泽那坦

造成出生缺陷

不要怀孕

表1每月所需的iPLEDGE交互

泽那坦描述

异维A酸USP，一种类维生素A，可以以10毫克，20毫克，30毫克和40毫克软明胶胶囊的Zenatane（异维A酸胶囊USP）获得。每个胶囊包含丁基化羟基茴香醚，乙二胺四乙酸二钠，氧化铁红，氧化铁黄，氢化植物油（I型和II型），中链甘油三酸酯，精制大豆油和白色蜡。明胶胶囊包含明胶，甘油，对羟基苯甲酸甲酯，对羟基苯甲酸丙酯，含D＆C黄色10号的莱克掺和蓝（LB-332），FD＆C蓝色1号（10毫克），含D＆C红色的莱克掺和红（LB-1574） 27号，D＆C 30号红色（20 mg），含D＆C黄色10号的湖水绿色（LB-333），FD＆C 1号蓝色（40 mg）的湖水绿色，TLB-1774 FD＆C蓝色2号，二氧化钛，不透明黑色S-1-27794，包含氧化铁黑，N-丁醇，丙二醇，工业亚甲基精油和紫胶（分别为10 mg，20 mg和40 mg）和不透明黑色S- 1-17823含氧化铁黑，N-丁醇，丙二醇，氢氧化铵和虫胶（30毫克）。

化学上，异维A酸是13-顺-维甲酸，与维甲酸和视黄醇（维生素A）有关。它是黄色或浅橙色结晶粉末，分子量为300.44。它几乎不溶于水，溶于氯仿。微溶于醇，异丙醇和聚乙二醇400。结构式为：

符合USP溶出度测试5。

泽那坦-临床药理学

异维甲酸是类视黄醇，其中，当在0.5至1mg / kg /天的剂量的药理学（见给药剂量和管理），抑制皮脂腺功能和角化。异维A酸的确切作用机理尚不清楚。

结节性痤疮

结节性痤疮患者的临床改善与皮脂分泌减少有关。皮脂分泌的减少是暂时的，与泽那坦治疗的剂量和持续时间有关，反映出皮脂腺大小的减少和皮脂腺分化的抑制。 1个

药代动力学

由于其高亲脂性，因此与高脂膳食一起服用时，异维A酸的口服吸收会增加。在一项交叉研究中，74名健康成人受试者在禁食和进食条件下接受了单次80 mg口服剂量的Zenatane（2 x 40 mg胶囊）。两个峰血浆浓度（C max）和异维A酸的总暴露（AUC）当与禁食条件（见表2）下给出Zenatane相比分别增加了一倍以上以下的标准化高脂肪膳食。观察到的消除半衰期没有变化。这种半衰期缺乏变化表明，食物可增加异维A酸的生物利用度，而不会改变其分布。食物中达到峰值浓度的时间（T max ）也增加了，可能与吸收阶段更长有关。因此，泽那坦应始终与食物一起服用（请参阅剂量和用法）。临床研究表明，结节性痤疮患者与皮肤健康的健康受试者之间异维A酸的药代动力学没有差异。

表2异维A酸平均值（％CV），N = 74的药代动力学参数

*吃标准化的高脂餐

异维A酸与血浆蛋白（主要是白蛋白）的结合率超过99.9％。

口服异维A酸后，已在人血浆中鉴定出至少三种代谢物：4-氧-异维A酸，视黄酸（维A酸）和4-氧-维甲酸（4-氧维A酸）。维甲酸和13-顺式维甲酸是几何异构体，显示可逆的相互转化。一种异构体的给药将产生另一种异构体。异维A酸也被不可逆地氧化成4-氧-异维A酸，形成其几何异构体4-氧-维A酸。

与74名健康成人受试者单次口服80 mg的Zenatane口服剂量后，与禁食条件下形成代谢物的程度相比，同时服用食物会增加血浆中所有代谢物的形成程度。

所有这些代谢物都具有类维生素A活性，在某些体外模型中比类异体维甲酸具有更大的活性。但是，这些模型的临床意义尚不清楚。对成年囊性痤疮患者（≥18岁）多次口服异维A酸后，在禁食和进食条件下，稳态下患者暴露于4-氧代异维A酸的量约为异维A酸的3.4倍。

