2010年9月22日;美国食品药品监督管理局(FDA)批准口服多发性硬化症(MS)治疗Gilenya (芬戈莫德) 0.5 mg 每天，一线治疗复发性多发性硬化症- 疾病的最常见型。FDA批准使Gilenya成为在美国可得到的第一个适用于MS复发型的口服治疗。

美国多发性硬化症协会医疗保健服务和政策研究副主席Nicholas LaRocca说“今天对美国复发型MS的人是重要和鼓舞人的一天”。“在方便胶囊中提供显著疗效，对有这种慢性病经常注射的个体是受欢迎另一种新治疗选择”

Gilenya减少MS复发的频数(发作)和有助于减缓MS引起某些身体问题的增强。在临床试验中，Gilenya有充分研究的安全性和耐受性谱形，已被超过2,600例临床试验患者确定其特征，其中一些7年治疗，已有4,500患者年以上的经验。

西奈山医学院多发性硬化症Corinne Goldsmith Dickinson中心Saunders家庭神经病学教授Fred Lublin, MD 说“通过新作用机制，在复发型MS患者中Gilenya可显著改善临床结局”，“当按照批准说明书使用Gilenya提供显著疗效和可处理的安全性，使之对正在复发MS患者和治疗患者的医生是有价值的进展，”

Gilenya批准是根据迄今为止向FDA的一个新的MS药物的最大的临床试验计划并包括来自临床研究复发型MS病人显示减少复发，残疾进展的风险和用核磁(MRI)检出的脑病变数，测量疾病活动度显著疗效的合并资料。

Novartis Pharma AG公司全球发展主管Trevor Mundel, MD说“我们骄傲与MS社会成功地工作走向带来新有效治疗对复发型MS人们共同点目标”，“我们正在积极促进在欧洲和世界其它地方批准”。
 
Gilenya是新类型药物被称为神经鞘氨醇1-磷酸受体(S1PR)调节剂中的第一个。在MS中，免疫系统损伤保护中枢神经系统(CNS)中神经纤维覆盖物，包括脑和脊髓，Gilenya的新机制是未知的，但被认为to work by通过保留在淋巴结内某些白细胞(淋巴细胞)减低免疫系统对CNS的攻击。这预防白细胞达到CNS，在CNS可能潜在地攻击神经纤维周围保护性覆盖层，导致对神经细胞较轻的炎症损伤。如Gilenya治疗停止白细胞保留是可逆的。.

适应证和用途
GILENYA是一种神经鞘氨醇1-磷酸受体调节剂适用于复发性多发性硬化症患者的治疗减少临床加重的频数和延缓身体残疾的积蓄。
 
剂量和给药方法
推荐剂量：0.5 mg口服每天1次，有或无食物。

剂型和规格
0.5 mg硬胶囊。

禁忌证
无。

警告和注意事项
（1）首次给予GILENYA后心率和/或房室传导减慢：首次剂量后6小时所有患者观察到心动过缓的征象和症状。心动过缓高风险患者中如无最近可利用首次剂量前得到基线ECG。患者接受类别Ia或类别III 抗心律失常药, β阻滞剂, 钙通道阻滞剂, 有慢心率患者, 昏厥史, 病态窦房结综合征, 二级或更高级传导阻滞, 缺血性心脏病,或充血性心衰是处在发生心动过缓或心阻断风险增加。
（2）感染：GILENYA可能增加感染的风险。开始用GILENYA治疗前应得到最近的CBC。治疗期间及停药后2个月监查感染的征象和症状以。有活动性急性或慢性感染患者中不要开始GILENYA治疗。
（3）黄斑水肿：可能发生有或无视力症状。开始GILENYA前和在治疗起始后3-4个月时应进行眼科评价。在基线时和常规评价患者期间监查视力。有糖尿病或葡萄膜炎史患者是增加风险和应定期眼科评价。
（4）用GILENYA肺功能试验中减低：当临床上有指征时获取肺活量和对一氧化碳肺弥散量(DLCO)。
（5）肝效应：GILENYA可能增加肝转氨酶。开始用GILENYA治疗前应可得到最近肝酶结果。如症状提示肝发生损伤评估肝酶。如证实显著肝损伤停止GILENYA。
（6）胎儿风险：GILENYA治疗期间和停止后2个月内育龄潜能妇女应使用有效避孕。

