Calculators, Algorithms, Drug Interaction CheckersTools
Back To Search Results

Fingolimod

Author: Milena Lobaina Editor: Elena Shanina Updated: 5/30/2024 2:13:21 AM

Indications

Fingolimod is the first oral disease-modifying agent approved by the US Food and Drug Administration (FDA) for treating relapsing-remitting multiple sclerosis (RRMS).[1] This drug is also indicated for active secondary progressive disease with superimposed relapse and for treating clinically isolated syndromes.[2][3] 

FDA-Approved Indications

The efficacy of fingolimod in treating RRMS has been demonstrated in 3 separate double-blind, randomized, phase III clinical trials. In the placebo-controlled FREEDOMS trial (FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis), fingolimod demonstrated improved relapse rate, decreased disease disability progression, reduced number of active or enlarging magnetic resonance imaging (MRI) lesions, and brain atrophy over 2 years. The FREEDOMS II trial evaluated fingolimod's safety profile and found that daily administration of 0.5 mg had a favorable benefit-risk ratio when treating RRMS.

The TRANSFORMS trial (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis) demonstrated the superiority of fingolimod therapy in reducing disease activity and relapses in RRMS when compared to interferon β-1a.[2][4][5] Studies in specific patient populations, including the IRST LATAM study, analyzed fingolimod's effect on Latin American patients with diagnosed multiple sclerosis. The medication's pharmacodynamics and safety profile did not differ among these patients.[6]

Mechanism of Action

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

Mechanism of Action

Fingolimod is a nonselective functional antagonist of sphingosine-1-phosphate receptors (S1PRs).[1] Since the emergence of fingolimod in 2010 as the first medication of this class, similar medications with higher receptor specificity have been synthesized and FDA-approved, such as siponimod (2019), ozanimod (2020), and ponesimod (2021).[3]

Fingolimod's molecular structure resembles a bioactive lipid called sphingosine, which is produced in the cell membrane and transported extracellularly to modulate a series of biological responses. Sphingosine receptors are a group of 5 G-protein–coupled receptors expressed throughout the body and are associated with various biological processes.[5][7]

S1PRs (S1PR1, S1PR2, and S1PR3) are highly expressed within the brain, heart, spleen, lung, thymus, and skeletal muscle cells.[5] The S1PR signaling pathway is an essential regulator of lymphocyte trafficking from lymph nodes to circulation.[8] Additionally, this pathway mediates several nonimmune essential functions, such as vascular and neurogenic angiogenesis, vessel permeability, basal vascular tone, dendritic cell migration, and bacteremia.[9][8][10][11][12] S1PR1 and S1PR3 are expressed in the membranes of the atrium myocytes and provide a chronotropic effect on the heart.[5] S1PR4 is involved in immunological aspects of carcinogenesis by regulating the proliferation and survival of natural killer cells, while both S1PR4 and S1PR5 modulate innate immune cell response.[13][14]

Fingolimod requires in vivo phosphorylation to activate S1PR.[15][16] The drug binds nonselectively to S1PR, primarily receptors 1, 3, 4, and 5.[5] This binding leads to receptor internalization and recycling, except for S1PR1, which undergoes irreversible degradation within the formed endosomes.[1] Continued administration causes a stepwise reduction in available receptors and desensitization.[1] Fingolimod Fingolimod exhibits a high affinity for S1PR1, which is prominently expressed in lymphocytes.[17][5] Activation of S1PR1 by sphingosine-1-phosphate stimulates lymphocyte migration, thereby promoting inflammation. Therefore, inhibiting S1PR1 with fingolimod reduces circulating lymphocytes and limits the inflammatory response. Fingolimod affects T- and B-cell trafficking, as well as oligodendrocytes, where S1PR5 receptors are expressed.[1] Moreover, fingolimod crosses the blood-brain barrier, helping to preserve its integrity and potentially reducing brain edema.[18][19]

The cardiovascular effect of fingolimod is directly related to S1PR1 activation. Fingolimod binding to S1PR1 on endothelial cells leads to enhanced endothelial cell junction and decreased vascular permeability. This function is dose-dependent, as prolonged fingolimod administration causes vascular injury and increased permeability. Fingolimod causes bradycardia and hypotension by activating endothelial nitric oxide synthase—a Gi-protein–coupled process.[1] Additionally, the binding of fingolimod to S1PR3 leads to neuronal regeneration, bradycardia, arterial vasodilation, and macrophage phagocytosis.[20][21][22][23] Furthermore, the drug may suppress the immune response by downregulating Th17 proliferation and Th17-central memory cells in the peripheral circulation, thereby substantially decreasing the neuroinflammation seen in multiple sclerosis.[24][25]

Pharmacokinetics

Absorption: Fingolimod has an oral bioavailability of 93%, unaffected by food intake. The drug achieves a steady state within 8 to 36 hours after administration, with a half-life ranging from 6 to 9 days.[4]

Distribution: Approximately 86% of fingolimod is distributed via red blood cells, with a volume of distribution of approximately 1200 ± 260 L.

