fingolimod

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fingolimod

Gilenya

Pharmacologic class: Sphingosine 1-phosphate receptor modulator

Therapeutic class: Immunologic agent

Pregnancy risk category C

Action

Blocks capacity of lymphocytes to egress from lymph nodes, reducing number of lymphocytes in peripheral blood. Mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis (MS) is unknown, but may involve reduction of lymphocyte migration into CNS.

Availability

Capsules: 0.5 mg

Indications and dosages

Relapsing forms of MS

Adults: 0.5 mg P.O. daily

Contraindications

• Recent (within last 6 months) occurrence of myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, Class III/IV heart failure
• History or presence of Mobitz Type II second- or third-degree AV block or sick sinus syndrome, unless patient has pacemaker
• Baseline QTc interval 500 ms or greater
• Treatment with Class Ia or Class III antiarrhythmics

Precautions

Use cautiously in:
• hepatic or severe renal impairment
• compromised respiratory function, AV conduction abnormalities, bradycardia, hypertension
• infections, macular edema
• patients without history of chickenpox or without vaccination against varicella zoster virus (VZV)
• concurrent use of drugs that slow heart rate or AV conduction
• concurrent use of vaccines (avoid use during treatment and for 2 months after treatment)
• concurrent use of antineoplastics, immunosuppressants, or immunomodulators
• elderly patients
• pregnant or breastfeeding patients
• children younger than age 18 (safety and efficacy not established).

Administration

• Administer with or without food.
• Be aware that patients with active acute or chronic infections shouldn't start treatment until infection is resolved.
• Before starting treatment, make sure recent CBC (within 6 months) is available.
• Before starting treatment, obtain liver enzyme values, particularly transaminase and bilirubin levels (within 6 months).
• Before starting treatment, test patient without history of chickenpox or without vaccination against VZV for antibodies to VZV. Consider VZV vaccination of antibody-negative patients before beginning treatment, after which initiation of fingolimod treatment should be postponed for 1 month to allow for full effect of vaccination.
• Be aware that decrease in heart rate and AV conduction may occur after first dose. To identify underlying risk factors for bradycardia and AV block before starting therapy: If a recent ECG (within 6 months) isn't available, obtain an ECG in patients using antiarrhythmics (including beta blockers and calcium channel blockers), in those with cardiac risk factors, and in those who on examination have a slow or irregular heartbeat.
• Obtain baseline ophthalmologic evaluation.

Adverse reactions

CNS: headache, dizziness, paresthesia, migraine, asthenia, depression, vascular events (including posterior reversible encephalopathy syndrome)

CV: hypertension, bradycardia, AV conduction abnormalities, vascular events (including ischemic and hemorrhagic strokes, peripheral arterial occlusive disease)

EENT: macular edema, blurred vision, eye pain, sinusitis

GI: gastroenteritis, diarrhea

Hematologic: lymphopenia, leukopenia, lymphomas

Hepatic: increased liver enzyme levels

Metabolic: increased triglyceride levels

Musculoskeletal: back pain

Respiratory: dyspnea, bronchitis, cough

Skin: alopecia, eczema, pruritus

Other: influenza-type viral infections, herpes viral infections, tinea infections

Interactions

Drug-drug.Antineoplastics, immunomodulators, immunosuppressants: increased risk of immunosuppression

Beta blockers (atenolol), Class Ia (such as procainamide, quinidine) or Class III (such as amiodarone, sotalol) antiarrhythmics: decreased heart rate

Ketoconazole: increased fingolimod and fingolimod-phosphate blood levels

Vaccines: reduced vaccine effectiveness

Live attenuated vaccines: increased risk of infection

Drug-diagnostic tests.Lymphocytes: reduced levels

Serum transaminases: elevated levels

Patient monitoring

• Continue to closely monitor CBC with differential; be aware that because drug reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts can't be utilized to evaluate lymphocyte status during therapy.

Be aware that patient with preexisting liver disease may be at increased risk for developing elevated liver enzyme levels. Closely monitor liver enzyme levels if hepatic injury is suspected. Discontinue drug if significant hepatic injury is confirmed.
• Monitor renal function tests in patients with renal impairment.

At start of therapy, carefully watch for reduced heart rate in patients receiving concurrent beta blockers or heart rate-lowering calcium channel blockers, such as diltiazem, verapamil, or digoxin.

Observe patient for 6 hours after first dose for bradycardia. Should post-dose bradyarrhythmia-related signs and symptoms occur, initiate appropriate management and continue observation until signs and symptoms have resolved.

Closely monitor patients receiving Class Ia or Class III antiarrhythmics for bradycardia for development of torsades de pointes.
• Monitor patient for conduction abnormalities, which are usually transient and asymptomatic. Such abnormalities may resolve within first 24 hours of treatment, but occasionally may require treatment.
• Monitor blood pressure during treatment.

