药品简介

药物名称：芬戈莫德（Gilenya） 
适应症：多发性硬化症 
简要说明：Gilenya可以阻止淋巴腺中的部分血细胞向大脑和脊髓移动，降低多发性硬化症患者疾病复发的频率，从而延缓多发性硬化症患者的病情恶化程度。作为多发性硬化症的首个口服药物，。 

药理作用： 
芬戈莫德块淋巴细胞离开淋巴结肿大，外周血淋巴细胞的数量减少。在MS的影响的确切机制尚不清楚，但它可能涉及中枢神经系统的淋巴细胞迁移减少。 

不良反应： 
头痛，感冒，腹泻，腰痛，增加肝转氨酶，咳嗽，高血压;瞬态降低心率和房室传导，增加感染的风险，黄斑水肿，肺功能下降。 

美国食品和药物管理局（FDA）批准诺华制药公司（Novartis）生产的新型多发性硬化症的治疗药物—Gilenya(盐酸芬戈莫德)上市销售。盐酸芬戈莫德是世界上第一个治疗多发性硬化症的药丸性药物。 

盐酸芬戈莫德适用于复发性多发性硬化症患者(MS)的治疗减少临床加重频数和延缓身体残疾积蓄。推荐剂量为0.5 mg口服每天1次。首次剂量后应观察患者6小时以监查心动过缓的征象和症状。芬戈莫德剂量较高于0.5 mg是伴随更高不良反应发生率而效益没有增加。 

芬戈莫德是一种鞘氨醇1-磷酸受体(S1PR)调节剂。药理研究证实，芬戈莫德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称，芬戈莫德这种药理作用过程是可逆的，如果停止用药，循环中的淋巴细胞水平就会恢复正常。 

多发性硬化症是一种使人衰弱的神经系统疾病，可能导致病人失去平衡感，出现肌肉痉挛和其他运动功能障碍，该疾病一直以来都用注射性药物进行治疗。该疾病还没有治愈的案例，但类固醇药物能在短期内减少病情的持续时间和症状的严重程度，在市场上的已经有7种药物能够成功减少症状的复发。但是，这些药物都需要每日或定期注射，给患者用药带来极大的不便。 

临床II期试验数据显示，在试验的前六个月当中，每天服用一次盐酸芬戈莫德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，继续服用盐酸芬戈莫德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盐酸芬戈莫德的病人身上。 

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，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。 

多发性硬化症是目前医学上公认的难治性疾病，现行一线治疗多发性硬化的药物，只能减少复发率30%左右。盐酸芬戈莫德的出现，打破了现行一线治疗多发性硬化的药物全是注射剂的局面，给患者自行用药带来了极大的方便，更有利于患者长期治疗，并能提高疗效，更好改善患者症状，提高生活质量，为是人类治疗多发性硬化历史上的一个新的里程碑

リンパ球に作用し、リンパ節などの二次リンパ組織から、自分の神経を攻撃する自己反応性T細胞を含むリンパ球が出ていくのを抑えることにより、神経の炎症を抑えます。
通常、多発性硬化症の再発予防および身体的障害の進行抑制に用いられます。

以前に薬を使用して、かゆみ、発疹などのアレルギー症状が出たことがある。感染症、第II度以上の房室ブロック、洞不全症候群、虚血性心疾患、うっ血性心不全、心拍数が低い、黄斑浮腫、糖尿病、ブドウ膜炎の既往歴、肝機能障害またはその既往歴がある。水痘・帯状疱疹にかかったことがなく、予防接種を受けていない。

妊娠中、妊娠している可能性がある、授乳中

他に薬などを使っている（お互いに作用を強めたり、弱めたりする可能性もありますので、他に使用中の一般用医薬品や食品も含めて注意してください）。

通常、成人は1回1カプセル（フィンゴリモドとして0.5mg）を1日1回服用します。必ず指示された服用方法に従ってください。

最初に飲む前と最初に飲んでから6時間後に心電図が測定されます。また最初に飲んでから24時間は、心拍数、血圧が測定され、心電図が連続的に観察されることがあります。徐脈性不整脈の症状（浮動性めまい、疲労、動悸など）があらわれたら、すぐに医師に相談してください。

