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聚氨酯说明

异维A酸，一种类维生素A，可以10毫克，20毫克和40毫克软明胶胶囊的形式作为Accutane口服。每个胶囊包含蜂蜡，丁基化羟基茴香醚，乙二胺四乙酸二钠，氢化大豆油薄片，氢化植物油和大豆油。明胶胶囊含有甘油和对羟基苯甲酸酯（甲基和丙基），以及以下染料体系：10 mg-氧化铁（红色）和二氧化钛； 20 mg-FD＆C红色3号，FD＆C蓝色1号和二氧化钛； 40毫克— FD＆C黄色6号，D＆C黄色10号和二氧化钛。

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。它是黄色至橙色的结晶性粉末，分子量为300.44。结构式为：

Accutane-临床药理学

异维A酸是一种类维生素A，当以0.5至1.0 mg / kg /天的药理剂量给药时（参见剂量和用法），可抑制皮脂腺功能和角质化。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，并且与用维甲酸治疗的剂量和持续时间有关，并且反映了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，因此与高脂餐一起服用时，异维A酸的口服吸收会增加。在一项交叉研究中，在禁食和进食条件下，74名健康成人受试者接受了单次80 mg口服剂量（2×40 mg胶囊）的Accutane。与在禁食条件下给予的维甲酸相比，在标准高脂饮食后，异维A酸的血浆峰值浓度（C max ）和总暴露量（AUC）均增加了一倍以上（见表2 ）。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，应始终将Accutane胶囊与食物一起服用（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。

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-氧代-异维A酸，视黄酸（维A酸）和4-氧代-维甲酸（4-氧代-维甲酸）。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为4-氧代-异维A酸，形成其几何异构体4-氧代-维A酸。

与74名健康成人受试者单次口服80毫克的维甲酸后，与禁食相比，食物的同时给药增加了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。在成年囊性痤疮患者（≥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酸液体悬浮液后，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。在喂食条件下对74名健康成人受试者单次口服80毫克维甲酸后，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酸累积率在0.90至5.43之间。

特殊患者人群

单次和多次给药后，对接受维甲酸治疗严重顽固性结节性痤疮的38名儿科患者（12至15岁）和19名成年患者（≥18岁）进行了异维A酸的药代动力学评估。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-氧代维甲酸。表3汇总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。

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。

牛磺酸的适应症和用法

严重顽固性结节性痤疮

Accutane适用于治疗严重顽固性结节性痤疮。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的意思是“许多”，而不是“几个或几个”结节。由于其使用会产生严重的不良反应，因此应保留Accutane供严重结节性痤疮患者使用，而这些患者对常规治疗（包括全身性抗生素）无反应。此外，由于Accutane可能会导致严重的先天缺陷，因此Accutane仅适用于未怀孕的女性患者（请参阅带框的禁忌症和警告）。

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周开始进行治疗，因为经验表明，在服用维甲酸时，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

对这种药物或其任何成分过敏的患者禁止使用维甲酸。对对羟基苯甲酸酯敏感的患者不宜使用维甲酸，对羟基苯甲酸酯在明胶胶囊中用作防腐剂（请参见注意事项：超敏反应）。

警告事项

精神病

Accutane可能会导致抑郁，精神病，很少有自杀意念，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，在开始使用维甲酸治疗前，应询问患者及其家属任何精神病史，并且在治疗期间的每次拜访中，应对患者的抑郁，情绪障碍，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gui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。患者应停止使用维甲酸，如果患者出现抑郁，情绪低落，精神病或攻击性，应立即与开处方者联系，而不必等到下一次就诊。终止维甲酸治疗可能不足；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。患者可能会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。医生应考虑在这种情况下是否适合使用维甲酸治疗；对于某些患者，风险可能超过Accutane治疗的益处。

假瘤脑

在许多假性脑小脑（良性颅内高压）病例中都使用了维甲酸，一些病例中同时使用了四环素。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维甲酸，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：神经科）。

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，如有必要，应考虑停用维甲酸。

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。如果高甘油三酯血症不能控制在可接受的水平或出现胰腺炎症状，应停止使用维甲酸。

血脂

据报道，用维甲酸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，据报道约有25％的接受Accutane的患者血清甘油三酯明显升高。另外，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，终止维甲酸治疗后对甘油三酸酯，高密度脂蛋白和胆固醇的作用是可逆的。一些患者通过减轻体重，限制饮食中的脂肪和酒精含量以及减少剂量，同时继续使用维甲酸，可以逆转甘油三酯的升高。 5

应在给予Accutane之前进行血脂测定，然后间隔一定时间，直到建立对Accutane的脂质反应为止，这通常在4周内发生。对于在Accutane治疗期间可能处于高风险的患者（患有糖尿病，肥胖，酒精摄入量增加，脂质代谢紊乱或脂质代谢紊乱的家族病史的患者），必须特别谨慎地考虑其风险/益处。如果采用维甲酸治疗，建议更频繁地检查血脂和/或血糖的血清值（请参阅预防措施：实验室检查）。

