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双汰芝复合片Combivir(Lamivudine/Zidovudine Tablets)

 

 

简介： 英文药名: Combivir(Lamivudine/Zidovudine Tablets) 中文药名: 双汰芝（拉米夫定齐多夫定片）

品牌药生产厂家: Glaxo Smith Kline 药品名称 【药品名称】 药品名（中）：齐多夫定/拉米夫定片

 

关键字： 双汰芝（拉米夫定齐多夫定片）Combivir(Lamivudine/Zidovudine Tablets)

英文药名: Combivir(Lamivudine/Zidovudine Tablets) 中文药名: 双汰芝（拉米夫定齐多夫定片） 品牌药生产厂家: Glaxo Smith Kline 药品名称 【药品名称】  药品名（中）：齐多夫定/拉米夫定片  英文名：Combination of Lamivudineand Zidovudine  英文商品名：Combivir  【性状】本品为白色至类白色胶囊型薄膜衣片，一面印有GXFC3。  药理毒性 拉米夫定和齐多夫定合用时无协同的毒性作用，二者合用与临床有关的毒性反应为贫血，中性粒细胞少及白细胞减少。 致突变性：细菌实验中，拉米夫定和齐多夫定均无致突变作用。但在哺乳动物体外试验中，如小鼠淋巴瘤实验，它们和其它核苷类似物一样有活性作用。体内研究表明，拉米夫定的血药浓度在达到临床血药浓度的40-50倍时，无遗传学毒性。体外的致突变作用不能在体内试验中得到证实，因此接受拉米夫定进行治疗不会有遗传毒性的危险。小鼠多剂量口服齐多夫定的微核试验中观察到齐多夫定对染色体的诱裂性。艾滋病病人接受过齐多夫定的治疗后，周围血淋巴细胞内也可见很多染色体碎片。上述发现的临床意义尚不明确。 致癌性：大鼠和小鼠的长期口服致癌试验中，未发现拉米夫定的致癌性。小鼠和大鼠口服齐多夫定的致癌试验中，可观察到晚期出现的阴道表皮癌，但在两个种属的任何性别中未观察到齐多夫定有关的其它肿瘤。随后的阴道内致癌试验证实了阴道癌的出现为啮齿类动物阴道表皮长期局部暴露在尿液中未被代谢的高浓度的齐多夫定所致。上述齐多夫定啮齿类动物致癌作用的预言对于人类是否有意义不能肯定，上述发现是否有临床意义尚不明确。另外，在小鼠中进行了两个经胎盘的致癌性研究。其中一项由美国国立癌症研究所进行的研究中，从妊娠的第12天到18天给予怀孕的小鼠以最大耐受剂量的齐多夫定。出生1年后，曾暴露于最高剂量组（420mg/kg体重）的仔鼠的肺、肝，以及雌鼠的生殖器官的肿瘤的发生率增加。在第二项研究中，从妊娠第10天起以40mg/kg的剂量连续给予齐多夫定24个月。治疗相关性发现仅限于晚期出现的阴道表皮肿瘤，其发生率和出现时间与标准剂量口服的致癌试验相似。因此，第二个试验表明齐多夫定并非为经胎盘的致癌物。可得出结论，第一个试验中的经胎盘的致癌性数据表明一个假设的危险性，同时可证明感染HIV的怀孕妇女使用齐多夫定可减少HIV对未感染儿童母婴传播的危险。 生殖毒性：在动物生殖试验中，拉米夫定和齐多夫定均可进入胎盘，并已在人体试验中得到证实。在相对较低的全身药物暴露下，拉米夫定可增加兔子早期胚胎的死亡，这与人的情况一致。但在很高的全身药物暴露下，大鼠试验却未出现。齐多夫定在上述两种动物中的作用相似，但仅在很高的全身药物暴露下。拉米夫定在动物试验中未见致畸性。在器官形成时给予大鼠以产科的毒性剂量会导致畸形发生率的增加但在低剂量下未见致胎儿畸形的证据。 药代动力学 吸收： 拉米夫定和齐多夫定从胃肠道内吸收良好，成人口服拉米夫定和齐多夫定的生物利用度正常情况下分别为80-85%，60-70%。比较本品与同时服用拉米夫定片150mg和齐多夫定胶囊300mg进行生物等效性研究，同时还研究了食物对药物的吸收速度和吸收程度的影响。结果表明，空腹服用时，本品与同时服用拉米夫定片150mg和齐多夫定胶囊300mg的单制剂具有生物等效性。服用本品后，拉米夫定和齐多夫定的Cmax（95%可信限）分别为1.5（1.3-1.8）mg/mL和1.8(1.5-2.2)mg/mL，Tmax的中位数分别为0.75（0.50-2.00）小时和0.50（0.25-2.00）小时。与空腹服用相比，本品与食物同服时吸收速度慢（Cmax，Tmax），但是拉米夫定和齐多夫定的吸收程度（AUC）及服用后的半衰期相似，因此，本品可与或不与食物同服。 分布： 静脉注射研究表明，拉米夫定和齐多夫定的平均分布容积分别为1.3和1.6L/kg。在大于治疗剂量范围时，拉米夫定的药代动力学呈线性，其主要血浆蛋白的结合率有限（体外试验中，拉米夫定与血清蛋白的结合率<36%）。而齐多夫定与血浆蛋白的结合率为34-38%。未发现使用本品时，药物相互作用影响了药物结合位点的转换。 资料表明，拉米夫定和齐多夫定能透过中枢神经系统而进入脑脊液。口服2-4小时后，脑脊液和血清中拉米夫定和齐多夫定的浓度平均比例约分别为0.12和0.50。拉米夫定透过的实际量及其与临床疗效的关系尚不清楚。 代谢： 拉米夫定的代谢是其清除的次要途径，其原型主要通过肾脏排泄。由于拉米夫定肝脏的代谢少（5-10%），和血浆蛋白的结合低，因而发生较少的药物相互作用。血浆和尿液中齐多夫定的主要代谢物为5'-葡萄糖醛酸，使用剂量中约50-80%由肾排出。已证实齐多夫定在静脉注射后的一个代谢物为3'-氨基-3'脱氧嘧啶（AMT）。 清除： 拉米夫定的清除半衰期为5-7小时，平均全身清除率为0.32L/h/kg。主要通过有机阳离子转运系统经肾清除（>70%）。肾损害病人由于肾功能不全而使拉米夫定的清除率减低。肌酐清除率≤(smallerthanorequalto)50mg/kg的病人需减少剂量。从静脉注射齐多夫定的研究知其平均终末血浆半衰期为1.1小时，平均全身清除率为1.6L/h/kg，肾清除率约为0.34L/h/kg，提示通过肾小球滤过及肾小管分泌排出。 肾损害： 对肾损害患者的研究表明，由于肾清除率的降低，使得拉米夫定的清除受到影响。对于肌酐清除率小于50mL/分的患者，剂量应作相应的减少。同时可见齐多夫定在晚期肾衰患者体内的增加。 肝损害： 肝硬化患者的有限资料表明，葡萄糖醛酸化作用的降低可能导致肝损伤病人体内齐多夫定的蓄积。严重肝损害的患者应调整齐多夫定的剂量。 老年患者： 65岁以上老年患者，拉米夫定和齐多夫定的药代动力学尚未研究。 妊娠期： 妊娠妇女的拉米夫定和齐多夫定的药代动力学资料与未妊娠妇女相似。由于拉米夫定可被动穿过人类胎盘，因此，拉米夫定在新生儿血清中的浓度与母体和出生时脐带血中的相同。血清中的齐多夫定与观察到拉米夫定有相似的结果。   适应症 适用于HIV感染的成人及12岁以上儿童，这些病人有进行性免疫缺陷(CD4计数≤(smallerthanorequalto)500个/mm3)。本品可降低HIV-1的病毒量，增加CD4+细胞数。临床结果表明拉米夫定单独和齐多夫定的联合治疗，或联合齐多夫定和其它药物的方案，结果能显著地降低疾病进展的危险率和死亡率。   用法用量 成人及12岁以上儿童： 推荐剂量为每天2次，每次1片，可与或不与食物同服。如果临床需要减少本药的剂量，或需减少或停用本药中的某一成分(拉米夫定或齐多夫定)时，则用拉米夫定(Epivir)及齐多夫定(Retrovir)的单独片剂/胶囊和口服液。 暴露后预防： 国际上认可的指导原则（疾病控制和预防中心-1998年6月），推荐在意外接触HIV感染的血液事件中如：针刺伤，应立即给予齐多夫定和拉米夫定进行联合治疗（在1-2小时内）。在高危情况下，治疗方案中还应包含一种蛋白酶抑制剂。建议对抗逆转录病毒的预防持续4周。没有关于接触HIV病毒后预防的对照临床研究且支持资料有限。尽管立即给予抗逆转录病毒制剂进行治疗，血清转换可能仍会发生。 肾脏损害： 肾损害的患者由于肾脏对药物的清除率降低而使拉米夫定和齐多夫定的血药浓度升高。因此，对于肾功能不全者(肌酐清除率≤(smallerthanorequalto)50mL/分)，可能需要调整个别药的剂量，建议分别服用拉米夫定和齐多夫定的单制剂，同时对这两个药分别开处方。 肝脏损害： 拉米夫定的血浆水平对肝损伤的影响尚在研究中。拉米夫定大部分是通过肾清除的。 根据药物安全性资料的初步结果表明，对于肝损伤的病人不必调整个别药的剂量，然而，肝硬化病人的有限数据提示，肝损伤病人由于葡萄糖醛酸化作用的降低会导致齐多夫定的累积，因此，对于严重肝损伤的病人可能需要调整齐多夫定的剂量，建议分别使用拉米夫定和齐多夫定的单制剂，对这两个药应掌握完全分开处方的要点。 对血象出现不良反应的患者应调整剂量： 如果病人的血红蛋白水平<9g/dL或中性粒细胞计数<1.0x109/L，可能就要调整齐多夫定的剂量。这种情况对于治疗前骨髓增生差的病人更可能发生，特别是进展的HIV感染者。 由于本药是一合剂，单一药的剂量是无法调整的，因而应分开服拉米夫定和齐多夫定的单制剂。 