飲み忘れた場合は、気がついた時にできるだけ早く飲んでください。ただし、次に飲む時間が近い場合は、忘れた分は飲まないで1回分を飛ばしてください。絶対に2回分を一度に飲んではいけません。

誤って多く飲んだ場合は医師または薬剤師に相談してください。

医師の指示なしに、自分の判断で飲むのを止めないでください。飲むのを止めて、再び飲み始める場合は、医師に相談してください。

主な副作用として、鼻咽頭炎、徐脈、頭痛などが報告されています。このような症状に気づいたら、担当の医師または薬剤師に相談してください。

まれに下記のような症状があらわれ、[　]内に示した副作用の初期症状である可能性があります。
このような場合には、使用をやめて、すぐに医師の診療を受けてください。

・けん怠感、発熱 [感染症]

・浮動性めまい、疲労、動悸 [徐脈性不整脈（徐脈、房室ブロックなど）]

・霧視、視力の低下 [黄斑浮腫]

・全身のリンパ節のはれ、発熱、体重減少 [悪性リンパ腫]

・意識障害、けいれん、視力障害 [可逆性後白質脳症症候群]

以上の副作用はすべてを記載したものではありません。上記以外でも気になる症状が出た場合は、医師または薬剤師に相談してください。

乳幼児、小児の手の届かないところで、直射日光、高温、湿気、凍結を避けて25℃以下で保管してください。

薬が残った場合、保管しないで廃棄してください。廃棄については、受け取った薬局や医療機関に相談してください。

Pronunciation

(fin GOL i mod)

Index Terms

Fingolimod HCl

FTY720

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Gilenya: 0.5 mg

Brand Names: U.S.GilenyaPharmacologic CategorySphingosine 1-Phosphate (S1P) Receptor ModulatorPharmacology

Fingolimod-phosphate, active metabolite of fingolimod, binds to sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the lymphocytes' ability to emerge from lymph nodes; therefore, the amount of lymphocytes available to the central nervous system is decreased, which reduces central inflammation.

Distribution

Vd: ~1,200 L: distributes into red blood cells (86%)

Metabolism

Hepatic via CYP4F2 to fingolimod-phosphate (active) and other metabolites (inactive); CYP2D6, 2E1, 3A4, and 4F12 also contribute to metabolism

Excretion

Urine (~81% as inactive metabolites); feces (fingolimod and fingolimod phosphate: <2.5% of dose)

Time to Peak

Plasma: 12 to 16 hours

Half-Life Elimination

6 to 9 days; prolonged by approximately 50% in patients with moderate or severe hepatic impairment

Protein Binding

>99.7% (fingolimod and fingolimod-phosphate)

Special Populations: Renal Function Impairment

Fingolimod Cmax and AUC are increased by 32% and 43%, respectively, and by 25% and 14%, respectively, for fingolimod-phosphate in patients with severe renal impairment.

Special Populations: Hepatic Function Impairment

Fingolimod area under the curve (AUC) increased by 12%, 44%, and 103% in patients with mild, moderate, or severe hepatic impairment, respectively. Fingolimod-phosphate maximal drug concentration (Cmax) was decreased by 22% in patients with severe hepatic impairment.

Use: Labeled Indications

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

Contraindications

Hypersensitivity to fingolimod (including rash, urticaria, and angioedema) or any component of the formulation; MI, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or New York Heart Association (NYHA) class III/IV heart failure in the past 6 months; Mobitz Type II second- or third-degree atrioventricular (AV) block or sick sinus syndrome (unless patient has a functioning pacemaker); baseline QTc interval ≥500 msec; concurrent use of a class Ia or III antiarrhythmic.