体外研究表明，参与异维A酸代谢的主要P450同工型为2C8、2C9、3A4和2B6。异维A酸及其代谢产物被进一步代谢成结合物，然后被尿液和粪便排泄。

口服80 mg的14 C-异维A酸作为液体混悬液后，血液中的14 C活性下降，半衰期为90小时。异维A酸和任何结合物的代谢物最终以相对相等的量（总计65％至83％）排泄到粪便和尿液中。在74名健康成年受试者中，口服单剂量80 mg的Zenatane后，异维A酸和4-氧代异维A酸的平均±SD消除半衰期（t 1/2 ）为21.0±8.2小时和24.0±5.3小时， 分别。单次和多次给药后，在囊性痤疮患者中观察到的异维A酸的累积比率在0.9至5.43之间。

特殊患者人群

小儿患者

在接受单剂​​量和多次剂量的38名小儿患者（12至15岁）和19名成年患者（≥18岁）接受泽那坦治疗严重顽固性结节性痤疮后，对异维A酸的药代动力学进行了评估。在两个年龄组中，4-氧代-异维A酸是主要的代谢产物。还观察到了维甲酸和4-氧维甲酸。表3总结了小儿患者单次和多次服用异维A酸的剂量标准化药代动力学参数。小儿和成年患者之间异维A酸的药代动力学差异无统计学意义。

表3. 12至15岁平均年龄（ ± SD），N = 38 *的小儿患者单次和多次给药后异维A酸的药代动力学参数

*此表中的单次和多次剂量数据是在非标准餐后获得的，该餐与表2的研究中使用的高脂餐不具有可比性。

†中位数（范围）

在儿科患者（12至15岁）中，异维A酸和4-氧代异维A酸的平均±SD消除半衰期（t 1/2 ）分别为15.7±5.1小时和23.1±5.7小时。小儿患者异维A酸的累积比率在0.46至3.65之间。

泽那坦的适应症和用法

严重顽固性结节性痤疮

泽那坦可用于治疗严重顽固的结节性痤疮。结节是直径大于等于5 mm的炎症性病变。结节可能化脓或出血。根据定义，“严重” 2表示“许多”，而不是“少数或几个”结节。由于其使用会产生严重的不良反应，因此，Zenatane应该保留给对常规疗法（包括全身性抗生素）无反应的严重结节性痤疮患者。此外，Zenatane表示只对那些女性患者谁没有怀孕，因为Zenatane可导致严重的出生缺陷（见盒装禁忌和警告S）。

研究表明，单疗程15到20周可导致许多患者完全，长期缓解疾病。 1,3,4如果需要第二个疗程，则应在完成第一个疗程后至少8周才开始治疗，因为经验表明，在停用Zenatane的情况下患者可能会继续改善。对于尚未完成骨骼生长的患者，尚未定义再治疗之前的最佳间隔（请参阅警告：骨骼：骨矿物质密度，骨质增生和骨Epi过早闭合）。

禁忌症

怀孕：X类。请参阅带框的禁忌症和警告。

过敏反应

对该药物或其任何成分过敏的患者禁忌使用Zenatane（请参阅预防措施：超敏反应）。对对羟基苯甲酸酯敏感的患者不宜使用Zenatane，后者在明胶胶囊中用作防腐剂。

