Fingolimod is a sphingosine 1-phosphate receptor modulator. The drug is indicated for the treatment of adult and pediatric patients 10 years and older with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. The drug reduces the frequency of clinical exacerbations and delays the accumulation of physical disability. In a year-long comparative study, fewer adult patients who received fingolimod 0.5 mg orally each day as compared with interferon beta-1a 30 mcg IM once weekly had a relapse (17% vs. 30%). The annualized relapse rate was 0.16 for fingolimod recipients and 0.33 for interferon beta-1a recipients. Because of the risk of bradycardia, monitor patients for 6 hours after the first dose upon treatment initiation, a dose increase, or a significant interruption in treatment. Hypersensitivity, cardiac or ocular conditions, or severe hepatic disease may preclude treatment with the drug. Fingolimod was initially approved by the FDA in 2010; pediatric approval was attained in 2018 (capsules) and 2021 (orally disintegrating tablet). Financial assistance and other information is available by calling 1-877-408-4974.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
First dose monitoring
-Ensure that pre-initiation testing has been completed (e.g., ECG, liver function tests, CBC, eye exams) and that current medications have been reviewed.
-Administer the first dose in a setting that has adequate resources to manage symptomatic bradycardia.
-Monitor patients for 6 hours after the first dose for signs and symptoms of bradycardia. Perform hourly pulse and blood pressure assessment.
-Obtain an ECG in all patients at the end of the 6-hour observation period.
-At the 6-hour time point, institute additional observation if:-the heart rate is less than 45 beats per minute (bpm) in adults
-heart rate is less than 55 bpm in patients 12 to 17 years or less than 60 bpm in patients 10 to 11 years
-if the heart rate is at the lowest value after fingolimod receipt; or if the ECG shows new onset second degree or higher AV block.
-Begin continuous ECG monitoring if symptomatic bradycardia occurs at any time point. Continue observation until symptoms have resolved. If pharmacologic intervention is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose.
When to repeat recommended monitoring procedures
-Repeat first dose monitoring procedures if fingolimod dosing/administration is interrupted for 1 day or more during the first 2 weeks of treatment, more than 7 days during weeks 3 and 4 of treatment, or more than 14 days after the first month of treatment.
-Repeated first dose monitoring procedures are also recommended when the dose is increased in pediatric patients.
-Patients who underwent first-dose monitoring at initiation and are switched to the orally disintegrating tablets at the same daily dose, do not need to repeat first-dose monitoring, unless the previous treatment was discontinued more than 14 days prior.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-May administer with or without food.
The safety profile of fingolimod in pediatric patients was similar to that seen in adults during controlled clinical trials.
Initiation of fingolimod results in a transient decrease in heart rate. Symptomatic bradycardia after the first dose was reported in 0.6% of adult patients during clinical trial evaluation. Among 783 adult patients who received fingolimod 0.5 mg on a daily basis, 3% of patients had bradycardia as compared with 1% of 773 placebo recipients. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced hypotension, dizziness, fatigue, palpitations, and chest pain (unspecified) that usually resolved within the first 24 hours on treatment. In clinical trials, less than 1% of patients who received fingolimod had dizziness. After the first dose, the decrease in heart rate starts within an hour, and the maximal decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8 to 10 hours after the dose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, the heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. After the second dose, a further decrease in heart rate may occur as compared with the heart rate before the second dose, but this change is of a smaller magnitude than that observed after the first dose; 70% of the negative chronotropic effect is achieved on the first day. With continued dosing, the heart rate progressively returns to baseline within 1 month of chronic treatment. Heart rates below 40 bpm in adult patients and below 50 bpm in pediatric patients were rarely observed. In addition to bradycardia, transient AV conduction delays may occur with fingolimod initiation. In adult clinical trials, first degree AV block (prolonged PR interval on electrocardiogram) after the first dose was reported in 4.7% of patients. Among patients with 24-hour Holter monitoring data after their first dose, second degree AV blocks usually Mobitz type I (Wenckebach) were reported in 4% of 351 patients taking fingolimod 0.5 mg and in 2% of 346 patients taking placebo. Five patients who took fingolimod had 2:1 AV block. The conduction abnormalities were usually transient and asymptomatic with resolution within the first 24 hours of treatment. However, conduction abnormalities occasionally required treatment with atropine or isoproterenol. In the postmarketing setting, third degree AV block and AV block with junctional escape have been observed during the first-dose 6-hour observation period. Isolated delayed onset events including transient asystole and unexplained death have occurred within 24 hours of the first dose. These events were confounded by concomitant medications and/or pre-existing disease, and the relationship to fingolimod is uncertain. Syncope has also been noted after the first dose. Autonomic responses of the heart including diurnal variation of heart rate and response to exercise are not affected by fingolimod. Further, fingolimod is not associated with a decrease in cardiac output, and no clinically relevant prolongation of QT interval was noted among patients in clinical studies, but patients at risk for QT prolongation were not included in clinical studies. At higher than indicated doses of 1.25 mg or 2.5 mg, a prolongation of QTc with the upper bound of the 90% confidence interval of 14 msec was noted at steady-state when a negative chronotropic effect of fingolimod was still present. In December 2011, the FDA received a report of a patient with multiple sclerosis who died within 24 hours of taking the first dose of fingolimod. The FDA evaluated this report and additional clinical trial and postmarketing data including reports of patients who died of cardiovascular events or unknown causes. The FDA could not definitively conclude that fingolimod was related to any of the deaths, but the FDA remains concerned about the cardiovascular effects of fingolimod after the first dose. Prescribers are advised to follow the initiation and monitoring recommendations in the approved drug label. When used as directed, fingolimod offers an important benefit to appropriately selected patients with MS. Healthcare professionals and patients are encouraged to report adverse events or side effects related to fingolimod to the FDA's MedWatch Safety Information and Adverse Event Reporting Program by calling 1-800-332-1088.
Fingolimod causes a dose-dependent reduction in peripheral lymphocyte count to 20% to 30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. Do not utilize peripheral blood lymphocyte counts to assess lymphopenia; fingolimod reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, so a peripheral blood count will not be indicative of the lymphocyte population. Among 783 adult fingolimod recipients, 7% had lymphopenia, and 18% reached a nadir of less than 200 cells/mcL on at least 1 occasion. In contrast, less than 1% of 773 placebo recipients had lymphopenia. Low lymphocyte counts are maintained with chronic daily fingolimod dosing. In addition to lymphopenia, neutropenia and leukopenia may occur. Chronic fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of baseline. Of 783 fingolimod recipients, 2% had leukopenia as compared with less than 1% of 773 placebo recipients. Hemolytic anemia and thrombocytopenia have been reported with postmarketing use. Due to lymphopenia and/or neutropenia, patients who receive fingolimod may develop an infection. In controlled studies, the overall rate of infections (72%) and serious infections (2.3%) with fingolimod was similar to placebo. However, bronchitis, herpes zoster, influenza, sinusitis, and pneumonia (less than 1%) were more common among fingolimod recipients. Among 783 fingolimod recipients, influenza occurred in 11%, herpes zoster in 2%, bronchitis in 8%, sinusitis in 11%, and tinea infections in 2%. In contrast, among 773 placebo recipients, influenza occurred in 8%, herpes zoster in 1%, bronchitis in 5%, sinusitis in 8%, and tinea infections in less than 1%. The incidence of all herpetic infections was 9% in patients who received fingolimod. Two patients who received a higher than indicated fingolimod dose with high-dose corticosteroid therapy died of herpetic infections: 1 patient had disseminated primary herpes zoster, and 1 patient had herpes simplex encephalitis. No deaths due to viral infections occurred in patients treated with the indicated dose of 0.5 mg. Cases of disseminated varicella-zoster and herpes simplex infections, during which encephalitis and multiorgan failure occurred, have been observed postmarketing. Human papillomavirus (HPV) infection, including papilloma, cervical dysplasia, warts, and HPV-related cancer (e.g., cervical cancer) have also been reported. Fatal cryptococcal meningitis and other cryptococcal infections have also occurred in the postmarketing setting; patients with symptoms suggestive of cryptococcal meningitis should undergo an immediate evaluation and receive appropriate treatment. Cryptococcal infections typically occurred following 2 years of treatment, but they may occur earlier. Serious unspecified infections with opportunistic pathogens [e.g., John Cunningham virus (JCV), herpes simplex viruses 1 and 2, varicella-zoster virus, cryptococci, and atypical mycobacteria] have been observed in the postmarketing setting. Additionally, cases of Kaposi's sarcoma (an antiproliferative disorder associated with human herpesvirus 8 (HHV-8) infection) have been reported. A complete blood count within the past 6 months is needed for all patients before fingolimod initiation. Do not start fingolimod in a patient with active acute or chronic infections; the infection needs to be resolved before fingolimod initiation. If a patient develops a serious infection, consider fingolimod discontinuation; reassess the benefits and risks before reinitiation of fingolimod. Increases in peripheral lymphocyte count are evident within days of stopping fingolimod, and typically normal counts occur within 1 to 2 months of fingolimod discontinuation. Fingolimod may persist in the body for up to 2 months after discontinuation, so continue to monitor patients for infection. Instruct patients to report any signs or symptoms of infection.