Canadian labeling: Additional contraindications (not in US labeling): Patients at increased risk for opportunistic infections, including those who are immunocompromised due to treatment (eg, antineoplastic, immunosuppressive or immunomodulating therapies, total lymphoid irradiation or bone marrow transplantation) or disease (eg, immunodeficiency syndrome); severe active infections including active chronic bacterial, fungal or viral infections (eg, hepatitis, tuberculosis); known active malignancy (excluding basal cell carcinoma); severe hepatic impairment (Child-Pugh class C)

Dosing: Adult

Multiple sclerosis: Oral: 0.5 mg once daily; doses >0.5 mg daily are associated with increased adverse events and no additional benefit. Note: The first dose and doses following therapy interruption (longer than 14 days) should be administered in a setting in which resources to appropriately manage symptomatic bradycardia are available.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution in severe renal impairment (exposure is increased). A small pharmacokinetic study in patients with stable severe impairment (CrCl <30 mL/minute) and not on dialysis suggests that increases in exposure to fingolimod and the active metabolite (fingolimod-P) are not clinically meaningful and dosage adjustment may not be necessary (David 2015).

Dosing: Hepatic Impairment

Mild to moderate impairment (Child-Pugh classes A and B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling; use with caution and closely monitor; exposure is doubled in severe hepatic impairment.

Administration

Administer with or without food.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from moisture.

Drug Interactions

Antiarrhythmic Agents (Class Ia): Fingolimod may enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class Ia). Avoid combination

Antiarrhythmic Agents (Class III): Fingolimod may enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class III). Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Beta-Blockers: May enhance the bradycardic effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and beta-blockers if possible. If coadministration is necessary, patients should have overnight continuous ECG monitoring conducted after the first dose of fingolimod. Monitor patients for bradycardia. Consider therapy modification

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents.Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Fingolimod. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

DilTIAZem: May enhance the bradycardic effect of Fingolimod. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Esmolol: May enhance the bradycardic effect of Fingolimod. Avoid combination

Immunosuppressants: May enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Ketoconazole (Systemic): May increase serum concentrations of the active metabolite(s) of Fingolimod. Ketoconazole (Systemic) may increase the serum concentration of Fingolimod. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

QTc-Prolonging Agents (Moderate Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Fingolimod may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting fingolimod. If vaccinated during fingolimod therapy, revaccinate 2 to 3 months after fingolimod discontinuation. Consider therapy modification

Vaccines (Live): Fingolimod may enhance the adverse/toxic effect of Vaccines (Live). Vaccinal infections may develop. Fingolimod may diminish the therapeutic effect of Vaccines (Live). Avoid combination

Verapamil: May enhance the bradycardic effect of Fingolimod. Monitor therapy

Zoster Vaccine (Live/Attenuated): Fingolimod may enhance the adverse/toxic effect of Zoster Vaccine (Live/Attenuated). The risk of herpes zoster infection may be increased. Fingolimod may diminish the therapeutic effect of Zoster Vaccine (Live/Attenuated). Management: Wait 1 month after zoster vaccine administration to initiate fingolimod therapy. Avoid the use of the zoster vaccine during fingolimod treatment, and for 2 months following treatment discontinuation. Consider therapy modification

Adverse Reactions

>10%:

Central nervous system: Headache (25%)

Endocrine & metabolic: Increased gamma-glutamyl transfer (5% to ≤15%)

Gastrointestinal: Nausea (13%), diarrhea (12% to 13%), abdominal pain (11%)

Hepatic: Increased serum ALT (14% to ≤15%), increased serum AST (14% to ≤15%)

Infection: Influenza (11% to 13%)

Neuromuscular & skeletal: Back pain (10% to 12%)

Respiratory: Cough (10% to 12%), sinusitis (7% to 11%)

1% to 10%:

Cardiovascular: Hypertension (6% to 8%), atrioventricular block (first degree: 5%; second degree: 4%; third degree: ≤1%), bradycardia (≤4%)

Central nervous system: Depression (8%), dizziness (7%), migraine (5% to 6%), paresthesia (5%)

Dermatologic: Alopecia (3% to 4%), tinea (2% to 4%), eczema (3%), pruritus (3%), actinic keratosis (2%)

Endocrine & metabolic: Weight loss (5%), increased serum triglycerides (3%)

Gastrointestinal: Gastroenteritis (5%)

