注射用睾酮已获准用于治疗性腺功能低下

一种长效肌肉注射的睾酮制剂已通过美国食品药品管理局(FDA)核准，用于治疗性腺功能低下。说明书中包括一项关于治疗相关性肺部油微栓(POME)和过敏反应风险的加框警告。

这种溶于蓖麻油和苯甲酸苄酯的十一酸睾酮储库给药系统(TU)已获准用于治疗成年男性先天性或获得性的原发性性腺功能低下或低促性腺激素性性腺功能低下。适应证部分包括以下陈述：该药物应仅用于需要睾酮替代治疗且使用该药物的获益超出POME和过敏反应严重风险的患者。

生产商Endo制药公司表示，目前已能够有限地通过Aveed风险评估与减轻策略(REMS)获取这种药物，商品名为Aveed。根据该公司的观点，在REMS之下，将需要进行处方医生教育和认证，并且产品的发售将受到限制。

该产品为单次使用瓶装制剂；建议剂量为，开始治疗时使用3 ml(750 mg)，治疗间隔为4周，之后治疗间隔为10周。每次注射后，应在诊室等用药场所留观30分钟，观察患者是否出现POME或过敏反应症状。严重POME反应的症状包括想咳嗽、呼吸困难、咽喉紧迫感、胸痛、头晕和晕厥。

早在2007年，Endo公司就提交了审批文档，但因为安全性原因(在已批准该产品的国家开展的临床和上市后研究显示，注射用药期间及用药后短时间内有发生过敏性反应和POME的报告)，TU的核准被搁置。在2013年4月的会议上，FDA的生殖健康药物顾问委员会和药物安全性与风险管理顾问委员会关于安全性问题形成对峙，赞成票和反对票均为9票。

这项批准令是基于在130例性腺功能低下男性患者（平均年龄为54岁）中进行的一项为期84周的Ⅲ期、单组研究的结果。该研究基于血清睾酮水平，确认TU为一种有效的睾酮替代治疗药物。有1例患者在第3次注射后发生轻微咳嗽，之后根据处方信息判断为POME所致。

在美国之外的已批准该药的国家有更多的病例报告。一篇针对18项临床研究的综述纳入了大约3,500例患者，结果显示有8例患者发生9例POME，另外还发生了2例过敏反应。

该产品由拜耳制药公司及其子公司负责销售。该公司通过www.AveedREMS.com网站和电话855-755-0494提供关于REMS的信息。

如发现与十一酸睾酮相关的严重不良事件，请致电800-332-1088或通过ww.fda.gov/medwatch向FDA的MedWatch项目报告。

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By: ELIZABETH MECHCATIE, Internal Medicine News Digital Network

A long-acting intramuscular formulation of testosterone has been approved by the Food and Drug Administration for treating hypogonadism, with a label that includes a boxed warning about the risks of pulmonary oil microembolism and anaphylaxis associated with treatment.

The depot formulation of testosterone undecanoate (TU), in castor oil and benzoyl benzoate, has been approved for treating adult men with primary hypogonadism or hypogonadotropic hypogonadism, congenital or acquired. The indications section includes the statement that it "should only be used in patients who require testosterone replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis."

The drug will be available, with restrictions, through the Aveed Risk Evaluation and Mitigation Strategy (REMS), according to the manufacturer, Endo Pharmaceuticals, which is marketing the product as Aveed. Under the REMS, prescriber education and certification will be required and distribution of the product will be restricted, according to the company.

The product is available in single-use vials; the recommended dosing is 3 mL (750 mg) at the start of treatment, at 4 weeks, and then at 10-week intervals. After each injection, patients are observed for symptoms of pulmonary oil microembolism (POME) or anaphylaxis for 30 minutes in the physician’s office, clinic, or hospital, the only places where the drug can be administered. Symptoms of serious POME reactions include an urge to cough, dyspnea, throat tightening, chest pain, dizziness, and syncope.

Since Endo filed for approval in 2007, approval of TU has been held up for safety reasons, namely reports of anaphylaxis and POME during or shortly after injections were administered, in clinical and postmarketing studies in countries where the product was approved. At a meeting in April 2013, the FDA’s Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee split on the safety issue, voting 9-9 on whether they believed the drug had an acceptable safety profile for the proposed use.

Approval was based on the results of a phase III, 84-week, single-arm study of 130 hypogonadal men (mean age, 54 years), which determined that TU was an effective testosterone replacement therapy, based on serum testosterone levels. There was one case of a patient who had mild coughing after the third injection, which was later attributed to POME, according to the prescribing information.

But more cases have been reported after approval in countries outside the United States and in a review of 18 clinical studies; where possible cases of POME were adjudicated, of about 3,500 patients there were 9 cases of POME in 8 patients and 2 cases of anaphylaxis.

The product has been available since 2003 outside the United States, where it is marketed by Bayer Pharma and its subsidiaries.

The company is providing information about the REMS at www.AveedREMS.com and 855-755-0494.

Serious adverse events associated with testosterone undecanoate should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch.