GILENYA HAS A
WELL-DOCUMENTED
SAFETY AND
TOLERABILITY
PROFILE IN PIVOTAL
CLINICAL TRIALS¹

DEMONSTRATED IN ADULT PATIENTS

Adverse reactions occurring in ≥1% of adult patients and reported for GILENYA 0.5 mg at ≥1% higher rate than for placebo in FREEDOMS and FREEDOMS II*

*In placebo-controlled clinical trials (FREEDOMS and FREEDOMS II), a total of 783 adult patients received GILENYA 0.5 mg during a 2-year period.

Most common adverse reactions (≥10% and > placebo): headache, liver transaminase elevation, diarrhea, nausea, cough, influenza, sinusitis, abdominal pain, back pain, and pain in extremity
AEs that led to treatment discontinuation and occurred in more than 1% of adult patients taking GILENYA 0.5 mg were serum transaminase elevations (4.7% compared with 1% on placebo) and basal cell carcinoma (1% compared with 0.5% on placebo)

See full study designs for FREEDOMS and FREEDOMS II below

SAFETY PROFILE IN PEDIATRIC PATIENTS SIMILAR TO ADULTS¹

In PARADIGMS, the controlled pediatric trial, the safety profile in pediatric patients (10 to less than 18 years of age) 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 patients treated with GILENYA and 0.9% of patients treated with interferon beta-1a
The safety and efficacy of GILENYA in children less than 10 years of age have not been studied

See full PARADIGMS study design below.

DEMONSTRATED SAFETY AND TOLERABILITY PROFILE IN ADULT PATIENTS^2-4

UP TO 4 YEARS

*Serious AEs occurring in ≥2 patients included appendicitis, basal cell carcinoma, uterine leiomyoma, and epilepsy.

UP TO 4.5 YEARS

*Serious AEs occurring in at least 2 patients included basal cell carcinoma, MS relapse, cholelithiasis, cystitis, breast cancer, spontaneous abortion, lower limb fracture, and road traffic accident.

UP TO 7 YEARS

*Serious AEs reported in at least 0.2% of patients were cholelithiasis, pneumonia, urinary tract infection, appendicitis, herpes zoster, basal cell carcinoma, squamous cell carcinoma, MS relapses, and depression.

POSTMARKETING EXPERIENCE

Additional serious AEs, some fatal, have been reported in the real-world, postmarketing setting
Please see Important Safety Information, including postmarketing events, below

See full FREEDOMS EXTENSION, TRANSFORMS EXTENSION, and LONGTERMS study designs below

Download the GILENYA START FORM to get your patients started now.

STUDY DESIGNS

A 2-year, randomized, double-blind, placebo-controlled phase III study of 1,272 adults with RRMS
Patients were randomly assigned to receive GILENYA at a once-daily dose of 0.5 mg (n=425) or 1.25 mg (n=429) or matching placebo once daily (n=418) for 2 years
Patient baseline characteristics
- Between 18 and 55 years of age
- A diagnosis of RRMS with at least 1 documented relapse during the previous year or at least 2 documented relapses during the previous 2 years
- A score of 0.0 to 5.5 on the EDSS. Median score at baseline was 2.0
Primary end point: ARR
Key secondary end point: time to 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5-point increase for patients with baseline EDSS of 5.5) sustained for 3 months*
Additional secondary end points included number of Gd+ T1 lesions and number of new or newly enlarged lesions on T2-weighted MRI scans
The FDA-approved dose of GILENYA is 0.5 mg orally once daily. Doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefits
81.2% (345/425) of patients assigned to GILENYA 0.5 mg completed the study on GILENYA 0.5 mg at 2 years while 18.8% (80/425) discontinued GILENYA

*The analysis of a key secondary end point includes the same intent-to-treat population as the primary end point(s), as well as logistic regression adjusting for certain baseline characteristics of the sample.

A 2-year, randomized, double-blind, placebo-controlled phase Ill study of 1,083 adults with RRMS
Patient baseline characteristics
- Between 18 and 55 years of age
- A diagnosis of RRMS with at least 1 documented relapse during the previous year or at least 2 documented relapses during the previous 2 years
- A score of 0.0 to 5.5 on the EDSS. Median score at baseline was 2.0
The primary end point was ARR
A key secondary end point was time to 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5-point increase for patients with baseline EDSS of >5.0) sustained for 3 months*
Additional secondary end points included proportion of relapse-free patients and effect on MRI measurements of inflammatory disease activity (including number of Gd+ T1 lesions and number of new or newly enlarged T2 lesions)
The FDA-approved dose of GILENYA is 0.5 mg orally once daily. Doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefits

PARADIGMS

A double-blind, randomized, clinical trial that compared the efficacy and safety of GILENYA 0.25 mg or 0.5 mg (dose selected based on body weight) once daily to intramuscular (IM) interferon beta-1a 30 mcg in 215 pediatric patients 10 to less than 18 years of age with RRMS. One patient received no study drug and was excluded from the analysis of efficacy
Patient baseline characteristics
- RRMS diagnosis based on the revised consensus definition for pediatric MS, which includes the 2010 McDonald criteria
- Expanded Disability Status Scale (EDSS) score: 0-5.5. Median score at baseline was 1.5
- Previously treated or treatment-na�ve patients with at least 1 relapse in the past year, or 2 relapses in the previous 2 years, or evidence of at least 1 Gd+ T1 lesion on MRI in 6 months before randomization
- No evidence of progressive MS or other immune system diseases or other demyelinating disorders, acute disseminated encephalomyelitis, or neuromyelitis optica
Primary end point: The annualized relapse rate, defined as the average number of confirmed relapses per year over the period of active treatment
Key secondary end point: The annualized rate of new or newly enlarged lesions detected on T2-weighted MRI as compared with baseline
Other secondary end points:
- Effect on Gd+ T1 lesions
- Safety and tolerability
Patients were required to remain at the site for at least 6 hours after receiving the first dose of study drug (ie, first-dose monitoring on Day 1). First-dose observation included monitoring of vital signs (heart rate and blood pressure), for potential signs of bradycardia, and electrocardiography
Prior therapy with interferon-beta, dimethyl fumarate, or glatiramer acetate up to the time of randomization was permitted
Baseline assessments and neurologic evaluations were performed at screening. Additional neurological evaluations were completed every 3 months and at the time of suspected relapses
MRI evaluations were performed at screening, and every 6 months throughout the study

EXTENSION

An optional, dose-blinded, parallel-group extension study of 1,033 adults with RRMS who completed the core FREEDOMS study on either a once-daily dose of GILENYA 0.5 mg or 1.25 mg or matching placebo once daily for 2 years. Efficacy and safety were evaluated at 48 months
- Of the 1,272 patients who completed the core trial, 1,033 (81.2%) opted to continue on the extension study
All patients in the extension either continued GILENYA 0.5 mg/day or 1.25 mg/day, or switched from placebo to either dose, randomized 1:1
Patient baseline characteristics
- Eligible for inclusion in the core study with a diagnosis of RRMS and 1 or more documented relapses in the year before randomization, or 2 or more documented relapses in the 2 years prior to randomization
- A score of 0 to 5.5 on the EDSS. Median score at baseline was 2.0
- Aged 18 to 55 years
Primary end point: ARR
Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study
- Within-group analyses compared years 0 to 2 (FREEDOMS) and years 2 to 4 (extension) in the extension ITT population
The FDA-approved dose of GILENYA is 0.5 mg orally once daily. Doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefits

EXTENSION

An optional, 12-month, randomized phase III extension study of 1,027 adults with RRMS who completed the core TRANSFORMS study on either IFNβ-1a IM 30 mcg, GILENYA 0.5 mg, or GILENYA 1.25 mg. Efficacy and safety were followed up to 4.5 years

Of the 1,123 patients who completed the core trial, 1,027 (92%) opted to continue on the extension study
All patients in the extension received a once-daily dose of either GILENYA 0.5 mg or GILENYA 1.25 mg
Patients who received GILENYA during the TRANSFORMS core trial continued at their prior dosage of either 0.5 mg (n=356) or 1.25 mg (n=330)
Patients who received IFNβ-1a IM 30 mcg during the TRANSFORMS core trial were randomly assigned to receive GILENYA at a once-daily dose of 0.5 mg (n=167) or 1.25 mg (n=174)

Patient baseline characteristics
- Eligible for inclusion in the core study with a diagnosis of RRMS and 1 or more documented relapses in the year before randomization, or 2 or more documented relapses in the 2 years prior to randomization
- A score of 0 to 5.5 on the EDSS. Median score at baseline was 2.0
- Aged 18 to 55 years
- Neurologically stable, with no evidence of relapse or corticosteroid treatment within 30 days before randomization
Efficacy end points were ARR, disability progression, and MRI outcomes
- No variable was specifically designated as the "primary variable" in the extension phase
- Core phase
  - Primary efficacy variable was the aggregate ARR
  - Key secondary variables were the number of new or newly enlarged T2 lesions and the time to first 3-month confirmed disability progression as measured by EDSS*
For patients who transitioned to GILENYA, leading causes of discontinuation were withdrawal of consent, unsatisfactory therapeutic effect, and adverse events
For patients who continued on GILENYA, leading causes of discontinuation were withdrawal of consent, abnormal laboratory values, and adverse events
The FDA-approved dose of GILENYA is 0.5 mg orally once daily. Doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefits

LONGTERMS

An open-label, single-arm, long-term follow-up extension study of phase II, phase Ill, and phase lllb trials, monitoring the long-term safety, tolerability, and effectiveness of GILENYA 0.5 mg in adults with RRMS
Safety analysis
- This analysis included the core plus extension periods of the phase Ill trials (FREEDOMS, TRANSFORMS, FREEDOMS II)
- Two patient cohorts treated with fingolimod 0.5 mg were evaluated:
  - A long-term cohort (LC; n=1,655) previously enrolled in the 3 core phase Ill trials plus their extensions (including nonparticipants of LONGTERMS)
  - A core cohort (CC; n=1,212) pooled from core phase Ill trials

AE=adverse event; ALT=alanine aminotransferase; ARR=annualized relapse rate; AST=aspartate aminotransferase; EDSS=Expanded Disability Status Scale; Gd+=gadolinium-enhancing; GGT=gamma-glutamyl transpeptidase; IFN=interferon; IM=intramuscular; MRI=magnetic resonance imaging; MS=multiple sclerosis; RRMS=relapsing-remitting multiple sclerosis.

References: 1. Gilenya [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; December 2019. 2. Kappos L, O'Connor P, Radue E-W, et al. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology. 2015;84(15):1582-1591. 3. Cohen JA, Khatri B, Barkhof F, et al; TRANSFORMS (TRial Assessing injectable interferoN vS. FTY720 Oral in RRMS) Study Group. Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study. J Neurol Neurosurg Psychiatry. 2016;87(5):468-475. 4. Data on file. LONGTERMS Full Clinical Study Report (CFTY720D2399). Novartis Pharmaceuticals Corp; November 2017.

Indication and Important Safety
Information

EXPAND

COLLAPSE

Important Safety Information

Contraindications

Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure (HF) requiring hospitalization or Class III/IV HF
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

Indication

GILENYA is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in patients 10 years of age and older.

Baseline QTc interval ≥500 msec
Cardiac arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs
Patients who have had a hypersensitivity reaction to fingolimod or any of the excipients in GILENYA. Observed reactions include rash, urticaria, and angioedema upon treatment initiation

Bradyarrhythmia and Atrioventricular (AV) Block: Monitor patients during GILENYA initiation because of a risk of bradyarrhythmia and AV block. Prior to dosing and at the end of the observation period, obtain an electrocardiogram (ECG) in all patients (10 years of age and older). Monitor all patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure (BP) measurement.

Continue monitoring until the abnormality resolves if any of the following is present after 6 hours: (1) The heart rate (HR) 6 hours postdose is <45 bpm in adults, <55 bpm in pediatric patients 12 years of age and older, or <60 bpm in pediatric patients 10 or 11 years of age. (2) The HR 6 hours postdose is at the lowest value postdose suggesting that the maximum pharmacodynamic effect on the heart may not have occurred. (3) The ECG 6 hours postdose shows new onset second degree or higher atrioventricular (AV) block.

Begin continuous ECG monitoring in patients with symptomatic bradycardia until resolution. If pharmacological intervention is required, continue ECG monitoring overnight in a medical facility, and repeat 6-hour monitoring after the second dose. Some patients may experience a second decrease in HR within 24 hours after the first dose.

Patients with pre-existing ischemic heart disease, history of MI or cardiac arrest, CHF, cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia or recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block, or on concomitant drugs that slow HR or AV conduction should be evaluated by a physician and, if treated with GILENYA, monitored overnight with continuous ECG in a medical facility after first dose due to higher risk of symptomatic bradycardia or heart block. Patients with or at risk for QT prolongation or on concomitant QT-prolonging drugs with a known risk of torsades de pointes should also be monitored overnight with continuous ECG.