老年组的剂量： 对于这个年龄组的病人，尚无特殊资料可循。但是对这组病人建议进行特殊的关注。因为，伴随年龄的增加，会发生许多变化，诸如肾功能降低和血液学方面的变化。 任何疑问，请遵医嘱！   不良反应 在治疗HIV感染中，拉米夫定和齐多夫定单独或联用的副作用已有报道，其中大多数尚不清楚。这些副作用可能与拉米夫定、齐多夫定有关，或者与治疗HIV感染中大量药物的使用有关，或者本身就是由潜在的疾病进展引起的。由于本药含有拉米夫定和齐多夫定，预见不良反应的类型和严重程度和其所含两个成分有关。常规联合使用拉米夫定和齐多夫定未见明显毒性增加。 拉米夫定： 其常见副作用有头痛，不适，乏力，恶心，腹泻，呕吐，上腹痛，发热及皮疹。有胰腺炎和外围神经痛(或感觉异常)的病例报道，但未发现这些与拉米夫定的剂量有关。 拉米夫定和齐多夫定联用时可引起中性粒细胞减少和贫血(有时很严重)。也有报道能引起血小板减少，一过性肝酶(AST，ALT)升高和血清淀粉酶的升高。 齐多夫定： 最严重的副作用有贫血(可能需要验血)，中性粒细胞和白细胞减少。这些常见于大剂量(1200-1500mg/天)的使用，进展的HIV感染者(尤其是治疗前骨髓增生差的病人)，特别是CD4+细胞计数<100/mm3的病人的治疗中，此时可能需要减少剂量或停止治疗。齐多夫定治疗开始时，中性粒细胞数、血红蛋白水平、血清维生素B12水平低，以及同时服用扑热息痛的病人在使用齐多夫定时，中性粒细胞数减少的机率也会增加（与其他药物的相互作用及其它形式的相互作用）。在一组大规模、设对照的临床试验中，其它常见的不良反应有恶心、呕吐、厌食、腹痛、头痛、皮疹、发热、肌痛、感觉异常、失眠、不适、乏力及消化不良。在接受齐多夫定治疗的所有病人中，最常见的副作用是恶心，除此之外，其它不良反应与安慰剂试验相比较并不多见。严重的头痛、肌痛及失眠在齐多夫定治疗的进展性HIV感染者中更为常见，而呕吐、厌食、体虚及乏力则常见于齐多夫定治疗的早期HIV感染者。其它副作用有嗜睡、腹泻、头晕、盗汗、呼吸困难、气胀、味觉异常、胸痛、精神异常、焦虑、尿频、忧郁、全身疼痛、寒战、荨麻疹、瘙痒及流感样综合征。这些和其它不常见的副作用在齐多夫定和安慰剂治疗的病人中发生率相似。 从安慰剂作为对照试验及开放性试验研究中获得的资料表明，在齐多夫定治疗的最初几个星期后，恶心及其它常见临床副作用发生率会逐渐减少。以下不良反应在齐多夫定治疗的病人中也有报道，这些副作用与使用齐多夫定之间的关系难于评价，尤其是在进展性HIV感染者，临床情况很复杂。肌病，伴有骨髓增生不良的全血细胞减少症及单发性血小板减少症，非低氧血症的乳酸酸中毒，肝功能异常（诸如肝大伴有脂肪肝，血液中肝酶及胆红素水平升高），胰腺炎，指(趾)甲、皮肤及口腔粘膜色素沉着。在齐多夫定开放性治疗试验中，有报道病人出现抽搐及其它脑部症状。这些情况反过来也表明了齐多夫定对HIV相关的神经功能异常的治疗整体上是有效的。若症状严重，减少齐多夫定的剂量或停药有助于这些临床状况的改善。在这种情况下，应该停用双汰芝，而改用齐多夫定及拉米夫定的单制剂。 禁忌 已知对拉米夫定、齐多夫定或对制剂中的任何赋形剂过敏者忌用本药。齐多夫定忌用于中性粒细胞<0.75x109/L或血红蛋白水平<7.5g/dL或(4.65mmol/L)的病人，故而本药也忌用于这类病人。拉米夫定治疗儿童的资料还不多，因此，拉米夫定对于12岁以下的儿童忌用。 注意事项 当需要对拉米夫定或齐多夫定单独进行剂量调整时，建议分别用其单制剂。病人在服用本药的同时，自我服药要谨慎。本药用于治疗慢性乙型肝炎引起的进行性肝硬化时应慎重，因为曾有停用拉米夫定引起肝炎复发的危险之报道。对驾驶及仪器使用能力的影响：目前，尚无对拉米夫定或齐多夫定影响驾驶及仪器操作能力的研究，而且，这些活动的决定性因素并不能通过药物的临床药理预测出来。但是，在考虑病人的驾驶及仪器操作能力时，应考虑病人的临床状况和拉米夫定及齐多夫定的副作用。  妇女和哺乳期妇女用药 动物生殖研究表明，拉米夫定和齐多夫定都能通过胎盘并增加早期胎儿的死亡。拉米夫定能导致兔子早期胚胎的丝网增加，而齐多夫定对大鼠和兔子都有影响。拉米夫定在动物试验中不会致畸，在大鼠器官形成期给以母体中毒剂量的齐多夫定会增加畸胎发生率，而低剂量则发现有畸胎的产生。动物生殖实验研究无法完全预示人体反应，故而建议怀孕的最初3个月不服用本药，除非治疗对母体的益处超过对胎儿造成的危险性。