Side Effects of Gilenya (fingolimod)

Gilenya (fingolimod) is a sphingosine 1-phosphate receptor modulator used to treat relapsing forms of multiple sclerosis (MS). 

Its mechanism of action is unknown, although it may work by reducing the number of circulating lymphocytes (a type of white blood cell), leading to reduced migration of white blood cells into the central nervous system. 

White blood cells cause inflammation and destruction of nerves in patients with MS. Gilenya does not cure MS. It decreases the number of MS flares and slows down the development of physical disability caused by MS. 

Common side effects of Gilenya include

• headache,
• flu,
• diarrhea,
• back pain,
• elevations of liver enzymes and
• cough.

Gilenya may decrease heart rate, especially after the first dose. 

Serious side effects of Gilenya include

• increased risk of infections,
• inflammation of the eye (uveitis) and other eye problems,
• difficulty breathing, and
• reduced white blood cell count.

Drug interactions of Gilenya include ketoconazole, because when taken together, blood levels of Gilenya are increased which may increase the incidence of side effects.

• Vaccines may be less effective during and up to 2 months after discontinuation of Gilenya treatment.
• Live attenuated vaccines should not be administered during and for 2 months after Gilenya treatment because of the risk of infection.
• When combined with drugs that decrease heart rate (for example, atenolol) there is an additional 15% reduction of heart rate. 

Gilenya has not been adequately studied in pregnant women. It is unknown if Gilenya is secreted in breast milk. Consult your doctor before breastfeeding.

The most common side effects are:

• headache,
• flu,
• diarrhea,
• back pain,
• elevations of liver enzymes and
• cough.

Fingolimod may decrease heart rate, especially after the first dose. Patients should be observed for signs and symptoms of low heart rate for 6 hours after the first dose.

Fingolimod may increase the risk of infections. Signs and symptoms of infection should be monitored during treatment and for two months after discontinuation of treatment. Fingolimod should not be administered to patients who have an infection.

Fingolimod may cause inflammation of the eye (uveitis) and other eye problems. Therefore, visual acuity should be checked prior to starting therapy, 3 to 4 months after initiation of therapy, and during routine patient evaluation.

Fingolimod has also been associated with difficulty breathing. Fingolimod reduces the white blood cell count, and this effect may last for 2 months after treatment is discontinued.

The following serious adverse reactions are described elsewhere in labeling:

• Bradyarrhythmia and Atrioventricular Blocks
• Infections
• Progressive Multifocal Leukoencephalopathy
• Macular Edema
• Liver Injury
• Posterior Reversible Encephalopathy Syndrome
• Respiratory Effects
• Fetal Risk
• Severe Increase in Disability After Stopping Gilenya
• Increased Blood Pressure
• Malignancies
• Immune System Effects Following Gilenya Discontinuation
• Hypersensitivity Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults

In clinical trials (Studies 1, 2, and 3), a total of 1212 patients with relapsing forms of multiple sclerosis received Gilenya 0.5 mg. This included 783 patients who received Gilenya 0.5 mg in the 2-year placebo-controlled trials (Studies 1 and 3) and 429 patients who received Gilenya 0.5 mg in the 1-year active-controlled trial (Study 2).

The overall exposure in the controlled trials was equivalent to 1716 person-years. Approximately 1000 patients received at least 2 years of treatment with Gilenya 0.5 mg. In all clinical studies, including uncontrolled extension studies, the exposure to Gilenya 0.5 mg was approximately 4119 person-years.

In placebo-controlled trials, the most frequent adverse reactions (incidence ≥ 10% and greater than placebo) for Gilenya 0.5 mg were

• headache,
• liver transaminase elevation,
• diarrhea,
• cough,
• influenza,
• sinusitis,
• back pain,
• abdominal pain, and
•  pain in extremity.

Adverse events that led to treatment discontinuation and occurred in more than 1% of patients taking Gilenya 0.5 mg were serum transaminase elevations (4.7% compared to 1% on placebo) and basal cell carcinoma (1% compared to 0.5% on placebo).

Table 1 lists adverse reactions in clinical studies in adults that occurred in ≥ 1% of Gilenya-treated patients and ≥ 1% higher rate than for placebo.

Table 1: Adverse Reactions Reported in Adult Studies 1 and 3 (Occurring in ≥ 1% of Patients and Reported for Gilenya 0.5 mg at ≥ 1% Higher Rate than for Placebo)

Adverse reactions of seizure, dizziness, pneumonia, eczema, and pruritus were also reported in Studies 1 and 3, but did not meet the reporting rate criteria for inclusion in Table 1 (difference was less than 1%).

Adverse reactions with Gilenya 0.5 mg in Study 2, the 1-year active-controlled (versus interferon beta-1a) study were generally similar to those in Studies 1 and 3.

Vascular Events

• Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received Gilenya doses (1.25-5 mg) higher than recommended for use in MS.
• Similar events have been reported with Gilenya in the postmarketing setting although a causal relationship has not been established.

Seizure

• Cases of seizures, including status epilepticus, have been reported with the use of Gilenya in clinical trials and in the postmarketing setting in adults.
• In adult clinical trials, the rate of seizures was 0.9% in Gilenya-treated patients and 0.3% in placebo-treated patients.
• It is unknown whether these events were related to the effects of multiple sclerosis alone, to Gilenya, or to a combination of both.

Pediatric Patients 10 Years Of Age And Older

• In the controlled pediatric trial (Study 4), the safety profile in pediatric patients receiving Gilenya 0.25 mg or 0.5 mg daily was similar to that seen in adult patients.
• In the pediatric study, cases of seizures were reported in 5.6% of Gilenya-treated patients and 0.9% of interferon beta-1a-treated patients.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Gilenya. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hepatobiliary Disorders: Liver injury
• Infections: infections including cryptococcal infections, progressive multifocal leukoencephalopathy
• Musculoskeletal and connective tissue disorders: arthralgia, myalgia
• Nervous system disorders: posterior reversible encephalopathy syndrome, seizures, including status epilepticus
• Neoplasms, benign, malignant, and unspecified (incl cysts and polyps): melanoma, Merkel cell carcinoma, and cutaneous T cell lymphoma (including mycosis fungoides)
• Skin and subcutaneous tissue disorders: hypersensitivity

QT Prolonging Drugs

• Gilenya has not been studied in patients treated with drugs that prolong the QT interval.
• Drugs that prolong the QT interval have been associated with cases of torsades de pointes in patients with bradycardia.
• Since initiation of Gilenya treatment results in decreased heart rate and may prolong the QT interval, patients on QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility.

Ketoconazole

• The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole.
• Patients who use Gilenya and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater.

Vaccines

• Gilenya reduces the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with Gilenya.
• Avoid the use of live attenuated vaccines during and for 2 months after treatment with Gilenya because of the risk of infection.
• It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Gilenya therapy.

Antineoplastic, Immunosuppressive, Or Immune-Modulating Therapies

• Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with Gilenya.
• When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating Gilenya.

Drugs That Slow Heart Rate Or Atrioventricular Conduction (e.g., beta blockers or diltiazem)

• Experience with Gilenya in patients receiving concurrent therapy with drugs that slow the heart rate or AV conduction (e.g., beta blockers, digoxin, or heart rate-slowing calcium channel blockers such as diltiazem or verapamil) is limited.
• Because initiation of Gilenya treatment may result in an additional decrease in heart rate, concomitant use of these drugs during Gilenya initiation may be associated with severe bradycardia or heart block.
• Seek advice from the physician prescribing these drugs regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating Gilenya.
• Patients who cannot switch should have overnight continuous ECG monitoring after the first dose.

Laboratory Test Interaction

• Because Gilenya reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient treated with Gilenya.
• A recent CBC should be available before initiating treatment with Gilenya.