Fingolimod

Fingolimod is a prescription medicine used to treat patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of exacerbations and delay physical disability.

• Fingolimod is available under the following different brand names: Gilenya, Tascenso ODT

Adult and pediatric dosage

Capsule

• 0.25mg
• 0.5mg

Tablet, oral disintegrating

• 0.25mg

Multiple Sclerosis

Adult dosage

• 0.5 mg orally once daily
• Doses more than 2 times the recommended doses are associated with a greater incidence of adverse reactions without additional benefit

Pediatric dosage

• Children below 10 years: Safety and efficacy not established
• Children above 10 years weighing less than or equal to 40 kg: 0.25 mg orally once daily
• Children above 10 years weighing more than 40 kg: 0.5 mg orally once daily
• Doses more than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

Common side effects of Fingolimod include:

• headache,
• tired feeling,
• influenza,
• stuffy nose,
• sinus pain,
• diarrhea,
• back pain,
• liver transaminase elevations, and
• cough.

Serious side effects of Fingolimod include:

• shiny nodules on the skin, 
• sores that do not heal, 
• unusual moles that change in color or size,
• blurred vision, 
• eye pain, 
• a blind spot or shadows in the center of vision,
• new or worsened breathing problems,
• sores in the mouth and throat, cold sores, sores on the genital or anal area,
• blood vessel problems in the brain--headache, confusion, change in mental status, sudden vision loss, seizure (convulsions),
• heart problems--chest pain, slow or irregular heartbeats, and feeling dizzy or tired,
• liver problems--nausea, upper stomach pain, tiredness, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes),
• signs of infection--fever, chills, body aches, tiredness, nausea and vomiting, neck stiffness, increased sensitivity to light.

Rare side effects of Fingolimod include:

• none 

This is not a complete list of side effects and other serious side effects or health problems that may occur as a result of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Fingolimod has severe interactions with the following drugs:
  • amiodarone
  • disopyramide
  • dofetilide
  • dronedarone
  • ibutilide
  • procainamide
  • quinidine
  • sotalol
  • thioridazine
• Fingolimod has serious interactions with at least 99 other drugs.
• Fingolimod has moderate interactions with at least 205 other drugs.
• Fingolimod has minor interactions with no other drugs. 

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• Hypersensitivity; observed reactions include rash, urticaria, and angioedema upon treatment initiation
• History within past 6 months of MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure
• History or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless the patient has a functioning pacemaker
• Baseline QTc interval more than or equal to 500 ms
• Coadministration with Class Ia or Class III antiarrhythmic drugs

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Fingolimod?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Fingolimod?”