不良反应
最常见不良反应(发生率 ≥10%和> 安慰剂)：头痛、流感、腹泻、背痛、肝转氨酶升高和咳嗽。

药物相互作用
（1）类别Ia或类别III抗心律失常药：因为严重节律紊乱的风险，用类别Ia或类别III抗心律失常药治疗患者开始期间仔细监查。
（2）β阻滞剂：因为对心率相加作用的风险，用β阻滞剂治疗患者开始期间仔细监查。
（3）酮康唑[Ketoconazole]：因为与全身酮康唑同时使用期间GILENYA暴露增加70%，和不良反应的风险更大，严密监查患者。
（4）疫苗：由于感染的风险，避免减毒活疫苗时，和GILENYA治疗停止后2个月。
 
在特殊人群中的使用
（1）妊娠：根据动物资料, 可能引起胎儿危害。可得到妊娠注册。
（2）儿童患者：尚未确定安全性和有效性。
（3）肝损伤：严密监查严重肝损伤患者，因GILENYA暴露加倍，和不良反应的风险较大。

---------------------------------------------------------------
原产地英文商品名:
GILENYA 0.5mg/cap 28caps/box
原产地英文药品名:
FINGOLIMOD
中文参考商品译名:
GILENYA 0.5毫克/胶囊 28胶囊/盒
中文参考药品译名:
芬戈莫德
生产厂家中文参考译名:
诺华
生产厂家英文名:
NOVARTIS
---------------------------------------------------------------

The FDA approved Gilenya, a Novartis Pharmaceuticals' product for relapsing multiple sclerosis.  The approved labeling indicates it reduces the frequency of clinical exacerbation and delays accumulation of physical disability.
A Closer Look at New FDA Actions
Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease characterized by central nervous system (CNS) demyelination.

The FDA approved Gilenya (fingolimod), a Novartis Pharmaceuticals’ product for relapsing ms, on September 21, 2010. Its approved labeling indicates it reduces the frequency of clinical exacerbations and delays accumulation of physical disability. It joins a limited number of other agents (interferons, COPAXONE, Novantorne, Tysarbi) used to treat MS, but is the first oral treatment. Fingolimod’s mechanism of action is unknown, but probably related to its ability to block lymphocyte egress from lymph nodes once it binds to sphinosine 1-phosphate receptors. Its active metabolite fingolimod-phosphate traps T cells in lymph nodes, reduces the number of lymphocytes in peripheral blood, and prevents their subsequent migration into the CNS.1,2

Pharmacokinetics
Fingolimod’s half-life is approximately 14 days. It has a slow rate of absorption with Tmax of greater than 12 hours. Its volume of distribution is high and it is lipophilic. It clears slowly, and its pharmacokinetic profile is uninfluenced by age, sex, ethnicity, gender, or weight. It is not removed by dialysis or plasma exchange. Dose adjustments are unnecessary in renal or hepatic impairment.3,4

Clinical Trials
The TRANSFORMS study randomized 1292 patients with relapsing and remitting MS (RRMS) in a double-blind, parallel- group, double-dummy trial. Subjects received fingolimod 0.5 mg once daily, fingolimod 1.25 mg once daily, or interferon beta-1a (IFN b-1a) 30 mg weekly. At 1 year, researchers found no significant difference between fingolimod groups (P = 0.159); these values represent reductions in annualized relapse rate (ARR) of 52% and 38% vs IFN b-1a. Discontinuation rates were 8% to 13% for fingolimod and 11% for IFN b-1a. Further, 86% to 91% of fingolimod patients and 92% of IFN b-1a patients reported adverse events (AEs). Most common AEs were headache, nasopharyngitis, and fatigue. Serious AEs included bradycardia and atrioventricular (AV) block, usually at the first dose. Approximately half of subjects experienced infections; serious infections occurred in 0.2% to 1.7% and 1.4% of participants in the fingolimod and IFN b-1a groups, respectively.5