与维甲酸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，建议的临床剂量1.0毫克/千克/天的1.3至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，服用维甲酸的患者听力受损；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Accutane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

据报道有可能与维甲酸治疗有关的临床肝炎。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。如果不容易出现正常化或怀疑在使用Accutane治疗期间怀疑患有肝炎，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，Accutane与炎症性肠病（包括局部回肠炎）有关。在某些情况下，据报道，在停止维甲酸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Accutane（请参阅不良反应：胃肠道）。

骨骼的

未知的多个过程的维甲酸对发展中的骨骼肌肉系统的影响。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。在一项针对急性顽固性结节性痤疮的单一治疗过程中，使用Accutane进行单一疗程的开放标签临床试验（N = 217），在多个骨骼部位的骨密度测量值没有显着降低（腰椎脊柱改变> -4％，总髋关​​节改变> -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）。对8名骨矿物质密度降低的患者进行了长达11个月的随访研究，结果表明5例腰椎骨密度增加，而其他3例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（范围-1.6％至-7.6％）。

在一项针对10名年龄在13-18岁的患者的开放标签扩展研究中，他们在第一疗程后四个月开始了第二次Accutane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Accutane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Accutane的因果关系，但不能排除影响。尚未研究长期影响。重要的是，建议剂量的维甲酸不能超过建议的持续时间。

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。多个痤疮的Accutane治疗疗程的骨骼作用尚不清楚。

在一项针对217例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，在分两次服用约1 mg / kg /天的Accutane的治疗16至20周后未观察到骨肥厚。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。

有自然报告称接受建议剂量的维甲酸的痤疮患者会出现骨epi过早闭合。多个疗程的维甲酸对骨epi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Accutane患者都应停止Accutane治疗并进行眼科检查（请参阅“不良反应：特殊感觉” ）。

角膜不透明度

接受Accutane治疗痤疮的患者发生角膜混浊，并且在角质化疾病患者中使用更高剂量的药物时，角膜混浊更加频繁。在停药后6至7周，在接受Accutane治疗的临床试验患者中观察到的角膜混浊已经完全缓解或正在缓解（请参阅“不良反应：特殊感觉” ）。

夜视力下降

据报道，在维甲酸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

Accutane只能由在iPLEDGE程序中注册并激活的开处方者开处方。 Accutane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符合iPLEDGE的所有要求的患者。注册和激活的药店只能从在iPLEDGE注册的批发商那里获得Accutane。

iPLEDGE计划对批发商，开处方者和药剂师的要求如下：

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Accutane，批发商必须在iPLEDGE上注册，并同意满足iPLEDGE对异维A酸产品进行批发分销的所有要求。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计划中注册并激活的药房

• 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
• 如果制造商撤销注册或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，以进行咨询，由制造商赔偿。
• 我将遵守题为《 iPLEDGE程序最佳实践指南》和《 iPLEDGE程序处方者避孕咨询指南》的小册子中所述的iPLEDGE程序要求。
• 在开始使用异维A酸对有生育能力的女性患者进行治疗之前和每月一次，将建议患者在异维A酸治疗的一个月之前，期间和之后一个月同时连续使用两种避孕方式，避免怀孕，除非该患者致力于持续的禁欲。
• 在确认她的筛查妊娠试验阴性并且每月经CLIA认证的（临床实验室改善修正案）阴性试验之前，我不会对任何有生育能力的女性患者开药异维A酸。患者应在异维A酸的整个疗程结束时进行妊娠试验，并在1个月后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1个月内向我报告任何我意识到的怀孕病例。

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程序中注册每个患者。

2）

每月确认每个患者都已接受咨询和教育。

3）

对于有生育能力的女性患者：

• 每月输入患者选择的两种避孕方式。
• 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。满足有生育能力的女性患者的要求表示她：

• 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。

  –

  对于月经周期规律的患者，应在开始异维A酸治疗前的月经周期的前5天以及患者使用2种避孕方法1个月后进行第二次妊娠试验。

  –

  对于有闭经，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酸治疗之前以及在使用2种避孕形式1个月后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2种有效避孕方式，其中至少1种必须是主要避孕方式，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2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. 如果正在治疗，立即停止服用维甲酸
  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Accutane治疗之前的1个月内，同时再次开始使用2种有效避孕方式
  4. 根据她是否有规律的月经，如上所述使用2种有效避孕方式进行1个月后进行第二次怀孕测试。