Hematologic & oncologic: Lymphocytopenia (4% to 7%), cutaneous papilloma (3%), leukopenia (2% to 3%), basal cell carcinoma (2%)

Neuromuscular & skeletal: Leg pain (≤10%), upper extremity pain (≤10%), weakness (2% to 3%)

Ophthalmic: Blurred vision (4%), eye pain (3%)

Respiratory: Dyspnea (8% to 9%), bronchitis (8%)

Miscellaneous: Herpes virus infection (9%), herpes zoster (2%)

<1% (Limited to important or life-threatening): Angiodema, asystole, cerebrovascular accident (ischemic and hemorrhagic), cholestatic hepatitis, hepatocellular hepatitis, macular edema, malignant lymphoma (including B-cell and T-cell), multiorgan failure, non-Hodgkin's lymphoma, peripheral arterial disease, pneumonia, progressive multifocal leukoencephalopathy (FDA Safety Alert, Aug 4, 2015), prolonged Q-T interval on ECG, reversible posterior leukoencephalopathy syndrome, skin rash, syncope

Warnings/Precautions

Concerns related to adverse reactions:

• Atrioventricular (AV) block: May result in transient and asymptomatic AV conduction delays, which typically resolve within 24 hours of treatment initiation; recurrence may be observed following discontinuation and subsequent reinitiation of therapy. Third-degree AV block and AV block with junctional escape occurred within the first 6 hours of the initial dose, and transient asystole and unexplained death have occurred within the first 24 hours; syncope has also occurred.

• Bradycardia: Initiation must occur in a setting with resources and personnel capable of appropriately managing symptomatic bradycardia. Following the first dose, heart rate may decrease as soon as 1 hour postdose, with the maximal decrease usually occurring ~6 hours postdose with recovery (but not to baseline levels) 8 to 10 hours postdose. A second heart rate decrease occurs within 24 hours after the first dose and may be more pronounced than the first 6-hour rate decrease. Most patients are asymptomatic; however, hypotension, dizziness, fatigue, palpitations, and/or chest pain may occur; symptoms usually resolve within 24 hours. With the second dose, heart rate may also decrease, but to a lesser magnitude than observed with the first dose. Heart rate typically returns to baseline after 1 month of chronic therapy.

• Cryptococcal infections: Cases of cryptococcal meningitis and disseminated cryptococcal infections have been reported. Cryptococcal infections have generally occurred after ~2 years of treatment, although may occur earlier (relationship between risk and duration of treatment is unknown). Patients with signs and symptoms of cryptococcal infections should undergo prompt diagnostic evaluation and treatment.

• Hepatic effects: Elevated liver enzymes may occur; most elevations occurred within 6 to 9 months. Recurrence of liver transaminase elevations may occur with rechallenge. Liver injury with hepatocellular and/or cholestatic hepatitis has been reported. Obtain baseline liver enzymes and bilirubin in all patients prior to therapy initiation (within 6 months); monitor liver enzymes in patients who develop symptoms of hepatic dysfunction (eg, nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine). Discontinue treatment with confirmation of liver injury; transaminases tend to return to normal within 2 months of discontinuation.

• Herpes infection: Serious, life-threatening herpes infections, including fatalities (eg, disseminated primary herpes zoster and herpes simplex encephalitis) have occurred. Consider disseminated herpes infections as an etiology if an atypical MS relapse or multiorgan failure occurs. Consider varicella zoster virus vaccination prior to initiation of treatment in patients without a health care professional-confirmed history of chickenpox, without a documented full course of varicella zoster vaccination, and patients who are VZV antibody negative; postpone fingolimod treatment for 1 month after varicella zoster vaccination. Cases of Kaposi sarcoma (associated with human herpes virus-8) have been reported; if suspected, prompt diagnostic evaluation and management is required.

• Hypersensitivity reaction: Hypersensitivity reactions, including rash, urticaria, and angioedema upon treatment initiation, have been reported.

• Hypertension: Increased blood pressure may occur ~1 month after initiation of therapy; monitor blood pressure throughout treatment.