齐多夫定用于孕妇及新生儿时，可降低HIV经母婴传播的机率。但拉米夫定没有这些数据可查，人类妊娠时使用拉米夫定的安全性尚未肯定。总之，在妊娠期，只有用药的预期益处超过可能发生的危险时，才能考虑用本药。基于在动物试验中发现的致癌作用及突变的产生，不能排除本药对人有致癌作用的危险性。齐多夫定对啮齿动物致癌作用的研究结果能否适用于人类尚不确定，而在终身服用齐多夫定的啮齿动物中发现晚期有阴道瘤的发生（发生于连续19个月每日使用口服剂量的齐多夫定后）。这些发现与经齐多夫定治疗的感染及未感染HIV的婴儿之间的相关性尚不清楚。但是应将这些发现告知那些考虑使用本药的孕妇。对雌、雄鼠的研究中，未发现拉米夫定和齐多夫定对繁殖力有影响。目前尚无关于药物对女性生殖力影响的资料，未发现齐多夫定对男性精子的数目、形态及运动力的影响。 哺乳：研究口服治疗的哺乳期大鼠时发现其乳液中有拉米夫定和齐多夫定。人乳中是否同样如此尚不清楚。鉴于这些药有分泌到乳液中的可能性，建议服用本药的母亲不要用乳液哺育新生儿。  儿童用药 12岁以下儿童禁用本品，因为不能根据儿童的体重准确的减少药物剂量。 老年患者用药 对于该年龄组的病人，尚无特殊资料可循。但是对这组病人建议进行特殊的关注，因为伴随年龄的增加，会发生诸如肾功能降低和血液学参数改变等变化。   药物相互作用 由于本药含有拉米夫定和齐多夫定，所有分别能与这两种药物发生的相互作用同样都可发生于双汰芝。由于拉米夫定有限代谢和有限的血浆蛋白结合，以及完全由肾排出，因而它与其它药相互作用的可能性很小。齐多夫定与之相似，也是有限的血浆蛋白结合，但它主要在肝脏内结合成一种非活性的葡萄糖醛酸化代谢物后排出。以下列出的药物相互作用并非全部，它仅代表了使用时应注意的药物类型。与拉米夫定有关的相互作用：TMP是复方新诺明中的一种组分，它能使治疗剂量的拉米夫定有效浓度增加40%。除非病人有肾损害，一般情况不需调整剂量(见剂量及用药方法)。拉米夫定不影响复方新诺明的药代动力学，用复方新诺明与拉米夫定联合治疗肾损害病人时，要谨慎考虑。目前，拉米夫定与其它药物联用时，应考虑它们之间的相互作用，特别是一些主要由肾清除的药物。与齐多夫定有关的相互作用：齐多夫定和拉米夫定合并用药可使齐多夫定的作用增加13%，血浆峰值水平增加28%。这对病人的安全性无影响，因此，不必调整其剂量。齐多夫定对拉米夫定的药代动力学无影响。有报道显示，接受齐多夫定和苯妥英联合治疗时，有些病人苯妥英的血药浓度降低。但是有一例苯妥英的血液浓度升高，这些发现提示对接受本药和苯妥英联合治疗的病人，应密切监测苯妥英的水平。在扑热息痛与齐多夫定联用安慰对照试验中，尤其是长期使用时，会使中性粒细胞减少的发生率增加。但是，所获药代动力学资料表明，这种剂量的扑热息痛不会增加齐多夫定及其葡萄糖醛酸代谢产物在血浆中的浓度。其它药物，包括阿斯匹林、可待因、吗啡、消炎痛、酮洛芬、萘普生、奥沙西泮、西咪替丁、氯贝丁酯、氨苯砜和isoprinosine及其它药物可通过竞争性抑制葡萄糖醛酸化作用，或直接抑制肝脏的微粒体代谢来改变齐多夫定的代谢。这些药物与本药联用前，特别是进行长期治疗时，应考虑药物相互作用的可能性。联合治疗，尤其是急性期治疗时，用药中若含有可能会引起肾中毒或骨髓抑制的药物(如全身用喷他脒、氨苯砜、乙胺嘧啶、复方新诺明、两性霉素B、氟胞嘧啶、丙氨鸟苷、干扰素、长春新碱、长春碱和多柔比星)也可增加与齐多夫定产生相互作用的危险性。若需要采用本药与这些药联用时，应特别注意监测病人的肾功能和血象变化。需要时，应将其中一种或几种药的剂量减少。体外试验中，由于核苷类药物利巴韦林对齐多夫定的抗病毒活性有拮抗作用，应避免将二者联合使用。一些用本药治疗的病人可能会不断有机会性感染，故宜应同时用抗微生物药物预防。预防药物包括复方新诺明、喷他咪气雾剂、乙胺嘧啶和阿昔洛韦。少数临床试验表明，这些药与齐多夫定联用时不会使副作用增加。有限的数据提示，丙磺酸减少葡萄糖醛酸化作用，使肾对葡萄糖醛酸化合物（也可能就是齐多夫定）的排出减少，从而延长齐多夫定的半衰期，扩大药时曲线下面积。   药物过量 过量本药的服用尚缺乏经验。关于人急性过量服用拉米夫定及齐多夫定的后果仅有少量的数据。所有病人都恢复，无死亡，同时也未发现特殊的症状及体征。一旦发生服用过量，应对病人进行毒理监测，必要时要进行正规的支持疗法。由于拉米夫定是可通过透析排出，过量时可用特殊血透的方法处理。虽然此法还没试验过，血透及腹膜透析对齐多夫定的清除作用有限，但可以促进葡萄糖醛酸代谢物的清除

