Type of information: Positive opinion for the granting of a Market Authorisation in the EU
Product name: Gilenya®
Therapeutic area: Autoimmune diseases - Neurodegenerative diseases
- sphingosine 1-phosphate receptor (S1PR) modulator. Gilenya®, licensed from Mitsubishi Tanabe Pharma Corporation, is the first in a new class of drugs called sphingosine 1-phosphate receptor (S1PR) modulators. In multiple sclerosis, the immune system damages the covering that protects nerve fibers in the central nervous system which includes the brain and spinal cord. Fingolimod reduces the ability of T cells to move from the lymph nodes towards the brain and spinal cord thus limiting the damage they cause in multiple sclerosis. It does this by blocking the action of a receptor on the T cells called the sphingosine-1-phosphate receptor, which is involved in regulating the movement of these cells in the body.
Company: Novartis (Switzerland)
- highly active relapsing-remitting multiple sclerosis (RRMS) despite treatment with beta interferon, or in patients with rapidly evolving severe RRMS.
- On September 20, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive
opinion recommending a change to the terms of the marketing authorisation for Gilenya®.The CHMP adopted an extension to the existing indication as follows:
“Gilenya is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following groups of adult patients and paediatric patients aged 10 years and older:
• Patients with highly active disease despite a full and adequate course of treatment with at least one
disease modifying therapy
• Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.”
- If approved, Gilenya® is expected to be the first oral disease-modifying therapy indicated for these patients based on a randomized controlled clinical study. The younger patient population experiences two-to-three times as many relapses as adults, often leading to a more severe prognosis and earlier disability compared to adult-onset MS.
- • On 24 September 2015, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Gilenya®. The CHMP adopted a change to the existing indication to reflect a modification in the criteria for disease activity that need to be fulfilled in order to enable a switch from a first line disease modifying therapy to Gilenya®. The amended indication reads as follows: “Gilenya® is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following adult patient groups:
- Patients with highly active disease activity despite a full and adequate course of treatment with at least one disease modifying therapy. These patients may be defined as those who have failed to respond to a full and adequate course (normally at least one year of treatment) of at least one disease modifying therapy. Patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gadolinium-enhancing lesion. A “non-responder” could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year.”
The full indication for Gilenya® will be as follows:
“Gilenya® is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following adult patient groups:
- Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy
- Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.”
- • On April 29, 2014, Novartis has announced that the Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion to expand the EU label for Gilenya® (fingolimod) in relapsing remitting multiple sclerosis (RRMS). The recommendation is to expand the label to include adult patients who have not responded to at least one disease-modifying therapy (DMT), including newly-approved oral DMTs.
- • On May 14, 2012, the FDA announced that it has completed its evaluation of a report of a patient who died after the first dose of multiple sclerosis drug Gilenya® (fingolimod). The agency also has evaluated additional clinical trial and postmarket data for Gilenya®, including reports of patients who died of cardiovascular events or unknown causes. FDA could not definitively conclude that Gilenya was related to any of the deaths. However, based on its reevaluation of the data, FDA remains concerned about the cardiovascular effects of Gilenya after the first dose. Data show that, although the maximum heart rate lowering effect of Gilenya usually occurs within 6 hours of the first dose, the maximum effect may occur as late as 20 hours after the first dose in some patients. For this reason, Gilenya® is now contraindicated in patients with certain pre-existing or recent (within last 6 months) heart conditions or stroke, or who are taking certain antiarrhythmic medications.
FDA continues to recommend that all patients starting Gilenya® be monitored for signs of a slow heart rate (bradycardia) for at least 6 hours after the first dose. FDA is now recommending hourly pulse and blood pressure measurement for all patients starting Gilenya®. Electrocardiogram (ECG or EKG) testing should be performed prior to dosing and at the end of the observation period. Cardiovascular monitoring should continue until any symptoms resolve.In addition, FDA is now also recommending that the time of cardiovascular monitoring be extended past 6 hours in patients who are at higher risk for or who may not tolerate bradycardia. Extended monitoring should include continuous ECG monitoring that continues overnight. These higher risk patients include those:
Who develop severe bradycardia after administration of the first dose of Gilenya®
With certain pre-existing conditions in whom bradycardia may be poorly tolerated
Receiving therapy with other drugs that slow the heart rate or atrioventricular conduction
With QT interval prolongation (a type of heart rhythm abnormality) prior to starting Gilenya®, or at any time during the cardiovascular monitoring period
Receiving therapy with other drugs that prolong the QT interval and that can cause a serious and life-threatening abnormal heart rhythm called Torsades de pointes.