  有效的避孕形式包括主要和次要避孕形式：

  主要形式 输卵管绝育 伴侣的输精管切除术 宫内节育器 激素（口服避孕药，透皮贴剂，注射剂，植入物或阴道环组合）

  次要形式 屏障： 带或不带杀精剂的男性乳胶避孕套 隔膜与杀精子剂 杀精子宫颈帽 其他： 阴道海绵（包含杀精子剂）

任何节育方法都可能失败。有使用口服避孕药以及透皮贴剂/注射剂/植入剂/阴道环激素避孕产品的女性患者怀孕的报道；这些怀孕发生在这些患者服用维甲酸时。对于仅使用一种避孕方法的女性患者，这些报告更为常见。因此，至关重要的是，有生育能力的女性患者同时使用2种有效避孕方式。患者必须收到有关可能避孕失败率的书面警告（包括在患者教育工具包中）。

同时使用两种避孕方式可大大降低女性因单独使用任何一种避孕方式而怀孕的机会。尚未完全排除会降低荷尔蒙避孕药有效性的药物相互作用（请参阅预防措施：药物相互作用）。尽管荷尔蒙避孕药非常有效，但建议开处方者咨询与荷尔蒙避孕药同时服用的任何药物的包装说明书，因为某些药物可能会降低这些节育产品的有效性。

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 1 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).

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 fill and pick up the prescription within 7 days of the date of specimen collection for the pregnancy test for female patients of childbearing potential
• Must fill and pick up the prescription within 30 days of the office visit for male patients and female patients not of childbearing 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

Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, female patients of childbearing 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 fill and pick up 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 forms 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 1 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 for the iPLEDGE Program .
• I will obtain Accutane product only from 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 registration is revoked by the manufacturer or 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) 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.

Accutane must only be dispensed:

• in no more than a 30-day supply
• with an Accutane 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 female patients not of childbearing potential and within 7 days of the date of specimen collection for female patients of childbearing potential)
• with a new prescription for refills and another authorization from the iPLEDGE program (No automatic refills are allowed)

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

Accutane must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved Accutane products must be distributed, prescribed, dispensed, and used. Patients must fill Accutane 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)

The 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)

The iPLEDGE Program 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)

The Pharmacist Guide for the iPLEDGE Program 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 isotretinoin which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription.

5)

Female patients not of childbearing potential and male patients, and female patients of childbearing 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 2 languages.

6)

The booklet for female patients not of childbearing potential and male patients, The iPLEDGE Program 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 1 month following discontinuation of isotretinoin.

7)

The booklet for female patients of childbearing potential, The iPLEDGE Program 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, The iPLEDGE Program 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, there is a patient educational DVD with 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 Accutane on bone loss is not established, physicians should use caution when prescribing Accutane 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 Accutane or following cessation of therapy with Accutane while involved in these activities. While causality to Accutane 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 Accutane 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 patients of childbearing potential must be instructed that they must not be pregnant when Accutane therapy is initiated, and that they should use 2 forms of effective contraception simultaneously for 1 month before starting Accutane, while taking Accutane, and for 1 month after Accutane 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 Accutane therapy. They should be given an opportunity to view the patient DVD provided by the manufacturer to the prescriber. The DVD includes information about contraception, the most common reasons that contraception fails, and the importance of using 2 forms 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 Accutane 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 Accutane prescription is written (see Boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS ).
• Accutane is found in the semen of male patients taking Accutane, 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 postmarketing reports include 4 with isolated defects compatible with features of retinoid exposed fetuses; however 2 of these reports were incomplete, and 2 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 Accutane 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 Accutane 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 Accutane 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 Accutane therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Accutane therapy.
• Patients must be informed that some patients, while taking Accutane or soon after stopping Accutane, 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 Accutane 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 Accutane becoming aggressive or violent. No one knows if Accutane caused these behaviors or if they would have happened even if the person did not take Accutane. Some people have had other signs of depression while taking Accutane.
• Patients must be informed that they must not share Accutane 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 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Accutane.
• Patients should be reminded to take Accutane 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 Accutane 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 Accutane 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 Accutane, but in some cases persisted (see ADVERSE REACTIONS: Musculoskeletal ). There have been rare postmarketing 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 Accutane 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. 22％（79/358）的小儿患者患有关节痛。 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 Accutane. Consideration should be given to discontinuation of Accutane if any significant abnormality is found.
• Neutropenia and rare cases of agranulocytosis have been reported. Accutane 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. Accutane should be discontinued if clinically significant skin reactions occur.

Hypersensitivity

Anaphylactic reactions and other allergic reactions have been reported.有皮肤过敏反应和严重的过敏性血管炎病例，常伴有四肢紫癜（瘀斑和红斑）和皮肤外受累（包括肾脏）。严重的过敏反应需要停止治疗和适当的医疗管理。

药物相互作用

• Vitamin A: Because of the relationship of Accutane to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with Accutane and tetracyclines should be avoided because Accutane use has been