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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Fingolimod - StatPearls - NCBI Bookshelf</title>
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<meta name="citation_title" content="Fingolimod">
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<meta name="citation_publisher" content="StatPearls Publishing">
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<meta name="citation_date" content="2024/05/30">
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<meta name="citation_author" content="Milena Lobaina">
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<meta name="citation_author" content="Elena Shanina">
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<meta name="citation_pmid" content="38861621">
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<meta name="DC.Contributor" content="Milena Lobaina">
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<meta name="DC.Contributor" content="Elena Shanina">
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<meta name="DC.Date" content="2024/05/30">
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<meta name="description" content="Fingolimod is the first oral disease-modifying agent approved by the US Food and Drug Administration (FDA) for treating multiple sclerosis. The drug effectively manages relapsing and remitting multiple sclerosis (RRMS), clinically isolated syndromes, and active secondary progressive disease. The primary function of fingolimod is to inhibit lymphocyte migration into peripheral circulation by antagonizing sphingosine-1-phosphate receptor-1 (S1PR1) functions, thereby reducing the body's inflammatory response. Additionally, fingolimod modulates various immune system activities, including T-cell central and peripheral tolerance, autoreactivity, T-cell differentiation, and regulation of the innate immune system. However, concerns exist regarding fingolimod's impact on the cardiovascular system, particularly cardiac chronotropy, which may elevate mortality risk.">
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<meta name="og:description" content="Fingolimod is the first oral disease-modifying agent approved by the US Food and Drug Administration (FDA) for treating multiple sclerosis. The drug effectively manages relapsing and remitting multiple sclerosis (RRMS), clinically isolated syndromes, and active secondary progressive disease. The primary function of fingolimod is to inhibit lymphocyte migration into peripheral circulation by antagonizing sphingosine-1-phosphate receptor-1 (S1PR1) functions, thereby reducing the body's inflammatory response. Additionally, fingolimod modulates various immune system activities, including T-cell central and peripheral tolerance, autoreactivity, T-cell differentiation, and regulation of the innate immune system. However, concerns exist regarding fingolimod's impact on the cardiovascular system, particularly cardiac chronotropy, which may elevate mortality risk.">
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</svg> Books</a></div><div class="jr-rhead f1 flexh"><div class="head"></div><div class="body"><div class="t">Fingolimod</div><div class="j">StatPearls [Internet]</div></div><div class="tail"></div></div><div id="jr-tb2"><a id="jr-bkhelp-sw" class="btn wsprkl hidden" title="Help with NLM PubReader">?</a><a id="jr-help-sw" class="btn wsprkl hidden" title="Settings and typography in NLM PubReader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 512 512" preserveAspectRatio="none"><path d="M462,283.742v-55.485l-29.981-10.662c-11.431-4.065-20.628-12.794-25.274-24.001 c-0.002-0.004-0.004-0.009-0.006-0.013c-4.659-11.235-4.333-23.918,0.889-34.903l13.653-28.724l-39.234-39.234l-28.72,13.652 c-10.979,5.219-23.68,5.546-34.908,0.889c-0.005-0.002-0.01-0.003-0.014-0.005c-11.215-4.65-19.933-13.834-24-25.273L283.741,50 h-55.484l-10.662,29.981c-4.065,11.431-12.794,20.627-24.001,25.274c-0.005,0.002-0.009,0.004-0.014,0.005 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600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-fip-done" class="wsprkl btn" title="Dismiss find">✘</a></nav><nav id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK604198_"><span class="title" itemprop="name">Fingolimod</span></h1><p class="contribs">Lobaina M, Shanina E.</p><p class="fm-aai"><a href="#_NBK604198_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="article-159964.s1"><h2 id="_article-159964_s1_">Continuing Education Activity</h2><p>Fingolimod is the first oral disease-modifying agent approved by the US Food and Drug Administration (FDA) for treating multiple sclerosis. The drug effectively manages relapsing and remitting multiple sclerosis (RRMS), clinically isolated syndromes, and active secondary progressive disease. The primary function of fingolimod is to inhibit lymphocyte migration into peripheral circulation by antagonizing sphingosine-1-phosphate receptor-1 (S1PR1) functions, thereby reducing the body's inflammatory response. Additionally, fingolimod modulates various immune system activities, including T-cell central and peripheral tolerance, autoreactivity, T-cell differentiation, and regulation of the innate immune system. However, concerns exist regarding fingolimod's impact on the cardiovascular system, particularly cardiac chronotropy, which may elevate mortality risk.</p><p>This activity reviews the indications, mechanism of action, contraindications, potential interactions, and necessary monitoring parameters for fingolimod. This activity also emphasizes the importance of an interdisciplinary healthcare team in optimizing care for patients with RRMS undergoing fingolimod treatment, thereby aiming to enhance patient outcomes through coordinated care.</p><p>
