北美的Esai公司宣布，美国食品药物管理局(FDA)核rufinamide (Banzel)作为4岁以上小孩及成人与痉挛相关之雷葛氏症候群(Lennox-Gastaut syndrome，LGS)的辅助治疗。
　　
　　Esai公司的声明指出，该产品将在2009年1月上市用于此适应症。
　　
　　不过， Esai公司接获回应表示，rufinamide目前作为小发作合并或未合并次发性泛发之成人和12岁以上小孩的辅助治疗，指出FDA虽完成回顾但尚未核准前述运用。
　　
　　声明指出，该药物是一个 triazole衍生物，构造上与目前上市的抗癫痫药物(AEDs)无关，相信它可调节脑中的钠离子通道。
　　
　　【LGS难以治疗】
　　声明指出，雷葛氏症候群特征是多次且频繁的抽搐，约影响达4%的孩童癫痫案例，在美国，有将近300,000名14岁以下的小孩有癫痫，通常在1至5岁间发生LGS，将近3%至7%病患在平均不到10年的追踪期间死亡。
　　
　　这个症状难以治疗，通常需要多种药物，且发生率因各种抽搐类型而异。强直发作(Tonic seizures)、失张力性发作(atonic seizure)与失神性发作(小发作)( absence seizures)最常见，不过强直阵挛发作(tonic-clonic)、肌抽跃发作(myoclonic)与其它类型抽搐也会发生，抽搐的各种类型和频率会造成发育迟缓及行为异常。
　　
　　核准用于LGS之抽搐辅助治疗是根据一个单一药物、多中心双盲研究，在138名年纪4至30岁的病患进行rufinamide和安慰剂的比较(Glauser T 等人，Neurology 2008;70:1950-1958)，纳入使用1至3种稳定剂量的AEDs仍未能适当控制的病患；每位病患必须至少曾经发作过90次，包括在研究前一个月内非典型的小发作和强直-失张力性发作。
　　
　　完成4周开始期的稳定治疗之后，病患进入12周的随机双盲期，包括1至2周的滴定期(titration period)，与1周的维持期；在滴定期间，剂量增加到每天45 mg/kg的目标值，每天给药两次。如果发生耐受方面的问题，可以在滴定期间降低剂量，但是最后的剂量得在维持期维持稳定。治疗组有88%达到目标剂量。
　　
　　初级效果终点是每28天的总发作频率改变百分比、每28天的强直-失张力性发作频率改变百分比、并使Parent/Guardian Global Evaluation评估抽搐的严重度。
　　
　　结果显示与开始期有关，使用rufinamide治疗之病患，其每28天发作频率平均减少32.7%，安慰剂组平均只减少11.7% (P < .002)。
　　
　　治疗期与开始期相比，使用rufinamide的病患每28天的强直-失张力性发作频率平均减少42.5%，而安慰剂组增加1.4%(P < .0001)。
　　
　　此外，根据Parent/Guardian Global Evaluation的抽搐严重度评分，和安慰剂组相比，使用rufinamide的病患的抽搐严重度有显著改善，达30.6% (P < .005)。
　　
　　声明指出，在双盲试验中所有接受rufinamide治疗的病患，最常见的副作用是头痛、晕眩、疲劳、困倦与恶心。
　　
　　主要研究者、辛辛那提儿童医院医学中心综合癫痫计画主任Tracy Glauser医师在Esai公司的声明中表示，受LGS之苦的病患需要更多选择。我们对此研究感到振奋的是，rufinamide对原本使用其它抗癫痫药物控制不佳的LGS孩童有效且一般耐受良好。
　　
　 【注意与禁忌】
　　抗癫痫药物增加了自杀思想或行为的风险，病患需监控其急症、忧郁恶化、自杀思想与行为、其它任何异常的心情或行为改变。使用与中枢神经系统有关的药物–相关的副作用包括困倦或疲劳、协调性异常、晕眩、步态不稳与运动失调。
　　
　　该公司也指出，rufinamide禁用于家族性短QT症状(familial short-QT syndrome)的病患，且在并用rufinamide和其它会缩短QT间隔的药物时要小心。
　　
　　声明指出，一如其它AEDs，rufinamide需渐渐停用，以减少增加抽搐频率的风险。此外，曾报导过多器官过敏症状(multiorgan hypersensitivity syndrome)，大部份发生在小儿且通常在开始治疗后4周内发生。声明指出，若有怀疑此反应，应停用rufinamide且开始其它治疗方式。用药后发生红疹的病患也需要密切追踪。

November 25, 2008 — Esai Corporation of North America announced US Food and Drug Administration (FDA) approval for rufinamide (Banzel) as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in children aged 4 years and older, as well as adults.