Cautions

• Bradyarrhythmia and atrioventricular blocks
• Also see contraindications, dosing considerations, and drug interaction overview
  • Heart rate reduction
    • After the first dose, heart rate (HR) decrease starts within an hour; on Day 1, the maximum HR decline generally occurs within 6 hours and recovers, although not to baseline levels, by 8-10 hours post-dose
    • Because of physiological diurnal variation, there is a second period of HR decrease within 24 hours after the first dose; in some patients, the HR decrease during the second period is more pronounced than the decrease observed in the first 6 hours
    • Patients with some preexisting conditions (eg, ischemic heart disease, history of MI, CHF, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block) may poorly tolerate fingolimod-induced bradycardia, or experience serious rhythm disturbances after the first dose
    • Before initiating treatment, evaluate patients at risk by a physician appropriately trained to conduct such evaluation, and, if treated with fingolimod, monitor the patient overnight with continuous ECG in a medical facility after the first dose
  • Atrioventricular blocks
    • Transient AV conduction delays were observed after initiating fingolimod
    • Conduction abnormalities were usually transient and asymptomatic and resolved within the first 24 hours of treatment, but they occasionally required treatment with atropine or isoproterenol
• Infections
• Causes dose-dependent reduction in peripheral lymphocyte count to 20-30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues
• May, therefore, increase the risk of life-threatening and fatal infections (eg, disseminated varicella-zoster, herpes simplex, or cryptococcal infections), including fatal meningitis, encephalitis, and multiorgan failure
• Do not initiate with active acute or chronic infections until resolved; before initiation, a recent CBC (ie, within 6 months or after discontinuation of prior therapy) should be available
• Patients without a confirmed history of chickenpox or documentation of a full course of vaccination against varicella-zoster virus (VZV) should be tested for antibodies to VZV before initiating therapy
• Vaccination of antibody-negative patients is recommended before commencing therapy; postpone therapy 1 month to allow the full effect of vaccination to occur
• Postmarketing reports of serious infections include opportunistic pathogens including viruses John Cunningham virus (JCV), herpes simplex viruses 1 and 2, varicella-zoster virus), fungi (eg, cryptococci), and bacteria (eg, atypical mycobacteria) reported; patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and treatment
• Cases of Kaposi’s sarcoma reported; patients with symptoms or signs consistent with Kaposi’s sarcoma should receive prompt diagnostic evaluation and management
• Human papillomavirus (HPV) infections, including papilloma, dysplasia, warts, and HPV-related cancer, are reported; vaccination against HPV should be considered before treatment initiation, taking into account vaccination recommendations; cancer screening, including Papanicolaou (Pap) test, is recommended as per standard of care for patients using an immunosuppressive therapy
• Progressive multifocal leukoencephalopathy
  • Progressive multifocal leukoencephalopathy (PML) is reported; symptoms are diverse and include sudden onset of severe headache, altered mental status, progressive unilateral weakness, clumsiness, visual disturbances, and seizure
  • Symptoms are usually reversible but may evolve into an ischemic stroke or cerebral hemorrhage and delay in diagnosis and treatment may lead to permanent neurological sequelae
  • An MRI scan may find brain lesions before symptoms develop Majority of cases occurred after 2 years of treatment
• Macular edema
  • Increases risk of macular edema (with or without visual symptoms)
  • Examine the fundus including the macula in all patients before initiating treatment and 3-4 months after starting a treatment or any time after a patient reports visual disturbances while in therapy
  • History of diabetes mellitus or uveitis has increased the risk of macular edema
• Posterior reversible encephalopathy syndrome
  • Rare cases of posterior reversible encephalopathy syndrome (PRES) reported in adults
  • Symptoms reported included sudden onset of severe headache, altered mental status, visual disturbances, and seizure
  • Symptoms are usually reversible but may evolve into an ischemic stroke or cerebral hemorrhage
  • Transient AV conduction delays were observed after initiating fingolimod
  • Conduction abnormalities were usually transient and asymptomatic and resolved within the first 24 hours of treatment, but they occasionally required treatment with atropine or isoproterenol
  • Delay in diagnosis and treatment may lead to permanent neurological sequelae; discontinue therapy if PRES suspected
• Respiratory effects
  • Dose-dependent reduction in FEV 1 and diffusion lung capacity for carbon monoxide (DLCO) observed as early as 1 month after fingolimod initiation
  • Spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy if clinically indicated
• Liver injury
  • Liver injury with hepatocellular and/or cholestatic hepatitis reported
  • Recent (ie, within the last 6 months) transaminase and bilirubin levels should be available before initiation
  • Monitor liver enzymes and bilirubin if symptoms develop suggestive of hepatic dysfunction (eg, unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine)
  • Monitor patients for signs and symptoms of any hepatic injury; measure liver transaminase and bilirubin levels promptly in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice; cases of acute liver failure requiring liver transplant reported
  • Obtain transaminase levels and total bilirubin levels periodically until two months after therapy discontinuation
  • If the patient is found to have alanine aminotransferase (ALT) levels greater than three times the reference range with serum total bilirubin greater than two times the reference range, interrupt treatment; do not resume treatment if a plausible alternative etiology for signs and symptoms cannot be established; these patients are at risk for severe drug-induced liver injury
  • Discontinue if significant liver injury is confirmed
• Fetal risk
  • Based on animal studies, may cause fetal harm
