare reports of death in neonates and infants associated with excessive exposure to benzyl alcohol (see CONTRAINDICATIONS ).

老人用

In clinical studies of Roferon-A in chronic hepatitis C, 101 patients were 65 years old or older. The numbers were insufficient to determine if antiviral responses differ from younger subjects. There were greater proportions of geriatric patients with serious adverse reactions (9% vs. 6%), withdrawals due to adverse reactions (11% vs. 6%), and WHO grade III neutropenia and thrombocytopenia.

Clinical studies of Roferon-A in chronic myelogenous leukemia or hairy cell leukemia did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently from younger subjects.

This drug is known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, these patients should receive careful monitoring, including renal function.

不良反应

Depressive illness and suicidal behavior, including suicidal ideation, suicide attempt, and suicides, have been reported in association with the use of alfa-interferon products. The incidence of reported depression has varied substantially among trials, possibly related to the underlying disease, dose, duration of therapy and degree of monitoring, but has been reported to be 15% or higher (see WARNINGS ).

For Patients With Chronic Hepatitis C

The most frequent adverse experiences were reported to be possibly or probably related to therapy with 3 MIU tiw Roferon-A, were mostly mild to moderate in severity and manageable without the need for discontinuation of therapy. A relative increase in the incidence, severity and seriousness of adverse events was observed in patients receiving doses above 3 MIU tiw.

Adverse reactions associated with the 3 MIU dose include:

Flu-like Symptoms: Fatigue (58%), myalgia/arthralgia (51%), flu-like symptoms (33%), fever (28%), chills (23%), asthenia (6%), sweating (5%), leg cramps (3%) and malaise (1%).

Central and Peripheral Nervous System: Headache (52%), dizziness (13%), paresthesia (7%), confusion (7%), concentration impaired (4%) and change in taste or smell (3%).

Gastrointestinal: Nausea/vomiting (33%), diarrhea (20%), anorexia (14%), abdominal pain (12%), flatulence (3%), liver pain (3%), digestion impaired (2%) and gingival bleeding (2%).

Psychiatric: Depression (16%), irritability (15%), insomnia (14%), anxiety (5%) and behavior disturbances (3%).

Pulmonary and Cardiovascular: Dryness or inflammation of oropharynx (6%), epistaxis (4%), rhinitis (3%), arrhythmia (1%) and sinusitis (<1%).

Skin: Injection site reaction (29%), partial alopecia (19%), rash (8%), dry skin or pruritus (7%), hematoma (1%), psoriasis (<1%), cutaneous eruptions (<1%), eczema (<1%) and seborrhea (<1%).

Other: Conjunctivitis (4%), menstrual irregularity (2%) and visual acuity decreased (<1%).

Patients receiving 6 MIU tiw experienced a higher incidence of severe psychiatric events (9%) than those receiving 3 MIU tiw (6%) in two large US studies. In addition, more patients withdrew from these studies when receiving 6 MIU tiw (11%) than when receiving 3 MIU tiw (7%). Up to half of patients receiving 3 MIU or 6 MIU tiw withdrawing from the study experienced depression or other psychiatric adverse events. At higher doses anxiety, sleep disorders, and irritability were observed more frequently. An increased incidence of fatigue, myalgia/arthralgia, headache, fever, chills, alopecia, sleep disturbances and dry skin or pruritus was also generally observed during treatment with higher doses of Roferon-A.

Generally there were fewer adverse events reported in the second 6 months of treatment than in the first 6 months for patients treated with 3 MIU tiw. Patients tolerant of initial therapy with Roferon-A generally tolerate re-treatment at the same dose, but tend to experience more adverse reactions at higher doses.

Infrequent adverse events (>1% but <3% incidence) included: cold feeling, cough, muscle cramps, diaphoresis, dyspnea, eye pain, reactivation of herpes simplex, lethargy, edema, sexual dysfunction, shaking, skin lesions, stomatitis, tooth disorder, urinary tract infection, weakness in extremities.

Triglyceride levels were not evaluated in the clinical trials. However, hypertriglyceridemia has been reported postmarketing in patients receiving Roferon-A therapy for chronic hepatitis C.