警告事项

精神病

泽那坦（Zenatane）会导致抑郁，精神病，很少引起自杀念头，自杀未遂，自杀以及攻击性和/或暴力行为。对于这些事件，尚未建立任何作用机制（请参阅“不良反应：精神病学”）。处方者应阅读手册《识别青少年和年轻人的精神疾病：异维A酸处方者指南》 。处方者应警惕精神疾病的警告征兆，以指导患者获得所需的帮助。因此，在开始进行泽那坦治疗之前，应向患者及其家人询问任何精神病史，并且在治疗期间的每次拜访中，应对患者的抑郁，情绪低落，精神病或攻击性症状进行评估，以确定是否需要进一步评估可能是必要的。手册（“识别青少年和年轻人的精神病”）中描述的抑郁症的症状和体征包括悲伤的心情，绝望，内感，一文不值或无助，对活动的兴趣或兴趣丧失，疲劳，难以集中注意力，睡眠方式改变，体重或食欲改变，自杀念头或企图，烦躁不安，易怒，对危险冲动起作用以及对治疗无反应的持续性身体症状。患者应停止使用Zenatane，如果患者出现抑郁，情绪低落，精神病或攻击性，则应立即与开处方者联系，而不必等到下一次就诊。停用Zenatane治疗可能不足；可能需要进一步评估。尽管这种监视可能会有所帮助，但可能无法检测到所有处于危险之中的患者。患者可能报告精神健康问题或精神疾病家族史。这些报告应与患者和/或患者家属讨论。可能需要转介精神卫生专业人员。在这种情况下，医师应考虑使用Zenatane是否合适；对于某些患者，风险可能超过Zenatane治疗的益处。

假瘤脑

使用泽那坦与许多假性脑小脑（良性颅内高压）病例有关，其中一些病例同时使用四环素。因此应避免与四环素同时治疗。假肿瘤脑的早期体征和症状包括乳头状浮肿，头痛，恶心和呕吐以及视力障碍。应对具有这些症状的患者进行乳头水肿筛查，如果存在乳突性水肿，应告知他们立即停用泽那坦，并转介给神经科医生进行进一步的诊断和护理（请参阅不良反应：神经病学）。

严重的皮肤反应

上市后出现异形红斑和与异维A酸相关的严重皮肤反应[例如史蒂文斯-约翰逊综合征（SJS），中毒性表皮坏死溶解（TEN）]。这些事件可能很严重，并可能导致死亡，威胁生命的事件，住院或致残。应严密监测患者的严重皮肤反应，并在必要时考虑停用泽那坦。

胰腺炎

据报道，血清甘油三酯水平升高或正常的患者均患有急性胰腺炎。在极少数情况下，已经报道了致命的出血性胰腺炎。如果无法将高甘油三酯血症控制在可接受的水平或发生胰腺炎症状，则应停止使用Zenatane。

血脂

曾用泽那坦治疗的患者血清甘油三酸酯升高超过800 mg / dL。在临床试验中，据报道约25％的接受Zenatane的患者血清甘油三酸酯明显升高。此外，大约15％的人高密度脂蛋白减少，大约7％的胆固醇水平增加。在临床试验中，停止使用Zenatane治疗对甘油三酸酯，HDL和胆固醇的作用是可逆的。一些患者已经能够通过减轻体重，限制饮食中的脂肪和酒精以及减少剂量来逆转甘油三酸酯的升高，同时继续使用Zenatane 5 。

应该在给予Zenatane之前进行血脂测定，然后间隔一定时间，直到建立对Zenatane的脂质反应为止，这通常在4周内发生。对于在Zenatane治疗期间可能处于高风险的患者（患有糖尿病，肥胖，饮酒量增加，脂质代谢紊乱或脂质代谢紊乱的家族史）的患者，必须特别谨慎地考虑其风险/获益。如果Zenatane治疗提起，被推荐用于脂质和/或血糖值的血清的更频繁的检查（见注意事项：实验室试验）。

与泽那坦有关的高甘油三酸酯血症的心血管后果尚不清楚。

动物研究：在大鼠中，给予异维A酸8或32 mg / kg /天（正常化后总体表面积为1.0 mg / kg /天，推荐的临床剂量1.0 mg / kg /天的1.3到5.3倍），持续18个月或更长时间，心肌钙化，纤维化和炎症，冠状动脉，肺动脉和肠系膜动脉钙化以及胃黏膜转移性钙化均高于对照组。在以60至120毫克/千克/天的剂量异维A酸治疗大约6至7个月后，在两只狗中观察到与冠状动脉钙化相关的局部心内膜和心肌钙化（是1.0推荐临床剂量的30至60倍）将总表面积标准化后，分别为mg / kg /天）。

