捷灵亚®（盐酸芬戈莫德胶囊）简短处方信息

剂型规格：

胶囊剂。0.5mg盐酸芬戈莫德胶囊（以芬戈莫德计）

适应症：

本品用于10岁及以上患者复发型多发性硬化（RMS）的治疗。

用法用量：

成人和10岁及以上且体重超过40kg的儿童患者：

推荐剂量为每日一次，口服0.5mg。

禁忌：

♦免疫缺陷综合征患者。♦机会性感染风险升高的患者，包括免疫抑制患者（目前接受免疫抑制治疗或由于既往治疗导致的免疫抑制患者）。♦重度活动性感染、活动性慢性感染（肝炎、肺结核）。♦活动性恶性肿瘤患者。♦重度肝损伤（Child-Pugh C级）。♦近6个月罹患心肌梗死、不稳定性心绞痛、卒中/短暂性脑缺血发作、失代偿性心力衰竭（需住院治疗）或纽约心脏协会（NYHA）III级/IV级心力衰竭的患者（见【注意事项】）。♦需服用Ia或III类抗心律失常药物进行抗心律失常治疗的严重心律失常患者（见【注意事项】）。♦II度莫氏II型房室（AV）传导阻滞或III度房室传导阻滞，或未植入起搏器的病窦综合征患者（见【注意事项】）。♦基线QTc间期≥500 msec的患者（见【注意事项】）。♦已知对芬戈莫德或对任何辅料过敏者。

注意事项：

♦开始盐酸芬戈莫德治疗时，建议对所有患者进行观察，包括每小时测量一次脉搏和血压，连续6小时实时ECG监测和心动过缓症状、体征的监测。若发生给药后心动过缓相关症状，则应该进行相关临床管理，并继续监测，直至症状缓解为止。若患者在首次给药监测期间需要临床干预，则应在医疗机构整夜监测，在盐酸芬戈莫德第2次给药后应重复首次给药监测。若首次给药结束6小时心率为最低水平（提示对于心脏的最大药理学效应可能尚未出现），则监测应至少延长2小时，直至心率再次升高为止。此外，若在6小时后，成人心率＜45 bpm、12岁及12岁以上儿科患者心率＜55 bpm、或10至12岁以下儿科患者心率＜60 bpm、或ECG提示新发II度房室传导阻滞或QTc间期 ≥500 msec，则需要延长监测（至少整夜监测），直至这些症状缓解为止。不管在任何时间点发生III度房室传导阻滞均应延长监测（至少整夜监测）。

♦鉴于开始盐酸芬戈莫德治疗导致心率下降且QT间期延长，因此，有显著QT延长（成年女性QTc >470 msec，女性儿童QTc >460msec或成年男性或男性儿童>450msec）的患者不应使用盐酸芬戈莫德。有QT间期延长相关风险因素（例如，低血钾、低血镁或先天性QT间期延长）的患者应尽量避免使用盐酸芬戈莫德。鉴于有心脏停搏、未控制的高血压或重度未经治疗的睡眠呼吸暂停病史的患者可能对重度心动过缓耐受不良，上述患者不应使用盐酸芬戈莫德。至于此类患者，只有在预期获益大于潜在风险，并咨询心脏科医生的意见，确定了最适当的监测方案后，方可考虑使用盐酸芬戈莫德。至少在治疗启动后进行整夜延长监测。

♦合并接受β受体阻滞剂，降低心率的钙通道阻滞剂（如维拉帕米或地尔硫卓）和其他可能降低心率的药物（如伊伐布雷定或地高辛）治疗的患者使用盐酸芬戈莫德的经验有限。由于开始盐酸芬戈莫德治疗也会导致心率减慢，开始使用盐酸芬戈莫德期间同时使用这些药物可能会引起严重的心动过缓和心脏传导阻滞。由于对心率的潜在累积效应，一般不应对同时需接受这些药物治疗的患者开始盐酸芬戈莫德治疗。如果考虑需用盐酸芬戈莫德治疗，应寻求心脏病专家有关改用非降低心率药物的建议或治疗起始阶段给予适当的监测（应整夜监测）。