Among 783 adult patients receiving fingolimod 0.5 mg, macular edema with or without visual symptoms occurred in 0.5% of patients. A dose-dependent increase in the risk of macular edema has been observed; of 799 patients who received fingolimod 1.25 mg, 1.5% experienced macular edema. In contrast, 0.4% of 773 patients who received placebo had the event. Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during fingolimod receipt. In clinical trials, macular edema occurred predominantly in the first 3 to 4 months of therapy. Some patients presented with blurred vision or decreased visual acuity or visual impairment, but others were asymptomatic and diagnosed on routine ophthalmologic examination. Among 783 fingolimod recipients, 4% had blurred vision whereas 2% of 773 placebo recipients had the event. Macular edema generally improved or resolved with or without treatment after fingolimod discontinuation, but some patients had residual visual acuity loss even after resolution of macular edema. A decision as to whether or not to discontinue fingolimod should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after fingolimod rechallenge has not been evaluated. Also, fingolimod continuation in patients who develop macular edema has not been evaluated. Perform an adequate ophthalmologic evaluation at baseline and 3 to 4 months after fingolimod initiation. Also, an ophthalmologic evaluation is warranted if patients report visual disturbances at any time while taking fingolimod. Regular follow-up ophthalmologic evaluations during fingolimod receipt are advised for patients with diabetes mellitus or a history of uveitis.
Among 783 adult fingolimod recipients, dyspnea was reported in 9% of patients receiving fingolimod and in 7% of 773 patients receiving placebo. Cough occurred in 12% of fingolimod recipients and in 11% of placebo recipients. Several patients discontinued fingolimod because of unexplained dyspnea. As early as 1 month after fingolimod initiation, dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed. At month 24, the reduction from baseline in the percent of predicted values for FEV1 was 2.8% for patients who received fingolimod 0.5 mg and was 1% for patients who received placebo. For DLCO, the reduction from baseline in percent of predicted values was 3.3% for patients who received fingolimod 0.5 mg and was 0.5% for patients who received placebo. The changes in FEV1 appear to be reversible after fingolimod discontinuation. Reversibility of the decrease of DLCO after fingolimod discontinuation is unknown. Of note, receipt of fingolimod 0.5 mg/day, 1.25 mg/day, or 5 mg/day was not associated with impaired oxygenation, oxygen desaturation with exercise, or an increase in airway responsiveness to methacholine. Further, fingolimod recipients had a normal bronchodilator response to inhaled beta-agonists. If clinically indicated, perform spirometric evaluation of respiratory function and evaluation of DLCO during fingolimod receipt. Fingolimod has not been tested in MS patients with compromised respiratory function.
Nausea (13%), diarrhea (13%), abdominal pain (11%), and elevated hepatic enzymes including ALT, GGT, AST (15%) were reported during adult clinical trials for fingolimod and at rates higher than with placebo. Drug-induced liver injury (hepatotoxicity, hepatocellular and/or cholestatic hepatitis) and cases of acute hepatic failure requiring transplant have been reported during postmarketing use. Monitor serum transaminases (ALT and AST) and total bilirubin prior to treatment initiation (within 6 months) and periodically throughout therapy until 2 months after drug discontinuation. Promptly obtain liver transaminase and bilirubin concentrations in any patients who report symptoms that may indicate hepatotoxicity (e.g., new or worsening fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice). Interrupt fingolimod if the ALT is more than 3 times the upper limit of normal (ULN) with total bilirubin more than 2 times the ULN (hyperbilirubinemia). Do not resume treatment if a plausible alternative etiology for the signs and symptoms cannot be established; these patients are at risk for severe drug-induced liver injury (hepatotoxicity). Signs of hepatotoxicity have occurred as early as 10 days after the first dose and also after prolonged use. Elevated hepatic enzymes to 3-fold the ULN or more occurred in 14% of adult patients treated with fingolimod. Elevations 5-fold the ULN or more occurred in 4.5% of fingolimod-treated patients; fingolimod was discontinued if elevations exceeded 5 times the ULN during clinical trials. Most elevations occurred within 6 to 9 months. Serum transaminase concentrations returned to normal within approximately 2 months after drug discontinuation; however, recurrence of hepatic enzyme elevations occurred with rechallenge in some patients.
Blood pressure should be monitored during treatment with fingolimod. Among adult patients who took fingolimod 0.5 mg in multiple sclerosis clinical trials, 8% reported hypertension as compared with 4% of patients who took placebo. Patients who received fingolimod had an average increase of approximately 3 mmHg in systolic pressure and approximately 2 mmHg in diastolic pressure, which was first detected after approximately 1 month of fingolimod receipt. The increases persisted with continued treatment.
In the premarketing database, no vascular events were observed with fingolimod 0.5 mg, which is the indicated adult dose for multiple sclerosis. However, higher doses of 1.25 to 5 mg were associated with vascular events including ischemic and hemorrhagic stroke and peripheral arterial occlusive disease in adult patients.
Fingolimod may be associated with centrally-mediated effects including headache, depression, and migraine. Among 783 adult patients who received fingolimod, 25% had headache and 6% had migraine. In contrast, among 773 patients who received placebo, 24% had headache and 4% had migraine. Depression has been reported with fingolimod therapy. During post-hoc analysis of the EPOC trial, changes in the least squares mean Beck Depression Inventory-II scores from baseline to 6 months for fingolimod were superior after a switch from glatiramer acetate (-3.17 +/- 0.46 vs. -1.03 +/- 0.86, p = 0.03). Significant differences in favor of fingolimod were also observed when patients switched from subcutaneous interferon beta-1a (-2.73 +/- 0.47 vs. -0.1 +/- 0.86, p = 0.007) and interferon beta-1b (-4.16 +/- 0.52 vs. 0.14 +/- 0.93, p less than 0.001). No significant differences in scores were observed between patients who switched to fingolimod or those who remained on intramuscular interferon beta-1a.
Seizures, including status epilepticus, have been reported with use of fingolimod in clinical trials and during postmarketing use; it is unclear whether these events are related to the effects of multiple sclerosis alone, to fingolimod, or to a combination of both. In adult clinical trials, seizures were reported in 0.9% of fingolimod-treated patients compared to 0.3% of placebo-treated patients. In pediatric clinical trials, seizures were reported in 5.6% of fingolimod-treated patients compared to 0.9% of interferon beta-1a treated patients.