Monitor patient for infection during treatment and for 2 months after discontinuation of drug. Consider suspending treatment if patient develops serious infection; reassess benefits and risks before restarting therapy.
• Be aware that patients who develop unexplained dyspnea during therapy should have spirometric evaluation of respiratory function and evaluation of diffusion lung capacity for carbon monoxide if clinically indicated.
• Monitor visual acuity 3 to 4 months after treatment initiation; be aware that patients with diabetes mellitus or history of uveitis are at increased risk and should have regular ophthalmologic evaluations.
• Closely monitor patients taking fingolimod and systemic ketoconazole concomitantly, because risk of adverse reactions is greater.

Patient teaching

• Tell patient to take drug with or without food.
• Inform patient that he will need to be observed for 6 hours after first dose.
• Advise patient who hasn't had chickenpox or VZV vaccination to consider vaccination before treatment begins.
• Advise patient to avoid live attenuated vaccines during treatment and for 2 months post treatment because of risk of infection.
• Tell patient not to discontinue drug without first discussing with prescriber.

Advise patient to promptly report unexplained nausea, vomiting, abdominal pain, dizziness, fatigue, anorexia, dark urine, yellowing of skin or eyes, fever, infection, slow or irregular heartbeat, or unexplained shortness of breath.

Advise patient to have eye examinations 3 to 4 months after beginning therapy and to contact prescriber if vision changes occur. Instruct patient to immediately report blurriness or shadows in center of vision, blind spot in center of vision, sensitivity to light, or unusually colored (tinted) vision.
• Instruct patient to tell prescriber about all drugs he's taking because some drugs have potential for serious drug interactions and shouldn't be taken with fingolimod.
• Advise female patient of childbearing age to use effective contraception to avoid pregnancy during therapy and for 2 months after treatment ends.
• Advise breastfeeding patient that she should decide whether to discontinue breastfeeding or discontinue drug, taking into account importance of the drug for her treatment.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and tests mentioned above.

fingolimod

(fin-go-li-mod) ,

Gilenya

(trade name)

Classification

Therapeutic: anti multiple sclerosis agents
Pharmacologic: receptor modulators
Pregnancy Category: C

Indications

Treatment of relapsing forms of multiple sclerosis.

Action

Converted by sphingosine kinase to the active metabolite fingolimod-phosphate, which binds to sphingosine 1–phosphate receptors, resulting in ↓ migration of lymphocytes into peripheral blood. This may ↓ lymphocyte migration into the CNS.

Therapeutic effects

↓ frequency of relapses/delayed accumulation of disability.

Pharmacokinetics

Absorption: Well absorbed (93%) following oral administration.
Distribution: Extensively distributed to body tissues; 86% of parent drug distributes into red blood cells; active metabolite uptake 17%.
Metabolism and Excretion: Converted to its active metabolite, then metabolized mostly by the CYP450 4F2 enzyme system, with further degradation by other enzyme systems. Most inactive metabolites excreted in urine (81%); <2.5% excreted as fingolimod and fingolimod-phosphate in feces.
Protein Binding: >99.7%.
Half-life: 6–9 hr.

Time/action profile

ROUTEONSETPEAKDURATION
POunknown1–2 mo*2 mo†
*Time to steady state blood levels, peak blood levels after a single dose at 12–16 hr.†Time for complete elimination.

Contraindications/Precautions

Contraindicated in: MI, unstable angina, stroke, TIA, or class III or IV HF within previous 6 mo2nd- or 3rd-degree heart block or sick sinus syndrome (in the absence of a pacemaker)QT interval ≥500 msecConcurrent use of class Ia or III antiarrhythmicsActive acute/chronic untreated infections; Lactation: Breast feeding should be avoided.
Use Cautiously in: Concurrent use of beta blockers, diltiazem, verapamil, or digoxin (↑ risk of bradycardia/heart block);History of bradycardia, syncope, cardiac arrest, or severe sleep apnea (↑ risk of bradycardia/heart block)Severe hepatic impairment (↑ blood levels and risk of adverse reactions);Diabetes mellitus/history of uveitis (↑ risk of macular edema);Negative history for chickenpox or vaccination against varicella zoster virus vaccination; Geriatric: Risk of adverse reactions may be ↑; consider age-related ↓ in cardiac/renal/hepatic function, chronic illnesses, and concurrent drug therapy; Pediatric: Safety and effectiveness not established; Obstetric: Use only if potential benefit justifies potential risk to fetus;

Adverse Reactions/Side Effects

Central nervous system

  • progressive multifocal leukoencephalopathy
  • headache (most frequent)

Ear, Eye, Nose, Throat

  • blurred vision
  • eye pain
  • macular edema

Respiratory

  • cough (most frequent)
  • ↓ pulmonary function

Cardiovascular

  • asystole
  • bradycardia
  • heart block
  • QT interval prolongation
  • hypertension
  • syncope