听力障碍

据报道，服用Zenatane的患者听力受损。在某些情况下，据报道听力障碍在停止治疗后仍持续存在。尚未确定此事件的机制和因果关系。发生耳鸣或听力障碍的患者应停止使用Zenatane治疗，并转诊接受专门护理以进行进一步评估（请参阅“不良反应：特殊感觉” ）。

肝毒性

据报道有可能与泽那坦疗法有关的临床肝炎。此外，在临床试验期间约有15％的个体中观察到肝酶轻度至中度升高，其中一些随着剂量降低或持续给药而恢复正常。如果在使用泽那坦治疗期间不容易出现正常化或怀疑肝炎，则应停药并进一步调查病因。

炎症性肠病

在没有肠道疾病史的患者中，泽那坦已与炎症性肠病（包括局部回肠炎）相关。在某些情况下，据报道，在停止Zenatane治疗后症状仍然存在。出现腹痛，直肠出血或严重腹泻的患者应立即停用Zenatane（请参阅不良反应：胃肠道）。

骨骼的

骨密度

尚塔那坦的多个疗程对正在发展的肌肉骨骼系统的影响尚不清楚。有证据表明，对异种维甲酸的长期，大剂量或多疗程治疗比对骨骼肌系统的单程治疗具有更大的作用。在一项使用泽那坦治疗严重顽固性结节性痤疮的单一疗程的开放标签临床试验（N = 217）中，在多个骨骼部位的骨密度测量值没有显着降低（腰椎脊柱变化> -4％和总髋关节变化> -5％）或在大多数患者中增加。根据未经调整的数据，一名患者的腰椎骨矿物质密度降低> 4％。十六名（7.9％）患者的腰椎骨矿物质密度降低> 4％，其他所有患者（92％）均未显着降低或升高（根据体重指数调整）。根据未经调整的数据，有9名患者（4.5％）的总髋骨矿物质密度降低了> 5％。 21例（10.6％）患者的总髋骨矿物质密度降低了5％以上，而其他所有患者（89％）均未显着降低或升高（根据体重指数调整）。在八名骨密度降低的患者中进行了长达11个月的随访研究，结果表明五名腰椎患者的骨密度增加，而其他三名患者的腰椎骨密度测量值低于基线值。 8例患者中有5例（62.5％）的总髋骨矿物质密度仍低于基线（在-1.6％至-7.6％范围内）。

在一项针对10名年龄在13至18岁的患者的单独的开放标签扩展研究中，他们在第一疗程后4个月开始了Zenatane的第二疗程，其中两名患者的平均腰椎骨矿物质密度降低了3.25％（参见注意事项：小儿使用）。

在Zenatane人群中自发报告了骨质疏松症，骨质减少，骨折和骨折愈合延迟。虽然尚未确定对Zenatane的因果关系，但不能排除影响。尚未研究长期影响。重要的是，建议剂量的Zenatane的使用时间不得超过建议的持续时间。

骨肥大

在临床试验中发现，骨骼肌肥大症的患病率很高，平均剂量为2.24 mg / kg /天。此外，在一项关于角质化疾病的前瞻性研究中，在8名患者中有6名发现了骨骼肥大。 6在以推荐剂量单疗程治疗的结节性痤疮患者的前瞻性研究中，还通过X射线观察到了最小的骨骼过度增生以及韧带和腱的钙化。泽那坦治疗痤疮的多个疗程的骨骼作用尚不清楚。

在一项针对217名严重顽固性结节性痤疮的儿科患者（12至17岁）的临床研究中，以约1 mg / kg /天的Zenatane分两次服用，治疗16至20周后未观察到骨质增生。骨肥大可能需要更长的时间才能出现。临床过程和意义仍然未知。