For Patients With Chronic Myelogenous Leukemia

For patients with chronic myelogenous leukemia, the percentage of adverse events, whether related to drug therapy or not, experienced by patients treated with rIFNα-2a is given below. Severe adverse events were observed in 66% and 31% of patients on study DM84-38 and MI400, respectively. Dose reduction and temporary cessation of therapy were required frequently. Permanent cessation of Roferon-A, due to intolerable side effects, was required in 15% and 23% of patients on studies DM84-38 and MI400, respectively.

Flu-like Symptoms: Fever (92%), asthenia or fatigue (88%), myalgia (68%), chills (63%), arthralgia/bone pain (47%) and headache (44%).

Gastrointestinal: Anorexia (48%), nausea/vomiting (37%) and diarrhea (37%).

Central and Peripheral Nervous System: Headache (44%), depression (28%), decreased mental status (16%), dizziness (11%), sleep disturbances (11%), paresthesia (8%), involuntary movements (7%) and visual disturbance (6%).

Pulmonary and Cardiovascular: Coughing (19%), dyspnea (8%) and dysrhythmia (7%).

Skin: Hair changes (including alopecia) (18%), skin rash (18%), sweating (15%), dry skin (7%) and pruritus (7%).

Uncommon adverse events (<4%) reported in clinical studies included chest pain, syncope, hypotension, impotence, alterations in taste or hearing, confusion, seizures, memory loss, disturbances of libido, bruising and coagulopathy. Miscellaneous adverse events that were rarely observed included Coombs' positive hemolytic anemia, aplastic anemia, hypothyroidism, cardiomyopathy, hypertriglyceridemia and bronchospasm.

For Patients With Hairy Cell Leukemia

Constitutional (100%): Fever (92%), fatigue (86%), headache (64%), chills (64%), weight loss (33%), dizziness (21%) and flu-like symptoms (16%).

Integumentary (79%): Skin rash (44%), diaphoresis (22%), partial alopecia (17%), dry skin (17%) and pruritus (13%).

Musculoskeletal (73%): Myalgia (71%), joint or bone pain (25%) and arthritis or polyarthritis (5%).

Gastrointestinal (69%): Anorexia (43%), nausea/vomiting (39%) and diarrhea (34%).

Head and Neck (45%): Throat irritation (21%), rhinorrhea (12%) and sinusitis (11%).

Pulmonary (40%): Coughing (16%), dyspnea (12%) and pneumonia (11%).

Central Nervous System (39%): Dizziness (21%), depression (16%), sleep disturbance (10%), decreased mental status (10%), anxiety (6%), lethargy (6%), visual disturbance (6%) and confusion (5%).

Cardiovascular (39%): Chest pain (11%), edema (11%) and hypertension (11%).

Pain (34%): Pain (24%) and pain in back (16%).

Peripheral Nervous System (23%): Paresthesia (12%) and numbness (12%).

Rarely (<5%), central nervous system effects including gait disturbance, nervousness, syncope and vertigo, as well as cardiac adverse events including murmur, thrombophlebitis and hypotension were reported. Adverse experiences that occurred rarely, and may have been related to underlying disease, included ecchymosis, epistaxis, bleeding gums and petechiae. Urticaria and inflammation at the site of injection were also rarely observed.

In Other Investigational Studies of Roferon-A

The following infrequent adverse events have been reported with the investigational use of Roferon-A.

Gastrointestinal: Pancreatitis, colitis, gastrointestinal hemorrhage, stomatitis (<5%); constipation (<3%); hepatitis, abdominal fullness, hypermotility, excessive salivation, gastric distress (<1%).

Cardiovascular: Palpitations (<3%); myocardial infarction, congestive heart failure, ischemic retinopathy, Raynaud's phenomenon, hot flashes (<1%).

Pulmonary: Pneumonitis, some cases responded to interferon cessation and corticosteroid therapy (<5%); chest congestion (<3%); tachypnea (<1%).

Central Nervous System and Psychiatric: Stroke, coma, encephalopathy, transient ischemic attacks, dysphasia, hallucinations, gait disturbance, psychomotor retardation, apathy, sedation, irritability, hyperactivity, claustrophobia, loss of libido, ataxia, neuropathy, poor coordination, dysarthria, aphasia, aphonia, amnesia (<1%).

Autoimmune Disease: Vasculitis, arthritis, hemolytic anemia and lupus erythematosus syndrome (<3%).

Other: Thyroid dysfunction including hypothyroidism and hyperthyroidism, diabetes requiring insulin therapy in some patients (<5%); anaphylactic reactions, eye irritation, earache, cyanosis, flushing of skin (<1%).