Gastrointestinal

  • diarrhea (most frequent)
  • ↑ liver function tests (most frequent)

Hematologic

  • leukopenia
  • lymphopenia

Musculoskeletal

  • back pain (most frequent)

Miscellaneous

  • ↑ risk of infection

Interactions

Drug-Drug interaction

Concurrent use of class Ia or class III antiarrhythmics may ↑ risk of serious arrhythmias; careful monitoring recommended.Concurrent use of beta blockers, diltiazem, verapamil, or digoxin may ↑ risk of bradycardia; careful monitoring recommended.Concurrent use of ketoconazole may ↑ blood levels and of adverse reactions.↑ risk of immunosuppression with antineoplastics, immunosuppressants, or immune modulating therapies.Live-attenuated vaccines ↑ risk of infection.

Route/Dosage

Oral (Adults) 0.5 mg once daily.

Availability

Hard capsules: 0.5 mg

Nursing implications

Nursing assessment

  • Monitor pulse and BP hourly for bradycardia for at least 6 hr following first dose. Obtain baseline ECG before first dose and at end of observation period. If patient develops heart rate <45 bpm or new onset 2nd-degree or higher heart block, monitor until resolved. If bradycardia is symptomatic, patient has coexisting medical condition that effects heart rate, or if QTC prolongation occurs, monitor continuous ECG; if pharmacologic therapy is required, monitor in hospital overnight and repeat first-dose monitoring for 2nd dose. If fingolimod is stopped for 2 wk or more, first-dose monitoring must be followed when restarting.
  • Monitor for signs of infection (fever, sore throat) during and for 2 mo after discontinuation of therapy. Consider suspending therapy if serious infection develops.
  • Perform an opthalmologic exam prior to starting fingolimod, at 3–4 mo after treatment initiation, and if visual disturbances occur. Monitor visual acuity at baseline and during routine exams. Patients with diabetes or history of uveitis are at ↑ risk and should have regular ophthalmologic exams.
  • Monitor pulmonary function tests for decline periodically during therapy. Obtain spirometry and diffusion lung capacity for carbon monoxide when indicated clincally.
  • Assess for any new signs or symptoms that may be suggestive of progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain caused by the Jakob Cruzfeldt (JC) virus, that may be fatal; withhold dose and notify health care professional promptly. PML symptoms may begin gradually (hemiparesis, apathy, confusion, cognitive deficiencies and ataxia) and may include deteriorating renal function.
  • Lab Test Considerations: Obtain baseline liver function test before starting therapy. May cause ↑ liver transaminases. Monitor liver function tests if symptoms develop.
    • Before initiating therapy, obtain a recent (within 6 mo) CBC. May cause ↓ lymphocyte counts.

Potential Nursing Diagnoses

Deficient knowledge, related to medication regimen (Patient/Family Teaching)

Implementation

  • Oral: Administer once daily without regard to food.

Patient/Family Teaching

  • Instruct patient to take fingolimod as directed. Do not discontinue therapy without consulting health care professional. Advise patient to read the Medication Guide prior to starting therapy and with each Rx refill in case of changes.
  • Advise patient to notify health care professional if signs and symptoms of liver dysfunction (unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine), infection, new onset of dyspnea, or changes in vision develop.
  • Instruct patient not to receive live-attenuated vaccines during and for 2 mo after treatment due to risk of infection. Patients who have not had chickenpox or vaccination should consider varicella zoster virus vaccination prior to starting therapy, then postponing start of fingolimod for 1 mo to allow for full effect of vaccination.
  • Advise female patients to use contraception during and for at least 2 mo after discontinuation of therapy and to notify health care professional immediately if pregnancy is planned or suspected or if breast feeding. Encourage pregnant patients to enroll in the pregnancy registry by calling 1-877-598-7237.

Evaluation/Desired Outcomes

  • Reduction in frequency of clinical exacerbations and delay of accumulation of physical disability in patients with relapsing forms of multiple sclerosis.

fingolimod

An immunomodulatory agent derived from ISP-1, a metabolite of Isaria sinclairii, a soil fungus, which is a structural analogue of sphingosine that is phosphorylated in vivo by sphingosine kinase 2. Once phosphorylated, fingolimod binds a sphingosine-1-phosphate receptor, S1PR1, sequestering lymphocytes and preventing their migration to the CNS, where they trigger an autoimmune reaction in patients with multiple sclerosis, a condition which fingolimod is FDA-approved to manage.

fingolimod

An oral sphingosine-1-phosphate receptor modulator. Trials of this drug in cases of relapsing multiple sclerosis have shown that it is capable of reducing clionical activity and the number of lesions detected on MRI.
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