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Generic Name: Fingolimod Hydrochloride
Class: Immunomodulatory Agents
Chemical Name: 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride
Molecular Formula: C19H33NO2•HCl
CAS Number: 162359-56-0

Warning(s)

REMS:

FDA approved a REMS for fingolimod to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of fingolimod and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

A sphingosine 1-phosphate (S1P) receptor modulator with immunomodulatory and disease-modifying activity in multiple sclerosis.1 3 4 10 31

Uses for Gilenya

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

Slideshow: Multiple Sclerosis: What's New in Treatment Options?

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

Gilenya Dosage and Administration

General

First-dose Monitoring

  • Initiation of fingolimod therapy decreases heart rate and may cause transient AV conduction delays.1 3 4 46 47 (See Bradyarrhythmia and AV Block under Cautions.)

  • Administer first dose in a setting with available resources to appropriately manage symptomatic bradycardia.1

  • Observe all patients for signs and symptoms of bradycardia for at least 6 hours after first dose with hourly pulse and BP measurements.1 41 Obtain ECG prior to dosing and at the end of the observation period.1 41

  • Institute additional observation until the finding has resolved in the following situations: heart rate 6 hours post-dose is <45 bpm or ECG 6 hours post-dose shows new-onset second-degree or higher AV block.1 41 Monitor patients who are at their lowest post-dose heart rate at the end of the observation period until heart rate increases.1

  • If post-dose symptomatic bradycardia occurs, initiate appropriate management, begin continuous ECG monitoring, and continue observation until symptoms resolve.1 If pharmacologic intervention is required to treat bradycardia, continue to monitor overnight with continuous ECG monitoring in a medical facility; repeat first-dose monitoring procedures for the second dose.1

First-dose Monitoring in Higher-risk Patients

  • Patients at higher risk of symptomatic bradycardia or heart block because of a preexisting condition (e.g., ischemic heart disease, history of MI, CHF, history of cardiac arrest, cerebrovascular disease, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV or SA block): Perform cardiac evaluation by an appropriately trained clinician prior to initiating fingolimod.1 If decide to initiate therapy, monitor overnight with continuous ECG in a medical facility.1 (See Contraindications and Bradyarrhythmia and AV Block under Cautions.)

  • Patients with a prolonged corrected QT (QTc) interval (males: >450 msec; females: >470 msec) before dosing or during the 6-hour observation period: Institute overnight monitoring with continuous ECG in a medical facility.1

  • Patients at additional risk for QT-interval prolongation (e.g., those with hypokalemia, hypomagnesemia, or congenital long QT syndrome): Institute overnight monitoring with continuous ECG in a medical facility.1

  • Patients receiving concurrent therapy with QT-prolonging drugs with a known risk of torsades de pointes: Institute overnight monitoring with continuous ECG in a medical facility.1 46 (See Drugs that Prolong QT Interval and Specific Drugs and Laboratory Tests under Interactions.)

  • Patients receiving concurrent therapy with drugs that slow heart rate or AV conduction: Observe patient overnight with continuous ECG monitoring after the first dose of fingolimod.1 (See Drugs that Slow Heart Rate or AV Conduction and Specific Drugs and Laboratory Tests under Interactions.)

Reinitiation of Therapy Following Discontinuance

  • If fingolimod is discontinued for >14 days after the first month of treatment, effects on heart rate and AV conduction may recur upon reintroduction of drug; apply the same precautions (i.e., first-dose monitoring) as for initial dosing.1

  • Within the first 2 weeks of treatment, first-dose monitoring procedures are recommended after treatment interruption of ≥1 day.1 During weeks 3 and 4 of treatment, first-dose monitoring procedures are recommended after treatment interruption of >7 days.1 (See First-dose Monitoring under Dosage and Administration.)

Washout Period Following Discontinuance of Other MS Therapies

  • Washout period does not appear to be necessary when switching from interferon beta or glatiramer acetate to other MS treatments, including fingolimod.38 Use caution when switching from long-acting MS therapies with immunosuppressant effects (e.g., natalizumab, mitoxantrone) to fingolimod.1 38

  • Some clinicians recommend that approximately 6 months elapse following discontinuance of natalizumab and initiation of fingolimod.38

  • Some clinicians recommend that 2 months elapse following discontinuance of fingolimod prior to initiation of another MS therapy, although a shorter washout period may be adequate if switching to an agent without immunosuppressant effects.38 (See Infectious Complications and Immunosuppression Following Discontinuance under Cautions.)

Administration

Oral Administration

Administer orally once daily without regard to food.1 2 11

Dosage

Available as fingolimod hydrochloride; dosage expressed in terms of fingolimod.1

Adults

Multiple Sclerosis
Oral

0.5 mg once daily.1 Higher dosages associated with a greater incidence of adverse reactions without additional benefit.1 3 4

Special Populations

Hepatic Impairment

Severe hepatic impairment: Monitor closely.1 Routine dosage adjustment does not appear necessary.1

Mild or moderate hepatic impairment: Routine dosage adjustment not necessary.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Routine dosage adjustment does not appear necessary.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustment not necessary.1 13 (See Geriatric Use under Cautions.)

Cautions for Gilenya

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

Before initiating treatment, a recent CBC (i.e., within 6 months) 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, immunosuppressive, or immunomodulating therapies used for MS.1 Concomitant use expected to increase risk of immunosuppression.1

Test patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) for antibodies to VZV before initiating fingolimod.1 Consider VZV vaccination of antibody-negative patients prior to initiating fingolimod treatment; postpone initiation of fingolimod therapy for 1 month following vaccination.1

Progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain caused by the JC virus, reported in a patient receiving fingolimod; this is the first reported case of PML in a fingolimod-treated patient who had not previously received natalizumab.51 52 The patient had received interferon beta-1a and azathioprine (before fingolimod) and corticosteroids (IV courses before and during fingolimod therapy).52 PML usually leads to death or severe disability.51 52 FDA continues to evaluate the case and will notify healthcare professionals of its conclusions and recommendations when the evaluation is complete.51 52 Patients should not stop taking fingolimod without first discussing their concerns with their clinician.51 52

Macular Edema

Macular edema reported in 0.4% of patients in controlled studies, 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 adequate ophthalmologic evaluation 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

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

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

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

Hepatic Effects

May increase hepatic enzyme concentrations.1 4 Most elevations occur within 3–4 months.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 2 and 1 mm Hg, respectively; increases first detected approximately 2 months following treatment initiation and persisted with continued treatment.1 Hypertension reported in 5% 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

Pregnancy

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

Gilenya pregnancy registry (for clinicians and patients) at 877-598-7237.1 2 37

Effects on labor and delivery are unknown.1

Lactation

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

Pediatric Use

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

Geriatric Use

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

Hepatic Impairment

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

Renal Impairment

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 influenza,1 3 4 diarrhea,1 3 4 back pain,1 3 4 elevations in serum transaminase concentrations,1 3 4 cough.1 4

Interactions for Gilenya

Primarily metabolized by CYP4F2 with a minor contribution by CYP isoenzymes 2D6, 2E1, 3A4, and 4F12.1 27

Has little or no inhibitory activity on CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11.1 Similarly, fingolimod-phosphate (an active metabolite) has little or no inhibitory activity on CYP isoenzymes 1A2, 2A6, 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

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP isoenzymes 4F2, 2D6, 2E1, 3A4, and 4F12: Potential pharmacokinetic interaction (possible altered exposure of fingolimod and/or fingolimod-phosphate).1 Multiple CYP isoenzymes are involved in fingolimod’s metabolism; substantial inhibition unlikely in the presence of an inhibitor of a single specific CYP isoenzyme.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

Drug or Test

Interaction

Comments

Amantadine

Clinically important pharmacokinetic interaction unlikely1

Amitriptyline

Clinically important pharmacokinetic interaction unlikely1

Antiarrhythmic agents, class Ia (e.g., quinidine, procainamide) and class III (e.g., amiodarone, sotalol)

Possible increased risk of torsades de pointes in patients with bradycardia1

Concomitant use contraindicated1

Antidepressants, SSRIs (e.g., fluoxetine, paroxetine)

Pharmacokinetic interaction with fluoxetine and paroxetine unlikely1

Antipsychotic agents that prolong the QT interval (e.g., chlorpromazine, haloperidol, olanzapine, pimozide, quetiapine, risperidone, thioridazine, ziprasidone)

Potential additive effects on the QT interval and increased risk of torsades de pointes1 46 48

Monitor overnight with continuous ECG in a medical facility during fingolimod initiation (see First-dose Monitoring in Higher-risk Patients under Dosage and Administration)1

Atropine

Single-dose fingolimod and fingolimod-phosphate exposure not substantially altered1 16

Baclofen

Clinically important pharmacokinetic interaction unlikely1

β-Adrenergic blocking agents (e.g., atenolol)

Risk of severe bradycardia or heart block, particularly during fingolimod initiation1 17 31

Atenolol: Additional 15% reduction of heart rate upon fingolimod initiation; clinically important pharmacokinetic interaction unlikely17

Evaluate if possible to switch to drugs that do not slow heart rate or AV conduction;1 if switch not possible, overnight continuous ECG monitoring recommended after first dose (see First-dose Monitoring in Higher-risk Patients under Dosage and Administration)1

Calcium-channel blocking agents (e.g., diltiazem, verapamil)

Risk of severe bradycardia or heart block, particularly during fingolimod initiation1 17

Diltiazem: Clinically important pharmacokinetic interaction unlikely; additive effect on bradycardia not observed in healthy individuals1 17

Evaluate if possible to switch to drugs that do not slow heart rate or AV conduction;1 if switch not possible, overnight continuous ECG monitoring recommended after first dose (see First-dose Monitoring in Higher-risk Patients under Dosage and Administration)1

Carbamazepine

Pharmacokinetic interaction unlikely1

Citalopram

Potential additive effects on the QT interval and increased risk of torsades de pointes1

Monitor overnight with continuous ECG in a medical facility during fingolimod initiation (see First-dose Monitoring in Higher-risk Patients under Dosage and Administration)1

Corticosteroids

Increased risk of immunosuppression; clinically important pharmacokinetic interaction unlikely1

Cyclosporine

Pharmacokinetics of single-dose fingolimod and steady-state cyclosporine not altered1 19

Digoxin

Risk of severe bradycardia or heart block, particularly during fingolimod initiation1

Evaluate if possible to switch to drugs that do not slow heart rate or AV conduction;1 if switch not possible, overnight continuous ECG monitoring recommended after first dose (see First-dose Monitoring in Higher-risk Patients under Dosage and Administration)1

Erythromycin

Potential additive effects on the QT interval and increased risk of torsades de pointes1

Monitor overnight with continuous ECG in a medical facility during fingolimod initiation (see First-dose Monitoring in Higher-risk Patients under Dosage and Administration)1

Gabapentin

Clinically important pharmacokinetic interaction unlikely1

Immunomodulating therapies (e.g., antineoplastic or immunosuppressive therapies)

Increased risk of immunosuppression1

Use caution when switching from long-acting MS therapies with immunosuppressive effects (e.g., natalizumab, mitoxantrone) to fingolimod1 38

Isoproterenol

Single-dose fingolimod and fingolimod-phosphate exposure not substantially altered1 15

Ketoconazole

Blood concentrations of fingolimod and fingolimod-phosphate increased by 1.7-fold; possible increased risk of adverse effects1 18 31

Closely monitor patients receiving systemic ketoconazole concomitantly; consider fingolimod dosage reduction if necessary1 18 31

Lymphocyte counts

Fingolimod reduces blood lymphocyte counts via redistribution in secondary lymphoid organs1

Do not utilize peripheral blood lymphocyte count to evaluate lymphocyte subset status1

Ensure availability of a recent CBC before initiating fingolimod therapy1

Methadone

Potential additive effects on the QT interval and increased risk of torsades de pointes1

Monitor overnight with continuous ECG in a medical facility during fingolimod initiation (see First-dose Monitoring in Higher-risk Patients under Dosage and Administration)1

Modafinil

Clinically important pharmacokinetic interaction unlikely1

Oral contraceptives

Steady-state pharmacokinetics of ethinyl estradiol and levonorgestrel not substantially affected49

Oxybutynin chloride

Clinically important pharmacokinetic interaction unlikely1

Pregabalin

Clinically important pharmacokinetic interaction unlikely1

Vaccines

Vaccination may be less effective during and for up to 2 months following discontinuance of fingolimod1

Risk of infection with live attenuated vaccines1

Avoid use of live attenuated vaccines during and for 2 months after fingolimod treatment1 (see Infectious Complications under Cautions)

Gilenya Pharmacokinetics

Absorption

Bioavailability

Apparent absolute oral bioavailability is 93%.1 Peak blood concentrations attained approximately 12–16 hours following oral administration.1 6 12

Food

Food does not alter peak concentrations or AUC of fingolimod or fingolimod-phosphate.1 11

Plasma Concentrations

Steady-state concentrations achieved within 1–2 months following once-daily oral administration.1

Special Populations

Severe renal impairment: Peak blood concentrations and AUCs of fingolimod increased by 32 and 43%, respectively; peak blood concentrations and AUCs of fingolimod-phosphate increased by 25 and 14%, respectively.1 Systemic exposure of 2 fingolimod metabolites (M2 and M3) increased by threefold and 13-fold, respectively.1