Metabolism: Fingolimod undergoes metabolism via 3 different pathways. The first pathway involves reversible phosphorylation, catalyzed by lipid phosphate phosphohydrolases and specific sphingosine 1-phosphate phosphatase.[4] The second pathway includes fingolimod hydroxylation and oxidation by enzymes such as CYP4F2 and other CYP4F enzymes aimed at neutralizing carboxylic acid metabolites excreted by the kidneys.[4] The third metabolic pathway leads to the formation of nonpolar ceramides by dihydroceramide synthase, contributing to the least concentration in the blood.[1] 

Elimination: Fingolimod is primarily excreted in urine (81%), with the most common metabolic products in urine being the butanoic acid metabolites. Fingolimod and fingolimod-phosphate, comprising less than 2.5% of the dose, are detectable in both blood and feces.[4]

Protein binding: Fingolimod and its active metabolite, fingolimod phosphate, exhibit high binding to plasma albumin (>99.7%) and lipoproteins. This protein affinity is independent of renal or hepatic dysfunction.[1][4] However, even at a steady state, the medication's plasma concentration remains consistently low; thus, reducing fingolimod's affinity for plasma proteins does not increase its toxicity.[4]

Administration

Available Dosage Forms and Strengths

Fingolimod formulations are available as oral capsules in strengths of 0.25 mg and 0.5 mg. Food consumption does not affect drug administration. The recommended dosage for adults with a body weight of less than or equal to 40 kg (88 lb) is a 0.5 mg tablet once daily. For pediatric patients aged 10 or older with a body weight of less than 40 kg (88 lb), the recommended fingolimod dosage is a 0.25 mg tablet once daily.

Various Therapeutic Approaches of Fingolimod for Relapsing-Remitting Multiple Sclerosis

Fingolimod as first-line therapy for RRMS: Fingolimod has been effective for various conditions, as mentioned below. 

  • Fingolimod can be used as first-line therapy for treating clinically isolated syndrome without MRI-positive lesions that meet the dissemination in time according to the McDonald criteria.[26] 
  • Fingolimod therapy has also proven effective as a first-line treatment for patients with multiple sclerosis who have a high lesion burden, multiple active lesions on gadolinium-enhancing T1 MRI sequences, multiple relapses in a year, marked progression of deficits, or incomplete recovery from relapses.[2]
  • Fingolimod therapy can be initiated in patients with mild disease progression refractory to other medications, provided they understand the adverse effects of the medication and monitoring requirements.[2]

Fingolimod as escalation therapy for RRMS: Fingolimod is considered an escalation therapy for the patient profiles mentioned below.

  • Patients who are asymptomatic but have MRI demonstrating gadolinium-enhancing lesions, indicating clinically silent multiple sclerosis, are evaluated for alternative treatment.[2]
  • Patients who experience more than one relapse per year.[2]
  • Patients with more than 9 T2 lesions on MRI at any given time.[2]

Fingolimod as de-escalation therapy for RRMS: Fingolimod offers viable options under specific conditions when considering de-escalation strategies for RRMS.

  • Fingolimod therapy may be initiated after discontinuing disease-modifying therapy. Patients should be closely monitored for overlapping immunosuppressant effects.
  • Initiating fingolimod 8 to 12 weeks after natalizumab therapy has been shown to reduce relapse rates compared to glatiramer acetate or no treatment.[2][27]
  • Before initiating fingolimod therapy, physicians should rule out disease-modifying therapy–related diseases, such as progressive multifocal leukoencephalopathy (PML), infections, tumors, and cardiac pathology.[28]

Discontinuation of Fingolimod

  • Discontinuing fingolimod may cause relapse in up to 30% of patients within the first 6 months after discontinuing the therapy. Outcomes are better in patients who initiate a second medication within 2 months of fingolimod therapy.[29]
  • Predictors of disease relapse include a higher relapse rate in the year before discontinuing, female sex, younger age, and a higher Expanded Disability Status scale score.[30]

Specific Patient Populations

Hepatic impairment: Although dosage adjustment is not recommended, monitoring of liver function is advised in patients with mild-to-moderate hepatic dysfunction. Fingolimod is contraindicated in patients with severe hepatic dysfunction (Child-Pugh class C).[31] 

Renal impairment: Protein binding and half-life of fingolimod in patients with renal impairment are similar to those in healthy subjects. Standard dosing is generally considered safe for patients with mild, moderate, or severe renal impairment, although further studies would be beneficial.[32]

Pregnancy considerations: Fingolimod has a low molecular weight, allowing it to cross the placental membrane easily.[33] Preclinical data suggest that sphingosine receptors might help regulate placenta and embryonic angiogenesis.[33][34] Therefore, the FDA recommends that all women of childbearing age use at least two different forms of contraception while taking fingolimod and for 2 months after discontinuing the medication.[34] 

Abrupt discontinuation of fingolimod before and during pregnancy may increase the risk of disease relapse.[35] Fingolimod does not appear to interact with or affect the pharmacodynamic properties of contraceptive medications; therefore, oral contraceptives are considered effective birth control in this patient population.[36] The fingolimod pregnancy registry is available to monitor potential fetal or maternal complications further.