Hypersensitivity reactions to fingolimod including rash (unspecified), urticaria, and angioedema have occurred in the post-marketing setting. Fingolimod is contraindicated in patients who have had a hypersensitivity reaction to fingolimod or any of the excipients in the formulation. Allergic reactions appear to be more common during initiation of therapy, but may occur at any time. Fingolimod may be associated with dermatologic effects such as alopecia, atopic dermatitis, and pruritus. Among 783 adult fingolimod recipients, 3% had alopecia as compared with 2% of 773 placebo recipients. Eczema (atopic dermatitis) and pruritus were each noted in less than 1% of fingolimod recipients.
During clinical trials of multiple sclerosis patients, the following general effects not listed elsewhere were reported more frequently in adult patients receiving fingolimod than placebo: back pain (10%), extremity pain (10%), elevated triglycerides (3%, but unclear if elevations qualified as clinical hypertriglyceridemia), and asthenia (2%). Arthralgia and myalgia have been reported with postmarketing use.
Cases of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by the JC virus (JCV), have been reported in fingolimod-treated patients in the postmarketing setting. The majority of cases occurred in patients treated for at least 2 years; however, the relationship between the risk of PML and the duration of treatment is unknown. Withhold fingolimod and perform an appropriate diagnostic evaluation at the first sign or symptom of PML. Typical symptoms of PML are diverse, progress over days to weeks, and include progressive weakness on one side or clumsiness of the limbs; vision disturbance; and changes in thinking, memory, and orientation leading to confusion and personality changes. MRI findings may be visible before clinical signs and symptoms. Hence, MRI monitoring for signs that may be consistent with PML may be useful, and any suspicious findings should spark further investigation to allow for an early diagnosis of PML, if present. Cases of immune reconstitution inflammatory syndrome (IRIS) or immune reconstitution syndrome have been reported in patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment. PML-associated IRIS may lead to rapid onset of serious neurological complications or death, and is often associated with characteristic changes on MRI. PML-associated IRIS onset occurred within a few months following S1P receptor modulator discontinuation. Monitor patients and appropriately treat any inflammation associated with IRIS. In addition, rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in adult patients receiving fingolimod. Symptoms include sudden onset of severe headache, altered mental status, visual disturbance, and seizure. Symptoms of PRES are usually reversible but may progress into ischemic stroke or cerebral hemorrhage. If PRES is suspected, discontinue fingolimod. Delay in diagnosis and treatment may lead to permanent neurologic sequelae.
Fingolimod receipt may cause a new primary malignancy. Lymphoma (e.g., cutaneous T-cell lymphoproliferative disorders or diffuse B-cell lymphoma) was reported during clinical trials in adults receiving fingolimod. The relationship of the lymphoma cases to fingolimod receipt is unclear due to the small number of cases and the short duration of exposure. During clinical trials, skin papilloma occurred in 3% of adult patients receiving fingolimod vs. 2% on placebo. The risk of skin cancer is increased in patients receiving fingolimod, and practitioners should be alert to suspicious skin lesions and promptly evaluate them. During clinical trials, actinic keratosis (AK) was noted in 2% of fingolimod recipients and 1% taking placebo. The risk of basal cell carcinoma (BCC) and melanoma is increased in adult patients treated with fingolimod. In 2-year placebo-controlled trials in adult patients, the incidence of BCC was 2% in patients on fingolimod 0.5 mg vs. 1% on placebo. Melanoma, Merkel cell carcinoma, and cutaneous T-cell lymphoma (including mycosis fungoides) have been reported with postmarketing use. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer, and patients are advised to follow skin protection practices, such as using protective clothing and appropriate sunscreens. HPV-related cancers, such as cervical cancer, have also been reported with postmarketing use.
Monitor patients for severe multiple sclerosis exacerbation after fingolimod discontinuation. Rare cases of severely increased disability with multiple new lesions on MRI have been observed after fingolimod discontinuation, typically within 12 weeks, although cases up to 24 weeks after treatment have been reported. Most patients did not return to the functional status they had before fingolimod discontinuation, and permanent disease worsening occurred in some cases. Over 8 years, 35 cases of severe increases in disability with new MRI lesions occurred. Following drug discontinuation, disability began in less than 12 weeks in 29 cases, and between 12 to 24 weeks in 6 cases. Time on fingolimod before discontinuation ranged from 7 to 96 months. The disability was more severe than typical multiple sclerosis relapses, as several patients who were able to walk without assistance while taking fingolimod progressed to needing wheelchairs or became bedbound. Eight patients experienced permanent disability, 17 patients had a partial recovery, and 6 patients had a full recovery (reported as either a return in Expanded Disability Status Scale score reported while on fingolimod or complete recovery as recognized by clinical judgment). Advise patients of the potential risk of an exacerbation of their multiple sclerosis when fingolimod is discontinued, and to seek immediate medical attention if they experience new or worsened symptoms of multiple sclerosis. If an increase in disability occurs, test for new or enhancing lesions on MRI and begin appropriate treatment if clinically indicated. Optimal methods for the treatment of severe disability have not been defined; however, all 35 patients received corticosteroids as the initial treatment. Of those who fully recovered, 3 received only IV methylprednisolone, and the other 3 received plasma exchange, intrathecal triamcinolone, or re-started fingolimod.
Fingolimod is contraindicated with patients who have had a hypersensitivity reaction or a history of angioedema to fingolimod or any of the product excipients. Rash, urticaria, and angioedema have occurred with treatment initiation. The orally-disintegrating tablet (ODT) formulation contains mannitol and should not be used in patients with mannitol hypersensitivity.
Patients with active acute or chronic infections should not initiate fingolimod until the infection is resolved. Fingolimod may increase the risk of infections. Serious infections with opportunistic pathogens including viral infection (e.g., John Cunningham virus (JCV), herpes infection, varicella-zoster, human papilloma virus (HPV)), fungal infection (e.g., cryptococcal infection), and bacterial infection (e.g., atypical mycobacterial infection) have been reported with fingolimod use. Patients with signs and symptoms consistent with serious infections should undergo prompt diagnostic evaluation and appropriate treatment. Include disseminated herpetic infections in the differential diagnosis of fingolimod-treated patients who present with atypical MS relapse or multiorgan failure. Consider interrupting fingolimod treatment if a patient develops a serious infection and reassess benefits and risks prior to reinitiation. Continue to monitor for infections for up to 2 months after fingolimod discontinuation. Fingolimod may be inappropriate for use in patients with leukemia, lymphoma, human immunodeficiency virus (HIV) infection, or acquired immunodeficiency syndrome (AIDS). Concomitant use of fingolimod with chemotherapy or corticosteroid therapy may increase the risk of immunosuppression. When switching from immune-modulating or immunosuppressive medications to fingolimod, consider the mode of action and duration of effect of these therapies to avoid unintended additive immunosuppressive effects. A recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be available before initiating fingolimod treatment. Test patients without a confirmed history of chickenpox or without documentation of a full course of vaccination against varicella zoster virus (VZV) for antibodies to VZV prior to treatment initiation. Vaccinate antibody-negative patients prior to treatment initiation. Postpone fingolimod initiation for 1 month after vaccination to allow the full effect of vaccination to occur. Consider HPV vaccination prior to fingolimod treatment initiation, taking into account vaccination recommendations. Cancer screening, including a Papanicolaou (Pap) test in female patients, is recommended as per standard of care for patients using an immunosuppressive therapy. Pediatric patients should complete all immunization in accordance with current immunization guidelines prior to initiating fingolimod. Avoid vaccination with live vaccines due to potential immunosuppression and increased risk of infection during fingolimod therapy. Clearance of fingolimod may take up to 2 months after discontinuation of therapy.