骨Epi过早闭合

有自发的报告称接受推荐剂量的Zenatane治疗痤疮的患者骨epi过早闭合。泽那坦的多个疗程对骨s闭合的影响尚不清楚。

视力障碍

视觉问题应予以仔细监控。所有患有视力障碍的泽那坦患者均应停止泽那坦治疗并接受眼科检查（请参阅“高级反应：特殊感觉” ）。

角膜不透明度

接受泽那坦治疗痤疮的患者发生角膜混浊，当角质化疾病患者使用更高剂量的药物时，角膜混浊更为常见。在用Zenatane治疗的临床试验患者中观察到的角膜混浊已经完全消失，或者在停药后6至7周的随访中已经消失（请参阅“不良反应：特殊感觉” ）。

夜视力下降

据报道，在Zenatane治疗期间夜视能力下降，在某些情况下，该事件在停止治疗后仍持续存在。由于某些患者的发作是突然的，因此应告知患者该潜在问题，并警告在夜间驾驶或操作任何车辆时要谨慎。

预防措施

Zenatane只能由在iPLEDGE程序中注册并激活的开处方者开处方。 Zenatane只能由在iPLEDGE上注册并激活的药房分配，并且只能分配给已注册并满足iPLEDGE的所有要求的患者。注册和激活的药店只能从在iPLEDGE注册的批发商处接收Zenatane。

iPLEDGE计划对批发商，开处方者和药剂师的要求如下所述：

批发商：

就iPLEDGE计划而言，术语批发商是指批发商，分销商和/或连锁药房分销商。要分销Zenatane，批发商必须在iPLEDGE上注册，并同意满足iPLEDGE的所有有关异维A酸产品批发分销的要求。批发商必须通过签署并返回iPLEDGE批发商协议向iPLEDGE注册，该协议确认他们将遵守iPLEDGE分配异维A酸的所有要求。这些包括：

• 分发异维A酸之前先注册，此后每年重新注册
• 仅分发FDA批准的异维A酸产品
• 仅将异维A酸运送至

-经制造商事先书面同意，在iPLEDGE计划中注册的批发商或

-在美国获得许可并在iPLEDGE计划中注册和激活的药房

• 通知异维A酸制造商（或代表）任何试图订购异维A酸的未注册和/或未激活的药房或未注册的批发商
• 遵守批发商记录的检查，以验证异维A酸制造商（或代表）是否遵守iPLEDGE计划
• 如果批发商被iPLEDGE计划停用，或者批发商选择不每年重新注册，则将未分配的产品退还给制造商（或委托）

开处方者：

要开处方异维A酸，开处方者必须通过怀孕风险管理程序iPLEDGE注册并激活。处方者可以通过签名并返回完整的注册表来进行注册。开处方者只能通过确认满足要求来激活他们的注册，并通过证明以下几点来遵守所有iPLEDGE要求：

• 我知道异维A酸会导致胎儿受伤/出生缺陷的风险和严重性。
• 我知道计划外怀孕的危险因素以及避免计划外怀孕的有效措施。
• 我具有为患者提供详细的预防怀孕咨询的专业知识，或者我会将她转介给专家进行咨询，由制造商补偿。
• 我将遵守题为《 iPLEDGE计划最佳实践指南》和《处方药避孕咨询指南》的小册子中所述的iPLEDGE计划要求。
• 我了解并将遵守不遵守行为政策。
• 在开始使用异维A酸治疗具有生殖潜力的女性之前，每月一次，建议患者在开始异维A酸治疗之前，异维A酸治疗期间和同时使用两种避孕方法，同时连续连续使用两种避孕方法，避免怀孕。停止异维A酸治疗后一个月，除非患者持续戒酒
• 在确认她的筛查妊娠试验为阴性并每月通过CLIA认证的（临床实验室改进修正案）阴性试验之前，我不会给任何具有生殖潜力的女性开张异维A酸。患者应在异维A酸的整个疗程完成时进行妊娠试验，一个月后应进行另一次妊娠试验。
• 我将在女性患者使用异维A酸或最后一次给药后一个月向妊娠登记处报告我发现的任何妊娠病例。

要开处方异维A酸，开处方者必须通过互联网（www.ipledgeprogram.com）或电话（1-866-495-0654）访问iPLEDGE系统，以：

1）在iPLEDGE计划中注册每个患者。

2）每月确认每个患者都接受过咨询和教育。

3）对于具有生殖能力的女性：

• 每月输入患者选择的两种避孕方法。
• 输入由CLIA认证的实验室进行的妊娠试验的每月结果。

异维A酸仅可用于经CLIA认证实验室验证为阴性的已知未怀孕的女性患者。

异维A酸只能由在怀孕风险管理计划iPLEDGE中注册并激活的药房分配，并且仅当注册患者符合iPLEDGE计划的所有要求时才可分配。满足具有生殖潜力的女性的要求表示她：

• 已得到咨询并签署了有关出生缺陷的患者信息/知情同意书（适用于可能怀孕的女性患者）表格，其中包含有关如果胎儿暴露于异维A酸可能引起出生缺陷的风险的警告。患者必须在开始治疗之前签署知情同意书，并且还必须在那时和之后每月进行一次患者咨询。
• 接收到初始异维A酸的处方之前已经有两个负尿或血清妊娠测试具有至少25 MIU / mL的灵敏度。当决定对患者进行异维A酸的资格认定时，处方者将获得第一个测试（筛查测试）。第二次妊娠测试（确认测试）必须在经过CLIA认证的实验室中进行。两次测试之间的间隔至少应为19天。

-对于具有定期月经周期的患者，应在刚开始异维A酸治疗之前的月经周期的前5天以及患者使用两种避孕方法一个月后进行第二次妊娠试验。

-对于闭经，不规则周期或使用避孕方法以防止抽血的患者，必须在开始异维A酸治疗之前和在使用两种避孕方法一个月后立即进行第二次妊娠试验。

• 接收异维A酸的每个后续过程之前已经有从在CLIA认证实验室尿或血清妊娠试验阴性结果。在女性患者接受每张处方之前，必须每月在CLIA认证的实验室中重复进行妊娠试验。
• 已选择并承诺同时使用两种有效避孕方法，其中至少一种必须是主要方法，除非患者坚持持续进行异性接触禁欲，或者患者接受了子宫切除术或双侧卵巢切除术，或者已经接受过医学上确认为绝经后。在开始异维A酸治疗前至少1个月，在异维A酸治疗期间和停止异维A酸治疗后1个月，患者必须使用两种有效避孕方法。必须每月重复一次关于避孕和与增加妊娠风险有关的行为的咨询。

如果患者在治疗前，治疗中或治疗后1个月的任何时间进行了无保护的异性性交，则必须：

1.如果正在接受治疗，请立即停止服用Zenatane

2.最后一次无保护的异性性交行为后至少19天进行妊娠试验

3.在恢复泽那坦治疗之前的1个月内，同时开始同时使用两种有效避孕方法

4.根据她是否有规律的月经，使用如上所述的两种有效避孕方法，在1个月后进行第二次怀孕测试。

有效的避孕方式包括一级和二级避孕方法：

Any birth control method can fail. There have been reports of pregnancy from female patients who have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking Zenatane. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that females of reproductive potential use two effective methods of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits).

Using two methods of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either method alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for Zenatane (see PRECAUTIONS : Drug Interactions ). Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.

Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.

