Fingolimod Hydrochloride

Multiple Sclerosis (MS)

Used to reduce the frequency of clinical exacerbations and delay the accumulation of physical disability in adults with relapsing forms of MS (e.g., relapsing-remitting MS [RRMS]).1 2 3 4 10

Used as first-line therapy for relapsing MS;1 30 31 33 38 additional studies needed to determine optimal role and safety profile, particularly during long-term use and in comparison with other disease-modifying therapies (e.g., glatiramer acetate, interferon beta, natalizumab).3 33 34 38

May be useful in patients who prefer to avoid parenteral administration and/or those who have had an inadequate response to other first-line therapies (e.g., dimethyl fumarate, glatiramer acetate, interferon beta, teriflunomide).31 33

Currently not FDA-labeled for use in patients with primary-progressive MS†.1 40

Autoimmune Neuropathy

Designated an orphan drug by FDA for treatment of chronic inflammatory demyelinating polyneuropathy†; not labeled for this orphan indication by FDA.32

Contraindications

• Recent (in the past 6 months) MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or class III or IV heart failure.1

• History or presence of Mobitz type II second-degree or third-degree AV block or sick sinus syndrome unless patient has a functioning pacemaker.1

• Baseline QTc interval of ≥500 msec.1

• Concomitant use of class Ia or class III antiarrhythmic agents.1 (See Specific Drugs and Laboratory Tests under Interactions.)

Warnings/Precautions

Bradyarrhythmia and AV Block

Risk of fingolimod-associated bradyarrhythmia and AV block;1 3 4 46 47 monitor patients during initiation of therapy.1 (See First-dose Monitoring under Dosage and Administration.)

After the first dose, heart rate decrease starts within an hour; maximal decline on the first day generally occurs within 6 hours and recovery (although not to baseline levels) occurs by 8–10 hours post-dose.1 4 20 A second period of heart rate decrease occurs within 24 hours after the first dose and may be more pronounced in some patients.1 Heart rates <40 bpm observed rarely.1 46 47

Patients with bradycardia generally are asymptomatic; however, some experience hypotension, dizziness, fatigue, palpitations, and chest pain, which usually resolve within first 24 hours of therapy.1 45 47

Following the second dose, a further decrease in heart rate may occur but be of smaller magnitude than that observed after the first dose.1 With continued dosing, the heart rate returns to baseline within one month.1 20 Continue to be alert to patient reports of cardiac symptoms throughout this period.1

Transient AV conduction delays (e.g., first-degree or second-degree AV block) may occur when initiating therapy.1 4 20 Conduction abnormalities usually are transient, asymptomatic, and resolve within the first 24 hours of therapy, but occasionally require treatment with atropine or isoproterenol.1 (See Specific Drugs and Laboratory Tests under Interactions.)

During postmarketing surveillance, third-degree AV block and AV block with junctional escape observed during the first-dose, 6-hour observation period.1 Isolated delayed-onset events, including transient asystole and unexplained death, occurred within 24 hours of the first dose.1 45 46 These events were confounded by concomitant medications and/or preexisting disease; causal relationship to fingolimod is uncertain.1 45 46 Syncope also reported after the first dose.1

Infectious Complications

Fingolimod causes a dose-dependent reduction in peripheral lymphocyte count to 20–30% of baseline values (see Actions).1 May increase risk of infections; some are serious.1 (See Progressive Multifocal Leukoencephalopathy [PML] under Cautions.)

Serious, sometimes fatal herpetic infections (including disseminated primary herpes zoster, herpes simplex encephalitis, and varicella zoster) reported, sometimes with multiorgan failure.1 4 Some patients had received higher fingolimod dosages than recommended for treatment of MS and also had received high-dose corticosteroid therapy for suspected MS relapse.1 4 Include disseminated herpetic infections in the differential diagnosis of patients receiving fingolimod who present with an atypical MS relapse or multiorgan failure.1

Cryptococcal infections, including some cases of cryptococcal meningitis, reported.1 If signs and symptoms consistent with cryptococcal meningitis occur, prompt diagnostic evaluation and treatment are necessary.1