Abnormal Laboratory Test Values

The percentage of patients with chronic hepatitis C, hairy cell leukemia, and with chronic myelogenous leukemia who experienced a significant abnormal laboratory test value ( NCI or WHO grades III or IV ) at least once during their treatment with Roferon-A is shown in Table 2:

Elevated triglyceride levels have been observed in patients receiving interferon therapy, including Roferon-A.

Chronic Hepatitis C

The incidence of neutropenia ( WHO grades III or IV ) was over twice as high in those treated with 6 MIU tiw (21%) as those treated with 3 MIU tiw (10%).

Chronic Myelogenous Leukemia

In the two clinical studies, a severe or life-threatening anemia was seen in up to 15% of patients. A severe or life-threatening leukopenia and thrombocytopenia were observed in up to 20% and 27% of patients, respectively. Changes were usually reversible when therapy was discontinued. One case of aplastic anemia and one case of Coombs' positive hemolytic anemia were seen in 310 patients treated with rIFNα-2a in clinical studies. Severe cytopenias led to discontinuation of therapy in 4% of all Roferon-A treated patients.

Transient increases in liver transaminases or alkaline phosphatase of any intensity were seen in up to 50% of patients during treatment with Roferon-A. Only 5% of patients had a severe or life-threatening increase in SGOT. In the clinical studies, such abnormalities required termination of therapy in less than 1% of patients.

Hairy Cell Leukemia

Increases in serum phosphorus (≥1.6 mmol/L) and serum uric acid (≥9.1 mg/dL) were observed in 9% and 10% of patients, respectively. The increase in serum uric acid is likely to be related to the underlying disease. Decreases in serum calcium (≤1.9 mmol/L) and serum phosphorus (≤0.9 mmol/L) were seen in 28% and 22% of patients, respectively.

Postmarketing

Central and Peripheral Nervous System: Somnolence, hearing impairment, hearing loss.

Vision: Retinopathy including retinal hemorrhages and cotton-wool spots, papilledema, retinal artery and vein thrombosis and optic neuropathy.

Skin: Injection site necrosis.

Blood: Idiopathic thrombocytopenic purpura, cyanosis.

Renal and Urinary System: Increased blood urea and serum creatinine, decreased renal function and acute renal failure.

Endocrine: Hyperglycemia.

Immune System Disorder: Sarcoidosis.

Respiratory: Pulmonary edema.

Metabolic and Nutritional: Cases of hypertriglyceridemia/hyperlipidemia have been reported including some occurring in association with pancreatitis.

过量

There are no reports of overdosage, but repeated large doses of interferon can be associated with profound lethargy, fatigue, prostration, and coma. Such patients should be hospitalized for observation and appropriate supportive treatment given.

Roferon-A Dosage and Administration

Roferon-A recommended dosing regimens are different for each of the following indications as described below.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

Roferon-A is administered subcutaneously.

Chronic Hepatitis C

The recommended dosage of Roferon-A for the treatment of chronic hepatitis C is 3 MIU three times a week (tiw) administered subcutaneously for 12 months (48 to 52 weeks). As an alternative, patients may be treated with an induction dose of 6 MIU tiw for the first 3 months (12 weeks) followed by 3 MIU tiw for 9 months (36 weeks). Normalization of serum ALT generally occurs within a few weeks after initiation of treatment in responders. Approximately 90% of patients who respond to Roferon-A do so within the first 3 months of treatment; however, patients responding to Roferon-A with a reduction in ALT should complete 12 months of treatment. Patients who have no response to Roferon-A within the first 3 months of therapy are not likely to respond with continued treatment; treatment discontinuation should be considered in these patients.

Patients who tolerate and partially or completely respond to therapy with Roferon-A but relapse following its discontinuation may be re-treated. Re-treatment with either 3 MIU tiw or with 6 MIU tiw for 6 to 12 months may be considered. Please see ADVERSE REACTIONS regarding the increased frequency of adverse reactions associated with treatment with higher doses.

Temporary dose reduction by 50% is recommended in patients who do not tolerate the prescribed dose. If adverse events resolve, treatment with the original prescribed dose can be re-initiated. In patients who cannot tolerate the reduced dose, cessation of therapy, at least temporarily, is recommended.

Chronic Myelogenous Leukemia

For patients with Ph-positive CML in chronic phase: Prior to initiation of therapy, a diagnosis of Philadelphia chromosome positive CML in chronic phase by the appropriate peripheral blood, bone marrow and other diagnostic testing should be made. Monitoring of hematologic parameters should be done regularly (eg, monthly). Since significant cytogenetic changes are not readily apparent until after hematologic response has occurred, and usually not until several months of therapy have elapsed, cytogenetic monitoring may be performed at less frequent intervals. Achievement of complete cytogenetic response has been observed up to 2 years following the start of Roferon-A treatment.

The recommended initial dose of Roferon-A is 9 MIU daily administered as a subcutaneous injection. Based on clinical experience, 3 short-term tolerance may be improved by gradually increasing the dose of Roferon-A over the first week of administration from 3 MIU daily for 3 days to 6 MIU daily for 3 days to the target dose of 9 MIU daily for the duration of the treatment period.

The optimal dose and duration of therapy have not yet been determined. Even though the median time to achieve a complete hematologic response was 5 months in study MI400, hematologic responses have been observed up to 18 months after treatment start. Treatment should be continued until disease progression. If severe side effects occur, a treatment interruption or a reduction in either the dose or the frequency of injections may be necessary to achieve the individual maximally tolerated dose (see PRECAUTIONS ).

Limited data are available on the use of Roferon-A in children with CML. In one report of 15 children with Ph-positive, adult-type CML doses between 2.5 to 5 MIU/m 2 /day given intramuscularly were tolerated. 8 In another study, severe adverse effects including deaths were noted in children with previously untreated, Ph-negative, juvenile CML, who received interferon doses of 30 MIU/m 2 /day. 12

Hairy Cell Leukemia

Prior to initiation of therapy, tests should be performed to quantitate peripheral blood hemoglobin, platelets, granulocytes and hairy cells and bone marrow hairy cells. These parameters should be monitored periodically (eg, monthly) during treatment to determine whether response to treatment has occurred. If a patient does not respond within 6 months, treatment should be discontinued. If a response to treatment does occur, treatment should be continued until no further improvement is observed and these laboratory parameters have been stable for about 3 months. Patients with hairy cell leukemia have been treated for up to 24 consecutive months. The optimal duration of treatment for this disease has not been determined.

The induction dose of Roferon-A is 3 MIU daily for 16 to 24 weeks, administered as a subcutaneous injection. The recommended maintenance dose is 3 MIU, tiw. Dose reduction by one-half or withholding of individual doses may be needed when severe adverse reactions occur. The use of doses higher than 3 MIU is not recommended in hairy cell leukemia.

How is Roferon-A Supplied

Single Use Prefilled Syringes

(for subcutaneous administration)

3 million IU Roferon-A per syringe — Each 0

注意：本文档包含有关干扰素α-2a的副作用信息。此页面上列出的某些剂型可能不适用于Roferon-A品牌。

适用于干扰素alfa-2a：注射剂，注射剂，溶液

精神科

精神方面的副作用包括抑郁（16％至28％）和自杀行为，包括自杀观念，自杀未遂和自杀。还报告了烦躁（15％），失眠（14％），焦虑症（5％至6％）和行为障碍（3％）。在一项针对慢性粒细胞性白血病患者（n = 25）的研究中，评估了与阿尔法干扰素治疗相关的神经心理症状，这些患者在言语记忆，视觉记忆延迟，言语测验中在受损范围内得分的比例不成比例与对照组相比，首选手的流利性，视觉扫描和排序，执行功能和运动敏捷性。除了上述认知缺陷外，接受干扰素α治疗的患者还表现出人格和情绪障碍的迹象。 ^[参考]

据报道，在减少剂量或停止治疗后，抑郁症有时会持续下去。

最近的一项研究（n = 14）对接受干扰素α-2b治疗的慢性丙型肝炎患者的研究表明，干扰素α引起的抑郁症状的发生可能是由于中枢和外周5-HT的消耗和色氨酸的减少引起的。血浆水平。 ^[参考]

其他

其他副作用包括类似流感的症状，例如疲劳（58％至95％），发烧（25％至92％），肌痛（68％至71％），头痛（44％至66％），发冷（23％）至64％），关节痛/骨痛（25％至47％），乏力（6％），出汗（5％），腿抽筋（3％）和不适（1％）。体重减轻（25％至33％），口味或气味改变（3％至25％），疼痛（24％），背部疼痛（16％），盗汗（8％），月经不调（4％），也有可逆性听力损失和耳鸣的报道。 ^[参考]

