Fingolimod (Gilenya®) Update

Mitchell Wallin, MD, MPH, MSCoE-East, Washington, DC VA Medical Center
Ruth Whitham, MD, MSCoE-West, Portland VA Medical Center
Kathy Tortorice, PharmD, BCPS Pharmacy Benefits Management Services, Hines VA Medical Center

What is fingolimod and what are its indications for use?
Fingolimod is a sphingosine 1 phosphate (S1P) receptor modulator first synthesized in 1992 and derived from the fungus Isaria sinclairii. It acts as a functional antagonist of the S1P receptor on lymphocytes, inducing its uncoupling and internalization. The proposed mechanism of action for fingolimod in multiple sclerosis (MS) is a reversible retention of CD4 and CD8 T-cells and B-cells in lymph nodes which thereby reduces the number of inflammatory cells that have access to the central nervous system.  The average terminal half life for fingolimod is 6-9 days.  Peripheral lymphocyte counts decrease by about 30% from baseline after the first few weeks of fingolimod administration and recover in most patients within 1-2 months after stopping the drug.  T-lymphocytes are more vulnerable than B-lymphocytes and a significant drop in CD4 cell counts has been noted after initiating fingolimod. This medication was originally developed for the prevention of acute rejection after renal transplantation in adults.  The development was stopped, however, after evaluation of the risk benefit profile. The use of fingolimod in MS trials utilized a lower dose range.

Two phase 3 clinical trials provided evidence for the efficacy of fingolimod in patients with relapsing-remitting MS (RRMS).  Both studies were sponsored by Novartis.  The FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) study was a 2 year placebo controlled trial in 1,272 RRMS patients (Kappos, et al 2010).  The primary endpoint was the annualized relapse rate (ARR) with fingolimod doses of 1.25mg/day and 0.5mg/day compared with placebo.  An ARR of 0.16 and 0.18 were found in the 1.25mg/day and 0.5mg/day fingolimod groups, respectively, which was significantly lower than the 0.40 ARR in the placebo group.  Time to 3-month confirmed disability progression, a secondary study endpoint, was significantly longer in the two fingolimod groups compared to placebo. Brain MRI lesion activity and atrophy progression were reduced in the fingolimod treatment group compared with placebo.

The Trial Assessing Injectable Interferon vs. FTY720 Oral in RRMS (TRANSFORMS) was a 12-month study of 1,292 RR MS patients comparing fingolimod doses of 1.25mg/day and 0.5mg/day with IM interferon beta-1a (Cohen, et al 2010).  Similar to FREEDOMS, the ARR was significantly lower in the 1.25mg/day (0.20) and 0.5mg/day (0.16) doses compared with interferon beta-1a (0.33). MRI lesion activity and atrophy progression were significantly reduced in the fingolimod group compared with interferon beta-1a.  There was no significant change in time to 3-month confirmed disability progression between the groups, however.

The US Food and Drug Administration (FDA) approved fingolimod 0.5mg/day for use in relapsing forms of MS in September of 2010.  It is the first oral agent shown to reduce relapses and delay disability progression in relapsing forms of MS.  As of January 2012, a total of 33,000 patients with MS have received fingolimod.

What are the major side effects of fingolimod?
Infections: Serious herpes infections are the major risk seen in the fingolimod trials.  Fatal herpes infections (herpes encephalitis and disseminated zoster) occurred in two patients with MS on fingolimod 1.25mg/day who also received high dose IV corticosteroids for relapses.  An additional four patients receiving fingolimod in the controlled trials experienced a herpes infection requiring hospitalization (two on 1.25mg/day and two on 0.5mg/day).

Patients without a documented history of varicella zoster virus infection or vaccination against it should be evaluated for vaccination against varicella prior to fingolimod initiation. Zostavax® should NOT be used in these individuals. In these patients vaccination with the live attenuated varicella virus product (Varivax®) should be undertaken. Consult the CDC website for guidance. Two doses of the vaccine must be given at least 4 weeks apart and initiation of fingolimod delayed until 1 month after the second vaccine dose. www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm

Evaluating the entire safety database (controlled and uncontrolled studies), the percentage of infection-related side effects suggests a dose response for fingolimod (1.3%, 2.6%, and 3.6% respectively for fingolimod 0.5mg/day, 1.25mg/day, and 1.25 or 5.0 mg/day). 

Cardiac toxicity: Bradyarrhythmias: Initiation of fingolimod results in a decrease in heart rate.  The heart rate starts decreasing within an hour on day 1 and is reported to be maximal at 6 hours. For those patients taking fingolimod 0.5mg, at 6 hours after the first dose, the average decrease in heart rate was 13 beats per minute.  A baseline ECG should be obtained prior to initiating a patient on fingolimod.  Patients should be observed for symptoms and signs of bradycardia during at least the initial 6 hours post initiation of therapy. Subsequent doses of fingolimod produce less severe decrements in heart rate and the heart rate is reported to return to normal within one month of chronic treatment. 

A recent case report of a patient with MS who developed a 7 second period of asystole and sustained bradycardia 21 hours after the initial dose of fingolimod (Espinosa, et al, 2011) does raise concerns about the duration of the risk period for bradyarrhythmias after the initial dose.  This patient was also taking risperidone which may have contributed to the development of asystole and bradycardia.  Additionally, in December of 2011, Novartis reported a death of a patient with MS within the first 24 hours after receiving fingolimod (FDA, 2011).  Clinical details of this case are still pending.  This patient was reportedly taking metoprolol and amlodipine.  More prolonged monitoring may be considered for patients after their first dose, but neither Novartis nor the FDA have proposed any specific guidance on this issue yet. 

Atrioventricular blocks: Initiation of fingolimod has resulted in transient AV conduction delays. In clinical trials first degree AV block following first dose was reported in 0.1% of patients receiving fingolimod 0.5mg but no patients taking placebo.  Similarly, second degree AV block occurred in 0.1% in patients taking 0.5mg of fingolimod and none taking placebo. Most conduction abnormalities were transient and asymptomatic and resolved within 24 hours on therapy.  Occasionally, they required treatment with atropine or isoproterenol.

Re-initiation of fingolimod: If fingolimod is discontinued for more than two weeks, the effects on heart rate and AV conduction may recur.  Reintroduction of fingolimod should therefore be under the same precautions as for initial dosing.

Blood pressure effects: Over the initial two months of therapy, fingolimod 0.5mg was associated with an approximately 2mmHg increase in systolic blood pressure, and a 1mmHg increase in diastolic blood pressure. This effect persisted with continued treatment.  Blood pressure should be monitored in patients on fingolimod.

Pulmonary toxicity: Bronchoconstriction and an excess of dyspnea and pulmonary edema (undetermined origin) was seen in the fingolimod-treated patients in the renal transplant trials Dse-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in patients with MS treated with fingolimod. These changes occurred as early as 1 month after starting treatment.  At month 24, the reduction from baseline in percent of predicted values for FEV1 was 3.1% for fingolimod and 2% for placebo.  For DLCO, the decrement from baseline in percent of predicted values at month 24 was 3.8% for fingolimod and 2.7% for placebo. The changes in FEV1 appear to be reversible but there is insufficient data to determine the reversibility of the DLCO decrement.  Fingolimod has not been tested in patients with compromised respiratory function. 

Macular edema: In patients with MS receiving 0.5mg of fingolimod in controlled studies, macular edema occurred in 0.4% vs. 0.1% in those taking placebo. Effects were seen over the first 3-4 months of therapy.  Symptoms of blurred vision occurred in some but others were asymptomatic.  In general, macular edema symptoms improve after treatment discontinuation, but some patients have residual visual acuity loss even after resolution of macular edema. To evaluate for macular changes, a baseline ophthalmologic examination should be performed and repeated at 3-4 months after starting fingolimod. Rates of macular edema with fingolimod therapy are increased in patients with a history of diabetes mellitus (20%) and uveitis (6%).

Hepatotoxicity:  Elevations in liver enzymes occur in patients taking fingolimod. In clinical trials, a 3-fold the upper limit of normal elevation in liver transaminases occurred in 8% of patients receiving fingolimod 0.5mg compared with 2% on placebo. A 5-fold elevation in liver enzymes occurred in 2% of patients on fingolimod vs. 1% of patients on placebo. Most elevations occurred within 3-4 months of therapy and returned to normal within 2 months after discontinuation, but more delayed liver enzyme elevations later in the first year of therapy have been described.

Pregnancy and fingolimod: Animal studies have shown that fingolimod may cause fetal harm. As such, it is a pregnancy Category C medication. Because elimination of fingolimod can take up to 2 months following discontinuation, women of child bearing potential should be counseled regarding appropriate forms of contraception during fingolimod therapy and up to two months after stopping the medication.

How is fingolimod prescribed in the VA health care system? How will patients taking fingolimod be evaluated and monitored?
Currently, fingolimod is a non-formulary drug, available via facility procedures and National criteria for use (CFU) document. The fingolimod CFU has been developed by the Pharmacy Benefits Management (PBM) and the MSCoEs and has been vetted by practitioners across VA.. The CFU is available at the PBM website (www.pbm.va.gov) or the MSCoE website (www.va.gov/ms).  Specific inclusion and exclusion criteria for fingolimod and the ordering process are presented. In addition, monitoring for untoward effects is reviewed.  Specific recommendations are given for cardiac, hepatic, infectious, ophthalmologic, oncologic and pulmonary monitoring.  These are based on a thorough review of the literature including recent clinical trials. 

The February 2012 version of the Fingolimod CFU has new guidelines on cardiac assessment and monitoring (www.pbm.va.gov).  For example, 24-hour ECG telemetry monitoring for patients at high risk for bradycardia is recommended.  However, because there is no specific monitoring program for fingolimod therapy in the US, there may be additional risks and toxicities which become evident over time,  Providers are encouraged to contact the VA Adverse Events Reporting System (VA ADERS: https://medora.va.gov/adr) and VA Pharmacy Benefits Management Service/MSCoE (contact: Kathy.tortorice@va.gov or MSCoE staff: www.va.gov/ms)   with any significant new events.

How is fingolimod being monitored in Europe and in the US?
The European Medicines Agency (EMA) has started a safety review of fingolimod after reports issued on January 20, 2012, of 11 deaths among patients who received treatment with fingolimod (http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/01/news_detail_001425.jsp&mid=WC0b01ac058004d5c1&jsenabled=true). Some of the reported deaths appear to be due to cardiac events, but few details are available at this time.  The EMA is recommending that doctors increase patient monitoring after the first dose is given, with recommendations including “ECG monitoring before treatment and then continuously for the first 6 hours, and measurement of blood pressure and heart rate every hour.  After 6 hours, any patients with clinically important heart-related effects, such as bradycardia or atrioventricular block, should be managed and monitored until their condition has improved”.  Health care agencies in France are reportedly recommending 24 hours of continuous ECG monitoring after the initial dose of fingolimod.  The EMA expects to finalize its safety review by the time of its plenary meeting in March 2012.  There is also an investigation currently underway by the US FDA. 

References
1. Food & Drug Administration Background Package (NDA 22-527), June 10, 2010: 1-379.
2. Gilenya™ [Product Labeling] East Hanover, NJ: Novartis Pharmaceuticals Corp; September 2010.
3. O’Connor P, Comi G, Montalban X, et al. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 2009;72:73-79.
4. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO,et al; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4; 362(5):402-15.
5. Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R,et al; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4; 362(5):387-401.
6. Kappos, L. et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N. Engl. J. Med. 2006;355: 1124–1140.
7. Carroll WM. Oral therapy for multiple sclerosis--sea change or incremental step? N Engl J Med. 2010 Feb 4; 362(5):456-8.
8. Espinosa P, Berger J. Delayed fingolimod-associated asystole. Multiple Sclerosis Journal 2011;17:1387-1389.
9. FDA. Gilenya (fingolimod): Drug Safety Communication: Safety Review of a Reported Death after First Dose, December 20, 2011, http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm284355.htm, website accessed Jan 19. 2012

Date Posted: April 9, 2012