The product will be available for this indication in January 2009, a statement from Esai notes.

However, Esai received a complete response letter for rufinamide as adjunctive treatment for partial-onset seizures with and without secondary generalization in adults and adolescents 12 years of age and older, indicating the FDA review is complete and this application is not ready for approval.

The drug is a triazole derivative that is structurally unrelated to currently marketed antiepileptic drugs (AEDs), the statement says, and is believed to act by regulating the activity of sodium channels in the brain.

LGS Difficult to Treat

Lennox-Gastaut syndrome is characterized by multiple and frequent seizures, the statement notes. It accounts for up to 4% of all childhood epilepsy cases, and approximately 300,000 children under the age of 14 years have epilepsy in the United States. Onset of LGS is usually between 1 and 5 years of age, and approximately 3% to 7% of patients die within a mean follow-up of less than 10 years.

The condition is difficult to treat, often requiring multiple drugs, and manifests a variety of seizure types. Tonic, atonic, and absence seizures are the most common, although tonic-clonic, myoclonic, and other seizure types may occur. The multiple types and frequency of seizures can lead to developmental delays and behavioral disorders.

Approval as adjunctive treatment of seizures in LGS is based onasingle,multicenter, double-blind study comparing rufinamide with placebo in 138 male and female patients between the ages of 4 and 30 years(GlauserTetal.Neurology2008;70:1950-1958). Patients were included if their seizures were inadequately controlled on 1 to 3 concomitant stable-dose AEDs; each patient had to have at least 90 seizures, including both atypical absence seizures and tonic-atonic seizures, in the month prior to study entry.

After completing a 4-week baseline phase on stable therapy, patients were randomized in the double-blind 12-week phase, including a titration period of 1 to 2 weeks and a maintenance phase of 10 weeks. During titration, the dose was increased to a target of approximately 45 mg/kg per day, given on a twice-per-day schedule. Dosage reductions were permitted during titration if tolerability problems were encountered, but final doses were to remain stable during the maintenance phase. Target doses were achieved in 88% of the treated group.

Primary efficacy end points were the percent change in total seizure frequency per 28 days, the percent change in tonic-atonic seizure frequency per 28 days, and seizure severity using the Parent/Guardian Global Evaluation.

Results showed that relative to the baseline phase, patients treatedwithrufinamide had a 32.7% median reduction in total seizure frequency per 28 days vs an 11.7% median reduction in the placebo group (P < .002).

Patients on rufinamide had a 42.5% median reduction in tonic-atonic seizure frequency per 28 days vs a 1.4% increase in the placebo group in the treatment phase relative to the baseline phase (P < .0001).

In addition, a significant improvement in seizure severity was seen in 53.4% of rufinamide-treated patients compared with 30.6% of placebo-treated patients on the Seizure Severity Rating from the Parent/Guardian Global Evaluation (P < .005).

In all patients treated with rufinamide in double-blind trials, the most common adverse effects were headache, dizziness, fatigue, somnolence, and nausea, the company release states.

"People living with LGS need more treatment options," Tracy Glauser, MD, director of the Comprehensive Epilepsy Program at Cincinnati Children's Hospital Medical Center, in Ohio, and lead investigator of the trial, said in the Esai release. "What's exciting about this study is that [rufinamide] was effective and generally well tolerated in children with LGS whose seizures were previously uncontrolled on other multiple antiepileptic medications."

Cautions and Contraindications

Antiepileptic drugs increase the risk of suicidal thoughts or behavior, and patients should be monitored for the emergence or worsening of depression, suicidal thoughts, and behavior or any unusual changes in mood or behavior. Use of the drug has been associated with central nervous system–related adverse reactions, includingsomnolenceorfatigue,coordinationabnormalities,dizziness,gaitdisturbances, and ataxia.

The company also cautions that rufinamide is contraindicated in patients with familial short-QT syndrome and that caution should be used when givingrufinamide with other drugs that shorten the QT interval.

As with other AEDs, the release adds, rufinamide should be withdrawn gradually to minimize the risk of increased seizure frequency. In addition, multiorgan hypersensitivity syndrome has been reported, occurring in trials mostly in the pediatric population and usually within 4 weeks of starting therapy. "If this reaction is suspected, [rufinamide] should be discontinued and alternative treatment started," the release notes. Patients who develop a rash on the drug "must be closely supervised," the statement adds.

Esai Corporation acquiredanexclusiveworldwidelicensetodevelop,use,manufacture, and market rufinamide for any human therapeutic use with the exception of bipolar disorder, anxiety disorders, and ophthalmologic disorders from Novartis Pharma in 2004. Banzel is a trademark of Novartis Pharma, used under license, the statement notes.