Highlights
- •Fingolimod first-dose effects analyzed from a pool of 3635 phase 3 study patients.
- •Treatment was associated with transient, mostly asymptomatic, heart rate reductions.
- •Symptomatic bradycardia and 2nd degree AV blocks were infrequent.
- •First-dose effects mostly occurred during the first 6 h following treatment.
- •The clinical impact was limited and specific therapy was generally not required.
Abstract
Fingolimod treatment initiation is associated with a transient slowing of heart rate
and atrioventricular conduction. This report presents first-dose fingolimod effects
(0.5 mg or 1.25 mg) on cardiac parameters using phase 3 FREEDOMS, FREEDOMS II and TRANSFORMS pooled
study data (n=3635 patients). Vital signs were recorded hourly for ≥6 h; 12-lead electrocardiogram (ECG) was obtained at baseline and at 6 h 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 4–5 h after the first dose, with a maximum reduction of 8 (fingolimod 0.5 mg) and 11 beats per minute (fingolimod 1.25 mg) below baseline. Symptomatic bradycardia at treatment initiation was reported in
0.6% (fingolimod 0.5 mg) and 2.1% (fingolimod 1.25 mg) 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 0.5 mg, 0.2%; 1.25 mg, 1%: 2:1 AV block fingolimod, 0.5 mg, 0%; 1.25 mg, 0.2% on ECG 6-h post-dose). These were usually well tolerated and first occurred
within 6 h 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.
Abbreviations:
ACh (acetylcholine), AECG (ambulatory electrocardiogram), AV (atrioventricular), AVB (atrioventricular block), BP (blood pressure), bpm (beats per minute), ECG (electrocardiogram), fingolimod-P (fingolimod phosphate), FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis), Gαi (inhibitory G protein), Gβγ (G-protein subunits), GIRK (G-protein-gated, inward rectifying potassium), HR (heart rate), IFN (interferon), IM (intramuscular), K+ (potassium ion), M2 (muscarinic acetylcholine receptor M2), MS (multiple sclerosis), QTcI (corrected QT interval), S1P1 (sphingosine 1-phosphate receptor subtype 1), S1PR (sphingosine 1-phosphate receptor), SD (standard deviation), SVT (supraventricular tachycardia), TRANSFORMS (Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis), VPC (ventricular premature complex), VT (ventricular tachycardia)Keywords
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Article info
Publication history
Published online: June 16, 2014
Accepted:
May 27,
2014
Received in revised form:
May 23,
2014
Received:
March 27,
2014
Identification
Copyright
© 2014 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
