fingolimod (Gilenya)

Dosing and uses of Gilenya (fingolimod)

• Adult
• Pediatric

 

Adult dosage forms and strengths

capsule

• 0.5mg

 

Multiple Sclerosis

Indicated for relapsing forms of multiple sclerosis to reduce clinical exacerbation frequency and delay accumulation of physical disability

0.5 mg PO qDay

>0.5 mg PO qDay increases adverse effects with no clinical benefits

 

Hepatic Impairment

Mild to moderate impairment: Dose adjustment not necessary

Severe impairment: Monitor therapy; exposure the drug may double in severe hepatic impairment

 

Dosing Considerations

May take with or without food

First dose monitoring

• Due to decreased heart rate after the first dose, administer in setting with ability to manage symptomatic bradycardia; observe heart rate (HR) and blood pressure hourly for at least 6 hours post dose; obtain ECG prior to first dose and at the end of observation period
• Continue observing beyond 6 hours if post-dose heart rate is <45 bpm or at the lowest post-dose value (suggesting maximal effect on heart rate may not yet have occurred), or if new onset second-degree or higher AV block occurs
• In cases where pharmacologic intervention for symptomatic bradycardia is necessary, continuous overnight ECG monitoring required, because of this, repeat first-dose monitory for the second dose
• Cardiac evaluation and overnight monitoring required for some pre-existing conditions and for concomitant use of certain medications (see Cautions for more specifics)
• Heart rate generally returns to baseline 2-4 weeks after therapy initiation; physicians should continue to be alert to patient reports of cardiac symptoms

Reinitiation of therapy following discontinuation

• If discontinued for >14 days, after the first month of treatment, the same first dose monitoring should be applied upon reinitiation
• Within the first 2 weeks of treatment, first dose procedures are recommended after an interruption of 1 day or more
• During weeks 3 and 4 of treatment, first dose procedures are recommended after an interruption >7 days

 

Demyelinating Polyneuropathy (Orphan)

Treatment of chronic inflammatory demyelinating polyneuropathy

Orphan indication sponsor

• Novartis Pharmaceutical Corporation; One Health Plaza; East Hanover, NJ 07936

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Gilenya (fingolimod) adverse (side) effects

>10%

Headache (25%)

ALT/AST increased (14%)

Influenza viral infection (13%)

Diarrhea (12%)

Back pain (12%)

Cough (10%)

 

1-10%

Herpes viral infections (9%)

Depression (8%)

Bronchitis (8%)

Dyspnea (8%)

Sinusitis (7%)

Dizziness (7%)

Hypertension (6%)

Gastroenteritis (5%)

GGT increased (5%)

Weight decreased (5%)

Paresthesia (5%)

Migraine (5%)

Tinea infections (4%)

Bradycardia (4%)

Alopecia (4%)

Blurred vision (4%)

Lymphopenia (4%)

Leukopenia (3%)

Eye pain (3%)

Eczema (3%)

Pruritus (3%)

Asthenia (3%)

Blood triglycerides decreased (3%)

 

<1%

Macular edema (0.4%)

 

Postmarketing Reports

Third degree AV block and AV block with junctional escape

Delayed onset transient asystole and unexplained death

Syncope

 

Warnings

Contraindications

Hypersensitivity

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 patient has a functioning pacemaker

Baseline QTc interval ≥500 ms

Treatment with Class Ia or Class III anti-arrhythmic drugs

 

Cautions

Use caution in patients with certain pre-existing cardiac conditions (eg, ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, sino-atrial heart block, prolonged QTc interval, hypokalemia, hypomagnesemia, congenital long-QT syndrome) or those taking certain concomitant medications (eg, citalopram, chlorpromazine, haloperidol, methadone, erythromycin, beta-blockers, diltiazem, verapamil, digoxin) requre overnight monitoring following administration of first dose of medication

Transient decrease in heart rate occurs within 1 hour after the first dose, with maximal decline generally occurring after 6 hr and heart rate recovering, although not to baseline, by 8-10 hr; a second period of heart rate decline may occur at 24 hr post-dose due to physiological diurnal variation; heart rate generally returns to baseline after 1 month of treatment

Transient AV conduction delays have been observed after treatment initiation; most abnormalities are asymptomatic and usually resolve within 24 hours

Caution with other drugs that cause bradycardia (eg, beta-blockers, diltiazem); also see Contraindications for Class 1a and Class III antiarrhythmics

Increased risk of infection, do not initiate with active acute or chronic infections until resolved; prior to initiation, a recent CBC (ie, within 6 months or after discontinuation of prior therapy) should be available

Concomitant use with antineoplastic agents, immunosuppressives, or immune modulating therapies may increase risk of immunosuppression

Progressive multifocal leukoencephalopathy (PML) reported; symptoms are diverse and included sudden onset of severe headache, altered mental status, progressive unilateral weakness, clumsiness, visual disturbances, and seizure; symptoms usually reversible but may evolve into 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

Vaccination may be less effective during and for up to 2 months after discontinuing fingolimod; avoid live attenuated vaccines during and for 2 months after fingolimod because of increased risk for infection

May cause macular edema (with or without visual symptoms), evaluate before initiating treatment and 3-4 months after starting treatment or any time after a patient reports visual disturbances while in therapy; history of diabetes mellitus or uveitis have increased risk of macular edema

Decreases pulmonary function tests (FEV 1, diffusion lung capacity for carbon monoxide)

May increase liver transaminases; recent (ie, within last 6 months) transaminase and bilirubin levels should be available before initiating fingolimod

Discontinue therapy if posterior reversible encephalopathy syndrome (PRES) suspected

Women of childbearing potential should use effective contraception during and for 2 months after stopping

Monitor BP during treatment

Cryptococcal infections, including cases of cryptococcal meningitis, reported; patients with symptoms and signs consistent with cryptococcal meningitis should undergo prompt diagnostic evaluation and treatment

Patients without confirmed history of chickenpox or without documentation of 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 prior to commencing therapy; postpone therapy 1 month to allow full effect of vaccination to occur

Serious infections with opportunistic pathogens including viruses John Cunningham virus (JCV), herpes simplex viruses 1 and 2, varicella-zoster virus), fungi (e.g., cryptococci), and bacteria (e.g., 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

Liver injury with hepatocellular and/or cholestatic hepatitis reported

Basal cell carcinoma associated with therapy; monitor for suspicious skin lesions; if a suspicious skin lesion observed, promptly evaluate

 

Pregnancy and lactation

Pregnancy category: C; based on animal studies, may cause fetal harm; effective contraception needed for women of childbearing age during treatment and for 2 months after discontinuation

Gilenya pregnancy registry established 1-877-598-7237

Lactation: Unknown whether distributed in breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Gilenya (fingolimod)

Mechanism of action

Sphingosine 1-phosphate receptor modulator; metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate.  

Binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5; blocks lymphocyte capacity to egress from lymph nodes, and thereby reduces the lymphocyte count in peripheral blood

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

 

Absorption

Bioavailability: 93%

Plasma Time: 12-16 hr

Steady-State: Time to steady state is 1-2 months following daily dosing; steady-state levels approximately 10-fold greater than initial dose

 

Distribution

86% distributed in RBCs

Protein Bound: >99%

Vd: 1200 L

 

Metabolism

Primarily by CYP4F2, minor substrate of CYP2D6, 2E1, 3A4, and 4F12

 

Elimination

Half-life: 6-9 days

Clearance: 6.3 L/hr

Excretion: Feces (<2.5%), urine (81% as inactive metabolites)