Breastfeeding considerations: Patients should be informed that fingolimod can be present in breast milk, and therefore, breastfeeding is not recommended while taking this medication.

Adverse Effects

The most commonly reported adverse effects while taking fingolimod include headache, cough, nasopharyngitis, viral upper respiratory infections, elevated liver enzymes, back pain, nausea, diarrhea, and abdominal pain. Other potential adverse effects include bradycardia, hypotension, and heart blocks. Additionally, fingolimod administration increases the risk of high-mortality infections such as PML, human papillomavirus (HPV), meningitis, and encephalitis. However, skin carcinoma, melanoma, and lymphoma have also been documented in patients undergoing treatment with fingolimod.[2]

Warnings and Precautions 

  • Fingolimod phosphates bind to sphingosine receptors located on the sinoatrial and atrioventricular (AV) nodes, as well as in atrial myocytes. This binding induces inward potassium flow, resulting in a negative chronotropic effect on the heart.[37][38] Fingolimod is commonly associated with transient and asymptomatic bradycardia occurring 4 to 6 hours following the first dose administration. However, after 1 month of daily fingolimod administration, the heart rate typically normalizes to the pre-dose range.[39] Ventricular arrhythmia has not been reported in trials, likely due to the absence of inward rectifying potassium channels within the ventricle.[40]
  • Dose-dependent administration of fingolimod is linked to the AV node conduction block, with the first-degree block being the most frequently observed pattern in an electrocardiogram (ECG). Conduction abnormalities may manifest within 6 hours of treatment initiation; however, these typically do not include Mobitz type II or third-degree AV block.[39]
  • Patients treated with fingolimod commonly experience reversible lymphopenia, which heightens the risk of developing opportunistic infections such as cryptococcal, herpes simplex virus, and nasopharyngitis.[27][41][42] Coadministration of valacyclovir has proven beneficial and well-tolerated by patients, with resolution of herpetic diseases typically occurring within a few weeks.[6]
  • PML is not commonly associated with fingolimod therapy. However, in known cases of fingolimod-associated PML, the clinical presentation is nonspecific, which may delay or underestimate the diagnosis of the conditions.[43]
  • Fingolimod-associated cystic macular edema has been reported to be dose-dependent. While ophthalmological complications are rare at approved doses, patients with uveitis or diabetes may be at increased risk.[44][45] 
  • Transaminitis requiring persistent monitoring has been documented with fingolimod therapy. In cases where acute liver dysfunction develops, and other alternative etiologies have been ruled out, physicians should consider discontinuing fingolimod therapy. For viral hepatitis, discontinuation is recommended until the active phase of viremia resolves. Instances of fulminant hepatic failure requiring transplantation have been documented.[31]
  • A mild increase in blood pressure has been reported with fingolimod therapy. However, this increase has been effectively controlled with antiarrhythmics and typically does not necessitate discontinuation of fingolimod.[6]
  • In rare instances, the initiation or abrupt termination of fingolimod can precipitate tumefactive multiple sclerosis (TMS). Therefore, TMS should be suspected if a patient presents with a severe or atypical multiple sclerosis flare.[46]
  • HPV vaccines are recommended for patients initiating fingolimod treatment due to the marked immunosuppression associated with fingolimod therapy, which may increase the risk of infection or reactivation of HPV-related diseases.[47]
  • Multiple cases of basal cell carcinoma have been documented in patients receiving fingolimod treatment.[27]

Contraindications

Fingolimod is contraindicated in patients who have experienced cardiovascular events within the last 6 months, including myocardial infarction, unstable angina, stroke, transient ischemic attack, class III/IV heart failure, or decompensated heart failure requiring hospitalization. Additionally, patients with a history of Mobitz type II heart block, third-degree AV block, or sick sinus syndrome should avoid fingolimod unless they have a working pacemaker. Fingolimod can potentially prolong the QTc interval; therefore, physicians should refrain from initiating fingolimod treatment in patients with a baseline QTc of 500 ms or longer.[2]

Moreover, it is crucial for the medical team to thoroughly assess patients with a history of cardiac arrhythmias, as fingolimod is contraindicated in patients taking certain antiarrhythmic medications. If a patient is on antiarrhythmic medications that block fast sodium channels (class Ia) or potassium channels (class III), alternative treatments to fingolimod must be considered. Finally, if patients develop a hypersensitivity reaction to fingolimod, the medical team should immediately discontinue the treatment and take adequate actions to guarantee the patient's safety.[2]

Monitoring

Before starting fingolimod therapy, medical providers should complete the following measures:

  • Perform baseline vital signs assessments.
  • Conduct a complete blood count, hepatic function test, and pregnancy test.
  • Screen for severe liver failure, chronic hepatitis, and HIV infection.[2] 
  • Obtain varicella-zoster virus (VZV) antibody titers to assess immunity status.[2] 
  • Conduct an ophthalmological evaluation to rule out macular edema.[45]
  • Obtain an ECG to establish baseline QTc interval and evaluate for preexisting heart blocks.
  • Review the patient's medication list to identify any drugs that may cause bradycardia, such as β-blockers or antiarrhythmics, and consider alternative therapy if necessary.
  • Assess the patient's history for malignancy and consider dermatological evaluation to rule out skin malignancies.[2]
  • Evaluate for the presence of neuromyelitis optica by obtaining aquaporin-4 antibodies, especially in patients presenting with ocular symptoms suggestive of this condition.[48]
  • Advise patients to utilize at least 2 effective contraceptive methods during the course of fingolimod therapy and for 2 months following discontinuation of therapy.[2]
  • Educate patients about the risk of developing tumefactive lesions within 6 months of starting fingolimod therapy.[46]
  • Perform a brain MRI scan with and without contrast.[2]

After the first dose of fingolimod therapy is administered, various parameters, including vital signs, ECG, and baseline electrolytes, must be monitored. Hourly evaluation of vital signs, especially the patient's heart rate, is essential for up to 6 hours post-initiation due to fingolimod's potential to induce bradycardia. If the patient's heart rate falls below 40 bpm or 30% of the baseline value, or if symptomatic bradycardia develops, therapy should be immediately discontinued by the medical providers. Patients must then undergo prolonged cardiac monitoring for their safety.

An ECG should be repeated 6 hours after administration to monitor for QTc prolongation, new-onset cardiac block, or arrhythmias. Patients should be promptly transferred to the nearest cardiac center for further evaluation if abnormalities are detected on the ECG. Patients at risk for developing torsades de pointes should be monitored at the discretion of the medical team for an extended interval; however, it is advisable to correct electrolyte imbalances and keep a cardiologist informed to ensure a safe environment for the patient. Patients at risk for torsades de pointes include those with preexisting hypokalemia, hypomagnesemia, and congenital long QT syndrome.[37][38][39]

Parameters that should be regularly monitored during fingolimod treatment aim to prevent severe lymphopenia and macular edema. These include white blood cell count, inflammatory markers, complete metabolic panel, and pregnancy status, which should be assessed after 2 and 4 weeks of initiating fingolimod therapy. Subsequently, physicians should conduct laboratory monitoring every 3 months until the treatment is discontinued.[2] If the lymphocyte count drops below 200 cells/mL, physicians should halt fingolimod therapy until the count improves to 600 cells/mL.[2] Patients with a low baseline lymphocyte count or a baseline metabolic index below 18.5 kg/m2 are at higher risk of developing lymphopenia.[49] 

Fingolimod therapy should be discontinued if liver enzymes remain elevated to 5 times the upper limit on 2 consecutive labs 3 months apart.[2][31] For women of childbearing age, contraceptive treatment is imperative while on therapy; if pregnancy is desired, fingolimod treatment must be halted at least 2 months before conception.[34] Ophthalmological evaluation should be performed by an ophthalmologist 3 to 4 months after starting fingolimod therapy to rule out the development of macular edema. If macular edema is detected, physicians should promptly discontinue fingolimod treatment. Patients with diabetes or a history of uveitis should undergo annual ophthalmological evaluations due to their heightened risk for ophthalmological complications.[2]

Toxicity

The toxic effects associated with fingolimod primarily involve potential systemic complications. Cardiac toxicities such as asystole and sudden cardiac death can occur due to the development of heart blocks.[50] Severe immunosuppression, particularly notable in patients who have undergone postrenal transplant, may develop, significantly elevating the risk for potentially fatal opportunistic infections.[51] Myelosuppression is not an adverse effect of fingolimod therapy.[52] However, dose-dependent development of macular edema has been documented, affecting the patient's vision, with higher occurrence rates noted in those taking the 5 mg dose.[53] Efforts to mitigate toxicity are ongoing, with the development of multiple S1PR-specific antagonists aimed at reducing adverse effects. 

Enhancing Healthcare Team Outcomes

Patients with RRMS face significant challenges due to deteriorating motor and cognitive function, particularly when the disease manifests in young adulthood. Early diagnosis and effective management strategies are crucial for preserving function over time and alleviating the burden of the disease. Ensuring treatment efficacy, reducing disability, and enhancing patient outcomes in RRMS care require a collaborative, multidisciplinary approach among healthcare professionals. Neurologists, primary care physicians, nurses, physical and occupational therapists, pharmacists, and other specialists involved in treating patients with RRMS should possess a comprehensive understanding of the clinical diagnosis, disease progression, and available therapies, including potential complications.

The emergence of fingolimod as a novel disease-modifying therapy for RRMS expands the scope of patient care to encompass a collaborative approach. Patients receiving fingolimod treatment benefit from multidisciplinary care involving specialists such as cardiologists, infectious disease experts, immunologists, ophthalmologists, oncologists, and hematologists. This collaborative effort aims to implement preventive measures, conduct screenings, and promptly address any therapy-related complications to optimize patient outcomes.

Adopting a strategic approach is paramount to mitigate treatment-related adverse effects and ensure diligent monitoring during therapy initiation and maintenance. Effective communication between healthcare providers and patients is essential to uphold patient autonomy, compliance, safety, and treatment effectiveness. With a comprehensive understanding of fingolimod's mechanism of action, clinical indications, potential adverse effects, monitoring parameters, and contraindications, healthcare professionals can empower individuals with multiple sclerosis to achieve a more normal life.