 

Combivir

Generic Name: lamivudine and zidovudine
Dosage Form: tablet, film coated

Medically reviewed on Apr 1, 2018

 

 

 

WARNING: HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B

Zidovudine, a component of Combivir (lamivudine and zidovudine) tablets, has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV1) disease [see Warnings and Precautions (5.1)].

Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.2)].

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine and zidovudine (components of Combivir). Discontinue Combivir if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.3)].

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and HIV1 and have discontinued lamivudine, which is one component of Combivir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue Combivir and are coinfected with HIV1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.4)].

 

 

 

 

 

 

 

 

Indications and Usage for Combivir

See also: Atripla

Combivir, a combination of 2 nucleoside analogues, is indicated in combination with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV1) infection.

 

 

Combivir Dosage and Administration

Recommended Dosage for Adults and Adolescents

The recommended dosage of Combivir in HIV1infected adults and adolescents weighing greater than or equal to 30 kg is 1 tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) taken orally twice daily.

Recommended Dosage for Pediatric Patients

The recommended dosage of scored Combivir tablets for pediatric patients who weigh greater than or equal to 30 kg and for whom a solid oral dosage form is appropriate is 1 tablet administered orally twice daily.

Before prescribing Combivir tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a Combivir tablet, the liquid oral formulations should be prescribed: EPIVIR (lamivudine) oral solution and RETROVIR (zidovudine) syrup.

 

 

 

 

Not Recommended Due to Lack of Dosage Adjustment

Because Combivir is a fixeddose tablet and cannot be dose adjusted, Combivir is not recommended for:

•

pediatric patients weighing less than 30 kg [see Use in Specific Populations (8.4)].

•

patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations (8.6)].

•

patients with hepatic impairment [see Use in Specific Populations (8.7)].

•

patients experiencing doselimiting adverse reactions.

Liquid and solid oral formulations of the individual components of Combivir are available for these populations.

Dosage Forms and Strengths

Combivir tablets contain 150 mg of lamivudine and 300 mg of zidovudine. The tablets are white, scored, filmcoated, modified capsuleshaped tablets, debossed on both tablet faces, such that when broken in half, the full “GX FC3” code is present on both halves of the tablet (“GX” on one face and “FC3” on the opposite face of the tablet).

Contraindications

Combivir is contraindicated in patients with a previous hypersensitivity reaction to lamivudine or zidovudine.

Warnings and Precautions

Hematologic Toxicity/Bone Marrow Suppression

Zidovudine, a component of Combivir, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV1 disease. Combivir should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm3 or hemoglobin less than 9.5 grams per dL [see Adverse Reactions (6.1)].

Frequent blood counts are strongly recommended in patients with advanced HIV1 disease who are treated with Combivir. Periodic blood counts are recommended for other HIV1infected patients. If anemia or neutropenia develops, dosage interruption may be needed.

Myopathy

Myopathy and myositis, with pathological changes similar to that produced by HIV1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with Combivir.

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine and zidovudine (components of Combivir). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Treatment with Combivir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

Patients with Hepatitis B Virus Coinfection

Posttreatment Exacerbations of Hepatitis

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory followup for at least several months after stopping treatment.

Emergence of LamivudineResistant HBV

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV–1-infected subjects who have received lamivudinecontaining antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine).

Use with Interferon- and Ribavirin–Based Regimens

Patients receiving interferon alfa with or without ribavirin and Combivir should be closely monitored for treatmentassociated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Discontinuation of Combivir should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin).

Exacerbation of anemia has been reported in HIV–1/HCV co–infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and Combivir is not advised.

Pancreatitis

Combivir should be used with caution in patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with Combivir should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)].

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Combivir. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveciipneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Lipoatrophy

Treatment with zidovudine, a component of Combivir, has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to a non-zidovudine-containing regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine-containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.

Adverse Reactions

The following adverse reactions are discussed in other sections of the labeling:

•

Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and Precautions (5.1)].

•

Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.2)].

•

Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.3)].

•

Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.4)].

•

Hepatic decompensation in patients co-infected with HIV1 and hepatitis C [see Warnings and Precautions (5.5)].

•

Exacerbation of anemia in HIV1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions (5.5)].

•

Pancreatitis [see Warnings and Precautions (5.6)].

•

Immune reconstitution syndrome [see Warnings and Precautions (5.7)].

•

Lipoatrophy [see Warnings and Precautions (5.8)].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Lamivudine plus Zidovudine Administered as Separate Formulations

In 4 randomized, controlled trials of EPIVIR 300 mg per day plus RETROVIR 600 mg per day, the following selected adverse reactions and laboratory abnormalities were observed (Tables 1 and 2).

Table 1. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency) in 4 Controlled Clinical Trials with EPIVIR 300 mg per day and RETROVIR 600 mg per day
Adverse Reaction	EPIVIR plus RETROVIR (n = 251)
Body as a whole
Headache	35%
Malaise & fatigue	27%
Fever or chills	10%
Digestive
Nausea	33%
Diarrhea	18%
Nausea & vomiting	13%
Anorexia and/or decreased appetite	10%
Abdominal pain	9%
Abdominal cramps	6%
Dyspepsia	5%
Nervous system
Neuropathy	12%
Insomnia & other sleep disorders	11%
Dizziness	10%
Depressive disorders	9%
Respiratory
Nasal signs & symptoms	20%
Cough	18%
Skin
Skin rashes	9%
Musculoskeletal
Musculoskeletal pain	12%
Myalgia	8%
Arthralgia	5%

Pancreatitis was observed in 9 of the 2,613 adult subjects (0.3%) who received EPIVIR in controlled clinical trials [see Warnings and Precautions (5.6)].

Selected laboratory abnormalities observed during therapy are listed in Table 2.

Table 2. Frequencies of Selected Laboratory Abnormalities among Adults in 4 Controlled Clinical Trials of EPIVIR 300 mg per day plus RETROVIR 600 mg per daya
Test (Abnormal Level)	EPIVIR plus RETROVIR % (n)
Neutropenia (ANC <750/mm3)	7.2% (237)
Anemia (Hgb <8.0 g/dL)	2.9% (241)
Thrombocytopenia (platelets <50,000/mm3)	0.4% (240)
ALT (>5.0 x ULN)	3.7% (241)
AST (>5.0 x ULN)	1.7% (241)
Bilirubin (>2.5 x ULN)	0.8% (241)
Amylase (>2.0 x ULN)	4.2% (72)
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
n = Number of subjects assessed.
a Frequencies of these laboratory abnormalities were higher in subjects with mild laboratory abnormalities at baseline.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole

Redistribution/accumulation of body fat [see Warnings and Precautions (5.8)].

Cardiovascular

Cardiomyopathy.

Endocrine and Metabolic

Gynecomastia, hyperglycemia.

Gastrointestinal

Oral mucosal pigmentation, stomatitis.