Before initiating treatment, a recent CBC (i.e., within 6 months or after discontinuance of previous therapy) should be available.1 Do not begin treatment in patients with active acute or chronic infections until infection(s) has resolved.1

Monitor patients for signs and symptoms of infection during and for 2 months after discontinuing therapy.1 (See Advice to Patients.) If a serious infection develops, consider drug discontinuance, at least temporarily, and reassess benefits and risks prior to reinitiation of therapy.1

Has not been administered concomitantly with antineoplastic, non-corticosteroid immunosuppressive, or immunomodulating therapies used for MS.1 Concomitant use of these therapies, and also corticosteroid therapy, expected to increase risk of immunosuppression.1 When switching to fingolimod from immunomodulating or immunosuppressive therapies, consider duration of their effects and their mechanism of action to avoid unintentional additive immunosuppressive effects.1

Test patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against varicella zoster virus (VZV) for antibodies to VZV before initiating fingolimod.1 VZV vaccination of antibody-negative patients is recommended prior to initiating fingolimod treatment; postpone initiation of fingolimod therapy for 1 month following vaccination.1

Progressive Multifocal Leukoencephalopathy (PML)

PML, an opportunistic infection of the brain caused by the JC virus, reported in patients receiving fingolimod who had not previously received immunosuppressive agents.53

At the first sign or symptom suggestive of PML (see Advice to Patients), withhold fingolimod therapy and perform an appropriate diagnostic evaluation.1 53 MRI signs of PML may be apparent before clinical manifestations develop.1 53

Macular Edema

Fingolimod increases the risk of macular edema; the increased risk appears to be dose dependent.1 In 2-year, double-blind, placebo-controlled studies, macular edema (with or without visual symptoms) reported in 1.5% of patients receiving 1.25 mg daily of fingolimod and in 0.5% of patients receiving 0.5 mg daily, usually within the first 3–4 months of treatment.1 3 4 31 May occur with or without symptoms (e.g., blurred vision, decreased visual acuity).1 Generally improves or resolves after drug discontinuance with or without treatment, but residual visual acuity loss has occurred in some patients.1 3 4 31

Perform an ophthalmologic evaluation of the fundus, including the macula, at baseline and 3–4 months after treatment initiation.1 If visual disturbances occur at any time during therapy, perform an additional ophthalmologic evaluation.1 Continuation of fingolimod therapy in patients with macular edema not evaluated; any decision on whether to discontinue therapy should include an assessment of the potential benefits and risks for the individual patient.1 Risk of recurrence after rechallenge also not evaluated.1

Increased risk of macular edema in patients with diabetes mellitus or a history of uveitis; such patients should undergo regular ophthalmologic evaluations during therapy.1

Posterior Reversible Encephalopathy Syndrome (PRES)

PRES reported rarely.1 Symptoms in reported cases include sudden onset of severe headache, altered mental status, visual disturbances, and seizure.1 Although symptoms are usually reversible, they may evolve into ischemic stroke or cerebral hemorrhage; a delay in diagnosis and treatment of PRES may lead to permanent neurologic sequelae.1

If PRES is suspected, discontinue fingolimod.1

Respiratory Effects

May decrease pulmonary function tests.1 Dose-dependent reductions in FEV1 and diffusion lung capacity for carbon monoxide (DLCO) observed as early as 1 month after beginning therapy.1 FEV1 changes appear reversible after discontinuing fingolimod; insufficient information to determine reversibility of the DLCO decrease after drug discontinuance.1 Dyspnea reported in placebo-controlled and extension studies.1

Obtain spirometry and DLCO when clinically indicated (see Advice to Patients).1

Liver Injury

May increase hepatic enzyme concentrations.1 4 Most elevations occur within 6–9 months.1 Transaminase elevations returned to normal within approximately 2 months after discontinuance of fingolimod.1 3 Transaminase elevations recurred upon rechallenge in some patients.1 Patients with preexisting liver disease may be at increased risk for elevations.1

Recent (i.e., within last 6 months) transaminase and bilirubin concentrations should be available before initiating treatment.1

Monitor liver enzymes in patients who develop symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, anorexia, fatigue, jaundice, dark urine).1 Discontinue fingolimod if clinically important liver injury is confirmed.1

Fetal/Neonatal Morbidity and Mortality

Animal studies indicate fingolimod may cause fetal harm.1 Use effective contraception in women of childbearing potential during and for 2 months after discontinuance of therapy.1 (See Pregnancy under Cautions and also see Advice to Patients.)