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<ul><li class="half_rhythm"><div>Identify the appropriate indications for prescribing fingolimod in patients with multiple sclerosis.</div></li><li class="half_rhythm"><div>Implement a comprehensive monitoring plan to assess the effectiveness and safety of fingolimod treatment in patients with multiple sclerosis.</div></li><li class="half_rhythm"><div>Apply evidence-based guidelines to select the most suitable patients for fingolimod treatment based on individual clinical profiles and disease characteristics.</div></li><li class="half_rhythm"><div>Collaborate with multidisciplinary healthcare professionals, including neurologists, cardiologists, and ophthalmologists, to optimize the management of multiple sclerosis in patients undergoing fingolimod therapy.</div></li></ul>
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<a href="https://www.statpearls.com/account/trialuserreg/?articleid=159964&utm_source=pubmed&utm_campaign=reviews&utm_content=159964" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Access free multiple choice questions on this topic.</a>
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</p></div><div id="article-159964.s2"><h2 id="_article-159964_s2_">Indications</h2><p>Fingolimod is the first oral disease-modifying agent approved by the US Food and Drug Administration (FDA) for treating relapsing-remitting multiple sclerosis (RRMS).<a class="bibr" href="#article-159964.r1" rid="article-159964.r1">[1]</a> This drug is also indicated for active secondary progressive disease with superimposed relapse and for treating clinically isolated syndromes.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a><a class="bibr" href="#article-159964.r3" rid="article-159964.r3">[3]</a> </p><p>
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<b>FDA-Approved Indications</b>
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</p><p>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.</p><p>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.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a><a class="bibr" href="#article-159964.r4" rid="article-159964.r4">[4]</a><a class="bibr" href="#article-159964.r5" rid="article-159964.r5">[5]</a> 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.<a class="bibr" href="#article-159964.r6" rid="article-159964.r6">[6]</a></p></div><div id="article-159964.s3"><h2 id="_article-159964_s3_">Mechanism of Action</h2><p>Fingolimod is a nonselective functional antagonist of sphingosine-1-phosphate receptors (S1PRs).<a class="bibr" href="#article-159964.r1" rid="article-159964.r1">[1]</a> 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).<a class="bibr" href="#article-159964.r3" rid="article-159964.r3">[3]</a></p><p>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.<a class="bibr" href="#article-159964.r5" rid="article-159964.r5">[5]</a><a class="bibr" href="#article-159964.r7" rid="article-159964.r7">[7]</a></p><p>S1PRs (S1PR1, S1PR2, and S1PR3) are highly expressed within the brain, heart, spleen, lung, thymus, and skeletal muscle cells.<a class="bibr" href="#article-159964.r5" rid="article-159964.r5">[5]</a> The S1PR signaling pathway is an essential regulator of lymphocyte trafficking from lymph nodes to circulation.<a class="bibr" href="#article-159964.r8" rid="article-159964.r8">[8]</a> Additionally, this pathway mediates several nonimmune essential functions, such as vascular and neurogenic angiogenesis, vessel permeability, basal vascular tone, dendritic cell migration, and bacteremia.<a class="bibr" href="#article-159964.r9" rid="article-159964.r9">[9]</a><a class="bibr" href="#article-159964.r8" rid="article-159964.r8">[8]</a><a class="bibr" href="#article-159964.r10" rid="article-159964.r10">[10]</a><a class="bibr" href="#article-159964.r11" rid="article-159964.r11">[11]</a><a class="bibr" href="#article-159964.r12" rid="article-159964.r12">[12]</a> S1PR1 and S1PR3 are expressed in the membranes of the atrium myocytes and provide a chronotropic effect on the heart.<a class="bibr" href="#article-159964.r5" rid="article-159964.r5">[5]</a> 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.<a class="bibr" href="#article-159964.r13" rid="article-159964.r13">[13]</a><a class="bibr" href="#article-159964.r14" rid="article-159964.r14">[14]</a></p><p>Fingolimod requires in vivo phosphorylation to activate S1PR.<a class="bibr" href="#article-159964.r15" rid="article-159964.r15">[15]</a><a class="bibr" href="#article-159964.r16" rid="article-159964.r16">[16]</a> The drug binds nonselectively to S1PR, primarily receptors 1, 3, 4, and 5.<a class="bibr" href="#article-159964.r5" rid="article-159964.r5">[5]</a> This binding leads to receptor internalization and recycling, except for S1PR1, which undergoes irreversible degradation within the formed endosomes.<a class="bibr" href="#article-159964.r1" rid="article-159964.r1">[1]</a> Continued administration causes a stepwise reduction in available receptors and desensitization.<a class="bibr" href="#article-159964.r1" rid="article-159964.r1">[1]</a> Fingolimod Fingolimod exhibits a high affinity for S1PR1, which is prominently expressed in lymphocytes.<a class="bibr" href="#article-159964.r17" rid="article-159964.r17">[17]</a><a class="bibr" href="#article-159964.r5" rid="article-159964.r5">[5]</a> 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.<a class="bibr" href="#article-159964.r1" rid="article-159964.r1">[1]</a> Moreover, fingolimod crosses the blood-brain barrier, helping to preserve its integrity and potentially reducing brain edema.<a class="bibr" href="#article-159964.r18" rid="article-159964.r18">[18]</a><a class="bibr" href="#article-159964.r19" rid="article-159964.r19">[19]</a></p><p>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.<a class="bibr" href="#article-159964.r1" rid="article-159964.r1">[1]</a> Additionally, the binding of fingolimod to S1PR3 leads to neuronal regeneration, bradycardia, arterial vasodilation, and macrophage phagocytosis.<a class="bibr" href="#article-159964.r20" rid="article-159964.r20">[20]</a><a class="bibr" href="#article-159964.r21" rid="article-159964.r21">[21]</a><a class="bibr" href="#article-159964.r22" rid="article-159964.r22">[22]</a><a class="bibr" href="#article-159964.r23" rid="article-159964.r23">[23]</a> 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.<a class="bibr" href="#article-159964.r24" rid="article-159964.r24">[24]</a><a class="bibr" href="#article-159964.r25" rid="article-159964.r25">[25]</a></p><p>
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<b>Pharmacokinetics</b>
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</p><p>
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<b>Absorption: </b>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.<a class="bibr" href="#article-159964.r4" rid="article-159964.r4">[4]</a></p><p>
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<b>Distribution: </b>Approximately 86% of fingolimod is distributed via red blood cells, with a volume of distribution of approximately 1200 ± 260 L.</p><p>
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<b>Metabolism: </b>Fingolimod undergoes metabolism via 3 different pathways. The first pathway involves reversible phosphorylation, catalyzed by lipid phosphate phosphohydrolases and specific sphingosine 1-phosphate phosphatase.<a class="bibr" href="#article-159964.r4" rid="article-159964.r4">[4]</a> 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.<a class="bibr" href="#article-159964.r4" rid="article-159964.r4">[4]</a> The third metabolic pathway leads to the formation of nonpolar ceramides by dihydroceramide synthase, contributing to the least concentration in the blood.<a class="bibr" href="#article-159964.r1" rid="article-159964.r1">[1]</a> </p><p>
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<b>Elimination: </b>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.<a class="bibr" href="#article-159964.r4" rid="article-159964.r4">[4]</a></p><p>
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<b>Protein binding: </b>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.<a class="bibr" href="#article-159964.r1" rid="article-159964.r1">[1]</a><a class="bibr" href="#article-159964.r4" rid="article-159964.r4">[4]</a> 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.<a class="bibr" href="#article-159964.r4" rid="article-159964.r4">[4]</a></p></div><div id="article-159964.s4"><h2 id="_article-159964_s4_">Administration</h2><p>
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<b>Available Dosage Forms and Strengths</b>
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</p><p>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.</p><p>
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<b>Various Therapeutic Approaches of Fingolimod for Relapsing-Remitting Multiple Sclerosis</b>
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</p><p>
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<b>Fingolimod as first-line therapy for RRMS: </b>Fingolimod has been effective for various conditions, as mentioned below. </p><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r26" rid="article-159964.r26">[26]</a> </div></li></ul><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></div></li></ul><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></div></li></ul><p>
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<b>Fingolimod as escalation therapy for RRMS: </b>Fingolimod is considered an escalation therapy for the patient profiles mentioned below.</p><ul><li class="half_rhythm"><div>Patients who are asymptomatic but have MRI demonstrating gadolinium-enhancing lesions, indicating clinically silent multiple sclerosis, are evaluated for alternative treatment.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></div></li></ul><ul><li class="half_rhythm"><div>Patients who experience more than one relapse per year.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></div></li></ul><ul><li class="half_rhythm"><div>Patients with more than 9 T2 lesions on MRI at any given time.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></div></li></ul><p>
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<b>Fingolimod as de-escalation therapy for RRMS: </b>Fingolimod offers viable options under specific conditions when considering de-escalation strategies for RRMS<b>.</b></p><ul><li class="half_rhythm"><div>Fingolimod therapy may be initiated after discontinuing disease-modifying therapy. Patients should be closely monitored for overlapping immunosuppressant effects.</div></li></ul><ul><li class="half_rhythm"><div>Initiating fingolimod 8 to 12 weeks after natalizumab therapy has been shown to reduce relapse rates compared to glatiramer acetate or no treatment.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a><a class="bibr" href="#article-159964.r27" rid="article-159964.r27">[27]</a></div></li></ul><ul><li class="half_rhythm"><div>Before initiating fingolimod therapy, physicians should rule out disease-modifying therapy–related diseases, such as progressive multifocal leukoencephalopathy (PML), infections, tumors, and cardiac pathology.<a class="bibr" href="#article-159964.r28" rid="article-159964.r28">[28]</a></div></li></ul><p>
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<b>Discontinuation of Fingolimod</b>
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</p><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r29" rid="article-159964.r29">[29]</a></div></li></ul><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r30" rid="article-159964.r30">[30]</a></div></li></ul><p>
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<b>Specific Patient Populations</b>
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</p><p>
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<b>Hepatic impairment:</b> 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).<a class="bibr" href="#article-159964.r31" rid="article-159964.r31">[31]</a> </p><p>
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<b>Renal impairment: </b>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.<a class="bibr" href="#article-159964.r32" rid="article-159964.r32">[32]</a></p><p>
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<b>Pregnancy considerations: </b>Fingolimod has a low molecular weight, allowing it to cross the placental membrane easily.<a class="bibr" href="#article-159964.r33" rid="article-159964.r33">[33]</a> Preclinical data suggest that sphingosine receptors might help regulate placenta and embryonic angiogenesis.<a class="bibr" href="#article-159964.r33" rid="article-159964.r33">[33]</a><a class="bibr" href="#article-159964.r34" rid="article-159964.r34">[34]</a> 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.<a class="bibr" href="#article-159964.r34" rid="article-159964.r34">[34]</a> </p><p>Abrupt discontinuation of fingolimod before and during pregnancy may increase the risk of disease relapse.<a class="bibr" href="#article-159964.r35" rid="article-159964.r35">[35]</a> 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.<a class="bibr" href="#article-159964.r36" rid="article-159964.r36">[36]</a> The fingolimod pregnancy registry is available to monitor potential fetal or maternal complications further.</p><p>
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<b>Breastfeeding considerations:</b> Patients should be informed that fingolimod can be present in breast milk, and therefore, breastfeeding is not recommended while taking this medication.</p></div><div id="article-159964.s5"><h2 id="_article-159964_s5_">Adverse Effects</h2><p>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.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></p><p>
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<b>Warnings and Precautions </b>
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</p><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r37" rid="article-159964.r37">[37]</a><a class="bibr" href="#article-159964.r38" rid="article-159964.r38">[38]</a> 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.<a class="bibr" href="#article-159964.r39" rid="article-159964.r39">[39]</a> Ventricular arrhythmia has not been reported in trials, likely due to the absence of inward rectifying potassium channels within the ventricle.<a class="bibr" href="#article-159964.r40" rid="article-159964.r40">[40]</a></div></li></ul><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r39" rid="article-159964.r39">[39]</a></div></li></ul><ul><li class="half_rhythm"><div>Patients treated with fingolimod commonly experience reversible lymphopenia, which heightens the risk of developing opportunistic infections such as cryptococcal, herpes simplex virus, and nasopharyngitis.<a class="bibr" href="#article-159964.r27" rid="article-159964.r27">[27]</a><a class="bibr" href="#article-159964.r41" rid="article-159964.r41">[41]</a><a class="bibr" href="#article-159964.r42" rid="article-159964.r42">[42]</a> Coadministration of valacyclovir has proven beneficial and well-tolerated by patients, with resolution of herpetic diseases typically occurring within a few weeks.<a class="bibr" href="#article-159964.r6" rid="article-159964.r6">[6]</a></div></li></ul><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r43" rid="article-159964.r43">[43]</a></div></li></ul><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r44" rid="article-159964.r44">[44]</a><a class="bibr" href="#article-159964.r45" rid="article-159964.r45">[45]</a> </div></li></ul><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r31" rid="article-159964.r31">[31]</a></div></li></ul><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r6" rid="article-159964.r6">[6]</a></div></li></ul><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r46" rid="article-159964.r46">[46]</a></div></li></ul><ul><li class="half_rhythm"><div>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.<a class="bibr" href="#article-159964.r47" rid="article-159964.r47">[47]</a></div></li></ul><ul><li class="half_rhythm"><div>Multiple cases of basal cell carcinoma have been documented in patients receiving fingolimod treatment.<a class="bibr" href="#article-159964.r27" rid="article-159964.r27">[27]</a></div></li></ul></div><div id="article-159964.s6"><h2 id="_article-159964_s6_">Contraindications</h2><p>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.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></p><p>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.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></p></div><div id="article-159964.s7"><h2 id="_article-159964_s7_">Monitoring</h2><p>Before starting fingolimod therapy, medical providers should complete the following measures:</p><ul><li class="half_rhythm"><div>Perform baseline vital signs assessments.</div></li></ul><ul><li class="half_rhythm"><div>Conduct a complete blood count, hepatic function test, and pregnancy test.</div></li></ul><ul><li class="half_rhythm"><div>Screen for severe liver failure, chronic hepatitis, and HIV infection.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a> </div></li></ul><ul><li class="half_rhythm"><div>Obtain varicella-zoster virus (VZV) antibody titers to assess immunity status.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a> </div></li></ul><ul><li class="half_rhythm"><div>Conduct an ophthalmological evaluation to rule out macular edema.<a class="bibr" href="#article-159964.r45" rid="article-159964.r45">[45]</a></div></li></ul><ul><li class="half_rhythm"><div>Obtain an ECG to establish baseline QTc interval and evaluate for preexisting heart blocks.</div></li></ul><ul><li class="half_rhythm"><div>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.</div></li></ul><ul><li class="half_rhythm"><div>Assess the patient's history for malignancy and consider dermatological evaluation to rule out skin malignancies.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></div></li></ul><ul><li class="half_rhythm"><div>Evaluate for the presence of neuromyelitis optica by obtaining aquaporin-4 antibodies, especially in patients presenting with ocular symptoms suggestive of this condition.<a class="bibr" href="#article-159964.r48" rid="article-159964.r48">[48]</a></div></li></ul><ul><li class="half_rhythm"><div>Advise patients to utilize at least 2 effective contraceptive methods during the course of fingolimod therapy and for 2 months following discontinuation of therapy.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></div></li></ul><ul><li class="half_rhythm"><div>Educate patients about the risk of developing tumefactive lesions within 6 months of starting fingolimod therapy.<a class="bibr" href="#article-159964.r46" rid="article-159964.r46">[46]</a></div></li></ul><ul><li class="half_rhythm"><div>Perform a brain MRI scan with and without contrast.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></div></li></ul><p>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.</p><p>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.<a class="bibr" href="#article-159964.r37" rid="article-159964.r37">[37]</a><a class="bibr" href="#article-159964.r38" rid="article-159964.r38">[38]</a><a class="bibr" href="#article-159964.r39" rid="article-159964.r39">[39]</a></p><p>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.