Repeat first-dose monitoring if GILENYA is interrupted ≥1 day within first 2 weeks or >7 days during weeks 3 and 4, or >14 days after the first month of treatment because effects on HR and AV conduction may occur upon reinitiation. First-dose monitoring is also recommended when the dose is increased in pediatric patients switching from 0.25 mg to 0.5 mg.

Infections: GILENYA may increase risk of infections. Life threatening and fatal infections have occurred in association with GILENYA. A recent CBC should be available before initiating GILENYA. Consider suspending GILENYA if a patient develops a serious infection. Monitor for signs and symptoms of infection during treatment and up to 2 months after discontinuation. Do not start GILENYA in patients with active acute or chronic infections until infection is resolved. Two patients receiving a higher than recommended dose of GILENYA (1.25 mg) in conjunction with high-dose corticosteroid therapy died of herpetic infections. In the postmarketing setting with GILENYA, serious infections, some fatal, have been reported with opportunistic pathogens, including viruses (eg, John Cunningham virus [JCV], herpes simplex viruses 1 and 2, varicella zoster virus [VZV]), fungi (eg, cryptococci), bacteria (eg, atypical mycobacteria), and Kaposi's sarcoma. Patients with signs and symptoms consistent with any of these infections should undergo prompt diagnostic evaluation and treatment. Concomitant use with antineoplastic, immunosuppressive, or immune-modulating therapies are expected to increase the risk of additive immunosuppression. When switching to GILENYA from these types of therapies, consider their duration of effect and mode of action to avoid this risk.

Before initiating GILENYA, patients should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients is recommended prior to starting treatment. GILENYA initiation should be postponed for 1 month after vaccination. It is recommended that pediatric patients, if possible, complete all immunizations in accordance with current immunization guidelines prior to initiating GILENYA.

Human papilloma virus (HPV) infections, including papilloma, dysplasia, warts, and HPV-related cancer, have been reported with GILENYA in the postmarketing setting. Vaccination against HPV should be considered prior to treatment initiation, taking into account vaccination recommendations. Cancer screening, including Papanicolaou (Pap) test, is recommended as per standard of care for patients using an immunosuppressive therapy.

Progressive Multifocal Leukoencephalopathy (PML): Cases of PML occurred in patients with MS who received GILENYA in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and usually leads to severe disability or death. PML has occurred in patients who had not been treated previously with natalizumab, which has a known association with PML, and who were not taking concomitant immunosuppressive or immunomodulatory medications.

Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body, clumsiness of limbs, visual disturbances, and changes in thinking, memory, and orientation, leading to confusion and personality changes.

MRI findings may be apparent before clinical signs or symptoms. PML, diagnosed based on MRI findings and detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, has been reported in patients treated with MS medications associated with PML, including GILENYA. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful. Any suspicious findings should lead to further investigation to allow for an early diagnosis of PML. Lower PML-related morbidity and mortality have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or differences in disease in these patients.

At the first sign or symptom suggestive of PML, withhold GILENYA and perform an appropriate diagnostic evaluation.

Macular Edema: Fingolimod increases the risk of macular edema, with or without visual symptoms. Perform an exam of the fundus, including the macula, before starting GILENYA, and 3 to 4 months after initiation. Monitor visual acuity at baseline, during routine patient evaluations, and if a patient reports visual disturbances while on GILENYA. Patients with diabetes mellitus or history of uveitis are at increased risk and should have regular ophthalmologic evaluations.

Liver Injury: Clinically significant liver injury has occurred in patients treated with GILENYA in the postmarketing setting. Signs and symptoms of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as 10 days after the first dose and also have been reported after prolonged use. Cases of acute liver failure requiring liver transplant have been reported.

Elevation of liver enzymes (ALT, AST, and GGT) 3- and 5-fold the upper limit of normal and greater has occurred with GILENYA. The majority occurred within 6 to 9 months and returned to normal within 2 months after discontinuing GILENYA. Recurrence of liver transaminase elevations occurred with rechallenge in some patients.

Prior to starting treatment with GILENYA (within 6 months), obtain serum transaminases (ALT and AST) and total bilirubin levels, and periodically until 2 months after GILENYA discontinuation. Patients should be monitored for signs and symptoms of any hepatic injury. Treatment with GILENYA should be interrupted if the patient is found to have an ALT greater than 3 times the reference range with serum total bilirubin greater than 2 times the reference range. Patients with severe hepatic impairment should be closely monitored, as their risk of adverse reactions is greater.

Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported with GILENYA. Symptoms reported include sudden onset of severe headache, altered mental status, visual disturbances, and seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, GILENYA should be discontinued.

Respiratory Effects: Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in GILENYA patients as early as 1 month after initiation. Changes in FEV1 appear to be reversible after discontinuing GILENYA; however, there is insufficient information to determine reversibility of DLCO. Obtain spirometry and DLCO when clinically indicated.

Fetal Risk: GILENYA may cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Because it takes approximately 2 months to eliminate GILENYA from the body, advise females of reproductive potential to use effective contraception to avoid pregnancy during and for 2 months after stopping GILENYA treatment. A registry for women who become pregnant during GILENYA treatment is available. Contact the GILENYA Pregnancy Registry by calling 1-877-598-7237, sending an e-mail to gpr@quintiles.com, or visiting gilenyapregnancyregistry.com.

Severe Increase in Disability After Stopping GILENYA: Severe increase in disability accompanied by multiple new lesions on MRI has been reported following discontinuation of GILENYA in the postmarketing setting. Most of these reported cases did not return to the functional status they had before stopping GILENYA. The increase in disability generally occurred within 12 weeks after stopping GILENYA, but was reported up to 24 weeks after GILENYA discontinuation.

The possibility of severe increase in disability should be considered in patients who discontinue GILENYA, including those who are pregnant or planning for pregnancy. Monitor patients for development of severe increase in disability following discontinuation of GILENYA and begin appropriate treatment as needed.

Tumefactive Multiple Sclerosis: MS relapses with tumefactive demyelinating lesions on imaging have been observed during GILENYA therapy and after discontinuation in the postmarketing setting. Most reported cases occurred within the first 9 months after initiation, but may occur at any point during treatment. Cases have also been reported within the first 4 months after discontinuation of GILENYA. Tumefactive MS should be considered when a severe MS relapse occurs during treatment, especially during initiation, or after discontinuation, prompting imaging evaluation and initiation of appropriate treatment.

Increased Blood Pressure (BP): Monitor BP during treatment with GILENYA. An average increase of 3 mm Hg in systolic and 2 mm Hg in diastolic BP was observed in clinical trials versus placebo.

Malignancies: The risk of basal cell carcinoma (BCC) and melanoma is increased in patients treated with GILENYA. Melanoma, squamous cell carcinoma, and Merkel cell carcinoma have been reported with GILENYA in the postmarketing setting. Monitor and evaluate suspicious skin lesions.

Cases of lymphoma, including both T-cell and B-cell types and CNS lymphoma, have occurred in patients receiving GILENYA. The reporting rate of non-Hodgkin lymphoma with GILENYA is greater than that expected in the general population. Cutaneous T-cell lymphoma (including mycosis fungoides) has also been reported in the postmarketing setting.

Immune System Effects Following Discontinuation: Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts for up to 2 months following the last dose. Lymphocyte counts generally return to normal range within 1 to 2 months of stopping therapy. Initiating other drugs during this period warrants the same considerations needed for concomitant administration.

Hypersensitivity Reactions: Hypersensitivity reactions including rash, urticaria, and angioedema have been reported with GILENYA.

Drug Interactions: Closely monitor patients receiving systemic ketoconazole. The use of live attenuated vaccines should be avoided during, and for 2 months after stopping GILENYA.

Common Adverse Reactions: The most common adverse reactions with GILENYA 0.5 mg (incidence ≥10% and >placebo) were headache, liver transaminase elevations, diarrhea, nausea, cough, influenza, sinusitis, abdominal pain, back pain, and pain in extremity.

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.

Pediatric Patients 10 Years of Age and Older: In the pediatric study, the safety profile in pediatric patients receiving GILENYA 0.25 mg or 0.5 mg daily was similar to that seen in adult patients. Cases of seizures were reported in 5.6% of GILENYA-treated patients and 0.9% of interferon beta-1a-treated patients.

Indication

Click here for full Prescribing Information.

GILENYA Safety in Pivotal Clinical Trials

GILENYA HAS A WELL-DOCUMENTED SAFETY AND TOLERABILITY PROFILE IN PIVOTAL CLINICAL TRIALS1