Fingolimod is contraindicated for use in patients: with QT prolongation defined as a baseline QTc interval of 500 milliseconds or more; taking Class Ia or Class III antiarrhythmic drugs for cardiac arrhythmias; with a history or presence of Mobitz type II second- or third-degree AV block or sick sinus syndrome unless the patient has a functioning pacemaker; and who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Patients with ischemic cardiac disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled high blood pressure, history of symptomatic bradycardia, history of recurrent syncope, AV block, severe untreated sleep apnea, or sinoatrial heart block need a cardiac evaluation by an appropriately trained physician prior to fingolimod initiation. These patients may poorly tolerate fingolimod-induced bradycardia or may experience serious rhythm disturbances. If treated with fingolimod, monitor these patients overnight with a continuous electrocardiogram (ECG) in a medical facility after the first dose. Furthermore, because fingolimod treatment results in decreased heart rate and may prolong the QT interval, overnight monitoring after the first dose with continuous ECG in a medical facility is advised for patients: taking QT-prolonging drugs with a known risk of torsade de pointes (TdP); or with a prolonged QTc interval defined as more than 450 milliseconds for adult and pediatric males, more than 470 milliseconds for adult females, and more than 460 milliseconds for pediatric females before dosing or during the 6-hour observation. Use fingolimod with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus infection (HIV), fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.
Cautious use of fingolimod is warranted in patients who have hypertension throughout treatment. Patients with uncontrolled high blood pressure need a cardiac evaluation by an appropriately trained physician prior to fingolimod initiation. These patients may poorly tolerate fingolimod-induced bradycardia or may experience serious rhythm disturbances after the first dose. If treated with fingolimod, monitor these patients overnight with continuous electrocardiogram (ECG) in a medical facility after the first dose. Blood pressure elevation may occur with fingolimod use in any patient. Regularly monitor the blood pressure of any patient during fingolimod receipt.
Fingolimod increases the risk of macular edema. Perform an examination of the fundus including the macula in all patients before starting treatment, again 3 to 4 months after starting treatment, and again at any time after a patient reports visual disturbance while on fingolimod therapy. Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during fingolimod receipt. The incidence of macular edema was approximately 20% in patients with a history of uveitis as compared with 0.6% in patients without a history of uveitis. Fingolimod has not been tested in patients with diabetes mellitus. Regular follow-up ophthalmologic evaluations during fingolimod receipt are advised for patients with diabetes mellitus or a history of uveitis.
Progressive multifocal leukoencephalopathy (PML) has occurred with fingolimod. As PML can be fatal, instruct patients to notify their healthcare provider immediately if they notice new or worsening neurological signs or symptoms such as ataxia, visual changes, or confusion. Similarly, suspect PML in any patient presenting with neurological symptoms; discontinue fingolimod at the first sign or symptom of PML and perform a clinical evaluation. Consider MRI monitoring for signs that may be consistent with PML. MRI findings suggestive of PML and detection of JC virus (JCV) DNA in the CSF in the absence of clinical signs and symptoms of PML have been reported in patients treated with other multiple sclerosis medications; many cases progressed to symptomatic PML. Promptly investigate any suspicious findings to allow for early diagnosis. Monitor for the development of immune reconstitution inflammatory syndrome (IRIS) (also known as immune reconstitution syndrome), in patients treated with fingolimod who develop PML and subsequently discontinue treatment. Cases of IRIS typically occurred within a few months following sphinogosine 1-phosphate receptor modulator discontinuation. PML-associated IRIS may lead to rapid onset of serious neurological complications or death, and is often associated with characteristic changes on MRI. Appropriately treat any inflammation associated with IRIS. There have also been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in patients receiving fingolimod. Symptoms reported included sudden onset of severe headache, altered mental status, visual disturbances, and seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. A delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, discontinue fingolimod and perform a clinical evaluation.
Clinically significant drug-induced liver injury (hepatotoxicity), including acute liver failure requiring liver transplantation, has occurred in patients treated with fingolimod. Obtain serum transaminases (ALT and AST) and total bilirubin prior to treatment initiation (within 6 months) and periodically throughout therapy until 2 months after drug discontinuation. Monitor patients for signs of hepatotoxicity; those with preexisting severe hepatic disease are at greater risk of adverse reactions. Promptly obtain liver transaminase and bilirubin concentrations in any patients who report symptoms that may indicate liver injury, such as new or worsening fatigue, anorexia, righter upper abdominal discomfort, dark urine, or jaundice. Interrupt fingolimod if the ALT is more than 3 times the upper limit of normal (ULN) with total bilirubin more than 2 times the ULN. Do not resume treatment if a plausible alternative etiology for the signs and symptoms cannot be established; these patients are at risk for severe drug-induced liver injury. Signs of hepatotoxicity have occurred as early as 10 days after the first dose and also after prolonged use. The majority of hepatic enzyme elevations occurred within 6 to 9 months of treatment initiation and returned to normal within approximately 2 months after drug discontinuation during clinical trials. Recurrence of liver transaminase elevations occurred with rechallenge in some patients.
Fingolimod has not been tested in multiple sclerosis patients with compromised respiratory function. Cautious use of fingolimod may be warranted for patients with respiratory insufficiency or pulmonary disease, including asthma, chronic obstructive pulmonary disease (COPD), or severe untreated sleep apnea. Fingolimod may cause dyspnea and reductions in both forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) as early as 1 month after treatment initiation. Spirometric evaluation of respiratory function and evaluation of DLCO should be performed during fingolimod treatment if clinically indicated. Reduction from baseline in the percent of predicted FEV1 values at the time of last assessment was 2.8% for fingolimod and 1% for placebo in adult patients. For DLCO, the reduction from baseline was 3.3% for fingolimod and 0.5% for placebo. Changes in FEV1 appear to be reversible after treatment discontinuation. There is insufficient information to determine the reversibility of DLCO decreases after treatment discontinuation. Patients with severe untreated sleep apnea need a cardiac evaluation by an appropriately trained physician prior to fingolimod initiation, as these patients may poorly tolerate fingolimod-induced bradycardia or may experience serious rhythm disturbances. If treated with fingolimod, monitor these patients overnight with a continuous electrocardiogram (ECG) in a medical facility after the first dose.
Limit sunlight (UV) exposure during fingolimod therapy due to an increased risk for skin cancer. Wear protective clothing and use a sunscreen with high protection factor. The risk of basal cell carcinoma (BCC) and melanoma is increased in patients treated with fingolimod at rates higher than with placebo. Melanoma and Merkel cell carcinoma have been reported in the postmarketing setting. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated.
Although no adequate and well-controlled studies in pregnant women exist, fingolimod may cause fetal harm and poses a reproductive risk. Contraception requirements are advised. Women of child-bearing potential should use effective contraception to avoid pregnancy during therapy and for 2 months after fingolimod treatment is discontinued. Only use fingolimod during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus. The multinational pregnancy exposure registry for the drug reports a possible risk of drug-related developmental abnormalities, but the data available do not allow reliable risk or safety assessments. The receptor affected by fingolimod, sphingosine 1-phosphate receptor, is known to be involved in vascular formation during embryogenesis. Experts generally recommend, due to a lack of safety data and the potential hazards, to discontinue fingolimod when a woman is trying to conceive and throughout gestation and lactation; if the drug is stopped, the woman should wait 2 months before attempting to conceive. Consider the possibility of a severe increase in disability in women who discontinue or are considering discontinuation of fingolimod due to pregnancy or because of the desire to conceive. Disability increases with multiple new lesions on MRI have been observed following fingolimod discontinuation, typically within 12 weeks, although cases up to 24 weeks after treatment have been reported. Most patients did not return to the functional status they had prior to fingolimod discontinuation. Oral fingolimod administration to pregnant rats during the period of organogenesis increased incidences of fetal malformations, and embryo-fetal deaths were observed at all but the lowest dose of 0.03 mg/kg/day, which is less than the recommended human dose on an mg/m2 basis. In rats, the highest no-effect dose was less than the recommended human dose of 0.5 mg/day on a body surface area (mg/m2) basis. The most common fetal visceral malformations in rats included persistent truncus arteriosus and ventricular septal defects. Pup survival was decreased at doses of 0.05 to 0.5 mg/kg/day, and a learning deficit was seen in offspring at the 0.5 mg/kg/day dose. The dose of 0.05 mg/kg/day is similar to the recommended human dose on an mg/m2 basis. In addition to rats, adverse outcomes were noted in rabbits. For example, increased incidences of embryo-fetal mortality and fetal growth retardation were observed after oral administration of 1.5 to 5 mg/kg/day to pregnant rabbits. Of note, the no-effect dose for these effects in rabbits (0.5 mg/kg/day) is approximately 20 times the recommended human dose on an mg/m2 basis. Fingolimod's effect during labor and delivery is unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to fingolimod; information about the registry can be obtained at www.gilenyapregnancyregistry.com or by calling 1-877-598-7237.