The FREEDOMS study randomized 1272 subjects to oral fingolimod 0.5 or 1.25 mg once daily, or placebo for 24 months. In the fingolimod 0.5 mg, fingolimod 1.25 mg and placebo groups, 7.5%, 14.2%, and 13.4%, respectively, discontinued treatment due to AEs. Lymphocyte counts decreased at 1 month by 76% for fingolimod 1.25 mg and 73% for fingolimod 0.5 mg; this depletion persisted from 1 to 12 months. Oral fingolimod 0.5 mg and 1.25 mg significantly reduced ARR by 54% and 60%, respectively, versus placebo. Both doses of fingolimod demonstrated a significant reduction in magnetic resonance imaging end points over the course of 24 months. New or enlarging T2 lesions were also reduced. The 0.5-mg dose’s safety profile appeared better than the 1.25- mg dose (similar to TRANSFORMS), and no new safety signals were reported.6

Dosing and Precautions
Before starting Gilenya, prescribers need to draw baseline complete blood count, liver transaminase, and bilirubin levels, and monitor periodically. Fingolimod may increase macular edema risk—patients should undergo ophthalmologic examination at baseline and 3 to 4 months later; if they report visual disturbance; and regularly if they have diabetes or a history of uveitis. If patients are taking antiarrhythmics, or have a history of second degree or higher AV block, sick sinus syndrome, prolonged QT interval, ischemic cardiac disease, congestive heart failure, heart rate below 55 bpm, or irregular heartbeat, an electrocardiogram is needed. Patients who have not had or been vaccinated for chicken pox should received varicella zoster virus vaccine, and wait 1 month before starting Gilenya.1

Fingolimod is dosed at 0.5 mg once daily orally; it is a hard capsule that can be taken with or without food. The first dose must be administered under supervision after pulse and blood pressure are taken. The patient must be directly observed for 6 hours for possible bradycardia. Women of childbearing potential must use contraception during and for 2 months after treatment.1

Reduction in circulating lymphocyte, which may be associated with increased risk of infection, will usually resolve within 2 months of discontinuing Gilenya, but may persist.7 Instruct patients to report symptoms of infection for up to 2 months. Gilenya’s effects on heart rate and AV conduction may recur on therapy reinitiation if the product is discontinued for 14 days or more.1 PT
 
临床II期试验数据显示新药FTY720对治疗多发性硬化症有疗效

发表在近期新英格兰医学杂志（New England Journal of Medicine）上的关于FTY720 (Fingolimod)的临床研究数据显示，这种一天一次的口服新药对治疗各种复发性多发性硬化症（multiple sclerosis，MS）具有良好的疗效。鉴于II期临床研究的乐观结果，Novartis已经开始III期临床研究以深入评价FTY720在复发性多发性硬化症方面的疗效。
临床II期试验数据显示，在试验的前六个月当中，每天服用一次FTY720的试验组相对于服用安慰剂对照组来说可以降低80％的炎症（实验结果由磁共振成象仪器测得），也至少能够减少50％的复发率。之后的六个月当中，继续服用FTY720的病人炎症活动和复发率保持在一个较低的水平，同样的结果也出现在试验后期由服用安慰剂转服FTY720的病人身上。
负责该项研究的瑞士University Hospital Basel的神经科学系博士Ludwig Kappos认为，临床II期试验结果显示FTY720能够显著降低炎症和多发性硬化症的复发率。假如在扩大的III期临床实验中这样的结果能够得到再次的证实，那么FTY720就代表了在多发性硬化症治疗领域的一大进步，成为治疗多发性硬化症的希望。
最近开始的名为FREEDOMS 的临床III期试验将在世界各地100多个研究中心展开，涉及2，000多名病人。试验将采用随机双盲设计，对两种剂量 (1.25 mg 和 0.5 mg)FTY720的有效性和安全性进行评价。