BP Effects

May increase BP.1 In clinical studies average increases in SBP and DBP were approximately 3 and 2 mm Hg, respectively; increases first detected approximately 2 months following treatment initiation and persisted with continued treatment.1 Hypertension reported in 8% of fingolimod-treated patients in controlled trials.1

Monitor BP during therapy.1

Immunosuppression Following Discontinuance

Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts, for up to 2 months following the last dose.1 Initiating other drugs during this period warrants the same considerations needed for concomitant administration (e.g., risk of additive immunosuppressive effects).1 (See Specific Drugs and Laboratory Tests under Interactions.)

Specific Populations

Category C.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Gilenya pregnancy registry (for clinicians and patients) at 877-598-7237, by email to gpr@outcome.com, or on the website .1 2 37

Effects on labor and delivery are unknown.1

Distributed into milk in rats; not known whether distributed into human milk.1 2 Discontinue nursing or the drug.1 2

Safety and efficacy not established in patients <18 years of age.1

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 Use with caution because of possible age-related decreases in hepatic and/or renal function and concomitant disease and other drug therapy.1

Closely monitor patients with severe hepatic impairment (Child-Pugh class C) since fingolimod exposure is doubled and risk of adverse reactions is greater.1 13 14 (See Hepatic Impairment under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)

Increased systemic exposure (up to 13-fold) of some fingolimod metabolites observed in patients with severe renal impairment; toxicity of these metabolites not fully explored.1 (See Renal Impairment under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Headache,1 3 4 elevations in serum transaminase concentrations,1 3 4 diarrhea,1 3 4 nausea,1 cough,1 4 influenza,1 3 4 sinusitis,1 back pain,1 3 4 abdominal pain,1 pain in extremity.1

Primarily metabolized by CYP4F2 and possibly other CYP4F isoenzymes.1 27 In vitro studies in hepatocytes indicate that CYP3A4 also may contribute to metabolism if there is potent induction of CYP3A4.1

Has little or no inhibitory activity on CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11 (fingolimod only).1 Similarly, fingolimod-phosphate (an active metabolite) has little or no inhibitory activity on CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.1

Does not substantially induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 3A (including 3A4), or 4F2 or P-glycoprotein.1 Fingolimod-phosphate does not induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 3A, 4F2, 4F3B, or 4F12.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP isoenzyme 4F2 and possibly other CYP4F isoenzymes: Possible altered exposure of fingolimod and/or fingolimod-phosphate.1

Potent CYP450 enzyme inducers: Possible reduced exposure of fingolimod and/or fingolimod-phosphate.1

Drugs that Prolong QT Interval

Fingolimod initiation decreases heart rate and may prolong the QT interval; monitor patients concurrently receiving non-antiarrhythmic, QT-prolonging drugs with a known risk of torsades de pointes overnight with continuous ECG in a medical facility.1 46 48 (See First-dose Monitoring in Higher-risk Patients under Dosage and Administration and also see Specific Drugs and Laboratory Tests under Interactions.)

Drugs that Slow Heart Rate or AV Conduction

Limited experience.1 Concomitant use during fingolimod initiation may be associated with severe bradycardia or heart block.1

Before initiating fingolimod, consult prescribing clinician to determine if possible to switch to drugs that do not slow the heart rate or AV conduction.1

In patients who cannot switch to another drug, extended continuous ECG monitoring, including overnight monitoring, recommended after the first dose of fingolimod.1 (See First-dose Monitoring in Higher-risk Patients under Dosage and Administration.)