There is no data on the presence of fingolimod in human milk, the effects on the breast-fed infant, or the effects of the drug on milk production. The drug is excreted into the milk of treated rats. Because of the drug's significant risk of cardiovascular side effects, experts recommend against use during breast-feeding until more data are available regarding infant safety. Glatiramer, interferon beta-1a, interferon beta-1b, may be potential alternatives to fingolimod to consider for the patient with multiple sclerosis who is breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Monitor patients for severe multiple sclerosis exacerbation after fingolimod discontinuation. Rare cases of severe disability increases with multiple new lesions on MRI have been observed after fingolimod discontinuation, typically within 12 weeks, although cases up to 24 weeks after treatment have been reported. The disability was more severe than typical multiple sclerosis relapses, as several patients who were able to walk without assistance while taking fingolimod progressed to needing wheelchairs or became bedbound. Most patients did not return to the functional status they had before fingolimod discontinuation, and permanent disease worsening occurred in some cases. Advise patients of the potential risk of an exacerbation of their multiple sclerosis when fingolimod is discontinued, and to seek immediate medical attention if they experience new or worsened symptoms of multiple sclerosis. If an increase in disability occurs, test for new or enhancing lesions on MRI and begin appropriate treatment if clinically indicated. Disease relapse with tumefactive demyelinating lesions on imaging have been observed during fingolimod therapy and after discontinuation. Most cases have occurred within the first 9 months after treatment initiation; however, it may occur at any point in treatment and has been reported within 4 months after fingolimod discontinuation. Consider tumefactive multiple sclerosis when a severe disease relapse occurs during fingolimod treatment, especially during initiation or after discontinuation, prompting imaging evaluation and initiation of appropriate treatment.
Prior to fingolimod administration
-Obtain an electrocardiogram (ECG) in all patients prior to fingolimod initiation. Certain patients with preexisting conditions also require a cardiac evaluation by an appropriately trained physician prior to treatment initiation. These patients should be monitored overnight with continuous ECG in a medical facility after the first dose of fingolimod, as they may poorly tolerate fingolimod-induced bradycardia or may experience serious rhythm disturbances after the first dose.
-Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction prior to treatment initiation.
-Additionally, the history of use of immunosuppressive medications and their additive effects should be evaluated.
-Test patients without a confirmed history of chickenpox or without documentation of a full course of vaccination against varicella zoster virus (VZV) for antibodies to VZV prior to treatment initiation. Vaccinate antibody-negative patients prior to treatment initiation. Postpone fingolimod initiation for 1 month after vaccination to allow the full effect of vaccination to occur. Pediatric patients should complete all immunizations in accordance with current immunization guidelines prior to initiating fingolimod.
-Obtain serum transaminase (ALT and AST) and total bilirubin concentrations if they have not been acquired in the last 6 months. An ophthalmologic evaluation is also needed.
First dose monitoring
-Administer the first dose in a setting that has adequate resources to manage symptomatic bradycardia. Monitor patients for 6 hours after the first dose for signs and symptoms of bradycardia. Perform hourly pulse and blood pressure assessment.
-Obtain an ECG in all patients at the end of the 6-hour observation period.
-At the 6-hour time point, institute additional observation if:-the heart rate is less than 45 beats per minute (bpm) in adults
-heart rate is less than 55 bpm in patients 12 to 17 years or less than 60 bpm in patients 10 to 11 years
-if the heart rate is at the lowest value after fingolimod receipt; or if the ECG shows new onset second degree or higher AV block.
-Begin continuous ECG monitoring if symptomatic bradycardia occurs at any time point. Continue observation until symptoms have resolved. If pharmacologic intervention is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose.
When to repeat recommended monitoring procedures
-Repeat first dose monitoring procedures if fingolimod dosing/administration is interrupted for 1 day or more during the first 2 weeks of treatment, more than 7 days during weeks 3 and 4 of treatment, or more than 14 days after the first month of treatment.
-Repeated first dose monitoring procedures are also recommended when the dose is increased in pediatric patients.
-Patients who underwent first-dose monitoring at initiation and are switched to the orally disintegrating tablets at the same daily dose, do not need to repeat first-dose monitoring, unless the previous treatment was discontinued more than 14 days prior.
For the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease:
Oral dosage (capsule):
Adults: 0.5 mg PO once daily.
Children and Adolescents 10 to 17 years weighing more than 40 kg: 0.5 mg PO once daily.
Children and Adolescents 10 to 17 years weighing 40 kg or less: 0.25 mg PO once daily.
Oral dosage (orally disintegrating tablet):
Adults: 0.5 mg PO once daily.
Children and Adolescents 10 to 17 years weighing more than 40 kg: 0.5 mg PO once daily.
Children and Adolescents 10 to 17 years weighing 40 kg or less: 0.25 mg PO once daily.
Maximum Dosage Limits:
-Adults
0.5 mg/day PO.
-Geriatric
0.5 mg/day PO.
-Adolescents
Weighing more than 40 kg: 0.5 mg/day PO.
Weighing 40 kg or less: 0.25 mg/day PO.
-Children
10 to 12 years weighing more than 40 kg: 0.5 mg/day PO.
10 to 12 years weighing 40 kg or less: 0.25 mg/day PO.
1 to 9 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild impairment (Child-Pugh class A, total score of 5 or 6): No dose adjustment is needed.
Moderate impairment (Child-Pugh class B, total score of 7 to 9): No dose adjustment is needed.
Severe impairment (Child-Pugh class C, total score more than 10): Closely monitor patients, as the risk of fingolimod adverse reactions is greater.
Patients with Renal Impairment Dosing
No dosage adjustment required.
*non-FDA-approved indication
Acebutolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Adagrasib: (Major) Concomitant use of adagrasib and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Alemtuzumab: (Major) Concomitant use of fingolimod with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
Alfuzosin: (Moderate) Use caution when administering alfuzosin with fingolimod due to the potential for QT prolongation. Alfuzosin may prolong the QT interval in a dose-dependent manner. Additionally, fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Amiodarone: (Major) Concomitant use of amiodarone and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Monitor ECG continuously overnight in a medical facility after the first fingolimod dose if amisulpride is coadministered due to the potential for additive QT prolongation. Amisulpride causes dose- and concentration- dependent QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include clarithromycin.
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include fingolimod.
Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with fingolimod since concurrent use may increase the risk of QT prolongation. Fingolimod may cause a decreased heart rate and prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aripiprazole: (Moderate) Concomitant use of aripiprazole and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include arsenic trioxide.
Artemether; Lumefantrine: (Major) Artemether; lumefantrine is associated with QT prolongation. If possible avoid coadministration of artemether; lumefantrine and fingolimod. If concomitant use cannot be avoided, overnight monitoring with continuous ECG in a medical facility after the first fingolimod dose is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of torsades de pointes in patients with bradycardia.
Asenapine: (Major) Asenapine is associated with a possible risk for QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect. If concomitant use cannot be avoided, overnight monitoring with continuous ECG in a medical facility after the first fingolimod dose is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of torsades de pointes in patients with bradycardia. Fingolimod initiation results in decreased heart rate and may prolong the QT interval.
Atenolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Atenolol; Chlorthalidone: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Atomoxetine: (Moderate) Concomitant use of atomoxetine and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Azithromycin: (Major) Avoid coadministration of azithromycin with fingolimod due to the increased risk of QT prolongation. If concomitant use is unavoidable, overnight monitoring with continuous ECG in a medical facility is advised after the first dose of fingolimod; monitor ECG closely throughout therapy, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with fingolimod. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Beta-adrenergic blockers: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Betaxolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bisoprolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Bretylium: (Contraindicated) Fingolimod is contraindicated in patients requiring treatment with bretylium, a Class III antiarrhythmic.
Brimonidine; Timolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Buprenorphine: (Major) Buprenorphine should be used cautiously and with close monitoring with fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP), such as buprenorphine. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Buprenorphine; Naloxone: (Major) Buprenorphine should be used cautiously and with close monitoring with fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP), such as buprenorphine. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Cabotegravir; Rilpivirine: (Moderate) Exercise caution when administering fingolimod concomitantly with rilpivirine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Carteolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Carvedilol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Ceritinib: (Major) Avoid coadministration of ceritinib with fingolimod if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Initiation of other drugs during the 2 months after fingolimod discontinuation warrants the same considerations needed for concomitant administration because fingolimod remains in the blood and has pharmacodynamic effects for up to 2 months after the last dose. Ceritinib causes concentration-dependent prolongation of the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Chikungunya Vaccine, Live: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Chloroquine: (Major) Avoid coadministration of chloroquine with fingolimod due to the increased risk of QT prolongation. If use together is necessary, overnight monitoring with continuous ECG in a medical facility is advised after the first dose of fingolimod; monitor ECG closely throughout therapy, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Chlorpromazine: (Major) Phenothiazines have been associated with a risk of QT prolongation and/or torsade de pointes (TdP). This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine. Agents that prolong the QT interval could lead to torsade de pointes when combined with a phenothiazine, and therefore are generally not recommended for combined use. Drugs with a possible risk for QT prolongation and TdP that should be used with caution with chlorpromazine include fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Cisapride: (Contraindicated) QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Because of the potential for TdP, use of fingolimod with cisapride is contraindicated.
Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If coadministration is necessary, after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include citalopram.
Clarithromycin: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include clarithromycin.
Class IA Antiarrhythmics: (Contraindicated) Concurrent use of fingolimod with class Ia antiarrhythmics such as disopyramide, quinidine, and procainamide is contraindicated. Fingolimod initiation results in decreased heart rate, and class IA antiarrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia.
Clofazimine: (Moderate) Concomitant use of clofazimine and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Clozapine: (Moderate) Exercise caution when administering fingolimod concomitantly with clozapine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Codeine; Promethazine: (Major) Concomitant use of promethazine and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Crizotinib: (Major) Avoid coadministration of crizotinib with fingolimod due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Dasatinib: (Moderate) Use dasatinib with caution in combination with fingolimod as concurrent use may increase the risk of QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving fingolimod as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with fingolimod. Halogenated anesthetics can prolong the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Deutetrabenazine: (Moderate) The risk of QT prolongation may be increased with coadministration of deutetrabenazine and fingolimod. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of torsade de pointes (TdP) in patients with bradycardia.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Dextromethorphan; Quinidine: (Contraindicated) Concurrent use of fingolimod with class Ia antiarrhythmics such as disopyramide, quinidine, and procainamide is contraindicated. Fingolimod initiation results in decreased heart rate, and class IA antiarrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia.
Digoxin: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as digoxin. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Diltiazem: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as heart-rate slowing calcium channel blockers like diltiazem. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Disopyramide: (Contraindicated) Concurrent use of fingolimod with class Ia antiarrhythmics such as disopyramide, quinidine, and procainamide is contraindicated. Fingolimod initiation results in decreased heart rate, and class IA antiarrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia.
Dofetilide: (Contraindicated) Fingolimod is contraindicated in patients requiring treatment with dofetilide, a Class III antiarrhythmic. Fingolimod treatment results in decreased heart rate and may prolong the QT interval. Dofetilide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Dolasetron: (Moderate) Administer dolasetron with caution in combination with fingolimod as concurrent use may increase the risk of QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Dolutegravir; Rilpivirine: (Moderate) Exercise caution when administering fingolimod concomitantly with rilpivirine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Donepezil: (Moderate) After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP), such as donepezil. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Donepezil; Memantine: (Moderate) After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP), such as donepezil. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Dorzolamide; Timolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Dronedarone: (Contraindicated) Concurrent administration of fingolimod and dronedarone is contraindicated. Fingolimod may prolong the QT interval and is contraindicated for use by patients with a baseline QTc interval >= 500 msec. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If coadministration is necessary, after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with fingolimod as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fingolimod initiation results in decreased heart rate and may prolong the QT interval.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with fingolimod as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fingolimod initiation results in decreased heart rate and may prolong the QT interval.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with fingolimod as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fingolimod initiation results in decreased heart rate and may prolong the QT interval.
Eliglustat: (Major) Coadministration of fingolimod and eliglustat is not recommended. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If fingolimod must be coadministered with QT prolonging drugs with a known risk of torsade de pointes (TdP), overnight monitoring with continuous ECG in a medical facility is advised after the first fingolimod dose. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Overnight monitoring is also recommended if fingolimod therapy is interrupted 1 day or more during the first 2 weeks of fingolimod treatment, more than 7 days during the third and fourth week of treatment, and more than 14 days after the first month of treatment.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Exercise caution when administering fingolimod concomitantly with rilpivirine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Exercise caution when administering fingolimod concomitantly with rilpivirine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Encorafenib: (Major) Avoid coadministration of encorafenib and fingolimod due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Entrectinib: (Major) Avoid coadministration of entrectinib with fingolimod due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Eribulin: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Eribulin has been associated with QT prolongation. If coadministration is necessary, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Erythromycin: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include erythromycin.
Escitalopram: (Moderate) Concomitant use of escitalopram and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Esmolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Etrasimod: (Moderate) Concomitant use of etrasimod and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Fexinidazole: (Major) Concomitant use of fexinidazole and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Flecainide: (Major) Flecainide should be used cautiously and with close monitoring with fingolimod. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Fluconazole: (Moderate) Concomitant use of fluconazole and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Fluoxetine: (Moderate) Concomitant use of fluoxetine and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Fluphenazine: (Minor) Exercise caution when administering fingolimod concomitantly with fluphenazine. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Fluphenazine is associated with a possible risk for QT prolongation.
Fluvoxamine: (Moderate) Exercise caution when administering fingolimod concomitantly with fluvoxamine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine post-marketing use.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as fingolimod. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fostemsavir: (Moderate) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Moderate) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering fingolimod with gemifloxacin. Gemifloxacin may prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. Initiation of fingolimod results in decreased heart rate and may prolong the QT interval. Coadministration of fingolimod and gemifloxacin has not been studied. Health care providers are advised that the likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and fingolimod together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Gilteritinib: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and fingolimod is necessary. Gilteritinib has been associated with QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Glasdegib: (Major) Avoid coadministration of glasdegib with fingolimod due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving fingolimod as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Granisetron: (Moderate) Use granisetron with caution in combination with fingolimod due to the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Granisetron has been associated with QT prolongation.
Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with fingolimod. Halogenated anesthetics can prolong the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Haloperidol: (Moderate) Use haloperidol with caution in combination with fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP), such as haloperidol. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. QT prolongation and TdP have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving fingolimod as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Hydroxychloroquine: (Major) Avoid coadministration of fingolimod and hydroxychloroquine due to the risk of increased QT prolongation. If coadministration cannot be avoided, overnight monitoring with continuous ECG in a medical facility is advised after the first fingolimod dose for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). Also, avoid any non-essential QT prolonging drugs and correct electrolyte imbalances. Monitor ECG throughout therapy. Hydroxychloroquine prolongs the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Hydroxyzine: (Moderate) Concomitant use of hydroxyzine and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Ibutilide: (Contraindicated) Fingolimod is contraindicated in patients requiring treatment with ibutilide, a Class III antiarrhythmic. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Ibutilide can cause QT prolongation and torsade de pointes (TdP).
Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If coadministration is necessary, after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with fingolimod due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Specifically, overnight monitoring with continuous ECG in a medical facility is advised after the first fingolimod dose. Inotuzumab has been associated with QT interval prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Intranasal Influenza Vaccine: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Isoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with fingolimod. Halogenated anesthetics can prolong the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Itraconazole: (Moderate) Exercise caution when administering fingolimod concomitantly with itraconazole as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of torsade de pointes (TdP) in patients with bradycardia. Itraconazole has been associated with prolongation of the QT interval.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with fingolimod due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and fingolimod due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Labetalol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include clarithromycin.
Lapatinib: (Moderate) Exercise caution when administering fingolimod concomitantly with lapatinib as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
Lefamulin: (Major) Avoid coadministration of lefamulin with fingolimod as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with fingolimod due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Although fingolimod has not been studied in patients treated with drugs that prolong the QT interval, drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving fingolimod as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving fingolimod as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Levobunolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Levofloxacin: (Moderate) Concomitant use of levofloxacin and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and fingolimod due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Lithium: (Moderate) Concomitant use of lithium and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Live Vaccines: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Lofexidine: (Major) Monitor ECG continuously overnight in a medical facility after the first fingolimod dose if lofexidine is coadministered due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Loperamide: (Moderate) Exercise caution when administering fingolimod concomitantly with loperamide as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Loperamide; Simethicone: (Moderate) Exercise caution when administering fingolimod concomitantly with loperamide as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Lopinavir; Ritonavir: (Major) If possible, avoid coadministration of lopinavir; ritonavir and fingolimod. If concomitant use cannot be avoided, overnight monitoring with continuous ECG in a medical facility after the first fingolimod dose is advised. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of torsade de pointes in patients with bradycardia. Lopinavir; ritonavir is associated with a possible risk for QT prolongation and torsade de pointes (TdP) based on varying levels of documentation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod is contraindicated for use by patients with a baseline QTc interval >= 500 msec.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as fingolimod. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Maprotiline: (Moderate) Exercise caution when administering fingolimod concomitantly with maprotiline as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Mefloquine: (Moderate) Exercise caution when administering fingolimod concomitantly with mefloquine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with methadone include fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Metoprolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Metoprolol; Hydrochlorothiazide, HCTZ: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Metronidazole: (Moderate) Concomitant use of metronidazole and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Midostaurin: (Major) The concomitant use of midostaurin and fingolimod may lead to additive QT interval prolongation. If these drugs are used together, monitor the QT interval with electrocardiograms. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of torsade de pointes in patients with bradycardia.
Mifepristone: (Major) Concomitant use of fingolimod and mifepristone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mirtazapine: (Moderate) Concomitant use of mirtazapine and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Mobocertinib: (Major) Concomitant use of mobocertinib and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Moxifloxacin: (Major) Prolongation of the QT interval has been reported with administration of moxifloxacin. Post-marketing surveillance has identified very rare cases of ventricular arrhythmias including torsade de pointes (TdP), usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded. According to the manufacturer, moxifloxacin should be avoided in patients taking drugs that can result in prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP include fingolimod . Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If coadministration is necessary, after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Nadolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Nebivolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Nebivolol; Valsartan: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and fingolimod; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Ofatumumab: (Moderate) Concomitant use of ofatumumab with fingolimod may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as fingolimod. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Olanzapine: (Moderate) Exercise caution when administering fingolimod concomitantly with olanzapine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Moderate) Concomitant use of fluoxetine and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Exercise caution when administering fingolimod concomitantly with olanzapine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Samidorphan: (Moderate) Exercise caution when administering fingolimod concomitantly with olanzapine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ondansetron: (Major) Concomitant use of ondansetron and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with fingolimod as concurrent use may increase the risk of QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Osimertinib: (Major) Avoid coadministration of fingolimod with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Fingolimod initiation results in decreased heart rate and may prolong the QT interval; after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of fingolimod with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Pacritinib: (Major) Concomitant use of pacritinib and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, including fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If coadministration is necessary, after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include fingolimod.
Pasireotide: (Moderate) Use caution when using pasireotide in combination with fingolimod as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval, such as fingolimod, is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and fingolimod must be continued, closely monitor the patient for QT interval prolongation. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Pentamidine: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include pentamidine.
Perphenazine: (Minor) Exercise caution when administering fingolimod concomitantly with perphenazine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Perphenazine is associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Minor) Exercise caution when administering fingolimod concomitantly with perphenazine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Perphenazine is associated with a possible risk for QT prolongation.
Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If coadministration cannot be avoided, after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of fingolimod with pimozide is contraindicated.
Pindolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Pitolisant: (Major) Avoid coadministration of pitolisant with fingolimod as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Posaconazole: (Moderate) Exercise caution when administering fingolimod concomitantly with posaconazole as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes.
Primaquine: (Moderate) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval, such as fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Procainamide: (Contraindicated) Concurrent use of fingolimod with class Ia antiarrhythmics such as disopyramide, quinidine, and procainamide is contraindicated. Fingolimod initiation results in decreased heart rate, and class IA antiarrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia.
Prochlorperazine: (Minor) Exercise caution when administering fingolimod concomitantly with prochlorperazine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Promethazine: (Major) Concomitant use of promethazine and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of promethazine and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Phenylephrine: (Major) Concomitant use of promethazine and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Concomitant use of propafenone and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propranolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Quetiapine: (Major) Concomitant use of quetiapine and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quinidine: (Contraindicated) Concurrent use of fingolimod with class Ia antiarrhythmics such as disopyramide, quinidine, and procainamide is contraindicated. Fingolimod initiation results in decreased heart rate, and class IA antiarrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia.
Quinine: (Major) Concurrent use of quinine and fingolimod should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP, such as quinine. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Quizartinib: (Major) Concomitant use of quizartinib and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ranolazine: (Moderate) Exercise caution when administering fingolimod concomitantly with ranolazine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Relugolix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Fingolimod initiation results in decreased heart rate and may also prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Fingolimod initiation results in decreased heart rate and may also prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Ribociclib: (Major) Avoid coadministration of ribociclib with fingolimod due to an increased risk for QT prolongation and torsade de pointes (TdP); exposure to fingolimod may also increase. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Fingolimod initiation results in decreased heart rate and may prolong the QT interval; fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Concomitant use may increase the risk for QT prolongation. Coadministration with another strong CYP3A inhibitor increased fingolimod exposure by 70%.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with fingolimod due to an increased risk for QT prolongation and torsade de pointes (TdP); exposure to fingolimod may also increase. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Fingolimod initiation results in decreased heart rate and may prolong the QT interval; fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Concomitant use may increase the risk for QT prolongation. Coadministration with another strong CYP3A inhibitor increased fingolimod exposure by 70%.
Rilpivirine: (Moderate) Exercise caution when administering fingolimod concomitantly with rilpivirine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Risperidone: (Moderate) Monitor ECG continuously overnight in a medical facility after the first fingolimod dose if risperidone is coadministered due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with romidepsin as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Rotavirus Vaccine: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Saquinavir: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If no acceptable alternative therapy is available, after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with fingolimod is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Sertraline: (Moderate) Concomitant use of sertraline and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with fingolimod. Halogenated anesthetics can prolong the QT interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving fingolimod due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Fingolimod treatment results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of torsade de pointes in patients with bradycardia.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Solifenacin: (Moderate) Exercise caution when administering fingolimod concomitantly with solifenacin as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking fingolimod.
Sorafenib: (Major) Avoid coadministration of sorafenib with fingolimod due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval; it has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Sotalol: (Contraindicated) Avoid concomitant use of sotalol and fingolimod due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of torsade de pointes (TdP) in patients with bradycardia. Sunitinib can prolong the QT interval.
Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with fingolimod. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Telavancin: (Moderate) Exercise caution when administering fingolimod concomitantly with telavancin. Telavancin has been associated with QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If coadministration is necessary, after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP).[ Thioridazine is considered contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Because of the potential for TdP, use of fingolimod with thioridazine is contraindicated.
Timolol: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as beta-blockers. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Tolterodine: (Moderate) Exercise caution when administering fingolimod concomitantly with tolterodine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Toremifene: (Major) Avoid coadministration of fingolimod with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Trandolapril; Verapamil: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as verapamil. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Trazodone: (Major) Concomitant use of trazodone and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Trifluoperazine: (Minor) Exercise caution when administering fingolimod concomitantly with trifluoperazine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving fingolimod as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Typhoid Vaccine: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Vandetanib: (Major) Avoid coadministration of vandetanib with fingolimod due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, overnight monitoring with continuous ECG in a medical facility is advised after the first dose of fingolimod. Monitor ECGs for QT prolongation and monitor electrolytes during therapy; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Vardenafil: (Moderate) Concomitant use of vardenafil and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Vemurafenib: (Major) If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP), such as fingolimod, must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Vemurafenib has been associated with QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Venlafaxine: (Moderate) Concomitant use of venlafaxine and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Verapamil: (Major) If possible, do not start fingolimod in a patient who is taking a drug that slows the heart rate or atrioventricular conduction such as verapamil. Use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the prescribing physician regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients who cannot stop taking drugs that slow the heart rate or atrioventricular conduction. Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or atrioventricular conduction is limited.
Voclosporin: (Moderate) Concomitant use of voclosporin and fingolimod may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include clarithromycin.
Voriconazole: (Moderate) Exercise caution when administering fingolimod concomitantly with voriconazole as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes.
Vorinostat: (Moderate) Exercise caution when administering fingolimod concomitantly with vorinostat as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Vorinostat is associated with a risk of QT prolongation.
Yellow Fever Vaccine, Live: (Contraindicated) Do not administer live vaccines to a patient who is receiving fingolimod or has discontinued the drug in the last 2 months because of the risk of infection. No data are available regarding the risk of secondary transmission of infection by live vaccines, and the efficacy and safety of live vaccines have not been established in patients receiving fingolimod. Before fingolimod initiation, test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before fingolimod initiation, and do not start fingolimod for 1 month to allow the full effect of vaccination to occur. In addition to the concerns with live virus vaccines, the immune response to inactive vaccines or toxoids may be decreased, as fingolimod may interfere with normal immune response to new antigens. No data are available on the effectiveness of vaccination with inactivated antigens in patients receiving fingolimod. Vaccination may be less effective during and for up to 2 months after fingolimod discontinuation. For example, as compared with the response of placebo recipients, the capacity to mount a skin delayed-type hypersensitivity reaction to Candida and to tetanus toxoid was decreased by approximately 30% among fingolimod 0.5 mg daily recipients. Further, in healthy patients, antigen-specific IgM titers were decreased by 25% in response to pneumococcal polysaccharide vaccine (PPV-23) immunization as compared with the response by placebo recipients. Similarly, IgG titers were decreased by 50% among fingolimod recipients as compared with placebo.
Ziprasidone: (Major) Concomitant use of ziprasidone and fingolimod should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system (CNS). The active metabolite of fingolimod, fingolimod-phosphate, is a sphingosine 1-phosphate receptor modulator that binds with high affinity to 4 of the 5 sphingosine 1-phosphate receptors (1, 3, 4, and 5). Fingolimod-phosphate blocks the ability of lymphocytes to egress from the lymph nodes, rapidly reducing lymphocyte counts in the peripheral blood, inhibiting their recirculation, and potentially reducing movement of pathogenic cells into the CNS.
Fingolimod is administered orally. It highly (86%) distributes in red blood cells; fingolimod-phosphate has a smaller uptake in blood cells (less than 17%). Fingolimod and fingolimod-phosphate are more than 99.7% protein bound. Fingolimod is extensively distributed to body tissues, including the brain, with a Vd of approximately 1,200 L. Biotransformation occurs via 3 main pathways: reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod-phosphate; oxidative biotransformation catalyzed mainly via CYP4F2 and possibly other CYP4F isoenzymes with subsequent fatty acid-like degradation to inactive metabolites; and by formation of pharmacologically inactive non-polar ceramide analogs of fingolimod. After oral administration, the major fingolimod-related components in the blood are fingolimod itself (23.3%), fingolimod-phosphate (10.3%), and the inactive metabolites M3 carboxylic acid (8.3%), M29 ceramide (8.9%), and M30 ceramide (7.3%). Fingolimod blood clearance is 6.3 L/hour and the average terminal half-life is 6 to 9 days. Blood concentrations of fingolimod-phosphate decline in parallel with those of fingolimod in the terminal phase, which yields similar half-lives for both. After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod-phosphate are not excreted intact in urine but are the major components in the feces with amounts of each representing less than 2.5% of the dose.
Among 12 adult patients who received fingolimod 0.5 mg daily, the lymphocyte count decreased to approximately 60% of baseline within 4 to 6 hours of the first dose. Over a 2-week period, the lymphocyte count continued to decrease with a nadir of approximately 500 cells/microliter or approximately 30% of baseline. Low lymphocyte counts are maintained with continued daily dosing. Peripheral lymphocyte count increases are evident within days of stopping fingolimod, and typically normal counts are reached within 1 to 2 months. In addition to a reduced lymphocyte count, a mild decrease in the neutrophil count to approximately 80% of baseline occurs. Monocytes are unaffected.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP4F2, CYP3A4
Fingolimod is primarily metabolized via CYP4F2 and possibly other CYP4F isoenzymes. Inhibitors or inducers of CYP4F2 (and possibly other CYP4F isoenzymes) may alter the exposure of fingolimod or fingolimod-phosphate. In vitro studies indicate CYP3A4 may contribute to fingolimod metabolism in the case of strong CYP3A4 induction.
-Route-Specific Pharmacokinetics
Oral Route
Oral bioavailability of fingolimod is 93% and time to maximum concentration is 12 to 16 hours. Food does not alter exposure (Cmax or AUC) of fingolimod or fingolimod-phosphate. Steady-state blood concentrations are reached within 1 to 2 months after chronic administration; steady-state concentrations are approximately 10-fold greater than with the initial dose.
-Special Populations
Hepatic Impairment
Fingolimod AUC was increased by 12%, 44%, and 103% in patients with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, and C), respectively. In patients with severe hepatic impairment (Child-Pugh class C), the Cmax of fingolimod-phosphate was decreased by 22% and AUC was decreased by 29%. The pharmacokinetics of fingolimod-phosphate were not evaluated in patients with mild or moderate hepatic impairment. The apparent elimination half-life of fingolimod is unchanged in patients with mild hepatic impairment, but is prolonged by about 50% in subjects with moderate or severe hepatic impairment.
Renal Impairment
Fingolimod Cmax and AUC are increased 32% and 43%, respectively, and fingolimod-phosphate Cmax and AUC are increased by 25% and 14%, respectively, with no change in apparent elimination half-life, in adult patients with severe renal impairment. The systemic exposure of 2 metabolites (M2 and M3) is increased 3- and 13-fold, respectively, in patients with severe renal impairment; however, the toxicity of these metabolites has not been fully characterized. Neither dialysis nor plasma exchange results in removal of fingolimod from the body.
Pediatrics
The median fingolimod-phosphate concentration in pediatric patients (age 10 to 17 years) was 1.1 ng/mL, compared to 1.35 ng/mL in adult patients.
Gender Differences
Gender has no clinically significant influence on fingolimod and fingolimod-phosphate pharmacokinetic parameters.