If a pregnancy does occur during isotretinoin treatment isotretinoin must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or one month after isotretinoin therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE Pregnancy Registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

所有病人

Isotretinoin is contraindicated in female patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions:

• Must be registered with the iPLEDGE Program by the prescriber
• Must understand that severe birth defects can occur with the use of isotretinoin by female patients
• Must be reliable in understanding and carrying out instructions
• Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings about the potential risks associated with isotretinoin
• Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test for females of reproductive potential
• Must obtain the prescription within 30 days of the office visit for male patients and females of non-reproductive potential
• Must not donate blood while on isotretinoin and for 1 month after treatment has ended
• Must not share isotretinoin with anyone, even someone who has similar symptoms

Females of Reproductive Potential

Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, females of reproductive potential must meet the following conditions:

• Must NOT be pregnant or breast-feeding
• Must comply with the required pregnancy testing at a CLIA-certified laboratory
• Must obtain the prescription within 7 days of the date of specimen collection for the pregnancy test
• Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence from heterosexual intercourse, and understand behaviors associated with an increased risk of pregnancy
• Must understand that it is her responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy
• Must have signed an additional Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin
• Must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654), before starting isotretinoin, on a monthly basis during therapy, and 1 month after the last dose to answer questions on the program requirements and to enter the patient's two chosen methods of contraception
• Must have been informed of the purpose and importance of providing information to the iPLEDGE Program should she become pregnant while taking isotretinoin or within one month of the last dose

Pharmacists:

To dispense isotretinoin, pharmacies must be registered and activated with the pregnancy risk management program iPLEDGE.

The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I will train all pharmacists, who participate in the filling and dispensing of isotretinoin prescriptions, on the iPLEDGE Program requirements.
• I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE Program requirements described in the booklet entitled Pharmacist Guide, specifically the "Key Information for Pharmacists" section including the following dispensing information.
• Prescriptions must be obtained no later than the “DoNot Dispense To After” date, and if not obtained, thenthe RMA must be reversed in the iPLEDGE Programsystem and the product returned to inventory
• I will only obtain Zenatane product from only iPLEDGE registered wholesalers.
• I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another pharmacy.
• I will return to the manufacturer (or delegate) any unused product if the pharmacy is deactivated by the iPLEDGE Program of if the pharmacy chooses to not reactivate annually.
• I will not fill isotretinoin for any party other than a qualified patient.

To dispense isotretinoin, the pharmacist must:

1) be trained by the Responsible Site Pharmacist concerning the iPLEDGE Program requirements.

2) obtain authorization from the iPLEDGE Program via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) or through electronic telecommunication verification (via submission of an isotretinoin prescription claim) for every isotretinoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive isotretinoin.

3) write the Risk Management Authorization (RMA) number on the prescription.

Zenatane must only be dispensed:

• in no more than a 30-day supply
• with a Zenatane Medication Guide
• after authorization from the iPLEDGE Program
• prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 30 days of the office visit for male patients and females of non-reproductive potential and within 7 days of the date of specimen collection for females of reproductive potential)
• with a new prescription for refills and another authorization from the iPLEDGE program (No automatic refills are allowed)

A Zenatane Medication Guide must be given to the patient each time Zenatane is dispensed, as required by law. This Zenatane Medication Guide is an important part of the risk management program for the patients.

Zenatane must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE Program. Only FDA-approved Zenatane products must be distributed, prescribed, dispensed, and used. Patients must obtain Zenatane prescriptions only at US licensed pharmacies.

A description of the iPLEDGE Program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE Program requirements and to reinforce the educational messages.

1) Guide to Best Practices for the iPLEDGE Program includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified isotretinoin prescription.

2) Prescriber Contraception Counseling Guide includes: specific information about effective contraception, the limitations of contraceptive methods, behaviors associated with an increased risk of contraceptive failure and pregnancy and the methods to evaluate pregnancy risk.

3) Pharmacist Guide includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription.

4) The iPLEDGE Program is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE Program includes information on the risks and benefits of Zenatane which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription.

5) Females of non-reproductive potential and male patients, and females of reproductive potential are provided with separate booklets. Each booklet contains information on isotretinoin therapy including precautions and warnings, a Patient Information/Informed Consent (for all patients) form, and a toll-free line which provides isotretinoin information in two languages.

6) The booklet for females of non-reproductive potential and male patients, Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, also includes information about male reproduction and a warning not to share isotretinoin with others or to donate blood during isotretinoin therapy and for one month following discontinuation of isotretinoin.

7) The booklet for females of reproductive potential, Guide to Isotretinoin for Female Patients Who Can Get Pregnant, includes a referral program that offers female patients free contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; and a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form concerning birth defects.

8) The booklet, Birth Control Workbook includes information on the types of contraceptive methods, the selection and use of appropriate, effective contraception, the rates of possible contraceptive failure and a toll-free contraception counseling line.

9) In addition, to the booklets, patient educational material also include the iPLEDGE Program Birth Control Information Sheet and the the following videos — “Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on isotretinoin” (see Information for Patients ).

一般

Although an effect of Zenatane on bone loss is not established, physicians should use caution when prescribing Zenatane to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant.

Patients may be at increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with Zenatane or following cessation of therapy with Zenatane while involved in these activities. While causality to Zenatane has not been established, an effect must not be ruled out.

给患者的信息

See PRECAUTIONS and Boxed CONTRAINDICATIONS AND WARNINGS .

• Patients must be instructed to read the Medication Guide supplied as required by law when Zenatane is dispensed.本文末尾会重印《用药指南》的全文。 For additional information, patients must also be instructed to read the iPLEDGE program patient educational materials. All patients must sign the Patient Information/Informed Consent (for all patients) form.
• Female Females of reproductive potential must be instructed that they must not be pregnant when Zenatane therapy is initiated, and that they should use two methods of effective contraception simultaneously for 1 month before starting Zenatane, while taking Zenatane, and for 1 month after Zenatane has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning Zenatane therapy. They should be given an opportunity to view the patient video provided by the manufacturer to the prescriber. The video includes information about contraception, the most common reasons that contraception fails, and the importance of using two methods of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes Zenatane at any time during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another Zenatane prescription is written (see Boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS ).
• Zenatane is found in the semen of male patients taking Zenatane, but the amount delivered to a female partner would be about 1 million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of post-marketing reports include 4 with isolated defects compatible with features of retinoid exposed fetuses; however 2 of these reports were incomplete, and two had other possible explanations for the defects observed.
• Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of Zenatane treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment . Patients should stop Zenatane and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of Zenatane treatment may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient's family. A referral to a mental health professional may be necessary. The physician should consider whether Zenatane therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Zenatane therapy.
• Patients must be informed that some patients, while taking Zenatane or soon after stopping Zenatane, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking Zenatane have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on Zenatane becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take Zenatane. Some people have had other signs of depression while taking Zenatane.
• Patients must be informed that they must not share Zenatane with anyone else because of the risk of birth defects and other serious adverse events.
• Patients must be informed not to donate blood during therapy and for one month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Zenatane.
• Patients should be reminded to take Zenatane with a meal (see DOSAGE AND ADMINISTRATION ). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
• Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy.
• Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during Zenatane therapy and for at least 6 months thereafter due to the possibility of scarring (see ADVERSE REACTIONS : Skin and Appendages ).
• Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
• Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy.
• Patients should be informed that approximately 16% of patients treated with Zenatane in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of Zenatane, but in some cases persisted (see ADVERSE REACTIONS: Musculoskeletal ). There have been rare post marketing reports of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory Tests : CPK ).
• Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with Zenatane developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of Zenatane. Consideration should be given to discontinuation of Zenatane if any significant abnormality is found.
• Neutropenia and rare cases of agranulocytosis have been reported. Zenatane should be discontinued if clinically significant decreases in white cell counts occur.
• Patients should be advised that severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in post-marketing data. Zenatane should be discontinued if clinically significant skin reactions occur.

过敏症

Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.

药物相互作用

药物相互作用

• Vitamin A: Because of the relationship of Zenatane to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with Zenatane and tetracyclines should be avoided because Zenatane use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines.
• Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during Zenatane therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Zenatane. Therefore, it is critically important for females of reproductive potential to select and commit to use two methods of effective contraception simultaneously, at least one of which must be a primary method (see PRECAUTIONS ).
• Norethindrone/ethinyl estradiol: I