Fingolimod (Gilenya▼): not recommended for patients at known risk of cardiovascular adverse events
- Medicines and Healthcare products Regulatory Agency
- 22 May 2012
- Therapeutic area:
- Immunosuppression and transplantation
New advice for extended early monitoring for those with significant bradycardia or heart block after first dose.
Article date: May 2012
Fingolimod (Gilenya) is authorised to treat relapsing-remitting multiple sclerosis in patients whose disease has failed to respond to beta-interferon or is severe and getting worse rapidly. Fingolimod is a sphingosine -1 phosphate receptor ligand.
We first highlighted changes to the monitoring advice for fingolimod in February 2012.
We now provide updated advice to avoid use in high-risk groups and extend monitoring in some patients. The latest advice follows further review of world-wide data including 15 cases of sudden or unexplained death with fingolimod. Most of the deaths and cardiovascular events had occurred in patients with either a history of cardiovascular problems, such as atrioventricular block or bradycardia, or those who were also taking other medicines. However the data reviewed were not conclusive as to whether Gilenya was the cause of the deaths.
The maximum effect of fingolimod on decreasing the heart rate occurred within six hours after the first dose in most patients; this decrease in heart rate can be reversed if necessary by giving atropine or isoprenaline (see statement from the European Medicines Agency).
Fingolimod is now not recommended in the following high-risk patients:
- those with the following medical conditions:
- 2nd degree Mobitz Type II or higher degree atrioventricular block, sick sinus syndrome, or sino-atrial heart block
- significant QT prolongation (QTc >470 ms in women, or >450 ms in men)
- history of symptomatic bradycardia or recurrent syncope, known ischaemic heart disease, cerebrovascular disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, uncontrolled hypertension, or severe sleep apnea
- those receiving the following antiarrhythmic or heart-rate-lowering drugs:
- class Ia antiarrhythmics (eg, quinidine, disopyramide) or class III antiarrhythmics (eg, amiodarone, sotalol)
- beta blockers
- heart rate-lowering calcium channel blockers (eg, verapamil, diltiazem or ivabradine)
- other substances which may decrease heart rate (eg digoxin, anticholinesteratic agents or pilocarpine).
In such patients, treatment with Gilenya should be considered only if the anticipated benefits outweigh the potential risks, and advice from a cardiologist is sought prior to initiation of Gilenya treatment. This advice should include, if appropriate, the possibility to switch any concomitant medicine to treatments that are not antiarrhythmic and do not lower the heart rate. If treatment with Gilenya for these patients is considered, monitoring at least overnight following the first dose should be initiated.
Updated monitoring advice
For all patients receiving fingolimod, monitoring before, during and after the first dose should include:
- 12-lead ECG and blood pressure measurement before starting
- during the first 6 hours of treatment:
- continuous ECG monitoring for 6 hours
- blood pressure and heart rate measurement every hour
- after 6 hours of treatment:
- further 12-lead ECG and blood pressure measurement
- if the patient’s heart rate at the end of the 6-hour period is at its lowest since fingolimod was first administered, the monitoring should be extended by at least 2 hours and until the heart rate increases
Additional criteria for extended monitoring
In patients with evidence of clinically important cardiac effects during the first 6 hours of fingolimod treatment, monitoring should be extended, including at least overnight monitoring, until resolution. Recommended criteria for extending monitoring include:
- the occurrence at anytime during the monitoring period after first dose of:
- new-onset 3rd degree atrioventricular block
- the presence at the end of the monitoring period after first dose of:
- heart rate less than 45 beats per minute
- QTc interval ≥500 ms.
- persistent new-onset 2nd degree atrioventricular block, Mobitz Type I (Wenckebach) or higher degree atrioventricular block
If fingolimod therapy is discontinued for more than 2 weeks for any reason, the effects on heart rate and atrioventricular conduction may recur on its reintroduction and so the same monitoring precautions as for treatment initiation should apply.
Reporting of suspected adverse drug reactions
All suspected adverse reactions to fingolimod should be reported to us promptly on a Yellow Card, available at www.mhra.gov.uk/yellowcard.
Article citation: Drug Safety Update May 2012, vol 5 issue 10: A1
Published: 22 May 2012
Therapeutic area: Immunosuppression and transplantation