Children's Hospital of Orange County, Orange, CA, USA.
Zogenix, Inc., Emeryville, CA, USA.
Epilepsia. 2020 Nov;61(11):2386-2395. doi: 10.1111/epi.16638. Epub 2020 Aug 18.
Fenfluramine, which was previously approved as a weight loss drug, was withdrawn in 1997 when reports of cardiac valvulopathy emerged. The present study was conducted in part to characterize the cardiovascular safety profile of low-dose fenfluramine when used in a pediatric population to reduce seizure frequency in patients with Dravet syndrome.
Patients 2- to 18-years-old with Dravet syndrome who had completed any of three randomized, placebo-controlled clinical trials of fenfluramine were offered enrollment in this open-label extension (OLE) study. All patients were treated with fenfluramine starting at a dose of 0.2 mg/kg/day (oral solution dosed twice per day), which was titrated to maximal effect with a dose limit of 0.7 mg/kg/day (maximum 26 mg/day) or 0.4 mg/kg/day (maximum 17 mg/day) in patients receiving concomitant stiripentol. Standardized echocardiographic examinations were conducted at Week 4 or 6 and then every 3 months during the OLE study to monitor cardiac valve function and structure and pulmonary artery pressure. The primary end point for the echocardiography analysis was the number of patients who developed valvular heart disease or pulmonary artery hypertension (PAH) during treatment.
A total of 232 patients were enrolled in the study. The average age of patients was 9.1 ± 4.7 years, and 55.2% were male. The median duration of treatment with fenfluramine was 256 days (range = 58-634 days), and the mean dose of fenfluramine was 0.41 mg/kg/day. No cases of valvular heart disease or PAH were observed.
Longitudinal echocardiography over a median 8.4 months of treatment with fenfluramine suggests a low risk of developing cardiac valvulopathy and PAH when used to treat pediatric patients with Dravet syndrome.
芬氟拉明曾作为一种减肥药获得批准，但在 1997 年因出现心脏瓣膜病报告而被撤出市场。本研究旨在部分评估小剂量芬氟拉明在儿科人群中用于降低德拉维特综合征患者癫痫发作频率时的心血管安全性概况。
已完成芬氟拉明的三项随机、安慰剂对照临床试验之一的 2 至 18 岁德拉维特综合征患者可选择参加本开放性标签扩展（OLE）研究。所有患者均以 0.2mg/kg/天（口服溶液每日两次给药）的起始剂量接受芬氟拉明治疗，根据最大效应滴定剂量，最大剂量限制为 0.7mg/kg/天（最大 26mg/天）或 0.4mg/kg/天（最大 17mg/天），同时服用司替戊醇的患者剂量限制为 0.4mg/kg/天（最大 17mg/天）。在 OLE 研究期间，每 4 或 6 周进行一次标准化超声心动图检查，以监测心脏瓣膜功能和结构以及肺动脉压。超声心动图分析的主要终点是在治疗期间发生瓣膜性心脏病或肺动脉高压（PAH）的患者数量。
共有 232 名患者入组研究。患者的平均年龄为 9.1±4.7 岁，55.2%为男性。芬氟拉明治疗的中位时间为 256 天（范围=58-634 天），芬氟拉明的平均剂量为 0.41mg/kg/天。未观察到瓣膜性心脏病或 PAH 病例。
在使用芬氟拉明治疗德拉维特综合征儿科患者的 8.4 个月的中位时间内进行的纵向超声心动图检查表明，发生心脏瓣膜病和 PAH 的风险较低。