General

Vasculitis, weakness.

Hemic and Lymphatic

Anemia, (including pure red cell aplasia and anemias progressing on therapy), lymphadenopathy, splenomegaly.

Hepatic and Pancreatic

Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.3), (5.4), (5.6)].

Hypersensitivity

Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal

Muscle weakness, CPK elevation, rhabdomyolysis.

Nervous

Paresthesia, peripheral neuropathy, seizures.

Respiratory

Abnormal breath sounds/wheezing.

Skin

Alopecia, erythema multiforme, StevensJohnson syndrome.

Drug Interactions

Zidovudine

Agents Antagonistic with Zidovudine

Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro:

•

Stavudine

•

Doxorubicine

•

Nucleoside analogues, e.g., ribavirin

Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

Coadministration with the following drugs may increase the hematologic toxicity of zidovudine:

•

Ganciclovir

•

Interferon alfa

•

Ribavirin

•

Other bone marrow suppressive or cytotoxic agents

Lamivudine

Sorbitol

Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Combivir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Available data from the APR show no difference in the overall risk of birth defects for lamivudine or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.

In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see Data).

Data

Human Data: Lamivudine: Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trial assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8).

Zidovudine: Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens.

A randomized, double-blind, placebo-controlled trial was conducted in HIV–1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug [see Clinical Studies (14.2)].

Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)].

Animal Data: Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine.

Zidovudine: A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on gestation Days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on gestation Days 6 through 18) showed increased fetal resorptions at the 500 mg-per-kg-per-day dose, which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days 6 through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.

Lactation

Risk Summary

The Centers for Disease Control and Prevention recommends that HIV1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV1 infection. Lamivudine and zidovudine are present in human milk. There is no information on the effects of lamivudine or zidovudine on the breastfed infant or the effects of the drugs on milk production. Because of the potential for (1) HIV1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving Combivir.

Pediatric Use

Combivir is not recommended for use in pediatric patients who weigh less than 30 kg because it is a fixeddose combination tablet that cannot be adjusted for this patient population [see Dosage and Administration (2.2)].

Geriatric Use

Clinical trials of Combivir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of Combivir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

Patients with Impaired Renal Function

Combivir is not recommended for patients with creatinine clearance less than 50 mL per min because Combivir is a fixeddose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of the lamivudine or zidovudine components of Combivir is required for patients with renal impairment then the individual components should be used [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

Patients with Impaired Hepatic Function

Combivir is a fixeddose combination and the dosage of the individual components cannot be adjusted. Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.

Overdosage

There is no known specific treatment for overdose with Combivir. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

Lamivudine

Because a negligible amount of lamivudine was removed via (4hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

Zidovudine

Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.

Combivir Description

Combivir tablets are combination tablets containing lamivudine and zidovudine. Lamivudine (EPIVIR) and zidovudine (RETROVIR, azidothymidine, AZT, or ZDV) are synthetic nucleoside analogues with activity against HIV1.

Combivir tablets are for oral administration. Each filmcoated tablet contains 150 mg of lamivudine, 300 mg of zidovudine, and the inactive ingredients colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.

Lamivudine

The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the ()enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as ()2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3 g per mol. It has the following structural formula:

 

Lamivudine is a white to offwhite crystalline solid and is soluble in water.

Zidovudine

The chemical name of zidovudine is 3′-azido-3′-deoxythymidine. It has a molecular formula of C10H13N5O4 and a molecular weight of 267.24 g per mol. It has the following structural formula:

 

Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg per mL in water at 25°C.

Combivir - Clinical Pharmacology

Mechanism of Action

Combivir is an antiretroviral agent [see Microbiology (12.4)].

Pharmacokinetics

Pharmacokinetics in Adults

One Combivir tablet was bioequivalent to 1 EPIVIR tablet (150 mg) plus 1 RETROVIR tablet (300 mg) following singledose administration to fasting healthy subjects (n = 24).

Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination (approximately 5% of an oral dose after 12 hours). In humans, the only known metabolite is the transsulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

Zidovudine: Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV area under the curve (AUC) is about 3fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.

In humans, lamivudine and zidovudine are not significantly metabolized by cytochrome P450 enzymes.

The pharmacokinetic properties of lamivudine and zidovudine in fasting subjects are summarized in Table 3.

Table 3. Pharmacokinetic Parametersa for Lamivudine and Zidovudine in Adults
Parameter	Lamivudine		Zidovudine
Oral bioavailability (%)	86 ± 16	n = 12	64 ± 10	n = 5
Apparent volume of distribution (L/kg)	1.3 ± 0.4	n = 20	1.6 ± 0.6	n = 8
Plasma protein binding (%)	<36		<38
CSF:plasma ratiob	0.12 [0.04 to 0.47]	n = 38c	0.60 [0.04 to 2.62]	n = 39d
Systemic clearance (L/h/kg)	0.33 ± 0.06	n = 20	1.6 ± 0.6	n = 6
Renal clearance (L/h/kg)	0.22 ± 0.06	n = 20	0.34 ± 0.05	n = 9
Elimination half-life (h)e	5 to 7		0.5 to 3
a Data presented as mean ± standard deviation except where noted.
b Median [range].
c Children.
d Adults.
e Approximate range.

Effect of Food on Absorption of Combivir: Combivir may be administered with or without food. The lamivudine and zidovudine AUC following administration of Combivir with food was similar when compared with fasting healthy subjects (n = 24).

Specific Populations

Patients with Renal Impairment: Combivir: The effect of renal impairment on the combination of lamivudine and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components).

Patients with Hepatic Impairment: Combivir: The effect of hepatic impairment on the combination of lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual lamivudine and zidovudine components).