References

[1]

Pournajaf S, Dargahi L, Javan M, Pourgholami MH. Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod. Frontiers in pharmacology. 2022:13():807639. doi: 10.3389/fphar.2022.807639. Epub 2022 Feb 16     [PubMed PMID: 35250559]

[2]

Ayzenberg I, Hoepner R, Kleiter I. Fingolimod for multiple sclerosis and emerging indications: appropriate patient selection, safety precautions, and special considerations. Therapeutics and clinical risk management. 2016:12():261-72. doi: 10.2147/TCRM.S65558. Epub 2016 Feb 19     [PubMed PMID: 26929636]

[3]

Roy R, Alotaibi AA, Freedman MS. Sphingosine 1-Phosphate Receptor Modulators for Multiple Sclerosis. CNS drugs. 2021 Apr:35(4):385-402. doi: 10.1007/s40263-021-00798-w. Epub 2021 Apr 2     [PubMed PMID: 33797705]

[4]

David OJ, Kovarik JM, Schmouder RL. Clinical pharmacokinetics of fingolimod. Clinical pharmacokinetics. 2012 Jan 1:51(1):15-28. doi: 10.2165/11596550-000000000-00000. Epub     [PubMed PMID: 22149256]

Level 3 (low-level) evidence

[5]

McGinley MP, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis and other conditions. Lancet (London, England). 2021 Sep 25:398(10306):1184-1194. doi: 10.1016/S0140-6736(21)00244-0. Epub 2021 Jun 24     [PubMed PMID: 34175020]

[6]

Ordoñez-Boschetti L, Rey R, Cruz A, Sinha A, Reynolds T, Frider N, Alvarenga R. Safety and Tolerability of Fingolimod in Latin American Patients with Relapsing-Remitting Multiple Sclerosis: The Open-Label FIRST LATAM Study. Advances in therapy. 2015 Jul:32(7):626-35. doi: 10.1007/s12325-015-0224-2. Epub 2015 Jul 14     [PubMed PMID: 26170105]

Level 3 (low-level) evidence

[7]

Chen H, Wang J, Zhang C, Ding P, Tian S, Chen J, Ji G, Wu T. Sphingosine 1-phosphate receptor, a new therapeutic direction in different diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022 Sep:153():113341. doi: 10.1016/j.biopha.2022.113341. Epub 2022 Jul 1     [PubMed PMID: 35785704]

[8]

Anwar M, Mehta D. Post-translational modifications of S1PR1 and endothelial barrier regulation. Biochimica et biophysica acta. Molecular and cell biology of lipids. 2020 Sep:1865(9):158760. doi: 10.1016/j.bbalip.2020.158760. Epub 2020 Jun 22     [PubMed PMID: 32585303]

[9]

Yang C, Yamashita M, Suda T. A Novel Function of Sphingolipid Signaling via S1PR3 in Hematopoietic and Leukemic Stem Cells. Blood cancer discovery. 2021 Jan:2(1):3-5. doi: 10.1158/2643-3230.BCD-20-0200. Epub 2020 Dec 1     [PubMed PMID: 34661148]

[10]

Saba JD, Hla T. Point-counterpoint of sphingosine 1-phosphate metabolism. Circulation research. 2004 Apr 2:94(6):724-34     [PubMed PMID: 15059942]

Level 3 (low-level) evidence

[11]

Schwab SR, Cyster JG. Finding a way out: lymphocyte egress from lymphoid organs. Nature immunology. 2007 Dec:8(12):1295-301     [PubMed PMID: 18026082]

[12]

Shea BS, Opal SM. The Role of S1PR3 in Protection from Bacterial Sepsis. American journal of respiratory and critical care medicine. 2017 Dec 15:196(12):1500-1502. doi: 10.1164/rccm.201708-1726ED. Epub     [PubMed PMID: 28910137]

[13]

Olesch C, Sirait-Fischer E, Berkefeld M, Fink AF, Susen RM, Ritter B, Michels BE, Steinhilber D, Greten FR, Savai R, Takeda K, Brüne B, Weigert A. S1PR4 ablation reduces tumor growth and improves chemotherapy via CD8+ T cell expansion. The Journal of clinical investigation. 2020 Oct 1:130(10):5461-5476. doi: 10.1172/JCI136928. Epub     [PubMed PMID: 32663191]

[14]

Chun J, Giovannoni G, Hunter SF. Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects. Drugs. 2021 Feb:81(2):207-231. doi: 10.1007/s40265-020-01431-8. Epub     [PubMed PMID: 33289881]

[15]

Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S. The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS letters. 2003 Nov 6:554(1-2):189-93     [PubMed PMID: 14596938]

Level 3 (low-level) evidence

[16]

Tsai HC, Han MH. Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway: Therapeutic Targets in Autoimmunity and Inflammation. Drugs. 2016 Jul:76(11):1067-79. doi: 10.1007/s40265-016-0603-2. Epub     [PubMed PMID: 27318702]

[17]

Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, Foster CA, Zollinger M, Lynch KR. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. The Journal of biological chemistry. 2002 Jun 14:277(24):21453-7     [PubMed PMID: 11967257]

