Version May 2024
Note: Administer the initial dose, the first dose following therapy interruption (>14 days), and the first dose of a dose increase in a setting in which resources to appropriately manage symptomatic bradycardia are available; monitor for 6 hours postdose; additional monitoring may be necessary in select patients. Prior to initiating fingolimod therapy, complete all age-appropriate immunizations (particularly human papillomavirus and varicella zoster virus) according to current immunization guidelines, if possible. In high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other appropriate specialists (eg, liver specialists) regarding treatment options before initiating therapy (Ref).
Multiple sclerosis, relapsing:
Children ≥10 years and Adolescents: Capsule or orally disintegrating tablet:
≤40 kg: Oral: 0.25 mg once daily.
>40 kg: Oral: 0.5 mg once daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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 adult 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 (Ref).
Children ≥10 years and Adolescents:
Baseline hepatic impairment:
Mild to moderate impairment: No dosage adjustment necessary; use with caution and monitor closely.
Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution and closely monitor; exposure is increased.
Hepatotoxicity during therapy:
ALT >3 times ULN and total bilirubin >2 times ULN: Interrupt treatment; permanently discontinue fingolimod if alternative etiology for hepatic injury cannot be identified due to risk of severe drug-induced liver injury.
(For additional information see "Fingolimod: Drug information")
Note: First-dose, 6-hour monitoring is recommended for all patients; administer the first dose and doses following therapy interruption (longer than 14 days) in a setting in which resources to appropriately manage symptomatic bradycardia are available. Complete all immunizations according to current immunization guidelines, if possible, prior to initiating fingolimod therapy. In high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other appropriate specialists (eg, liver specialists) regarding treatment options before initiating therapy (Ref).
Multiple sclerosis, relapsing: Oral: 0.5 mg once daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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 (Ref).
Hepatic impairment prior to treatment initiation:
Mild to moderate impairment (Child-Pugh classes A and B): No dosage adjustment necessary; use with caution and monitor closely.
Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling; use with caution and monitor closely (exposure is increased).
Hepatotoxicity during treatment:
ALT >3 times ULN and total bilirubin >2 times ULN: Interrupt treatment; permanently discontinue fingolimod if alternative etiology for hepatic injury cannot be identified due to risk of severe drug-induced liver injury.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported in adults, unless otherwise noted.
>10%:
Gastrointestinal: Abdominal pain (11%), diarrhea (13%), nausea (13%)
Hepatic: Increased gamma-glutamyl transferase (≤15%), increased serum alanine aminotransferase (≤15%), increased serum aspartate transaminase (≤15%)
Infection: Influenza (11%)
Nervous system: Headache (25%)
Respiratory: Cough (12%), sinusitis (11%)
1% to 10%:
Cardiovascular: Bradycardia (3%), first-degree atrioventricular block (5%), hypertension (8%), second-degree atrioventricular block (4%)
Dermatologic: Actinic keratosis (2%), alopecia (3%), basal cell carcinoma of skin (2%), cutaneous papilloma (3%), tinea versicolor (2%)
Endocrine & metabolic: Increased serum triglycerides (3%)
Hematologic & oncologic: Leukopenia (2%), lymphocytopenia (7%)
Infection: Herpes virus infection (9%), herpes zoster infection (2%)
Nervous system: Asthenia (2%), migraine (6%), seizure (children and adolescents: 6%)
Neuromuscular & skeletal: Back pain (10%), limb pain (10%)
Ophthalmic: Blurred vision (4%)
Respiratory: Bronchitis (8%), dyspnea (9%)
Frequency not defined:
Hepatic: Increased serum bilirubin
Infection: Pneumonia
Postmarketing:
Cardiovascular: Asystole, complete atrioventricular block, syncope, ventricular tachycardia (Elounais 2017)
Dermatologic: Malignant melanoma (Robinson 2016), Merkel cell carcinoma
Hematologic & oncologic: Glioblastoma (Sharim 2016), hemolytic anemia, immune thrombocytopenia (Yuen 2017), Kaposi sarcoma, malignant lymphoma (including B-cell lymphoma, CNS lymphoma, non-Hodgkin lymphoma, T-cell lymphoma [including cutaneous T-cell lymphoma and mycosis fungoides]), squamous cell carcinoma, thrombocytopenia