  • It takes approximately 2 months to eliminate fingolimod from the body; therefore, women of childbearing potential should use effective contraception to avoid pregnancy during and for 2 months after stopping treatment (see Pregnancy)
• Increased blood pressure
  • In controlled clinical trials, adults treated with fingolimod 0.5 mg had an average increase of approximately 3 mmHg in systolic pressure and approximately 2 mmHg in diastolic pressure detected approximately 1 month after initiation, and persisting with continued treatment
  • Monitor blood pressure during treatment
• Cutaneous malignancies
  • Increases risk of basal cell carcinoma (BCC) and melanoma
  • Melanoma and Merkel cell carcinoma were reported postmarketing
  • Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer
  • Advise patients to promptly evaluate suspicious skin lesions and protect themselves from sunlight and UV light exposure
• Immune system effects
  • Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts, for up to 2 months following the last dose
  • Lymphocyte counts generally return normalizes within 1-2 months after discontinuing the drug
  • Because of the continuing pharmacodynamic effects, initiating other drugs during this period warrants the same considerations needed for concomitant administration (eg, additive immunosuppressant effects) (see Drug Interaction Overview)
• Hypersensitivity reactions
  • Hypersensitivity reactions, including rash, urticaria, and angioedema have been reported
  • Contraindicated in patients with a history of hypersensitivity to fingolimod or any of its excipients (see Contraindications)
• Severe increase in disability after discontinuing
  • Severe increase in disability accompanied by multiple new lesions on MRI reported after discontinuing fingolimod
  • Postmarketing reports describe patients in most of these cases who did not return to the functional status they had before stopping fingolimod
  • The onset of disability generally occurred within 12 weeks after discontinuing but was reported up to 24 weeks afterward
• Tumefactive multiple sclerosis
  • MS relapses with tumefactive demyelinating lesions on imaging observed during therapy and after discontinuation
  • Most reported cases of tumefactive MS in patients receiving therapy have occurred within the first 9 months after initiation, but may occur at any point during treatment
  • Cases of tumefactive MS were also reported within the first 4 months after therapy discontinuation
  • Tumefactive MS should be considered when a severe MS relapse occurs during treatment, especially during initiation, or after discontinuation, prompting imaging evaluation and initiation of appropriate treatment
  • Melanoma, squamous cell carcinoma, and Merkel cell carcinoma reported
• Drug interactions overview
• Inhibitors or inducers of CYP4F2 and possibly other CYP4F isozymes might alter the exposure of fingolimod
• Coadministration with ketoconazole (a potent inhibitor of CYP3A and CYP4F) increased fingolimod blood levels by 1.7-fold; monitor closely if coadministered
• Antineoplastic, immunosuppressive, or immunomodulating therapies
  • Risk for additive systemic immunosuppression if coadministered with antineoplastics, immunosuppressives, or immunomodulators
  • Avoid unintended additive immunosuppression when switching from drugs with prolonged immune effects (eg, natalizumab, teriflunomide, mitoxantrone)
• Vaccines
  • Fingolimod reduces immune response to vaccination; vaccination may be less effective during and for up to 2 months after discontinuing fingolimod
  • Avoid the use of live attenuated vaccines during and for 2 months after treatment because of the risk of infection
  • If possible, pediatric patients should be brought up to date with all immunizations in agreement with current immunization guidelines before initiating fingolimod
• QT-prolonging drugs
  • Not studied in patients treated with drugs that prolong the QT interval, which has been associated with cases of torsades de pointes in patients with bradycardia
  • Since treatment initiation of fingolimod results in decreased heart rate and may prolong the QT interval, patients on QT-prolonging drugs with a known risk of torsades de pointes should be monitored overnight with continuous ECG in a medical facility
• Drugs that slow HR or AV conduction
  • Experience with concurrent therapy with drugs that slow the heart rate or atrioventricular conduction (eg, beta-blockers, digoxin, or heart rate-slowing calcium channel blockers [diltiazem, verapamil]) is limited
  • Fingolimod may result in decreased heart rate; therefore, coadministration with the aforementioned drugs during fingolimod initiation may be associated with severe bradycardia or heart block
  • Seek advice from the physician prescribing these drugs regarding the possibility to switch to drugs that do not slow HR or AV conduction before initiating fingolimod
  • Patients who cannot switch should have overnight continuous ECG monitoring after the first fingolimod dose

Pregnancy and Lactation

• There are no adequate data on the developmental risk associated with drug use in pregnant women
• The pregnancy exposure registry monitors pregnancy outcomes in women exposed to fingolimod during pregnancy; physicians and patients are encouraged to enroll in the pregnancy registry by calling 1-877-598-7237, sending an email to [email protected], or visiting www.gilenyapregnancyregistry.com
• The pregnancy status of females of reproductive potential should be verified before starting treatment
• Advise pregnant women of the potential risk to a fetus
• Contraception
  • Before treatment initiation, counsel women of childbearing potential regarding the potential for serious fetal risk and the need for effective contraception during treatment
  • Since it takes approximately 2 months to eliminate the compound from the body after discontinuing treatment, the potential risk to the fetus may persist and women should use effective contraception during this period; for females planning to become pregnant, therapy should be stopped 2 months before conception
• Lactation
  • There are no data on the presence of fingolimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production
  • Fingolimod is excreted in the milk of treated rats; when a drug is present in animal milk, the drug will likely be present in human milk
  • Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for fingolimod and any potential adverse effects on the breastfed infant from fingolimod or the underlying maternal condition