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2012年5月14日，美国食品药品监督管理局(FDA)已完成一项多发性硬化症(MS)药物芬戈莫德[fingolimod](Gilenya)首次剂量 后死亡的患者报告的评价。管理局还评价了芬戈莫德的另外临床试验和上市后数据，包括死于心血管事件或未知原因患者的报告。FDA未能确定性结论芬戈莫德与任何死亡相关。
但是，根据其数据的再评价，FDA保持关注芬戈莫德首次剂量后的心血管作用。数据显示，虽然芬戈莫德的最大降低心率作用通常发生在首次剂量的6小时内，有些患者中最大效应可能发生晚至首次剂量后20小时。
因为这个理由，现在某些预先存在或最近(过去6个月内)心脏情况或卒中，或正在服用某些抗心律失常药患者禁忌使用芬戈莫德.
FDA继续建议开始使用芬戈莫德所有患者首次剂量后监视心动过缓的体征至少6小时。FDA现建议对开始用芬戈莫德所有患者每小时测量脉搏和血压。给药前和观察期结束应进行心电图(ECG或EKG) 测试。心血管监视应继续直至任何症状解决。
此外，FDA现在还建议过去6小时处于较高风险或不能耐受心动过缓患者心血管监视时间扩展包括连续过夜ECG监视，这些较高风险患者包括如下：
（1）芬戈莫德首次剂量给药后发生心动过缓
（2）某些预先存在情况其心动过缓可能耐受很差
（3）接受减慢心率或房室传导其它药物治疗
（4）芬戈莫德开始前，或心血管监视期任何时间QT间期延长
（5）接受延长QT间期和引起尖端扭转型室性心动过速其它药物治疗
Gilenya (Fingolimod Hydrochloride)-Indications and Dosage
INDICATIONS AND USAGE
GILENYA is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.
DOSAGE AND ADMINISTRATION
Recommended Dose
The recommended dose of GILENYA is 0.5 mg orally once daily. Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit. GILENYA can be taken with or without food.
First Dose Monitoring
Initiation of GILENYA treatment results in a decrease in heart rate [ see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ]. After the first dose of GILENYA, the heart rate decrease starts within an hour and the Day 1 nadir generally occurs within approximately 6 hours, although the nadir can be observed up to 24 hours after the first dose in some patients.
The first dose of GILENYA should be administered in a setting in which resources to appropriately manage symptomatic bradycardia are available. In order to assess patient response to the first dose of fingolimod, observe all patients for 6 hours for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain in all patients an electrocardiogram prior to dosing, and at the end of the observation period.
Additional observation should be instituted until the finding has resolved in the following situations:
The heart rate 6 hours post-dose is <45 bpm
The heart rate 6 hours post-dose is at the lowest value post-dose (suggesting that the maximum pharmacodynamic effect on the heart may not have occurred)
The ECG 6-hours post-dose shows new onset second degree or higher AV block
Should post-dose symptomatic bradycardia occur, initiate appropriate management, begin continuous ECG monitoring, and continue observation until the symptoms have resolved.
Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous overnight ECG monitoring in a medical facility should be instituted, and the first dose monitoring strategy should be repeated after the second dose of GILENYA.
Patients with some pre-existing conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, sino-atrial heart block) may poorly tolerate the GILENYA-induced bradycardia, or experience serious rhythm disturbances after the first dose of GILENYA. Prior to treatment with GILENYA, these patients should have a cardiac evaluation by a physician appropriately trained to conduct such evaluation, and, if treated with GILENYA, should be monitored overnight with continuous ECG in a medical facility after the first dose. GILENYA is contraindicated in patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization or Class III/IV heart failure) [ see Contraindications (4) ].
Since initiation of GILENYA treatment results in decreased heart rate and may prolong the QT interval, patients with a prolonged QTc interval (>450 msec males, >470 msec females) before dosing or during 6 hour observation, or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome), or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility [ see Drug Interactions (7) ].
Experience with GILENYA is limited in patients receiving concurrent therapy with drugs that slow heart rate or atrioventricular conduction (e.g., beta blockers, heart-rate lowering calcium channel blockers such as diltiazem or verapamil, or digoxin). Because the initiation of GILENYA treatment is also associated with slowing of the heart rate, concomitant use of these drugs during GILENYA initiation may be associated with severe bradycardia or heart block. The possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction should be evaluated by the physician prescribing these drugs before initiating GILENYA. In patients who cannot switch, overnight continuous ECG monitoring after the first dose is recommended [ see Drug Interactions (7) ].
Clinical data indicate effects of GILENYA on heart rate are maximal after the first dose although milder effects on heart rate may persist for, on average, 2-4 weeks after initiation of therapy at which time heart rate generally returns to baseline. Physicians should continue to be alert to patient reports of cardiac symptoms.
Re-initiation of Therapy Following Discontinuation
If GILENYA therapy is discontinued for more than 14 days, after the first month of treatment, the effects on heart rate and AV conduction may recur on reintroduction of GILENYA treatment and the same precautions (first dose monitoring) as for initial dosing should apply. Within the first 2 weeks of treatment, first dose procedures are recommended after interruption of one day or more, during week 3 and 4 of treatment first dose procedures are recommended after treatment interruption of more than 7 days.
DOSAGE FORMS AND STRENGTHS
GILENYA is available as 0.5 mg hard capsules with a white opaque body and bright yellow cap imprinted with "FTY 0.5 mg" on the cap and two radial bands imprinted on the capsule body with yellow ink.
HOW SUPPLIED/STORAGE AND HANDLING
0.5 mg GILENYA capsules are hard gelatin capsules with a white opaque body and bright yellow cap imprinted with "FTY 0.5 mg" on the cap and two radial bands imprinted on the capsule body with yellow ink.
GILENYA capsules are supplied in blister packs.
Carton of 28 capsules containing 2 folded blister cards of 14 capsules per blister card NDC 0078-0607-51
Carton of 7 capsules containing 1 blister card of 7 capsules per blister card NDC 0078-0607-89
GILENYA capsules should be stored at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF). Protect from moisture.
欧洲委员会批准诺华口服药物芬戈莫德(fingolimod，Gilenya)
近日，欧洲委员会已经批准诺华口服药物芬戈莫德(fingolimod，Gilenya)作为改变多发性硬化症（MS）疾病病程药物用于接受β干扰素治疗后的高活性复发-缓解型多发性硬化症患者，或病情发展迅速的患者。Gilenya获批实属意料之中，早在两个月以前它就获得了欧洲药品管理局下属人用医疗产品委员会的正面肯定。
相比2010年九月份美国食品和药物管理局（FDA）对Gilenya批准的适用范围，欧洲的批准要受限得多，但是这次获批助推了诺华在口服MS市场前进的更远。Gilenya主要对手——默克公司克拉屈滨片(cladribine，Movectro)的申请在2011年4月早些时候遭到FDA拒绝，而在2月的时候，默克主动撤回了Movectro在欧洲的药品上市许可申请。
Gilenya，由三菱田边制药公司（MitsubishiTanabe）授权诺华，是名为神经鞘氨醇1-磷酸受体调节剂的新类药物的首个获批产品。
Manufacturer:
Novartis Pharmaceuticals Corp
Pharmacological Class:
Sphingosine 1-phosphate ­receptor modulator.
Active Ingredient(s):
Fingolimod (as HCl) 0.5mg; caps.
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 shy;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 3months 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 1st 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 1st dose; consider baseline ECG. Bradycardia (<55bpm). History of syncope. Sick ­sinus syndrome. 2nd or 3rd 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
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