Mild or moderate renal impairment: Pharmacokinetics not evaluated.1

Mild, moderate, or severe hepatic impairment: Fingolimod AUCs increased by 12, 44, and 103%, respectively.1

Severe hepatic impairment: Peak concentrations of fingolimod-phosphate decreased by 22%; AUC not substantially changed.1

Distribution

Extent

Fingolimod extensively distributes into body tissues.1

Fingolimod: Highly distributes (86%) in RBCs.1

Fingolimod-phosphate: Smaller uptake in blood cells (<17%).1

Distributed into milk in rats; not known whether distributes into human milk.1 2

Plasma Protein Binding

Fingolimod and fingolimod-phosphate: >99.7%.1

Elimination

Metabolism

Biotransformation occurs by 3 main pathways: reversible stereoselective phosphorylation to the pharmacologically active S-enantiomer of fingolimod-phosphate, oxidative biotransformation mainly via the CYP4F2 isoenzyme and subsequent fatty acid-like degradation to inactive metabolites, and formation of pharmacologically inactive nonpolar ceramide analogs of fingolimod.1 28

Primarily metabolized via CYP4F2 with a minor contribution by CYP isoenzymes 2D6, 2E1, 3A4, and 4F12.1 27

Elimination Route

About 81% of the dose is slowly excreted in urine as inactive metabolites.1 28 Fingolimod and fingolimod-phosphate are not excreted intact in urine, but are the major components in feces with amounts of each representing <2.5% of the dose.1 28

Half-life

Fingolimod: 6–9 days; fingolimod-phosphate appears to have a similar half-life.1 6 11 12

Special Populations

Severe renal impairment: Half-life of fingolimod is unchanged.1

Mild hepatic impairment: Half-life of fingolimod is unchanged.1

Moderate or severe hepatic impairment: Half-life of fingolimod is prolonged by about 50%.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15-30°C); protect from moisture.1

Actions

  • 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

Advice to Patients

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

  • Importance of being counseled on and understanding the benefits and potential risks of treatment.1

  • 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

  • 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 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 For patients who have not had chickenpox or VZV vaccination, importance of considering VZV vaccination prior to starting fingolimod therapy.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

  • 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Fingolimod Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

0.5 mg (of fingolimod)

Gilenya

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Gilenya 0.5MG Capsules (NOVARTIS): 28/$4,099.07 or 84/$12,093.32

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 2, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Novartis Pharmaceuticals Corporation. Gilenya (fingolimod) capsules prescribing information. East Hanover, NJ; 2012 May.

2. Novartis Pharmaceuticals Corporation. Gilenya (fingolimod) capsules patient information. East Hanover, NJ; 2012 May.

3. Kappos L, Radue EW, O’Connor P et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010; 362:387-401. [PubMed 20089952]

4. Cohen JA, Barkhof F, Comi G et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010; 362:402-15. [PubMed 20089954]

5. Gilenya (fingolimod) 0.5 mg capsules risk evaluation and mitigation strategy (REMS). From FDA website.

6. Kovarik JM, Schmouder R, Barila D et al. Multiple-dose fty720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J Clin Pharmacol. 2004; 44:532-7. [PubMed 15102874]

7. Brinkmann V, Davis MD, Heise CE et al. The immune modulator fty720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002; 277:21453-7. [PubMed 11967257]

8. Mandala S, Hajdu R, Bergstrom J et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002; 296:346-9. [PubMed 11923495]

9. Chiba K, Yanagawa Y, Masubuchi Y et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol. 1998; 160:5037-44. [PubMed 9590253]

10. Kappos L, Antel J, Giancarlo C et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006; 355:1124-40. [PubMed 16971719]

11. Kovarik JM, Schmouder R, Barilla D et al. Single-dose fty720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br J Clin Pharmacol. 2004; 57:586-91. [PubMed 15089811]

12. Kovarik JM, Hartmann S, Bartlett M et al. Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects. Biopharm Drug Dispos. 2007; 28:97-104. [PubMed 17230596]

13. Kovarik JM, Schmmouder RL, Serra D et al. FTY720 pharmacokinetics in mild to moderate hepatic impairment. J Clin Pharmacol. 2005; 45:446-52. [PubMed 15778425]

14. Kovarik JM, Schmouder RL, Hartmann S et al. Fingolimod (FTY720) in severe hepatic impairment: pharmacokinetics and relationship to markers of liver function. J Clin Pharmacol. 2006; 46:149-56. [PubMed 16432266]

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