在治疗的第一周，类似流感的症状可能特别普遍。 ^[参考]

胃肠道

胃肠道（GI）副作用包括厌食症（14％至65％），腹泻（20％至42％），恶心/呕吐（33％至39％），腹痛（12％至15％），肠胃气胀（3 ％），肝痛（3％），消化不良（2％），牙龈出血（2％）和胃肠道出血。 ^[参考]

神经系统

在减少剂量或停止治疗后的几天至3周内，大多数中枢神经系统不良反应是轻度且可逆的。

一位有慢性粒细胞白血病病史的49岁女性经历了肌节律异常并伴有α-2a干扰素（Roferon-A所含活性成分）治疗。每天给她增加剂量的皮下干扰素alfa-2a直至6兆单位，并具有良好的临床和血液学反应。在使用干扰素1.5年后，她逐渐出现了不自主的面部运动。她的家人注意到她的额头和下脸两侧都有动作。脑磁共振成像（MRI）未显示任何结构异常。要求患者停用干扰素。在2周内，她报告了面部运动得到改善，在1个月时，她的症状几乎完全消失。

一名44岁的患有转移性肾细胞癌的女性发生脑病，同时伴有α-2a干扰素治疗。她表现出进行性冷漠和轻微的主观记忆丧失以及两次癫痫发作。脑电图显示多灶性癫痫样放电。腰穿检查结果正常。 MRI显示基底神经节和邻近的白质呈高信号，但无其他明显病变。停止干扰素治疗后，患者的临床状态恢复正常，三周后MRI也一样。 ^[参考]

神经系统副作用包括头痛（44％至64％），头晕（11％至40％），精神状态下降（10％至17％），感觉异常（7％至12％），麻木（3％至12） ％），睡眠障碍（10％至11％），精神错乱（5％至8％），非自愿运动（7％），嗜睡（6％），睡眠障碍（5％）和注意力不集中（4％）。除一例脑病外，也至少报告了一例肌节律异常。 ^[参考]

皮肤科

皮肤病副作用包括皮疹（8％至44％），注射部位反应（29％），发汗（7％至22％），部分脱发（17％至22％），皮肤干燥（7％至17％） ），瘙痒（7％至13％），血肿（1％）。也有不到1％的患者报告了牛皮癣，皮疹，湿疹和皮脂溢。 ^[参考]

呼吸道

呼吸道副作用包括咳嗽（19％至27％），喉咙刺激（21％），咳嗽（16％），鼻漏（12％），呼吸困难（8％至12％），肺炎（11％），鼻窦炎（大于1％至11％），口咽干燥或发炎（6％），鼻出血（4％）和鼻炎（3％）。 ^[参考]

心血管的

心血管副作用包括高血压（11％），水肿（9％至11％），胸痛（4％至11％），心律不齐（7％），低血压（4％）和心律不齐（1％）。很少有心肌梗塞的报道。很少有α干扰素治疗的患者出现心肌病病例。 ^[参考]

眼科

眼部副作用包括视力障碍（5％至6％）和结膜炎（4％）。 ^[参考]

肌肉骨骼

肌肉骨骼副作用包括关节炎或多关节炎（5％）。 ^[参考]

肝的

肝副作用包括多达50％的被诊断患有慢性骨髓性白血病的接受过Alfer-2a干扰素（Roferon-A包含的活性成分）的研究患者的肝转氨酶或碱性磷酸酶的短暂升高。其他罕见的肝副作用包括胰腺炎，高甘油三酸酯血症和肝炎。 ^[参考]

重度慢性活动性肝炎已经报道了干扰素α-2a治疗和慢性活动性肝炎B的成功治疗的患者后完成^{[参考文献]}

血液学

每周接受三次600万国际单位治疗的慢性丙型肝炎患者中性粒细胞减少症（WHO III或IV级）的发病率是每周三次三次300万国际单位的患者（10％）的两倍高。 ^[参考]

血液学方面的副作用包括白细胞减少（包括中性粒细胞减少症），血细胞比容和血小板计数。 ^[参考]

内分泌

内分泌副作用包括甲状腺疾病（甲状腺功能亢进或甲状腺功能减退）。 ^[参考]

新陈代谢

代谢副作用包括高血糖症。 ^[参考]

某些副作用可能没有报道。您可以将其报告给FDA。