• Immune suppression: May increase risk of infection (including serious infections) with opportunistic pathogens including viruses (eg, John Cunningham virus [JCV], herpes simplex virus 1 and 2, varicella-zoster virus), fungi (eg, cryptococci), and bacteria (eg, atypical mycobacteria), due to reversible dose-dependent reduction of lymphocytes. Lymphocyte counts may be decreased for up to 2 months following discontinuation of therapy. Obtain a complete blood cell count (CBC) (within 6 months or after discontinuation of prior therapy) before starting therapy. Monitor for signs and symptoms of infection; consider therapy interruption in patients who develop a serious infection; reassess benefits and risks prior to reinitiation of therapy. Do not initiate treatment in patients with acute or chronic infections until the infection has resolved. Use with caution in patients receiving concomitant immunosuppressant, immune modulating, or antineoplastic medications, or when switching from other immunosuppressants (consider the duration and mode of action for each substance to avoid additive effects). Patients with low lymphocyte counts at baseline and underweight females (BMI <18.5 kg/m2) are at higher risk for developing severe lymphopenia and should be monitored more closely (Warnke 2014).

• Macular edema: Macular edema may occur, typically within the first 6 months of treatment. Patients may present with blurred vision, decreased visual acuity, or without symptoms. Signs and symptoms generally improve or resolve with discontinuation of treatment; however, residual decreased visual acuity has occurred in some patients. Patients with a history of diabetes mellitus or uveitis are at increased risk; use with caution. Ophthalmologic exams (including the fundus and macula) should be performed prior to therapy, 3 to 4 months after treatment initiation, and anytime visual disturbances are reported; more frequent examination is warranted in patients with diabetes or a history of uveitis.

• Malignancy: Cases of lymphoma and skin cancers have been reported. Basal cell carcinoma is associated with fingolimod use; monitor for suspicious skin lesions. Promptly evaluate any suspicious skin lesion.

• Neurotoxicity: Posterior reversible encephalopathy syndrome (PRES) has been observed. Monitor for signs/symptoms of PRES (eg, sudden onset of severe headache, altered mental status, visual disturbances, seizure); symptoms are usually reversible, but may evolve into ischemic stroke or cerebral hemorrhage. Delayed diagnosis and treatment may result in permanent neurological sequelae. Discontinue use if PRES is suspected.

• Progressive multifocal leukoencephalopathy: Cases of progressive multifocal leukoencephalopathy (PML) due to the JC virus have been reported, including cases in patients who were not immunocompromised and had no prior exposure to immunosuppressant drugs, including natalizumab. PML cases occurred in patient treated with fingolimod for at least 2 years (relationship between risk and duration of treatment is unknown). At the first sign or symptom suggestive of PML, perform a diagnostic evaluation (MRI findings may appear before clinical signs/symptoms) and withhold therapy; symptoms progress over days to weeks and may include progressive weakness on one side of the body or clumsiness of limbs; vision disturbances; mental status changes.

• Respiratory effects: Reductions of forced expiratory volume in the first second of expiration (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) are dose dependent and may occur within the first month of therapy. FEV1 changes may be reversible with drug discontinuation. Use in multiple sclerosis (MS) patients with compromised respiratory function has not been evaluated. If clinically necessary, spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy.

• QT prolongation: May cause QT prolongation; patients with a prolonged QT interval at baseline (males: >450 msec; females: >470 msec) or during the first 6 hours of treatment initiation, or are at an increased risk of QT prolongation (eg, hypokalemia, hypomagnesemia, concomitant QT-prolonging drugs, congenital long-QT syndrome) require continuous overnight electrocardiogram (ECG) monitoring in a medical facility after the initial dose.

Disease-related concerns:

• Cardiovascular: Due to the risk of bradycardia and AV conduction delays, an ECG is required prior to initiation of therapy and after the initial observation period (6 hours) in all patients. Patients receiving concomitant therapy with drugs that slow heart rate or AV conduction (eg, beta-blockers, heart rate-lowering calcium channel blockers, digoxin) or with other cardiac risk factors (eg, AV block, sick sinus syndrome, prolonged QT interval, ischemic cardiac disease, history of myocardial infarction [MI], symptomatic bradycardia and/or cardiac arrest, heart failure, cerebrovascular disease, uncontrolled hypertension, recurrent syncope, severe sleep apnea [untreated]) require continuous overnight ECG monitoring in a medical facility after the first dose.