Level 3 (low-level) evidence

[18]

Qian Y, Gao C, Zhao X, Song Y, Luo H, An S, Huang J, Zhang J, Jiang R. Fingolimod Attenuates Lung Injury and Cardiac Dysfunction after Traumatic Brain Injury. Journal of neurotrauma. 2020 Oct 1:37(19):2131-2140. doi: 10.1089/neu.2019.6951. Epub 2020 Jun 10     [PubMed PMID: 32434456]

Level 2 (mid-level) evidence

[19]

Foster CA, Mechtcheriakova D, Storch MK, Balatoni B, Howard LM, Bornancin F, Wlachos A, Sobanov J, Kinnunen A, Baumruker T. FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. Brain pathology (Zurich, Switzerland). 2009 Apr:19(2):254-66. doi: 10.1111/j.1750-3639.2008.00182.x. Epub 2008 Jun 4     [PubMed PMID: 18540945]

Level 3 (low-level) evidence

[20]

Anastasiadou S, Knöll B. The multiple sclerosis drug fingolimod (FTY720) stimulates neuronal gene expression, axonal growth and regeneration. Experimental neurology. 2016 May:279():243-260. doi: 10.1016/j.expneurol.2016.03.012. Epub 2016 Mar 12     [PubMed PMID: 26980486]

[21]

Forrest M, Sun SY, Hajdu R, Bergstrom J, Card D, Doherty G, Hale J, Keohane C, Meyers C, Milligan J, Mills S, Nomura N, Rosen H, Rosenbach M, Shei GJ, Singer II, Tian M, West S, White V, Xie J, Proia RL, Mandala S. Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. The Journal of pharmacology and experimental therapeutics. 2004 May:309(2):758-68     [PubMed PMID: 14747617]

Level 3 (low-level) evidence

[22]

Tölle M, Levkau B, Keul P, Brinkmann V, Giebing G, Schönfelder G, Schäfers M, von Wnuck Lipinski K, Jankowski J, Jankowski V, Chun J, Zidek W, Van der Giet M. Immunomodulator FTY720 Induces eNOS-dependent arterial vasodilatation via the lysophospholipid receptor S1P3. Circulation research. 2005 Apr 29:96(8):913-20     [PubMed PMID: 15802614]

[23]

Bryan AM, You JK, McQuiston T, Lazzarini C, Qiu Z, Sheridan B, Nuesslein-Hildesheim B, Del Poeta M. FTY720 reactivates cryptococcal granulomas in mice through S1P receptor 3 on macrophages. The Journal of clinical investigation. 2020 Sep 1:130(9):4546-4560. doi: 10.1172/JCI136068. Epub     [PubMed PMID: 32484801]

Level 2 (mid-level) evidence

[24]

Liao JJ, Huang MC, Goetzl EJ. Cutting edge: Alternative signaling of Th17 cell development by sphingosine 1-phosphate. Journal of immunology (Baltimore, Md. : 1950). 2007 May 1:178(9):5425-8     [PubMed PMID: 17442922]

Level 3 (low-level) evidence

[25]

Mehling M, Lindberg R, Raulf F, Kuhle J, Hess C, Kappos L, Brinkmann V. Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology. 2010 Aug 3:75(5):403-10. doi: 10.1212/WNL.0b013e3181ebdd64. Epub 2010 Jun 30     [PubMed PMID: 20592255]

Level 2 (mid-level) evidence

[26]

Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of neurology. 2011 Feb:69(2):292-302. doi: 10.1002/ana.22366. Epub     [PubMed PMID: 21387374]

[27]

Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS, Haboubi M, Halper J, Hosey JP, Jones DE, Lisak R, Pelletier D, Potrebic S, Sitcov C, Sommers R, Stachowiak J, Getchius TSD, Merillat SA, Pringsheim T. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018 Apr 24:90(17):777-788. doi: 10.1212/WNL.0000000000005347. Epub     [PubMed PMID: 29686116]

Level 1 (high-level) evidence

[28]

Lyons J, Hughes R, McCarthy K, Everage N, Kapadia S, Miller C, Singhal P, Smirnakis K. Progressive multifocal leukoencephalopathy outcomes in patients with multiple sclerosis treated with dimethyl fumarate. Multiple sclerosis journal - experimental, translational and clinical. 2022 Oct-Dec:8(4):20552173221132469. doi: 10.1177/20552173221132469. Epub 2022 Nov 10     [PubMed PMID: 36387034]

[29]

Rinaldi F, Seppi D, Calabrese M, Perini P, Gallo P. Switching therapy from natalizumab to fingolimod in relapsing-remitting multiple sclerosis: clinical and magnetic resonance imaging findings. Multiple sclerosis (Houndmills, Basingstoke, England). 2012 Nov:18(11):1640-3. doi: 10.1177/1352458512464282. Epub     [PubMed PMID: 23100526]

[30]

Roos I, Malpas C, Leray E, Casey R, Horakova D, Havrdova EK, Debouverie M, Patti F, De Seze J, Izquierdo G, Eichau S, Edan G, Prat A, Girard M, Ozakbas S, Grammond P, Zephir H, Ciron J, Maillart E, Moreau T, Amato MP, Labauge P, Alroughani R, Buzzard K, Skibina O, Terzi M, Laplaud DA, Berger E, Grand'Maison F, Lebrun-Frenay C, Cartechini E, Boz C, Lechner-Scott J, Clavelou P, Stankoff B, Prevost J, Kappos L, Pelletier J, Shaygannejad V, Yamout BI, Khoury SJ, Gerlach O, Spitaleri DLA, Van Pesch V, Gout O, Turkoglu R, Heinzlef O, Thouvenot E, McCombe PA, Soysal A, Bourre B, Slee M, Castillo-Trivino T, Bakchine S, Ampapa R, Butler EG, Wahab A, Macdonell RA, Aguera-Morales E, Cabre P, Ben NH, Van der Walt A, Laureys G, Van Hijfte L, Ramo-Tello CM, Maubeuge N, Hodgkinson S, Sánchez-Menoyo JL, Barnett MH, Labeyrie C, Vucic S, Sidhom Y, Gouider R, Csepany T, Sotoca J, de Gans K, Al-Asmi A, Fragoso YD, Vukusic S, Butzkueven H, Kalincik T, MSBase and OFSEP. Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis. Neurology. 2022 Oct 25:99(17):e1926-e1944. doi: 10.1212/WNL.0000000000201029. Epub 2022 Aug 17     [PubMed PMID: 35977837]

Level 2 (mid-level) evidence

[31]

Biolato M, Bianco A, Lucchini M, Gasbarrini A, Mirabella M, Grieco A. The Disease-Modifying Therapies of Relapsing-Remitting Multiple Sclerosis and Liver Injury: A Narrative Review. CNS drugs. 2021 Aug:35(8):861-880. doi: 10.1007/s40263-021-00842-9. Epub 2021 Jul 28     [PubMed PMID: 34319570]

Level 3 (low-level) evidence

[32]

David OJ, Pryce M, Meiser K, Picard F, Emotte C, Kobalava Z, Moiseev V, Schmouder R. Pharmacokinetics of fingolimod and metabolites in subjects with severe renal impairment: An open-label, single-dose, parallel-group study. International journal of clinical pharmacology and therapeutics. 2015 Oct:53(10):847-54. doi: 10.5414/CP202356. Epub     [PubMed PMID: 26308173]

[33]

Varytė G, Arlauskienė A, Ramašauskaitė D. Pregnancy and multiple sclerosis: an update. Current opinion in obstetrics & gynecology. 2021 Oct 1:33(5):378-383. doi: 10.1097/GCO.0000000000000731. Epub     [PubMed PMID: 34310364]

Level 3 (low-level) evidence

[34]

Karlsson G, Francis G, Koren G, Heining P, Zhang X, Cohen JA, Kappos L, Collins W. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis. Neurology. 2014 Feb 25:82(8):674-80. doi: 10.1212/WNL.0000000000000137. Epub 2014 Jan 24     [PubMed PMID: 24463630]

[35]

Yeh WZ, Widyastuti PA, Van der Walt A, Stankovich J, Havrdova E, Horakova D, Vodehnalova K, Ozakbas S, Eichau S, Duquette P, Kalincik T, Patti F, Boz C, Terzi M, Yamout BI, Lechner-Scott J, Sola P, Skibina OG, Barnett M, Onofrj M, Sá MJ, McCombe PA, Grammond P, Ampapa R, Grand'Maison F, Bergamaschi R, Spitaleri DLA, Van Pesch V, Cartechini E, Hodgkinson S, Soysal A, Saiz A, Gresle M, Uher T, Maimone D, Turkoglu R, Hupperts RM, Amato MP, Granella F, Oreja-Guevara C, Altintas A, Macdonell RA, Castillo-Trivino T, Butzkueven H, Alroughani R, Jokubaitis VG, MSBase Study Group. Natalizumab, Fingolimod and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis. Neurology. 2021 Jun 15:96(24):e2989-e3002. doi: 10.1212/WNL.0000000000012084. Epub 2021 Jun 15     [PubMed PMID: 33879599]

[36]

David OJ, Ocwieja M, Meiser K, Emotte C, Jakab A, Wemer J, den Daas I, Schmouder R. Pharmacokinetics of fingolimod (FTY720) and a combined oral contraceptive coadministered in healthy women: drug-drug interaction study results. International journal of clinical pharmacology and therapeutics. 2012 Aug:50(8):540-4. doi: 10.5414/CP201675. Epub     [PubMed PMID: 22735460]

[37]

Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nature reviews. Drug discovery. 2010 Nov:9(11):883-97. doi: 10.1038/nrd3248. Epub 2010 Oct 29     [PubMed PMID: 21031003]

Level 3 (low-level) evidence

[38]

Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacology & therapeutics. 2007 Jul:115(1):84-105     [PubMed PMID: 17561264]

Level 3 (low-level) evidence

[39]

DiMarco JP, O'Connor P, Cohen JA, Reder AT, Zhang-Auberson L, Tang D, Collins W, Kappos L. First-dose effects of fingolimod: Pooled safety data from three phase 3 studies. Multiple sclerosis and related disorders. 2014 Sep:3(5):629-38. doi: 10.1016/j.msard.2014.05.005. Epub 2014 Jun 17     [PubMed PMID: 26265275]

