尽管心脏风险引人担忧 FDA仍批准减肥药氯卡色林

6月27日，美国食品药品管理局(FDA)正式批准减肥药盐酸氯卡色林在美国上市，尽管该药可能增加心脏瓣膜病的发病风险。

氯卡色林(Belviq) 属于选择性5-羟色胺2C受体激动剂，由瑞士的Arena制药公司生产，现获准作为饮食控制和运动锻炼的辅助手段，用于体重指数(BMI)≥30 kg/m2或BMI≥27 kg/m2且伴有体重相关合并症的成年患者的体重控制，获准剂量为每日2次，每次10 mg。

据美国疾病预防控制中心的数据显示，超过1/3的美国成年人患有肥胖症，肥胖症定义为BMI≥30 kg/m2。

Arena和卫材公司(Eisai Inc.，将负责该药的分销业务)称，FDA已经建议美国药品强制管理局(DEA)将氯卡色林归为“计划内药物(scheduled drug)”。

这两家企业在声明中表示，一旦DEA确定了最终的时间安排，卫材将公布该药何时能被医生和患者所用。

这一最终批复经历了相当长的时间，之前FDA顾问委员会曾就该药召开了2次评审会议。2010年9月，多数委员投票反对批准该药，一来是担心该药的减重效果不够明显，二来认为试验人群不能代表现实生活中可能使用该药的患者人群。于是，2012年5月再次召开委员评审会议。虽然大部分委员同意批准，但委员们对试验中与氯卡色林治疗相关的瓣膜病发生率升高这一问题展开了长时间的讨论。许多委员提出应该就这个问题开展进一步的研究，专家小组也建议患者在基线时以及治疗期间定期监测超声心动图。

出于这些担忧，美国公民健康研究组织在批复当晚就致信FDA敦促其拒绝批准该药。

FDA表示其已经考虑过该药的安全性问题，并在宣布这一批复的新闻发布会上指出，只要是按批准剂量用药，该药“不太可能激活5-羟色胺2B受体”。心脏组织中的5-羟色胺2B受体被激活可能正是导致服用减肥药芬氟拉明和右芬氟拉明者出现瓣膜病的原因所在。芬氟拉明和右芬氟拉明已于1997年被撤市。

FDA还指出，氯卡色林试验在8,000例患者中采用超声心动图对瓣膜功能进行了评价，结果显示“Belviq组与安慰剂组出现FDA定义的瓣膜异常的患者比例并无统计学差异”。不过，在药品标签上会注明心衰患者应慎用此药。

此外，也要求Arena公司开展6项上市后研究，包括1项长期心血管结局试验。

FDA称，试验表明与安慰剂组患者相比，坚持服用氯卡色林 1年的患者平均减重3%~3.7%。将近一半的非糖尿病患者体重至少下降了5%，而安慰剂组只有不到1/4的患者达到了这一效果。在合并2型糖尿病的受试者中，服用氯卡色林者有38%体重至少下降5%，而安慰剂组仅16%。

产品标签上建议服药12周后体重下降仍不足5%的患者停用氯卡色林。FDA说：“这部分患者即便继续服药，也很难达到具有临床意义的减重效果。”

此外，该药也不应用于妊娠期妇女。副作用可能包括5-羟色胺综合征，尤其是当lorcaserin与可能增加5-羟色胺水平或激活5-羟色胺受体的治疗药物同时使用时，比如偏头痛治疗药物和抗抑郁药。

Arena和卫材公司指出，氯卡色林还可能引发思维、嗜睡、意识模糊等问题，大剂量用药时甚至可能导致幻觉、欣快感或分离感。此外，由于该药可能导致男性阴茎异常勃起，因此存在这种倾向的男性患者应慎用此药。

爱思唯尔  版权所有

By: ALICIA AULT, Cardiology News Digital Network

The Food and Drug Administration on June 27 approved the obesity drug lorcaserin hydrochloride despite concerns that it might increase the risk of valvulopathy.

Lorcaserin (Belviq), a selective serotonin 2C receptor agonist manufactured by Swiss drug maker Arena Pharmaceuticals, was approved at a dosage of 10 mg twice a day as an adjunct to diet and exercise for weight management in adults with a body mass index of at least 30 kg/m2 or at least 27 kg/m2 with weight-related comorbidities.

More than one-third of American adults are considered obese, defined as having a BMI of at least 30, according to the Centers for Disease Control and Prevention.

According to Arena and Eisai Inc., which will distribute the drug, the FDA has recommended that lorcaserin be classified by the U.S. Drug Enforcement Administration as a scheduled drug.

The companies said in a statement that once the DEA has determined the final scheduling, Eisai will say when the drug will be available to patients and physicians.

The approval is a long time in coming, and after two advisory committee meetings were held about the drug. In September 2010, the majority of the committee voted against approval, expressing concerns about marginal weight loss and about a trial population that did not reflect the likely real-world use of the drug. In May of 2012, the committee met again. Although a majority was in favor of approval, there were lengthy discussions about the higher rate of valvulopathy associated with lorcaserin treatment in trials. Many called for further study of that issue, and the panel also recommended that patients be monitored with echocardiography at baseline and periodically during treatment.

Citing those concerns, Public Citizen’s Health Research Group sent a letter to the FDA on the eve of approval, urging the agency to reject the drug.

The FDA said it took safety issues into account, and noted in a press release announcing the approval that when the drug is used at the approved dose, it "does not appear to activate the serotonin 2B receptor." Activation of that receptor on heart tissue appears to have been the reason for valvulopathy that occurred in patients who took the weight loss drugs fenfluramine and dexfenfluramine, which were removed from the market in 1997.

The agency also said that valve function was assessed by echocardiography in 8,000 patients in lorcaserin trials and that there "was no statistically significant difference in the development of FDA-defined valve abnormalities between Belviq and placebo-treated patients." However, the drug will be labeled to be used with caution in patients with heart failure.

Arena is also being required to conduct six postmarketing studies, including a long-term cardiovascular outcomes trial.

In studies, when compared with those taking a placebo, patients taking lorcaserin for up to a year had an average weight loss of 3%-3.7%, said the FDA. Almost half of nondiabetic patients lost at least 5% of their body weight, compared with less than a quarter of those taking a placebo. Of the subjects with type 2 diabetes, 38% taking lorcaserin lost at least 5% of their body weight, compared with 16% taking a placebo.

The labeling recommends that lorcaserin be discontinued in patients who fail to lose 5% of their body weight after 12 weeks. They are "unlikely to achieve clinically meaningful weight loss with continued treatment," according to the FDA.

The drug also should not be used during pregnancy. Side effects may include serotonin syndrome, particularly when lorcaserin is taken with therapies that increase serotonin levels or activate serotonin receptors, such as antimigraine drugs or antidepressants.

According to Arena and Eisai, lorcaserin may also cause problems with thinking, sleepiness, confusion, and, in higher doses, hallucinations, euphoria, or disassociation. It may also cause priapism, so it should be used with caution in men who are predisposed to the condition, said the companies.