Pregnant Women: Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

Zidovudine: Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of non-pregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.

Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.

Geriatric Patients: The pharmacokinetics of lamivudine and zidovudine have not been studied in subjects over 65 years of age.

Male and Female Patients: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (lamivudine or zidovudine) based on the available information that was analyzed for each of the individual components.

Racial Groups: Lamivudine: There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics based on the available information that was analyzed for the individual lamivudine component.

Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined.

Drug Interaction Studies

No drug interaction trials have been conducted using Combivir tablets.

Lamivudine and Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).

Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV1/HCV coinfected subjects.

Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(∞); and 28%, 52%, and 55% in the Cmax: of lamivudine, respectively.

Table 4 presents drug interaction information for the individual components of Combivir.

Table 4. Effect of Coadministered Drugs on Lamivudine and Zidovudine AUCa
Coadministered Drug and Dose	Drug and Dose	n	Concentrations of Lamivudine or Zidovudine		Concentration of Coadministered Drug
			AUC	Variability
Nelfinavir    750 mg every 8 h x 7 to 10 days	Lamivudine single 150 mg	11	↑10%	95% CI: 1% to 20%	↔
Trimethoprim 160 mg/    Sulfamethoxazole 800 mg daily x 5 days	Lamivudine single 300 mg	14	↑43%	90% CI: 32% to 55%	↔
Atovaquone    750 mg every 12 h with food	Zidovudine 200 mg every 8 h	14	↑31%	Range: 23% to 78%b	↔
Clarithromycin    500 mg twice daily	Zidovudine 100 mg every 4 h x 7 days	4	↓12%	Range: ↓34% to ↑14%	Not Reported
Fluconazole    400 mg daily	Zidovudine 200 mg every 8 h	12	↑74%	95% CI: 54% to 98%	Not Reported
Methadone    30 to 90 mg daily	Zidovudine 200 mg every 4 h	9	↑43%	Range: 16% to 64%b	↔
Nelfinavir    750 mg every 8 h x 7 to 10 days	Zidovudine single 200 mg	11	↓35%	Range: 28% to 41%	↔
Probenecid    500 mg every 6 h x 2 days	Zidovudine 2 mg/kg every 8 h x 3 days	3	↑106%	Range: 100% to 170%b	Not Assessed
Rifampin    600 mg daily x 14 days	Zidovudine 200 mg every 8 h x 14 days	8	↓47%	90% CI: 41% to 53%	Not Assessed
Ritonavir    300 mg every 6 h x 4 days	Zidovudine 200 mg every 8 h x 4 days	9	↓25%	95% CI: 15% to 34%	↔
Valproic acid    250 mg or 500 mg every 8 h x 4 days	Zidovudine 100 mg every 8 h x 4 days	6	↑80%	Range: 64% to 130%b	Not Assessed
↑ = Increase; ↓= Decrease; ↔ = No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval.
a This table is not all inclusive.
b Estimated range of percent difference.

Microbiology

Mechanism of Action

Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TCTP). The principal mode of action of 3TCTP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.

Zidovudine: Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDVTP). The principal mode of action of ZDVTP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

Antiviral Activity

Lamivudine plus Zidovudine: In HIV1-infected MT4 cells, lamivudine in combination with zidovudine at various ratios was not antagonistic.

Lamivudine: The antiviral activity of lamivudine against HIV1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC50 values against HIV2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV1 activity of lamivudine by 3.5fold in MT4 cells.

Zidovudine: The antiviral activity of zidovudine against HIV1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine were 0.01 to 0.49 microM (1 microM = 0.27 mcg per mL) and 0.1 to 9 microM, respectively. HIV1 from therapynaive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.011 microM (range: 0.005 to 0.110 microM) from Virco (n = 92 baseline samples) and 0.0017 microM (range: 0.006 to 0.0340 microM) from Monogram Biosciences (n = 135 baseline samples). The EC50 values of zidovudine against different HIV1 clades (A-G) ranged from 0.00018 to 0.02 microM, and against HIV2 isolates from 0.00049 to 0.004 microM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.

Neither lamivudine nor zidovudine was antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine).

Resistance

In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks.

HIV1 strains resistant to both lamivudine and zidovudine have been isolated from subjects after prolonged lamivudine/zidovudine therapy. Dual resistance required the presence of multiple amino acid substitutions, the most essential of which may be G333E. The incidence of dual resistance and the duration of combination therapy required before dual resistance occurs are unknown.

Lamivudine: Lamivudineresistant isolates of HIV1 have been selected in cell culture and have also been recovered from subjects treated with lamivudine or lamivudine plus zidovudine. Genotypic analysis of isolates selected in cell culture and recovered from lamivudinetreated subjects showed that the resistance was due to a specific amino acid substitution in the HIV1 reverse transcriptase at codon 184 changing the methionine to either valine or isoleucine (M184V/I).

Zidovudine: HIV1 isolates with reduced susceptibility to zidovudine have been selected in cell culture and were also recovered from subjects treated with zidovudine. Genotypic analyses of the isolates selected in cell culture and recovered from zidovudinetreated subjects showed thymidine analogue mutation (TAM) substitutions in HIV1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of substitutions.

In some subjects harboring zidovudineresistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine.

CrossResistance

Crossresistance has been observed among NRTIs. Crossresistance between lamivudine and zidovudine has not been reported. In some subjects treated with lamivudine alone or in combination with zidovudine, isolates have emerged with a substitution at codon 184, which confers resistance to lamivudine.

TAM substitutions are selected by zidovudine and confer crossresistance to abacavir, didanosine, stavudine, and tenofovir.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Lamivudine: Longterm carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.

Zidovudine: Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatmentrelated anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279.

In mice, 7 lateappearing (after 19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One lateappearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.

In rats, 2 lateappearing (after 20 months), non-metastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drugrelated tumors were observed in either sex of either species.

At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.

It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Mutagenicity

Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.

Zidovudine: Zidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.

Impairment of Fertility

Lamivudine: Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg.

Zidovudine: Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is 7 times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.

Clinical Studies

One Combivir tablet given twice daily is an alternative regimen to EPIVIR tablets 150 mg twice daily plus RETROVIR 600 mg per day in divided doses.

Adults

The NUCB3007 (CAESAR) trial was conducted using EPIVIR 150mg tablets (150 mg twice daily) and RETROVIR 100mg capsules (2 x 100 mg 3 times daily). CAESAR was a multicenter, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor, randomized 1:2:1. A total of 1,816 HIV1-infected adults with 25 to 250 (median 122) CD4 cells per mm3 at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapynaive. The median duration on trial was 12 months. Results are summarized in Table 5.

Table 5. Number of Subjects (%) with at Least 1 HIV1 DiseaseProgression Event or Death
Endpoint	Current Therapy (n = 460)	EPIVIR plus Current Therapy (n = 896)	EPIVIR plus a NNRTIa plus Current Therapy (n = 460)
HIV1 progression or death	90 (19.6%)	86 (9.6%)	41 (8.9%)
Death	27 (5.9%)	23 (2.6%)	14 (3.0%)
a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.

Prevention of Maternal-Fetal HIV-1 Transmission

The utility of zidovudine alone for the prevention of maternal-fetal HIV1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial conducted in HIV1infected pregnant women with CD4+ cell counts of 200 to 1,818 cells per mm3 (median in the treated group: 560 cells per mm3) who had little or no previous exposure to zidovudine. Oral zidovudine was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of zidovudine during labor and delivery. Following birth, neonates received oral zidovudine syrup for 6 weeks. The trial showed a statistically significant difference in the incidence of HIV1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving zidovudine and the group receiving placebo. Of 363 neonates evaluated in the trial, the estimated risk of HIV1 infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. Zidovudine was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.

How Supplied/Storage and Handling

Combivir tablets, containing 150 mg lamivudine and 300 mg zidovudine, are white, scored, filmcoated, modifiedcapsule-shaped tablets, debossed on both tablet faces, such that when broken in half, the full “GXFC3” code is present on both halves of the tablet (“GX” on one face and “FC3” on the opposite face of the tablet). They are available as follows:

60 Tablets/Bottle                     (NDC 49702-202-18).

Store between 2° and 30°C (36° and 86°F).

Patient Counseling Information

Neutropenia and Anemia

Inform patients that the important toxicities associated with zidovudine are neutropenia and/or anemia. Inform them of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced HIV1 disease [see Boxed Warning, Warnings and Precautions (5.1)].

Myopathy

Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV1 disease, have been associated with prolonged use of zidovudine [see Warnings and Precautions (5.2)].

Lactic Acidosis/Hepatomegaly with Steatosis

Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking Combivir if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.3)].

Patients with Hepatitis B or C Co-infection

Advise patients coinfected with HIV1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider [see Warnings and Precautions (5.4)].

Inform patients with HIV1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV1/HCV co-infected patients receiving combination antiretroviral therapy for HIV1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.5)].

Drug Interactions

Advise patients that other medications may interact with Combivir and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of zidovudine, a component of Combivir [see Drug Interactions (7.1)].

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when Combivir is started [see Warnings and Precautions (5.7)].

Lipoatrophy

Advise patients that loss of subcutaneous fat may occur in patients receiving Combivir and that they will be regularly assessed during therapy [see Warnings and Precautions (5.8)].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Combivir during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].

Missed Dose

Instruct patients that if they miss a dose of Combivir, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)].

Trademarks are owned by or licensed to the ViiV Healthcare group of companies.

Manufactured for:

ViiV Healthcare
Research Triangle Park, NC 27709

by:

GlaxoSmithKline
Research Triangle Park, NC 27709

©2018 ViiV Healthcare group of companies or its licensor.

CMB:9PI

 

PRINCIPAL DISPLAY PANEL

NDC 49702-202-18

Combivir®

(lamivudine and zidovudine)

Tablets 150 mg/300 mg

Rx only

60 Tablets

Each tablet contains 150 mg of lamivudine and 300 mg of zidovudine.

Store between 2o and 30oC (36o and 86oF).

See prescribing information for dosage information.

Do not use if printed safety seal under cap is broken or missing.

Manufactured for:

ViiV Healthcare

Research Triangle Park, NC 27709

by:

GlaxoSmithKline

Research Triangle Park, NC 27709

Lamivudine is manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

Made in UK

 

10000000146182 Rev. 5/17

 

Combivir lamivudine and zidovudine tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:49702-202 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LAMIVUDINE (LAMIVUDINE) LAMIVUDINE 150 mg ZIDOVUDINE (ZIDOVUDINE) ZIDOVUDINE 300 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   HYPROMELLOSE, UNSPECIFIED   MAGNESIUM STEARATE   MICROCRYSTALLINE CELLULOSE   POLYETHYLENE GLYCOL, UNSPECIFIED   POLYSORBATE 80   SODIUM STARCH GLYCOLATE TYPE A POTATO   TITANIUM DIOXIDE

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (modified-capsule-shaped tablets) Size 17mm Flavor   Imprint Code GXFC3 Contains

Packaging # Item Code Package Description   1 NDC:49702-202-18 60 TABLET, FILM COATED in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020857 10/19/2010

Labeler - ViiV Healthcare Company (027295585)

 

ViiV Healthcare Company