[40]

Gaborit N, Le Bouter S, Szuts V, Varro A, Escande D, Nattel S, Demolombe S. Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. The Journal of physiology. 2007 Jul 15:582(Pt 2):675-93     [PubMed PMID: 17478540]

[41]

Cervera C. [Infections and fingolimod]. Revista de neurologia. 2012 Aug 16:55(4):227-37     [PubMed PMID: 22829086]

[42]

Ziemssen T, Lang M, Schmidt S, Albrecht H, Klotz L, Haas J, Lassek C, Lang S, Winkelmann VE, Ettle B, Schulze-Topphoff U, PANGAEA study group. Long-term real-world effectiveness and safety of fingolimod over 5 years in Germany. Journal of neurology. 2022 Jun:269(6):3276-3285. doi: 10.1007/s00415-021-10931-w. Epub 2022 Jan 4     [PubMed PMID: 34982201]

[43]

Nishiyama S, Misu T, Shishido-Hara Y, Nakamichi K, Saijo M, Takai Y, Takei K, Yamamoto N, Kuroda H, Saito R, Watanabe M, Tominaga T, Nakashima I, Fujihara K, Aoki M. Fingolimod-associated PML with mild IRIS in MS: A clinicopathologic study. Neurology(R) neuroimmunology & neuroinflammation. 2018 Jan:5(1):e415. doi: 10.1212/NXI.0000000000000415. Epub 2017 Nov 10     [PubMed PMID: 29725611]

[44]

Pul R, Osmanovic A, Schmalstieg H, Pielen A, Pars K, Schwenkenbecher P, Sühs KW, Yildiz Ö, Frank B, Stangel M, Skripuletz T. Fingolimod Associated Bilateral Cystoid Macular Edema-Wait and See? International journal of molecular sciences. 2016 Dec 14:17(12):     [PubMed PMID: 27983657]

[45]

Zarbin MA, Jampol LM, Jager RD, Reder AT, Francis G, Collins W, Tang D, Zhang X. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology. 2013 Jul:120(7):1432-9. doi: 10.1016/j.ophtha.2012.12.040. Epub 2013 Mar 24     [PubMed PMID: 23531349]

Level 3 (low-level) evidence

[46]

Croteau D, Tobenkin A, Brinker A, Kortepeter CM. Tumefactive multiple sclerosis in association with fingolimod initiation and discontinuation. Multiple sclerosis (Houndmills, Basingstoke, England). 2021 May:27(6):903-912. doi: 10.1177/1352458520938354. Epub 2020 Jul 14     [PubMed PMID: 32662718]

[47]

Triplett J, Kermode AG, Corbett A, Reddel SW. Warts and all: Fingolimod and unusual HPV-associated lesions. Multiple sclerosis (Houndmills, Basingstoke, England). 2019 Oct:25(11):1547-1550. doi: 10.1177/1352458518807088. Epub 2018 Nov 14     [PubMed PMID: 30427266]

[48]

Kleiter I, Gold R. Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2016 Jan:13(1):70-83. doi: 10.1007/s13311-015-0400-8. Epub     [PubMed PMID: 26597098]

[49]

Warnke C, Dehmel T, Ramanujam R, Holmen C, Nordin N, Wolfram K, Leussink VI, Hartung HP, Olsson T, Kieseier BC. Initial lymphocyte count and low BMI may affect fingolimod-induced lymphopenia. Neurology. 2014 Dec 2:83(23):2153-7. doi: 10.1212/WNL.0000000000001049. Epub 2014 Oct 31     [PubMed PMID: 25361781]

Level 2 (mid-level) evidence

[50]

Hengstman GJ, Kusters B. Sudden cardiac death in multiple sclerosis caused by active demyelination of the medulla oblongata. Multiple sclerosis (Houndmills, Basingstoke, England). 2011 Sep:17(9):1146-8. doi: 10.1177/1352458511408476. Epub 2011 May 17     [PubMed PMID: 21586485]

Level 3 (low-level) evidence

[51]

Tedesco-Silva H, Szakaly P, Shoker A, Sommerer C, Yoshimura N, Schena FP, Cremer M, Hmissi A, Mayer H, Lang P, FTY720 2218 Clinical Study Group. FTY720 versus mycophenolate mofetil in de novo renal transplantation: six-month results of a double-blind study. Transplantation. 2007 Oct 15:84(7):885-92     [PubMed PMID: 17984842]

Level 2 (mid-level) evidence

[52]

Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L, TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. The New England journal of medicine. 2010 Feb 4:362(5):402-15. doi: 10.1056/NEJMoa0907839. Epub 2010 Jan 20     [PubMed PMID: 20089954]

Level 1 (high-level) evidence

[53]

Jain N, Bhatti MT. Fingolimod-associated macular edema: incidence, detection, and management. Neurology. 2012 Feb 28:78(9):672-80. doi: 10.1212/WNL.0b013e318248deea. Epub     [PubMed PMID: 22371414]