美国FDA顾问专家组同意批准用于治疗多发性硬化症的新型口服药（2010年6月19日）

美国食品药品管理局(FDA)顾问专家组得出一致结论，即芬戈莫德的现有数据表明该药是一种用于治疗复发-缓解型多发性硬化症的有效药物，其在推荐剂量下的安全特性已获得认可。芬戈莫德将成为首例被批准用于治疗多发性硬化症(MS)的口服药物。
6月11日，FDA周围及中枢神经系统药物顾问专家组以25:0的投票结果通过了如下结论，即相关研究业已证明，芬戈莫德可有效降低复发-缓解型MS患者临床症状恶化的几率，此外，该专家组又以24:1的投票结果通过了另一项结论，即该药的临床试验数据业已提供的大量证据表明，该药可以延缓患者肢体残疾的发病进程。尽管专家组建议应在接受该药治疗患者中对该药所致的黄斑水肿和肺毒性(临床试验显示，芬戈莫德可能与这些严重不良事件有关，包括给药剂量0.5 mg/d时)进行密切监测，但大部分专家均同意将该药用于一线治疗。
芬戈莫德是一种鞘氨醇1-磷酸受体(S1PR)调节剂。该药可以作用于位于淋巴细胞上的鞘氨醇1-磷酸受体，致使循环中的淋巴细胞在淋巴结内滞留，“从而减少自身反应性淋巴细胞再次进入循环的几率，进而防止这些细胞浸润中枢神经系统(CNS)，”据该药的制药商诺华制药公司介绍。该过程是可逆的，如果停止用药，循环中的淋巴细胞水平就会恢复正常。
诺华公司已建议FDA批准将芬戈莫德作为一种改善病情的治疗药物用于治疗患有复发型MS的患者，以降低这些患者临床症状恶化的发生率，并且延缓其肢体残疾的病程进展速度——给药剂量为0.5 mg/d，因为与1.25 mg/d的给药剂量(及该临床试验检测的其他剂量)相比，在该剂量下药物产生的疗效类似且安全性更佳。
在两项总计纳入超过2,500例复发-缓解型MS患者的研究中，研究者对芬戈莫德(给药剂量为0.5与1.25 mg/d)和安慰剂或干扰素β -1a 进行了对比，两项研究的主要终点均为年化复发率，其中一项研究的评估时间在研究开始1年后，另一项则在研究开始2年后。在两项研究中，与安慰剂或干扰素β -1a相比，该药物在两种给药剂量下均能使患者的复发率显著降低，并减缓患者肢体残疾的病程进展速度。
因为更高给药剂量导致的不良事件，该公司已经放弃向FDA申请高剂量许可的计划，因为这些不良事件似乎与给药剂量有关。该专家组建议诺华公司对低于0.5 mg/d的给药剂量加以研究。
该研究指出，该药的主要安全问题是首次用药可能引起心动过缓和心脏传导功能异常，黄斑水肿(包括给药剂量为0.5 mg时)和肺功能逐步下降，这些效应似乎均与剂量相关。到目前为止，在应用过芬戈莫德的超过4,000例患者中已出现2例疱疹致死病例，这些病例与类固醇治疗无关，据该公司介绍。
公司业已打算针对0.5 mg的给药剂量进行为期5年的上市后药物安全性研究，其还计划进行妊娠登记项目。该公司同时已经申请欧盟及其他国家对该药进行审批。FDA预期将于9月作出决定。
FDA通常会遵循其顾问专家组的推荐意见。在会议召开前，FDA已确定其顾问专家组成员均不存在潜在利益冲突，但有时，FDA会准许某位存在利益冲突的顾问专家组成员弃权。

关于芬戈莫德：

芬戈莫德(fingolimod，FTY-720)最初由日本Mitsubishi制药公司研制，后期全球经营权转让给瑞士Novartis制药公司，并于2010年9月21日获得美国FDA批准上市，成为首个可经口服给药的用于治疗复发-缓解型多发性硬化症(multiplesclerosis，MS)的新型免疫抑制剂，其商品名为Gilenya。FDA表示，Gilenya可以阻止淋巴腺中的部分血细胞向大脑和脊髓移动，从而延缓多发性硬化症患者的病情恶化程度。 在两项总计纳入超过2，500例复发-缓解型MS患者的研究中，研究者对芬戈莫德(给药剂量为0.5与1.25mg/d)和安慰剂或干扰素β-1a进行了对比，两项研究的主要终点均为年复发率，其中一项研究的评估时间在研究开始1年后，另一项则在研究开始2年后。在两项研究中，与安慰剂或干扰素β-1a相比，盐酸芬戈莫德在两种给药剂量下均能使患者的复发率显著降低，并减缓患者肢体残疾的病程进展速度。 本品在美国上市剂型为胶囊剂，规格为0.5mg。另外，盐酸芬戈莫德作为免疫抑制剂在肾移植后的应用的III期临床研究正在国外进行中。 

Indication(s):

For relapsing forms of multiple sclerosis (MS): to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

Pharmacology:

Fingolimod blocks lymphocytes from leaving lymph nodes, reducing the numbers of circulating lymphocytes. The exact mechanism for its ­effects on MS is not known, but it may involve the reduction of lymphocyte migration in the CNS.

