FDA:警惕MS药物的癫痫发作风险

美国食品药品管理局(FDA)对多发性硬化症(MS)药物达伐吡啶(dalfampridine)上市后不良事件报告的评估结果表明，患者开始接受推荐剂量的达伐吡啶治疗后不久，癫痫发作风险即达到最高程度。

7月23日FDA发布声明指出，癫痫发作是该药物的已知风险，大部分患者的癫痫发作出现在开始治疗后数天至数周内，无任何癫痫史的患者也可能发生。癫痫发作风险随血药浓度增加而增加。鉴于该药物通过肾脏消除，因此肾功能损害患者的癫痫发作风险相对较高。

Acorda制药公司上市的达伐吡啶缓释制剂(商品名：Ampyra)属于钾离子通道阻断剂，于2010年1月获准用于改善MS患者行走功能，剂量为10 mg，2次/d。在该缓释制剂批准之前的20多年间，其普通剂型4-氨基吡啶(fampridine)被超适应证用于改善各种神经性疾病患者行走能力。但4-氨基吡啶的治疗窗较窄，控制血药浓度存在难度，而缓释制剂达伐吡啶克服了这一缺陷。

FDA在声明中对临床医生提出了如下建议，其中包括了对原说明书中有关信息的更新内容：

·达伐吡啶禁用于有癫痫史的患者或中重度肾功能损害患者(肌酐清除率<50 ml/min)。

·在向轻度肾功能损害患者(肌酐清除率51~80 ml/min)开具达伐吡啶处方之前应仔细权衡其潜在受益与癫痫发作风险。

·开始治疗前应测定患者肌酐清除率(应用Cockroft-Gault公式)，治疗期间应每年测定1次，即便患者血清肌酐水平显示正常。

·如果患者漏服，建议不服用加倍或额外剂量的达伐吡啶；患者应整片服用，不应将药片掰开、研碎、咀嚼或溶于水后服用。

·一旦患者出现癫痫发作，应永远停止服用达伐吡啶。

By: ELIZABETH MECHCATIE, Internal Medicine News Digital Network

The Food and Drug Administration’s evaluation of postmarketing adverse event reports for the multiple sclerosis drug dalfampridine indicate that the risk of seizures is highest soon after starting treatment with the recommended dose.

Seizures are a known risk of the drug, and the majority of them occurred within days to weeks of starting treatment. Seizures also occurred in patients without any history of them, according to the FDA statement issued on July 23.

The risk of seizures increases with higher blood levels of the drug, and because it is eliminated through the kidneys, the risk of seizures is higher in patients with kidney impairment, the agency said.

The sustained-release formulation of the potassium channel blocker dalfampridine, marketed as Ampyra by Acorda Therapeutics, was approved in January 2010 to improve walking in people with multiple sclerosis, at a dose of 10 mg twice a day. For more than 20 years before approval, a compounded formulation of the drug, called fampridine, was used off label to improve walking ability in people with different neurologic conditions. However, it was difficult to regulate blood levels of fampridine, which has a narrow therapeutic range, and the sustained formulation, dalfampridine, was developed to overcome this limitation.

The FDA statement provided the following recommendations aimed at clinicians, which includes information in the original label (now updated):

· Dalfampridine is contraindicated in patients with a history of seizures or who have moderate to severe renal impairment (a creatine clearance below 50 mL/min).

· The potential benefits of treatment with dalfampridine "should be carefully considered against the risk of seizures" before prescribing the drug to patients with mild renal impairment (creatine clearance 51 mL/min to 80 mL/min).

· Before starting treatment, a patient’s creatinine clearance level should be known (using the Cockroft-Gault equation), and should be checked annually during treatment, "even when serum creatinine levels appear to be normal."

· Patients should be advised not to take double or extra doses of dalfampridine if they miss a dose; and they should take the tablets whole, and not divide, crush, chew, or dissolve the tablets.

· Dalfampridine should be discontinued permanently if a patient has a seizure.