First-dose effects of fingolimod: Pooled safety data from three phase 3 studies.
Fingolimod treatment initiation is associated with a transient slowing of heart rate and atrioventricular conduction. This report presents first-dose fingolimod effects (0.5mg or 1.25mg) on cardiac parameters using phase 3 FREEDOMS, FREEDOMS II and TRANSFORMS pooled study data (n=3635 patients). Vital signs were recorded hourly for ≥6h; 12-lead electrocardiogram (ECG) was obtained at baseline and at 6h post-dose. Clinical events were graded at the first-dose administrator׳s discretion. At screening, on day 1 and at month 3, 1073 patients underwent 24-h ambulatory electrocardiogram monitoring. A transient decrease in mean measured heart rate occurred 4-5h after the first dose, with a maximum reduction of 8 (fingolimod 0.5mg) and 11 beats per minute (fingolimod 1.25mg) below baseline. Symptomatic bradycardia at treatment initiation was reported in 0.6% (fingolimod 0.5mg) and 2.1% (fingolimod 1.25mg) of patients; events were typically mild or moderate in severity, and most resolved spontaneously. Atrioventricular (AV) conduction delays were observed in a few patients (Wenckebach (Mobitz type I) second-degree AV block, fingolimod 0.5mg, 0.2%; 1.25mg, 1%: 2:1 AV block fingolimod, 0.5mg, 0%; 1.25mg, 0.2% on ECG 6-h post-dose). These were usually well tolerated and first occurred within 6h of dosing. Consistent with its effects on atrial myocytes, fingolimod treatment initiation induced a transient slowing of heart rate and AV conduction. However, symptomatic bradycardia and second-degree AV block were uncommon and did not require intervention.
Division of Cardiovascular Medicine, University of Virginia Health System, P.O. Box 800158, Charlottesville, VA 22908-0466, USA. Electronic address: jdimarco1@live.com.
John P
JP
DiMarco
St Michael׳s Hospital, 30 Bond Street, University of Toronto, Toronto, ON, Canada M5B 1W8. Electronic address: oconnorp@smh.toronto.on.ca.
Paul
P
O'Connor
Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: cohenj@ccf.org.
Jeffrey A
JA
Cohen
University of Chicago Medical Center, 5841 S. Maryland Ave, Chicago, IL 60637-1403, USA. Electronic address: areder@neurology.bsd.uchicago.edu.
Anthony T
AT
Reder
Novartis Pharma AG, CH-4056 Basel, Switzerland. Electronic address: lixin.zhang_auberson@novartis.com.
Lixin
L
Zhang-Auberson
Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936-1080, USA. Electronic address: dejun.tang@novartis.com.
Dejun
D
Tang
Novartis Pharma AG, CH-4056 Basel, Switzerland. Electronic address: william.collins@novartis.com.
William
W
Collins
Neurology, Departments of Medicine, Clinical Research and Biomedicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. Electronic address: ludwig.kappos@usb.ch.
Ludwig
L
Kappos
D000284:Administration, Oral; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis; D002170:Canada; D057915:Drug Substitution / Q000009:adverse effects / Q000379:methods; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage* / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis* / Q000188:drug therapy*; D016896:Treatment Outcome; D014481:United States
D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride
Cardiovascular events; FREEDOMS; FREEDOMS II; Fingolimod; TRANSFORMS; Treatment initiation