Hepatic: Hepatic injury (including acute hepatic failure [Biolato 2021]) (Memon 2017)
Hypersensitivity: Angioedema, hypersensitivity reaction
Immune: Immune reconstitution syndrome (Piñar Morales 2022)
Infection: Herpes simplex infection, human papilloma virus infection (including related cancer), opportunistic infection (including atypical mycobacterial infection, cryptococcosis, and JC virus infection), varicella zoster infection
Nervous system: Herpes simplex encephalitis (Pfender 2015), progressive multifocal leukoencephalopathy (Piñar Morales 2022), reversible posterior leukoencephalopathy syndrome, status epilepticus
Neuromuscular & skeletal: Arthralgia, myalgia
Ophthalmic: Macular edema (Jasani 2017), retinal hemorrhage (Ueda 2015)
Respiratory: Decreased lung function (diffusion lung capacity for carbon monoxide) (Bianco 2016), reduced forced expiratory volume (Bianco 2016)
Miscellaneous: Multi-organ failure
Hypersensitivity to fingolimod (including rash, urticaria, and angioedema) or any component of the formulation; myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or New York Heart Association class III/IV heart failure in the past 6 months; Mobitz Type II second- or third-degree atrioventricular 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; concurrent use with other products containing fingolimod (Tascenso ODT).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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, 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); pregnancy and women in childbearing years not using effective contraception.
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.
• 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.
• Infections: A dose-dependent decrease in lymphocyte counts may occur. Obtain a CBC, including lymphocyte count, prior to initiation of therapy, then every 3 months thereafter or as clinically indicated (AAN [Rae-Grant 2018]). Patients with lower lymphocyte counts at baseline, BMI <18.5 kg/m2, females, and those with previous exposure to natalizumab may be at increased risk (Baharnoori 2018; Warnke 2014). In patients who develop lymphopenia during fingolimod treatment, using an alternate dosing schedule (eg, every other day dosing or dosing 5 days out of 7 days) may raise circulating lymphocyte counts without increasing disease activity (Longbrake 2018). Interrupt therapy with fingolimod in patients who develop serious infections. Due to a potential for delayed lymphocyte recovery following treatment interruption or discontinuation, monitor lymphocyte counts for at least 2 months after stopping therapy. Do not initiate or restart fingolimod in patients with acute or chronic infections.
- Bacterial infections: Serious opportunistic bacterial infections (eg, atypical mycobacteria) have been reported with use. Promptly evaluate and treat patients with symptoms and signs of an infection.
- Cryptococcal infections: Cases of cryptococcal meningitis and disseminated cryptococcal infections (including fatalities) 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.
- Hepatitis: In high-risk populations, screen for latent hepatitis infections prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other specialists (eg, liver specialists) regarding treatment options before initiating therapy (AAN [Farez 2019]).
- Herpes: 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 multiple sclerosis (MS) relapse or multiorgan failure occurs. Cases of Kaposi sarcoma (associated with human herpes virus-8) have been reported; if suspected, prompt diagnostic evaluation and management is required.
- Human papilloma virus: Human papilloma virus (HPV) infections, including papilloma, dysplasia, warts, and HPV-related cancer, have been reported. Cancer screening (eg, Papanicolaou [Pap] test) is recommended per standard of care. Consider HPV vaccination prior to treatment initiation.
- Tuberculosis: In high-risk populations or in countries with high tuberculosis (TB) burden, screen for TB infection prior (latent TB) to initiating therapy. For patients who screen positive, consult infectious disease specialists regarding treatment options before initiating therapy (AAN [Farez 2019]).
- Varicella zoster: Serious, life-threatening events of disseminated varicella infections have occurred with fingolimod use. Varicella zoster virus vaccination is recommended 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.
• Liver injury: Liver injury has occurred (including acute liver failure requiring liver transplant); elevated serum liver enzymes and total bilirubin have been reported as early as 10 days after the first dose and with prolonged use (most elevations occurred within 6 to 9 months). Recurrence of liver transaminase elevations may occur with rechallenge. Obtain baseline liver enzymes and bilirubin in all patients prior to therapy initiation (within 6 months) and periodically during therapy and until 2 months after discontinuation of therapy. Monitor liver enzymes and bilirubin in patients who develop symptoms of hepatic injury (eg, right abdominal pain, fatigue, anorexia, jaundice, dark urine). Interrupt treatment if ALT and bilirubin are >3 times and >2 times the ULN, respectively; transaminases tend to return to normal within 2 months of discontinuation. Do not resume treatment if etiology of liver injury cannot be established.
• 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 (eg, non-Hodgkin, CNS, mycosis fungoides) and skin cancers (eg, melanoma, squamous cell carcinoma, Merkel cell carcinoma) have been reported. Basal cell carcinoma and melanoma risk is increased with fingolimod use; monitor for suspicious skin lesions periodically (especially in patients with risk factors for skin cancer) and promptly evaluate. Patients should minimize exposure to sunlight and ultraviolet light by wearing protective clothing and sunscreen with high protection factor.
• 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 and associated sequelae: Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients taking S1P receptor modulators; associated risk factors include use in immunocompromised patients and polytherapy with immunosuppressants. Symptoms progress over days to weeks and may include progressive weakness on one side of the body or clumsiness of limbs, vision disturbances, and mental status changes. Discontinue treatment if PML is confirmed. Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients who discontinued S1P receptor modulator therapy due to developing PML. In most cases, IRIS occurred within a few months after discontinuation. IRIS can result in a decline in patient condition, including characteristic changes on MRI, neurological symptoms, and death; initiate appropriate treatment of inflammation.
• 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 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 (adult and pediatric males: >450 msec; adult females: >470 msec; pediatric females: >460 msec) or during the first 6 hours of treatment initiation, or who are at an increased risk of QT prolongation (eg, hypokalemia, hypomagnesemia, concomitant QT-prolonging drugs [eg, citalopram, chlorpromazine, haloperidol, methadone, erythromycin], congenital long-QT syndrome) require continuous overnight electrocardiogram (ECG) monitoring in a medical facility after the initial dose.
• Tumefactive multiple sclerosis: MS relapses with tumefactive demyelinating lesions have been reported. May occur at any time during therapy, but most cases occurred within the first 9 months after treatment initiation; may also occur within the first 4 months after treatment discontinuation.
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 caution in patients with preexisting liver disease; may be at increased risk of increased liver enzymes.
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 the first 24 weeks after 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 2017). Patients who experience rebound symptoms may not return to the functional status attained during treatment with fingolimod. Monitor for development of IRIS in the setting of PML and severe increase in disability, especially during the first 12 weeks following discontinuation, and begin appropriate treatment as needed.
• Immunizations: Patients should complete all immunizations according to current immunization guidelines, if possible, prior to initiating fingolimod therapy. Avoid live-attenuated vaccines in patients who currently receive or have recently discontinued fingolimod; consider using live-attenuated vaccines only if risk of infection is high and killed vaccines are unavailable (AAN [Farez 2019]).
The safety profile in pediatric patients has been reported as similar to adults; however, pediatric patients have a higher incidence of seizures compared to adults (5.6% vs 0.9%); it is unclear if this is a drug-related or disease-related occurrence.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Gilenya: 0.25 mg, 0.5 mg
Generic: 0.5 mg
Tablet Disintegrating, Oral:
Tascenso ODT: 0.25 mg, 0.5 mg
May be product dependent
Capsules (Fingolimod HCl Oral)
0.5 mg (per each): $350.52 - $370.16
Capsules (Gilenya Oral)
0.25 mg (per each): $425.26
0.5 mg (per each): $425.26
Tablet, orally-disintegrating (Tascenso ODT Oral)
0.25 mg (per each): $416.92
0.5 mg (per each): $416.92
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Gilenya: 0.25 mg, 0.5 mg
Generic: 0.5 mg
Oral: Administer with or without food.
Orally disintegrating tablet: Do not remove tablet from blister pack until ready to administer; peel back foil to expose tablet; do not push tablet through foil. Use dry hands to remove tablet and place immediately on tongue; allow tablet to dissolve before swallowing; may be swallowed with or without water.
Oral: Administer with or without food.
Orally disintegrating tablet: Do not remove tablet from blister pack until ready to administer; peel back foil to expose tablet; do not push tablet through foil. Use dry hands to remove tablet and place immediately on tongue; allow tablet to dissolve before swallowing; may be swallowed with or without water.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from moisture. Keep oral disintegrating tablet in sealed blister pack until ready to use.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022527s038lbl.pdf#page=27, must be dispensed with this medication.
Treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease (FDA approved in ages ≥10 years and adults).
Substrate of CYP3A4 (minor), CYP4F2 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Amiodarone: Fingolimod may enhance the QTc-prolonging effect of Amiodarone. Risk X: Avoid combination
Antithymocyte Globulin (Equine): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Bradycardia-Causing Agents: May enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
CarBAMazepine: May decrease the serum concentration of Fingolimod. Risk C: 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. Risk D: Consider therapy modification
Chikungunya Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
Corticosteroids (Systemic): Sphingosine 1-Phosphate (S1P) Receptor Modulator may enhance the immunosuppressive effect of Corticosteroids (Systemic). Risk C: Monitor therapy
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Immunosuppressants (Cytotoxic Chemotherapy): Sphingosine 1-Phosphate (S1P) Receptor Modulator may enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy
Immunosuppressants (Miscellaneous Oncologic Agents): Sphingosine 1-Phosphate (S1P) Receptor Modulator may enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy
Immunosuppressants (Therapeutic Immunosuppressant Agents): Sphingosine 1-Phosphate (S1P) Receptor Modulator may enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy
Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Ketoconazole (Systemic): May increase serum concentrations of the active metabolite(s) of Fingolimod. Ketoconazole (Systemic) may increase the serum concentration of Fingolimod. Risk C: Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy
Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Methotrexate: May enhance the immunosuppressive effect of Sphingosine 1-Phosphate (S1P) Receptor Modulator. Risk C: Monitor therapy
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification
QT-prolonging Agents (Highest Risk): Fingolimod may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias (including TdP) with a continuous overnight ECG when fingolimod is combined with QT prolonging drugs. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
QT-prolonging Class IA Antiarrhythmics (Highest Risk): Fingolimod may enhance the QTc-prolonging effect of QT-prolonging Class IA Antiarrhythmics (Highest Risk). Risk X: Avoid combination
QT-prolonging Class III Antiarrhythmics (Highest Risk): Fingolimod may enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Risk X: Avoid combination
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ritlecitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Fingolimod may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). 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. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
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. Risk X: Avoid combination
Evaluate pregnancy status prior to use in females of reproductive potential. Elimination of fingolimod takes approximately 2 months; to avoid potential fetal harm, females of childbearing potential should use effective contraception to avoid pregnancy during therapy and for 2 months after discontinuing treatment.
In general, disease-modifying therapies for multiple sclerosis (MS) are stopped prior to a planned pregnancy except in females at high risk of MS activity (AAN [Rae-Grant 2018]). Consider use of agents other than fingolimod in females at high risk of disease reactivation who are planning a pregnancy. Delaying pregnancy is recommended for females with persistent high disease activity; when disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/EAN [Montalban 2018]). Females who are considering stopping fingolimod when planning pregnancy should be counseled on the possibility of severe worsening of disability. Patients should seek immediate medical attention if they experience new or worsened symptoms of MS after fingolimod is stopped.
Outcome information related to the use of fingolimod in pregnancy is limited (Geissbühler 2018; Karlsson 2014; Lopez-Leon 2020; Navardi 2018; Nguyen 2019; Pauliat 2020). Based on data from animal reproduction studies, in utero exposure to fingolimod may cause fetal harm.
In general, disease-modifying therapies for multiple sclerosis (MS) are not initiated during pregnancy, except in females at high risk of MS activity (AAN [Rae-Grant 2018]). When disease-modifying therapy is needed in these patients, agents other than fingolimod are preferred (ECTRIMS/EAN [Montalban 2018]). Clinical rebound (new neurologic symptoms and increased lesions) has been reported when fingolimod treatment was discontinued during pregnancy (Meinl 2018; Novi 2017; Sempere 2013). Females who are considering stopping fingolimod because of pregnancy should be counseled on the possibility of severe worsening of disability. Patients should seek immediate medical attention if they experience new or worsened symptoms of MS after fingolimod is stopped.
Data collection to monitor pregnancy and infant outcomes following exposure to fingolimod is ongoing. Health care providers are encouraged to enroll females exposed during pregnancy in the Gilenya Pregnancy Registry (1-877-598-7237 or https://www.gilenyapregnancyregistry.com). Pregnant females may also enroll themselves.
First dose cardiac monitoring: ECG (baseline and at the end of observation period); heart rate, blood pressure, signs and symptoms of bradycardia (hourly for 6 hours following first dose). Continued cardiac observation is required (until resolved, even if asymptomatic) in the following scenarios: If the 6-hour postdose heart rate is lower than the stated values (children 10 or 11 years: <60 bpm; children and adolescents ≥12 years: <55 bpm; adults: <45 bpm); if the 6-hour postdose heart rate is the lowest postdose heart rate (suggesting that maximum heart rate effects have not yet occurred); or if 6-hour postdose ECG shows new-onset second degree or higher atrioventricular block. If postdose symptomatic bradycardia occurs and no pharmacologic treatment is necessary, provide continuous ECG monitoring until symptoms are resolved. If postdose symptomatic bradycardia occurs and pharmacologic intervention is necessary, provide overnight continuous ECG monitoring in a medical facility and repeat the 6-hour observation period for the second dose. Patients also require overnight continuous ECG monitoring in a medical facility if baseline or 6-hour post dose QTc interval is prolonged (>450 msec for pediatric and adult males, >460 msec for pediatric females, >470 msec for adult females), if they have additional risks for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long-QT syndrome) or if they are receiving 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 in the following situations:
• Treatment interruption of ≥1 day during the first 2 weeks after treatment initiation
• Treatment interruption of >7 days during weeks 3 to 4 after treatment initiation
• Treatment interruption of >14 days after ≥1 month of treatment initiation
Hepatic monitoring: Bilirubin and transaminase levels (baseline [within 6 months of therapy initiation]; at months 1, 3, 6, 9, and 12 of therapy; and periodically thereafter, including for 2 months after therapy discontinuation; immediately in patients who develop symptoms of hepatic dysfunction).
CBC including lymphocyte counts (baseline, then every 3 months and as clinically necessary) (AAN [Rae-Grant 2018]); latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline); varicella-zoster virus (VZV) antibodies (prior to starting treatment in patients with no health care professional-confirmed history of chickenpox or without documented previous full series VZV vaccination) (AAN [Farez 2019]); signs and symptoms of infection (during treatment and for at least 2 months after discontinuation), progressive multifocal leukoencephalopathy (PML), immune reconstitution inflammatory syndrome (IRIS), and/or posterior reversible encephalopathy syndrome; MRI to monitor for early signs of PML (baseline, periodically, and as clinically indicated); blood pressure and heart rate; 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, diffusion lung capacity for carbon monoxide [DLCO]) if clinically indicated), skin examination and monitoring for suspicious skin lesions (periodically); severe increase in disability following discontinuation of therapy.
Evaluate pregnancy status prior to use in patients of reproductive potential.
Fingolimod-phosphate, a sphingosine-1-phosphate (S1P) receptor modulator and active metabolite of fingolimod, binds to S1P receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks lymphocytes' ability to emerge from lymph nodes, reducing the number of lymphocytes available to the CNS.
Distribution: Vd: ~1,200 L: distributes into red blood cells (86%)
Protein binding: >99.7% (fingolimod and fingolimod-phosphate)
Metabolism: Hepatic via CYP4F2 to fingolimod-phosphate (active) and other metabolites (inactive); CYP2D6, 2E1, 3A4, and 4F12 also contribute to metabolism
Bioavailability: 93%
Half-life elimination: 6 to 9 days; prolonged by approximately 50% in patients with moderate or severe hepatic impairment
Time to peak, plasma: 12 to 16 hours
Excretion: Urine (~81% as inactive metabolites); feces (fingolimod and fingolimod phosphate: <2.5% of dose)
Altered kidney function: 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.
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.
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