Specific Drugs and Laboratory Tests

• Derived from the fungal metabolite myriocin; used orally as a disease-modifying treatment for multiple sclerosis (MS).1 6 7 21 29 31

• Sphingosine kinase, predominantly type 2, metabolizes fingolimod to the active metabolite, fingolimod-phosphate.1 7 23 24 Fingolimod-phosphate is a sphingosine 1-phosphate (S1P) receptor modulator and binds with high affinity to S1P receptor subtypes 1, 3, 4, and 5.1 7 8

• The S1P1 receptor regulates lymphocyte egress from both the thymus and peripheral lymphoid organs and is essential for lymphocyte recirculation.25 26 Binding of fingolimod-phosphate to S1P1 blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in the peripheral blood and CNS.1 7 8 9 21 25 26

• Exact mechanism of fingolimod’s therapeutic effects in MS unknown; may involve reduction of lymphocyte migration into the CNS.1 21 22 25 26

• Preclinical findings suggest fingolimod may directly affect neuropathologic processes such as neurodegeneration, gliosis, and endogenous repair mechanisms within the CNS through modulation of S1P receptors expressed on neural cells.3 29 30

• Importance of reading the medication guide prior to initiating therapy and each time the prescription is refilled.1 2

• Risk of transient decrease in heart rate, particularly after the first dose; may recur when therapy is resumed after an interruption of >14 days.1 2 Medical observation for ≥6 hours required after the first dose or after interruption for >1 day during the first 2 weeks of therapy, for >7 days during weeks 3 and 4 of therapy, or for >14 days after the first month of therapy.1 2 Importance of immediately contacting clinician or seeking emergency care if dizziness, tiredness, or slow or irregular heartbeat occurs.2

• Importance of informing patients that PML has occurred in fingolimod-treated patients.1 53 Importance of informing clinician of any symptoms suggestive of PML (e.g., progressive weakness on one side of the body; clumsiness of limbs; vision disturbance; changes in thinking, memory, or orientation leading to confusion and personality changes) that have progressed over days to weeks.1 53 Importance of advising patients not to stop taking fingolimod without first consulting with their clinician.1 53

• Possible increased risk of infections, since fingolimod may reduce lymphocyte count.1 2 Importance of immediately contacting clinician if any symptoms of infection (e.g., fever, chills, tiredness, body aches, nausea, vomiting) develop during or within 2 months after fingolimod therapy.1 2 Importance of informing patients that prior or concomitant use of drugs that suppress the immune system may increase risk of infection.1

• Importance of informing clinicians of any vaccinations given within 1 month before starting fingolimod.2 Importance of avoiding some vaccines during treatment and for 2 months after drug discontinuance.1 Importance of advising patients to delay fingolimod therapy until after varicella zoster virus (VZV) vaccination if they have not had chickenpox or a previous VZV vaccination.1 2

• Risk of macular edema, particularly in individuals who are diabetic or have had uveitis.1 2 Some symptoms may resemble those of an MS attack (optic neuritis); some patients may not notice symptoms.1 2 Vision testing recommended before starting fingolimod therapy, 3–4 months after treatment initiation, and any time vision changes occur.1 2 Importance of immediately contacting clinician if any vision changes (e.g., blurriness or shadows in the center of vision, blind spot in the center of vision, sensitivity to light, unusually colored or tinted vision) occur.1 2 Inform patients that their risk of developing macular edema is higher if they have diabetes or have had uveitis.1 2

• Risk of breathing problems.1 2 Importance of immediately contacting clinician if any breathing difficulties (e.g., new onset or worsening of shortness of breath) occur.1 2

• Risk of increased liver enzymes.1 2 Importance of contacting clinician if unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine occurs.1 2

• Risk of fetal harm.1 2 Need for effective contraception in women of childbearing age during therapy and for 2 months after the last dose.1 2 Importance of women immediately informing their clinician if pregnancy occurs during this time period.1 2 Availability of pregnancy registry (see Pregnancy under Cautions).2

• Importance of women informing clinicians if they plan to breast-feed.2

• Importance of advising patients that fingolimod remains in the blood and continues to have effects (e.g., decreased lymphocyte counts) for up to 2 months after the last dose.1

• Importance of patient informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements, as well as any concomitant illnesses.1 2

• Importance of not discontinuing fingolimod without first talking with clinician.1 2 41 42 45

• Importance of informing patients of other important precautionary information.1 2 (See Cautions.)