Clinical Trials:

Two studies were conducted to assess the safety and efficacy of fingolimod in treating ­patients with relapsing remitting MS. Study 1 was a placebo-controlled study in patients who had not ­received ­interferon-beta or glatiramer acetate for at least the previous 3 months and had not received ­natalizumab for at least the previous 6 months. The primary endpoint was the annualized relapse rate. At randomization, patients had an Expanded Disability Status Score (EDSS) ranging from 0–5.5 (median 2.0). Patients given fingolimod 0.5mg daily had an annualized response rate of 0.18, compared to 0.4 for those given placebo. Seventy ­percent of patients in the fingolimod 0.5mg group were relapse-free, compared to 46% for placebo. The 1.25mg dose did not show any additional benefit.

Study 2 was a double-dummy, active-controlled study in patients who had not received any natalizumab in the previous 6 months; prior therapy with glatiramer acetate or interferon-beta was permitted up to the time of randomization. The median baseline EDSS score was 2.0. Patients were randomized to fingolimod 0.5mg/day, fingolimod 1.25mg/day, or interferon ­beta-1a 30mcg IM once weekly for up to 12 months. The annualized relapse rate for patients given fingolimod 0.5mg/day was 0.16, compared to 0.33 for those given interferon. Eighty-three percent of those on fingolimod 0.5mg were relapse-free, compared to 70% of those on interferon. There was no additional benefit seen with fingolimod dosed at 1.25mg daily. A secondary endpoint, the number of new or enlarging T2 lesions seen on MRI, showed an advantage for fingolimod as well.

Legal Classification:

Rx

Adults:

≥18years: 0.5mg once daily. Monitor 1^st dose (6 hours).

Children:

<18years: not recommended.

Warnings/Precautions:

Active acute or chronic ­infection: do not start treatment until infection ­resolved. Obtain recent CBC before starting treatment. Consider suspending therapy if serious infection ­develops; monitor for infections during treatment and for 2 months after discontinuation. Test for antibodies to varicella zoster virus; consider immunization before starting fingolimod. Immunosuppressed. Cardiac risk factors: monitor for bradycardia for 6 hours after 1^st dose; consider baseline ECG. Bradycardia (<55bpm). History of syncope. Sick ­sinus syndrome. 2^nd or 3^rd degree heart block. Cardiac ischemia. CHF. QT prolongation. Arrhythmias. Diabetes, history of uveitis: increased risk of macular edema. Monitor visual acuity and for visual disturbances. Do ophthalmic exam at baseline, and at 3–4 months after starting therapy. Recent LFTs (eg, within 6 months) should be available; monitor; discontinue if liver injury occurs. Respiratory dysfunc­tion. Renal or severe hepatic ­impairment. Pregnancy (Cat.C) (use effective contraception ­during and for 2 months after discontinuation), nursing mothers: not recommended.

Interaction(s):

Potentiated by ketoconazole. Class Ia (eg, quinidine, procainamide) or Class III anti­arrhythmics (eg, amiodarone, sotalol), β-blockers, calcium channel blockers: increased risk of bradycardia. Avoid live virus vaccines during treatment and for 2 months after discontinuing fingolimod; may have suboptimal response. Caution with antineo­plastic, immunosuppressant or immunomodulating therapies: increased risk of immunosuppression.

Adverse Reaction(s):

Headache, influenza, diarrhea, back pain, increased liver transaminases, cough, ­hypertension; transient decreased heart rate and AV conduction, increased infection risk, macular edema, decreased pulmonary function.

How Supplied:

Caps—7, 28

Last Updated:

8/12/2011