• Hepatic impairment: Use with caution and closely monitor patients with severe hepatic impairment. Use caution in patients with preexisting liver disease; may be at increased risk of increased liver enzymes.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings and precautions:

• Discontinuation of therapy: Cases of rebound syndrome (clinical and radiological signs of severe exacerbation beyond what was expected) have been reported; may occur within 4 to 16 weeks of stopping fingolimod treatment in patients with multiple sclerosis of varying severity and duration. In some cases, relapses have occurred despite the initiation of other disease-modifying therapies. Rebound symptoms have included back and extremity pain, confusion, constipation, diplopia, facial muscle spasms, fatigue, increased leg weakness, nausea paraparesis and paresthesias (Hatcher 2016; Willis 2016).

Monitoring Parameters

Complete blood cell count (CBC) including lymphocyte count (baseline [within 6 months of initiation] and periodically thereafter).

Hepatic monitoring: Baseline bilirubin and transaminase levels in all patients prior to therapy initiation (within 6 months) and periodically thereafter; monitor transaminases in patients who develop symptoms of hepatic dysfunction.

ECG (baseline; repeat after initial dose observation period); heart rate, blood pressure, and signs and symptoms of bradycardia (hourly for 6 hours following first dose; continued observation (until resolved) required if 6-hour postdose heart rate is <45 bpm, is lowest postbaseline measurement, or new-onset second degree or higher AV block occurs on repeat ECG); continuous (until symptoms resolved) ECG monitoring if postdose symptomatic bradycardia occurs (overnight continuous ECG in a medical facility and repeat observation period for second dose if pharmacologic intervention for bradycardia necessary); overnight continuous ECG monitoring in a medical facility if baseline or 6-hour post dose QT interval is prolonged [>450 msec (men), >470 msec (females)] or additional risks for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long-QT syndrome) or concurrent therapy with QT prolonging agents with a known risk of torsades de pointes.

Initial monitoring procedures (ECG, heart rate, blood pressure) must be repeated for

- treatment interruption of ≥1 day during the first 2 weeks after treatment initiation, or

- treatment interruption of >7 days during weeks 3 to 4 after treatment initiation, or

- treatment interruption of >14 days after ≥1 month of treatment initiation

Ophthalmologic exam at baseline and 3 to 4 months after initiation of treatment (continue periodic examinations for duration of therapy in patients with diabetes, history of uveitis, or visual complaints); respiratory function (FEV1, DLCO) if clinically indicated; VZV antibodies (patients with no health care professional–confirmed history of chickenpox or without documented previous full series VZV vaccination); signs and symptoms of infection (during treatment and at least 2 months after discontinuation), progressive multifocal leukoencephalopathy, and/or posterior reversible encephalopathy syndrome; monitor for suspicious skin lesions

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Elimination of fingolimod takes approximately 2 months; to avoid potential fetal harm, women of childbearing potential should use effective contraception to avoid pregnancy during and for 2 months after discontinuing treatment. Health care providers are encouraged to enroll pregnant women, or pregnant women may enroll themselves, in the Gilenya Pregnancy Registry (1-877-598-7237 or https://www.gilenyapregnancyregistry.com).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, flu-like symptoms, painful extremities, sinusitis, abdominal pain, diarrhea, or back pain. Have patient report immediately to prescriber signs of infection, signs of meningitis (headache with fever, stiff neck, nausea, confusion, or sensitivity to light), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), dizziness, bradycardia, abnormal heartbeat, fatigue, angina, mole changes, skin growth, passing out, wound healing impairment, excessive weight loss, night sweats, enlarged lymph nodes, shortness of breath, difficulty breathing, vision changes, eye pain, severe eye irritation, burning or numbness feeling, signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), or signs of progressive multifocal leukoencephalopathy (confusion, depression, memory impairment, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.