♦感染：在启动盐酸芬戈莫德治疗之前，应采集近期全血细胞计数（CBC）（即6个月内或既往治疗停止后）。重度活动性感染患者在感染未痊愈之前严禁启动盐酸芬戈莫德治疗。盐酸芬戈莫德治疗前，需评估患者对水痘的免疫力。在开始盐酸芬戈莫德治疗前，建议没有经医疗专业确诊水痘病史或水痘疫苗全程接种记录的患者接受水痘-带状疱疹病毒（VZV）抗体检测。开始盐酸芬戈莫德治疗前，建议水痘疫苗抗体阴性患者进行全程接种。应延期1个月开始盐酸芬戈莫德治疗，以便充分发挥接种疗效。若患者出现严重感染则应考虑暂停盐酸芬戈莫德治疗，在重新启动治疗之前应考虑获益-风险。上市后，在治疗大约2至3年后报告了一些隐球菌脑膜炎（真菌感染）病例，其中一些病例具有致死性，但与治疗持续时间的确切关系不明。伴有隐球菌脑膜炎体征和症状（如头痛伴精神改变（意识模糊、幻觉）和/或人格改变）的患者应立即接受诊断评估。若确诊隐球菌脑膜炎，则应中断芬戈莫德治疗，并启动适当治疗。若需要重新启动芬戈莫德治疗，则应进行多学科咨询（传染病专家）。自芬戈莫德上市以来已有进行性多灶性白质脑病（PML）相关报告。PML为John Cunningham病毒(JCV)诱发的机会性感染，具有致死性或可能导致重度残疾。在单药治疗（既往未接受那他珠单抗）后约2-3年发生PML病例，与治疗持续时间的确切关系不详。另有既往接受那他珠单抗（已知与PML相关）治疗的患者报告PML病例。只有在存在JCV感染的情况下才会发生PML。若进行JCV检验，则应考虑尚未在接受芬戈莫德治疗的患者中研究淋巴细胞减少症对于抗JCV抗体检验的准确性的影响。还应注意的是，抗JCV抗体检验结果呈阴性并不排除未来出现JCV感染的可能性。在启动芬戈莫德治疗之前应将基线MRI结果（通常为3个月内）作为参考。在常规MRI期间，医生应注意PML提示性病灶。至于被视为PML风险升高的患者，MRI监测可被视为增强的药物警戒的一部分。若怀疑PML，则应立即进行MRI（诊断目的），另外还应中断芬戈莫德治疗，直至排除PML为止。在上市后，芬戈莫德治疗报告有人乳头状瘤病毒（HPV）感染（包括乳头状瘤、发育不良、疣和与HPV相关的癌症）。由于芬戈莫德的免疫抑制特性，在开始使用芬戈莫德治疗前考虑疫苗接种，应考虑是否需要接种抗HPV感染疫苗。按照医疗标准的建议，要进行癌症筛查，包括Pap试验。治疗停止后大概需要2个月来清除芬戈莫德，在此周期内应持续进行感染警戒。应指导患者在芬戈莫德治疗停止2个月内报告感染症状。

♦黄斑水肿：有葡萄膜炎病史的患者和糖尿病患者罹患黄斑水肿的风险增加。建议在开始治疗的3-4个月时进行眼科评估。有关是否应终止盐酸芬戈莫德治疗的决定需考虑个体患者的潜在获益与风险。

♦在启动盐酸芬戈莫德治疗之前应采集近期（既往6个月内）转氨酶和胆红素水平。对于出现提示肝功能异常症状的患者，应检查肝酶水平，若确认显著肝损伤则应停用盐酸芬戈莫德。♦可逆性后部脑病综合征：若怀疑PRES，则应停用盐酸芬戈莫德。

♦鉴于那他珠单抗或特立氟胺的半衰期较长，在将患者的治疗方案由那他珠单抗或特立氟胺改为盐酸芬戈莫德时，要注意潜在合并免疫效应。不建议在阿伦单抗停用后启动盐酸芬戈莫德治疗，除非此类治疗的获益明确高于个体患者的风险。

♦接受盐酸芬戈莫德治疗的患者报告了基底细胞癌（BCC）和其他皮肤肿瘤，包括恶性黑素瘤、鳞状细胞癌、卡波氏肉瘤和梅克尔细胞癌。应对皮肤病变进行药物警戒，建议在启动治疗时对皮肤进行医学评价接受芬戈莫德治疗的患者应避免在未采取保护措施的情况下暴露于日光。

♦上市后部分停用芬戈莫德的患者观察到疾病严重恶化（罕见）。应该考虑可能是高度疾病活动性复发。由于停药存在反弹风险，停用芬戈莫德治疗同样应谨慎。若认为必须停用盐酸芬戈莫德，在该时间周期内应就潜在反弹相关体征对患者进行监测。

孕妇、哺乳期妇女、具有生育力的女性和男性：

孕妇：

不推荐，除非获益大于风险。

哺乳：

不推荐。

具有生育力的女性和男性：

女性在治疗期间不应妊娠，建议采取有效避孕措施。

不良反应：

 ♦非常常见（≥10%）：流感、鼻窦炎、头痛、咳嗽、腹泻、背痛、肝酶升高（ALT、γ谷氨酰转移酶、天冬氨酸转氨酶升高）。

♦常见（≥1 - <10%）：疱疹病毒感染、支气管炎、花斑藓、基底细胞癌、淋巴细胞减少症、白细胞减少症、抑郁症、头晕、偏头痛、 视力模糊、心动过缓、房室传导阻滞、高血压、呼吸困难、湿疹、脱发、瘙痒、肌痛、节痛、虚弱、血甘油三酯升高。

♦不常见（≥0.1% - <1%）：肺炎、恶性黑素瘤、血小板减少症、抑郁情绪、癫痫发作、黄斑水肿、恶心、中性粒细胞计数降低。

♦罕见（≥0.01% - <0.1%）：淋巴瘤、鳞状细胞癌、可逆性后部脑病综合征（PRES）。

♦非常罕见（<0.01%）：卡波氏肉瘤、T-波倒置。

♦频率未知：进行性多灶性白质脑病（PML）、隐球菌感染、梅克尔细胞癌、外周水肿、治疗启动后产生超敏反应，包括皮疹、荨麻疹和神经性水肿。

药物相互作用：

♦由于存在累加免疫系统效应的风险，禁止合并给予抗肿瘤、免疫调节或免疫抑制药物。

♦在盐酸芬戈莫德治疗期间以及治疗停止之后长达2个月内，疫苗接种的疗效可能降低。使用活体减毒疫苗可能存在感染风险，因此应避免使用。

♦由于潜在心率降低累加效应，服用β阻滞剂或下述可能导致心率降低的药物，如Ia类和III类抗心律失常药物、钙通道阻滞剂（如维拉帕米或地尔硫卓）、伊伐布雷定、地高辛、抗胆碱酯酶药物或匹鲁卡品时，患者禁用盐酸芬戈莫德。

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.