丙肝药物Incivik新标签警告严重皮肤反应

圣路易斯(MD Consult)——2012年12月19日，美国食品药品管理局(FDA)就Incivek(telaprevir)安全性发布了一则公告。该药物被用于与聚乙二醇干扰素α和利巴韦林的联合治疗(Incivek联合治疗)。Incivek是一种蛋白酶抑制剂，用于治疗基因1型慢性丙肝病毒感染的代偿性肝病成人患者，他们为初治或此前曾接受以干扰素为基础的治疗患者。

FDA已收到接受Incivek联合治疗患者严重皮肤反应的报告，其中有些是致死性的。因此，FDA在Incivek的说明书中添加一项黑框警告，提醒当患者出现全身症状皮疹或进展性严重皮疹时，应立即停止Incivek联合治疗，还应考虑停用其他任何可能与严重皮肤反应有关的药物。典型的全身症状或体征可能包括发热、恶心、腹泻、口腔溃疡、面部水肿、眼睛红肿、肝脏肿大或炎症。所有严重皮肤反应患者均应接受紧急医疗救治。

这些严重皮肤反应[中毒性表皮坏死松解(TEN)综合征、药物反应伴嗜酸性粒细胞增多和全身症状(DRESS) 综合征以及Stevens-Johnson(SJS)综合征]可以被认为是不同类型的严重皮肤反应，但难以区分。一旦发生上述任何严重皮肤反应，医护专业人员应立即停用Incivek联合治疗中的所有3种药物，并给予患者紧急医疗救治。

经过检索2011年5月23日~2012年6月19日FDA不良事件报告系统(AERS)数据库，FDA在接受Incivek联合治疗的患者中确认了92例DRESS和20例SJS。1例47岁女性患者在发生DRESS后继续接受Incivek联合治疗后死亡：患者接受4周三联治疗后下肢出现皮疹，她又继续接受了4周全部3种药物的联合治疗，当皮疹恶化后住院，出现低血压、发热、肌痛和急性肾损伤，然后又出现室颤，最终死于心源性休克。

FDA还收到来自日本的2例TEN报告。其中1例患者在出现症状后又继续接受了一段时间的Incivek联合治疗，最终死亡。第1例TEN报告患者为50岁女性，最后得以康复。她在接受治疗的第3天出现3级皮疹并被诊断为TEN，在接受了1个月的类固醇和抗组胺药物治疗后停用聚乙二醇干扰素，3天后停止Incivek和利巴韦林治疗，2个月后康复。

Incivek药物说明书中已经包含有关严重皮肤反应风险的信息。DRESS体征和症状可能包括皮疹、发热、面部水肿以及内脏受累(如肝炎)，患者有可能出现或不出现嗜酸性粒细胞增多症。SJS体征和症状可能包括发热、损伤以及眼部或唇部溃疡。Incivek制造商Vertex制药公司在批准上市时同意通过基因分析，研究与Incivek联合治疗后出现的严重皮肤反应相关因素，其目的是确定这些严重皮肤反应是否与患者基因类型相关。

与Incivek使用有关的不良反应应报告至FDA的AERS。

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ST LOUIS (MD Consult) - On December 19, 2012, the US Food and Drug Administration (FDA) issued an announcement concerning the safety of Incivek (telaprevir), which is used in combination with peginterferon alfa and ribavirin (Incivek combination treatment). Incivek is a protease inhibitor, and is used in the treatment of genotype 1 chronic hepatitis C in adults with compensated liver disease (including patients with cirrhosis), are treatment-naïve, or who have been previously received interferon-based treatment.

The FDA has received reports of serious skin reactions, some fatal, in patients who received combination therapy that included Invicik. As a result, the FDA is adding a Boxed Warning to the Incivek drug label stating that Incivek combination treatment must be immediately stopped in patients experiencing a rash with systemic symptoms or a progressive severe rash. Consideration should also be given to stopping any other medications that may be associated with serious skin reactions. Typical systemic symptoms and signs may include fever, nausea, diarrhea, mouth sores or ulcers, facial edema, red or inflamed eyes, or swelling or inflammation of the liver. All patients with serious skin reactions should receive urgent medical care.

These types of serious skin reactions (toxic epidermal necrolysis [TEN] syndrome, drug reaction with eosinophilia and systemic symptoms syndrome [DRESS], and Stevens-Johnson Syndrome [SJS]) may be considered different varieties along a spectrum of serious skin reactions and can be difficult to tell apart. When any of these serious skin reactions occur, it is necessary for health care professionals to immediately stop all 3 components of Incivek combination treatment and the patient should receive urgent medical care.

A search of the FDA Adverse Event Reporting System (AERS) database from May 23, 2011, through June 19, 2012, identified 92 cases of DRESS and 20 cases of SJS in patients taking Incivek combination treatment. The case of a 47-year-old woman who continued receiving Incivek combination treatment after the development of DRESS was fatal. The patient experienced a rash on her lower extremities after 4 weeks of triple therapy, and she continued taking all 3 drugs for another 4 weeks. She was hospitalized when the rash worsened. The patient experienced hypotension, fever, myalgia, and acute kidney injury. She then experienced ventricular fibrillation and died of cardiogenic shock.

The FDA has also received reports of 2 cases of TEN from Japan. One of the cases, in which the patient continued taking Incivek combination treatment for a period of time after symptoms developed, was fatal. The first TEN case was a 50-year-old female who recovered. She experienced a grade 3 rash on the third day of treatment and was diagnosed with TEN. She received steroid and antihistamine treatment for 1 month. After 1 month, the use of peginterferon was discontinued, and 3 days later, Incivek and ribavirin were stopped. The patient recovered after 2 months.

The Incivek drug label already contained information on the risk of serious skin reactions. The signs and symptoms of DRESS may include rash, fever, facial swelling, and evidence of internal organ involvement (eg, hepatitis). Patients may or may not experience eosinophilia. The signs and symptoms of SJS may include fever, lesions, and ulcerations on the eyes or lips. Incivek's manufacturer, Vertex Pharmaceuticals, agreed at the time of marketing approval to investigate, through genetic analysis, the factors associated with serious skin reactions that occurred after Incivek combination treatment. The purpose of the investigation is to determine whether such serious skin reactions may be linked to the genetic makeup of the patient.

Adverse reactions related to the use of Incivek should be reported to the FDA's AERS.