• On April 20, 2012, Novartis announced an agreement with the FDA on label changes for Gilenya®. The update to the Gilenya prescribing information includes patient selection parameters to aid in the identification of candidates for Gilenya treatment and more specific recommendations for treatment initiation for patients with relapsing forms of multiple sclerosis in the United States. The update marks the conclusion of discussions initiated in December 2011.
The updated FDA label for Gilenya® indicates that all patients initiating treatment with Gilenya® should have an electrocardiogram prior to the first dose of the medicine and after the six-hour first-dose observation period in addition to hourly measurement of blood pressure and heart rate. Additionally, specific initiation guidance for patients is now provided to better aid healthcare providers. Further, there are revised recommendations on how to re-initiate therapy should Gilenya® be interrupted. The label update in the US for Gilenya® recommends that patients with certain pre-existing cardiac conditions or those taking certain concomitant medications would require overnight monitoring following administration of first dose of medication, and for some patients prior evaluation with a specialist. Experience with the use of Gilenya® in such patients was limited in the pivotal clinical trials.
Gilenya® is contraindicated in patients with history or presence of certain cardiac conditions, including heart attack or stroke in the past six months, second- and third-degree AV block and other serious cardiac rhythm disturbances, and in patients treated with certain anti-arrhythmic drugs.
- • On April 20, 2012, the EMA also recommends new advice to healthcare professionals to reduce the risk of adverse effects on the heart associated with the use of Gilenya®. Following a review of the latest evidence of the safety of the medicine, the Agency’s Committee for Medicinal Products for Human Use (CHMP) recommends that doctors should not prescribe Gilenya® to patients with a history of cardiovascular and cerebrovascular disease or who take heart-rate lowering medication. However, when treatment with Gilenya® is considered necessary in these patients, their heart activity should be monitored at least overnight following the first dose of Gilenya® and doctors should seek advice from a cardiologist on appropriate monitoring.
- The CHMP also recommends that all patients starting treatment with Gilenya® should have their heart activity monitored before receiving the first dose of the medicine and continuously for at least six hours after. Monitoring should be extended for at least two hours in patients whose heart rate is lowest six hours after receiving the first dose of Gilenya®. In patients who develop clinically significant heart problems such as bradycardia or atrioventricular (AV) block monitoring should continue at least overnight and until the problems have been resolved.
- * On January 20, 2012, the European Medicines Agency (EMA) announced it has begun a review of the benefits and risks of Gilenya®. This follows concerns over the effects of the medicine on the heart after the first dose. The review was started following reports of heart problems in patients taking Gilenya®, as well as the death of one patient in the United States less than 24 hours after the first dose. The exact cause of this patient's death is still unexplained.
- While the review is ongoing, the Committee for Medicinal Products for Human Use (CHMP) is advising doctors to increase their level of monitoring of patients after the first dose of the medicine. This includes electrocardiogram (ECG) monitoring before treatment and then continuously for the first six hours after the first dose, and measurement of blood pressure and heart rate every hour. After six hours, any patients with clinically important heart-related effects, such as bradycardia (a slow heart rate) or atrioventricular block (a problem with the conduction of electricity in the heart), should continue to be managed and monitored until their condition has improved. The risk of bradycardia after the first dose of Gilenya® was known when it was authorised. The medicine's product information already includes recommendations to observe patients for signs and symptoms related to this side effect for at least six hours after the first dose. The Committee expects to finalise its review by the time of its plenary meeting in March 2012.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2011-09-22
UE authorization: 2011-03-17
Favourable opinion UE: 2011-01-20/2015-09-24/2018-09-20
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: