FDA Drug Safety Communication: Revised recommendations for cardiovascular monitoring and use of multiple sclerosis drug Gilenya (fingolimod)This update is in follow-up to the FDA Drug Safety Communication: Safety review of a reported death after the first dose of multiple sclerosis drug Gilenya (fingolimod) on 12/20/2011.
- An oral medication for the treatment of relapsing forms of multiple sclerosis (MS) in adults.
- Used to reduce the frequency of flare-ups (clinical exacerbations) and to delay the progression of the physical symptoms of MS.
Safety Announcement[05-14-2012] The U.S. Food and Drug Administration (FDA) 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 (see Data Summary, below). 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 (See Data Summary).
For this reason, Gilenya is now contraindicated (FDA advises against its use) in patients with certain pre-existing or recent (within last 6 months) heart conditions or stroke, or who are taking certain antiarrhythmic medications. See CONTRAINDICATION section of the drug label.
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. See DOSAGE AND ADMINISTRATION section of the drug label. 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
Patients should not stop taking Gilenya without talking to their healthcare professional. They should contact their healthcare professional and seek immediate care if they develop dizziness, tiredness, irregular heart beat, or palpitations--signs of a slowing heart rate. FDA continues to believe that the benefits of treatment with Gilenya outweigh its potential risks when it is used as described in the updated drug label.
FDA will update the public if any additional information on the cardiovascular risks of Gilenya becomes available.
December 2011, FDA issued a Drug Safety Communication (DSC) concerning a patient with multiple sclerosis (MS) who died within 24 hours of taking the first dose of Gilenya (fingolimod). Based on the reported information, a cause of death could not be identified. The patient also had extensive brainstem MS lesions; such lesions have been associated with sudden death. The patient was also taking two blood pressure medications (metoprolol and amlodipine), which can also affect heart rate; whether they could have played a role in the patient’s death is unknown. On the basis of the available data, a link between the first dose of Gilenya and the patient’s death could not be ruled out, however, there is not clear evidence that the drug played any role in the death.
After receipt of this case, FDA re-evaluated clinical trial data related to the effects of Gilenya on heart rate and blood pressure, including data from trials that were ongoing at the time the drug was approved by FDA. Analyses of changes in heart rate by 24 hour Holter monitoring confirmed that the heart rate-lowering effect of Gilenya is biphasic, with an initial decrease within 6 hours, and a second decrease, in part related to a circadian rhythm, around 12 to 20 hours post-dose. In order to allow an adequate response to possible severe symptomatic bradycardia in the 6- to 24-hour period after the first dose, FDA concluded that it would be prudent to extend the monitoring period beyond 6 hours in patients who experience a heart rate of less than 45 beats per minute in the first 6 hours, or in those who had their lowest heart rate at 6 hours post-dose, as further bradycardia is still possible after 6 hours. In addition, in order to reduce the risks related to bradycardia or atrioventricular block, extended monitoring is now recommended in patients with certain pre-existing conditions, such as QT prolongation, and in patients receiving concurrent drugs that slow the heart rate or atrioventricular conduction.
FDA also reviewed postmarket data reported for Gilenya, including other deaths from apparent cardiovascular origin or of unknown origin. For each of these deaths, Gilenya’s contribution to the death was unclear. The number of deaths of apparent cardiovascular origin or of unknown origin does not appear to be higher than in MS patients not treated with Gilenya.
In light of the findings of the clinical trial data and postmarketing data, including all reported deaths of cardiovascular or unknown origin, FDA has revised the Gilenya drug label with specific recommendations for monitoring patients and with new contraindications for use of Gilenya in certain patients.
FDA will communicate any important new information about the cardiovascular safety of Gilenya when it becomes available.