In May 2018, fingolimod (Gilenya, Novartis) became the first FDA-approved drug to treat relapsing multiple sclerosis (MS) in pediatric patients. It was initially approved in 2010 to treat adults with relapsing MS. Further clinical trials evaluating pediatric patients aged 10 to 17 years substantiated an expanded approval for these patients.1

MS is a chronic, autoimmune disease where the immune system causes inflammation within the central nervous system (CNS). CNS inflammation leads to damaged myelin and nerve fibers, preventing electrical impulses and signaling, leading to disability.2 Approximately 8000 to 10,000 children and adolescents in the United States have MS, indicating a potential target population fingolimod can be used in.1

Dosage and Administration

Fingolimod should be given at 0.5 mg orally, once-daily with or without food for adults and pediatric patients (10 years or older) weighing more than 40 kg, and 0.25 mg orally, once-daily for pediatric patients weighing less than or equal to 40 kg.3

Important Monitoring Instructions

The first dose, doses restarted after discontinuation for more than 14 days, and dose increases—especially in pediatric patients—require special monitoring. After the first dose, patients will need to be monitored for 6 hours for signs and symptoms of bradycardia through blood pressure and pulse measurements.3 For the first 2 weeks of treatment, first-dose monitoring is required after dose interruptions of 1 day or more; for weeks 3 and 4, monitoring is required after dose interruptions of greater than 7 days.

If the heart rate after 6 hours post-dose is less than 45 bpm in adults, less than 55 bpm in pediatric patients 12 years and older, less than 60 bpm in pediatric patients aged 10 to 11 years, if the heart rate 6 hours postdose is at the lowest value suggesting that the heart rate may be even lower later, or if the electrocardiogram (ECG) 6 hours post-dose shows new second degree or higher atrioventricular (AV) block, begin ECG monitoring and/or pharmacological treatment. If pharmacological treatment is given, overnight monitoring is required, and the next dose will require the same 6-hour monitoring.

Overnight monitoring is required in patients who needed pharmacological intervention for symptomatic bradycardia, have preexisting heart conditions, QT prolongation risks, and patients receiving other drugs that may slow heart rate or AV conduction.

Pharmacology

Fingolimod is a sphingosine 1-phosphate receptor modulator. It is metabolized to its active metabolite, fingolimod-phosphate, that reduces the number of lymphocytes in the peripheral blood. It is believed to be effective in treating MS due to the reduced lymphocytes into the CNS.3
 
Table 1. Method of Supply3
Drug Strength/Packaging NDC Information
0.25-mg fingolimod capsules
  • Bottle of 30 capsules
  • Carton containing 1 blister card of 7 capsules
 
  • 00078-0965-15
  • 00078-0965-89
0.5-mg fingolimod capsules
  • Bottle of 30 capsules
  • Carton containing 1 blister card of 7 capsules
 
  • 00078-0607-15
  • 00078-0607-89
NDC indicates National Drug Code.

Storage

Capsules should be stored at room temperature 25°C (77°F), with a permitted temperature range of 15 to 30°C (59-86°F). Keep it in a dry place.3

Drug Interactions/Contraindications

Drugs that prolong QT interval have been known to potentially cause torsades de pointes in patients with bradycardia, an adverse event (AE) that fingolimod can cause.3 Patients on QT-prolonging drugs with known risks of torsades de pointes (eg, haloperidol, methadone, citalopram) should be monitored overnight with a continuous ECG.

Systemic ketoconazole raises fingolimod blood levels, increasing the risk of AEs and should be carefully monitored.

Fingolimod’s effect on lymphocytes and the immune system reduces vaccination effectiveness for up to 2 months after discontinuing it. Do not administer live vaccines 2 months after treatment with fingolimod. Make sure pediatric patients are up to date with their immunizations before starting treatment. All other immune-modulating therapies such as immunosuppressive therapies, antineoplastic, may increase the risk of additive immune system effects when used together with fingolimod.
 
Drugs that slow heart rate or AV conduction (eg, β-blockers, digoxin, non-dihydropyridine calcium channel blockers) may cause further decrease in heart rate resulting in severe bradycardia or heart block. These drugs may need to be switched to something that does not slow heart rate before starting fingolimod. If the patient requires these drugs, overnight continuous ECG monitoring after the first dose is required, as mentioned under monitoring information.

Contraindications to fingolimod include myocardial infarction, stroke, unstable angina, transient ischemic attack, heart failure class III/IV, or requiring hospitalization in the last 6 months, Mobitz Type II second-degree or third-degree heart block unless patient has pacemaker, baseline QTc interval ≥ 500 msec, hypersensitivity to fingolimod, and usage of Class 1a or III anti-arrhythmic drugs (quinidine, procainamide, amiodarone, dronedarone).

Warning and Precautions

Fingolimod has been shown to reduce heart rate starting 1 hour after the first dose. Heart rates below 40 bpm in adults and below 50 bpm in pediatric patients occurred rarely.3 Decreased heart rates may prolong the QT interval in patients with a prolonged QTc interval, on QT prolonging drugs, or have risk factors for QT prolongation (eg, electrolyte abnormality). Patients with preexisting conditions such as heart failure, uncontrolled hypertension, bradycardia, syncope, and ischemic heart disease may not tolerate fingolimod, and if treated, should be monitored with continuous ECG for the first dose. Atrioventricular blocks have also been seen in clinical trials. The conduction abnormalities usually are asymptomatic and go away on their own within the first 24 hours, but sometimes require treatment with atropine or isoproterenol.

Infections can result from fingolimod therapy due to a reduction in lymphocyte count. Life-threatening and fatal infections have occurred. A recent complete blood count within 6 months or after discontinuation of prior therapy should be analyzed before starting treatment. For patients that develop a serious infection, fingolimod should be stopped and only restarted if the benefits outweigh the risks. Herpes viral infection, cryptococcal infections, and progressive multifocal leukoencephalopathy have been seen. Varicella vaccination is recommended prior to starting treatment, and treatment should be delayed for 1 month after vaccination for the full effect of the vaccine to occur.

Fingolimod can cause macular edema. An examination of the fundus prior to starting treatment, 3 to 4 months after starting treatment, and any time the patient complains of visual disturbance, is recommended. Caution in comorbid conditions such as diabetes and uveitis.

Posterior reversible encephalopathy syndrome (PRES) has also been seen in adult patients receiving fingolimod. Symptoms such as severe headache, altered mental status, visual disturbance, and seizures may foreshadow PRES. Although PRES is usually reversible, it can lead to ischemic stroke and cerebral hemorrhage, and a delay in diagnosis can lead to permanent neural damage. Discontinue fingolimod if PRES is suspected.

Respiratory symptoms such as dyspnea have been seen in patients taking fingolimod. Spirometry should be performed if patients are experiencing any clinical signs of respiratory depression. 

Elevated liver enzymes, hepatocellular/cholestatic hepatitis have been reported. In clinical trials, fingolimod was discontinued if it caused a liver enzyme elevation of 5 times the upper normal limit. Serum transaminase levels returned to normal after 2 months but were elevated again after fingolimod was initiated again. Monitor for signs of liver injury, such as dark urine and jaundice.

Immunosuppression, skin cancer, increased blood pressure, and hypersensitivity are also AEs that need to be monitored while on fingolimod. Immunosuppression can be evident even after 2 months of discontinuing therapy. Fingolimod can increase the risk of skin cancer, especially in patients with risk factors. Skin examinations should be done periodically by patients and clinicians, while also wearing protective clothing and sunscreen while out in the sun. Blood pressure increases have been seen in patients taking fingolimod (increased 3 mmHg systolic and 2 mmHg diastolic compared to placebo). Monitor blood pressure routinely. Allergic reactions have also been seen. 

Adverse Reactions

Adverse reactions with a ≥10% incidence are listed in the table below. The serious adverse reactions are mentioned in the warnings and precautions. The safety profile for pediatric patients is similar to those seen in adult patients. Cases of seizures in the pediatric controlled trial were 5.6% in the fingolimod-treated patients, while causes of seizures were 0.9% in fingolimod-treated adults.3
 
Table 2. Adverse Reactions From Adult Placebo-Controlled Clinical Trials
Adverse Reactions Percentages
Headache 25%
Liver transaminase elevations 15%
Nausea/diarrhea 13%
Cough 12%
Abdominal pain 11%
Influenza 11%
Sinusitis 11%
Back pain 10%
Pain in extremities 10%

Pregnancy and Lactation

Animal studies have shown that fingolimod may cause fetal harm in humans.3 There is no data on the presence of fingolimod for lactation. Proper contraception use is needed during treatment and for another 2 months after treatment. There is also a pregnancy registry that patients can enroll in that serves as data collection purposes in this population www.fingolimodpregnancyregistry.com.

Pediatric Use

The safety and effectiveness of fingolimod in pediatric patients aged 10 and older have been established.3 There is no data pertaining to pediatric patients below the age of 10.

Clinical Studies

In the phase 3 trial, TRANSFORMS, patients were randomized to receive either 0.5-mg fingolimod, 1.25-mg fingolimod, or interferon β-1a.3 Relapse rates were lower in the fingolimod groups compared to interferon β-1a. The number of new/newly enlarging T2 lesions were also significantly lower for fingolimod than interferon β-1a. Time-to 3-month confirmed disability progression were similar between all 3 groups. Outcomes from the higher-dose fingolimod group had no additional benefits compared to the lower-dose fingolimod group.

In another phase 3 clinical trial, pediatric patients aged 10 years and older received fingolimod 0.25 mg or 0.5 mg depending on body weight, or interferon β-1a. Patients treated with fingolimod had lower relapse rates than patients who received interferon β-1a, with a relative reduction in annualized relapse rate of 81.9%. The number of new/newly enlarging T2 lesions up to 24 months were also significantly lower for fingolimod than interferon β-1a.   

Guidelines Recommendations

Practice guidelines from the American Academy of Neurology have recommended that clinicians should prescribe fingolimod, alemtuzumab, and natalizumab in patients with highly active MS, as these disease-modifying therapies showed a reduction in relapses and magnetic resonance imaging measures.4 Treatment decisions should be made with the patient being aware of the risk and benefits of each drug therapy.

Costs and Availability

The cost of the 30-capsule bottle is listed below. There is a co-pay savings card at www.fingolimod.com. The savings card is only for patients with commercial insurance.5
 
Table 3. Costs of Fingolimod from Red Book Online
Drug NDC Quantity Wholesale Acquisition Cost Average Wholesale Price
Fingolimod 0.5 mg 00078-0607-15 30 Capsules $7857.07 $9428.48
NDC indicates National Drug Code.

Patient Counseling

Fingolimod is a prescription drug used to treat relapsing forms of MS.3 It should be taken once daily with or without food. After taking the first dose, patients will need to be monitored for 6 hours with an ECG, blood pressure, and pulse for any signs of slowed heart rate or other concerns. Further monitoring may be required if signs or symptoms or adverse events due to fingolimod are present.

Do not stop taking the drug until the clinician deems it appropriate to. Missed doses are significant and should be reported right away. If the dose is missed for a significant amount of days or missed when starting the medication, ECG, blood pressure, and pulse monitoring may need to be done at a health care facility for 6 hours. Any overdose should immediately be reported to the doctor or should be directly addressed at the nearest emergency room. 

Keep fingolimod at room temperature in a dry place in its original bottle. Like any medication, keep it out of all children’s reach.

Common AEs can include headache, diarrhea, abnormal liver tests, cough, flu, and pain in the extremities. If any of these AEs persist or bothers the patient, they need to inform their doctor immediately. Other AEs include breathing difficulties, liver toxicities, increased blood pressure, PRES (swelling/narrowing of blood cells in the brain), and allergic reactions.

Some of the serious AEs that can occur must be addressed immediately. Fingolimod is known to cause a slowed heart rate, leading to complications, such as QT prolongation. Patients should be advised to report any symptoms that may be attributed to a slowed heartbeat such as dizziness, tiredness, chest pain, or feeling that the heart is beating slowly or skipping beats.

Because fingolimod lowers the number of white blood cells in the blood, it predisposes the patient to infections. Progressive multifocal leukoencephalopathy is a brain infection that may occur and is associated with loss of coordination, weakness, confusion, and vision changes. Patients should be counseled to report any AEs that may potentially be an infection and be told that they should not receive live vaccines during treatment and 2 months after treatment.

Macular edema is another AE that may occur from taking fingolimod. Patients should tell their doctors of any vision abnormalities that they experience while taking fingolimod. Vision tests may be done to routinely the patient for any vision changes.  

Fingolimod can also increase the risk of melanoma. Patients should be advised to wear proper protective clothing and sunscreen while out in the sun.

Patients are advised not to become pregnant while taking the drug, as animal studies have shown fetal harm. Patients who become pregnant while taking fingolimod are advised to register for fingolimod pregnancy registry at www.fingolimodpregnancyregistry.com.

There are many drugs that may interact with fingolimod. Patients should inform their clinicians of all drugs that they are taking, including over the counter products. Some of the drugs that may cause serious AEs include corticosteroids, ketoconazole, carbamazepine, β-blockers, non-dihydropyridine calcium channel blockers, and QT-prolonging drugs.
REFERENCES
1. FDA expands approval of Fingolimod to treat multiple sclerosis in pediatric patients. FDA website. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm607501.htm?rel=0" . Updated May 11, 2018. Accessed August 22, 2018.
2. Definition of MS. National Multiple Sclerosis Society. www.nationalmssociety.org/What-is-MS/Definition-of-MS. Accessed August 22, 2018.
3. Fingolimod [prescribing information]. East Hanover, New Jersey: Novartis; 2010. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/fingolimod.pdf?rel=0" . Accessed August 22, 2018.
4. Practice guideline: disease-modifying therapies for adults with multiple sclerosis. American Academy of Neurology. www.aan.com/Guidelines/home/GetGuidelineContent/900. Updated April 24, 2018. Accessed August 22, 2018.
5. Fingolimod. Red Book Online. Micromedex Healthcare Series [online database]. Greenwood Village, CO: Truven Health Analytics; 2015. Accessed August 22, 2018.