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a> If the lymphocyte count drops below 200 cells/mL, physicians should halt fingolimod therapy until the count improves to 600 cells/mL.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a> Patients with a low baseline lymphocyte count or a baseline metabolic index below 18.5 kg/m<sup>2</sup> are at higher risk of developing lymphopenia.<a class="bibr" href="#article-159964.r49" rid="article-159964.r49">[49]</a> </p><p>Fingolimod therapy should be discontinued if liver enzymes remain elevated to 5 times the upper limit on 2 consecutive labs 3 months apart.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a><a class="bibr" href="#article-159964.r31" rid="article-159964.r31">[31]</a> 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.<a class="bibr" href="#article-159964.r34" rid="article-159964.r34">[34]</a> 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.<a class="bibr" href="#article-159964.r2" rid="article-159964.r2">[2]</a></p></div><div id="article-159964.s8"><h2 id="_article-159964_s8_">Toxicity</h2><p>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.<a class="bibr" href="#article-159964.r50" rid="article-159964.r50">[50]</a> Severe immunosuppression, particularly notable in patients who have undergone postrenal transplant, may develop, significantly elevating the risk for potentially fatal opportunistic infections.<a class="bibr" href="#article-159964.r51" rid="article-159964.r51">[51]</a> Myelosuppression is not an adverse effect of fingolimod therapy.<a class="bibr" href="#article-159964.r52" rid="article-159964.r52">[52]</a> 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.<a class="bibr" href="#article-159964.r53" rid="article-159964.r53">[53]</a> Efforts to mitigate toxicity are ongoing, with the development of multiple S1PR-specific antagonists aimed at reducing adverse effects. </p></div><div id="article-159964.s9"><h2 id="_article-159964_s9_">Enhancing Healthcare Team Outcomes </h2><p>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.</p><p>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.</p><p>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.</p></div><div id="article-159964.s10"><h2 id="_article-159964_s10_">Review Questions</h2><ul><li class="half_rhythm"><div>
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</div></li></ul></div><div id="article-159964.s11"><h2 id="_article-159964_s11_">References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="article-159964.r1">Pournajaf S, Dargahi L, Javan M, Pourgholami MH. Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod. <span><span class="ref-journal">Front Pharmacol. </span>2022;<span class="ref-vol">13</span>:807639.</span> [<a href="/pmc/articles/PMC8889014/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8889014</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35250559" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35250559</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="article-159964.r2">Ayzenberg I, Hoepner R, Kleiter I. 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<b>Disclosure: </b>Milena Lobaina declares no relevant financial relationships with ineligible companies.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_top_margin">
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<b>Disclosure: </b>Elena Shanina declares no relevant financial relationships with ineligible companies.</p></div></dd></dl></dl></div></div></div><div class="fm-sec"><h2 id="_NBK604198_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Milena Lobaina</span><sup>1</sup>; <span itemprop="author">Elena Shanina</span><sup>2</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> University Of Texas Medical Branch</div><div class="affiliation"><sup>2</sup> University of Texas Medical Branch</div><h3>Publication History</h3><p class="small">Last Update: <span itemprop="dateModified">May 30, 2024</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 2025, StatPearls Publishing LLC.<p class="small">
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This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
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(<a href="https://creativecommons.org/licenses/by-nc-nd/4.0/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">
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http://creativecommons.org/licenses/by-nc-nd/4.0/
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</a>), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.
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</p></div></div><h3>Publisher</h3><p><a href="https://www.statpearls.com/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">StatPearls Publishing</a>, Treasure Island (FL)</p><h3>NLM Citation</h3><p>Lobaina M, Shanina E. Fingolimod. [Updated 2024 May 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"></div><div class="small-screen-next"></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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