Cardiac Effects of Fingolimod: First-Dose Observation

Background: Fingolimod is a once-daily, oral therapy approved for relapsing forms of multiple sclerosis (MS) that is associated with transient dose-dependent decreases in heart rate (HR) and slowing of atrioventricular (AV) conduction on initiation.  

Objectives: To analyze the first-dose effects of fingolimod 0.5 mg in the FIRST and FREEDOMS II studies.

Methods: FIRST is a 4-mo, open-label, phase 3b study (N=2417) evaluating cardiac safety of fingolimod in a broader patient population than those of previous phase 3 studies, including patients with controlled diabetes, chronic asthma, and cardiac risks (including beta blocker use, resting HR 45–54 bpm, Mobitz Type I second-degree AV block (AVB), and recurrent symptomatic bradycardia). FREEDOMS II is a 2-y, double-blind, placebo-controlled, phase 3 study (N=1083) evaluating the efficacy and safety of fingolimod. For both studies, HR and blood pressure (BP) were recorded hourly for at least 6 h following first dose administration; electrocardiogram (ECG) was obtained 1 day pre-dose and 6 h post-dose. In addition, Holter 24-h ECG monitoring data on day of first dose for 1057 patients enrolled in FREEDOMS II are presented.

Results: In FIRST, nadir HR occurred 4–5 h post-dose; mean decrease in HR was –7.4  and –6.5 bpm in patients without and with cardiac risks, respectively. Post-dose Holter ECG data showed that the incidence of Mobitz Type I and 2:1 second degree AVB was 1.4% and 0.5%, respectively. No third degree AVB was observed. One patient had a >3 sec pause in both screening and post-dose Holter-ECG results, and 1 patient discontinued the study drug due to second-degree AVB. In FREEDOMS II, nadir HR occurred at 5 h postdose and mean decrease was –8.5 bpm. Holter 24 h ECG data showed that the incidence of second-degree AVB was 3.7% (Mobitz Type I) and 2.0% (2:1 AVB). Most first-occurrence 2nd-degree AVBs were observed <6 h post-first dose (Mobitz Type I: 2.6%; 2:1 AVB: 1.4%) vs 6–24h (Mobitz type I: 1.1%; 2:1 AVB: 0.6%). Mobitz type II or higher degree AVBs were not observed on day 1 of treatment.

Conclusions: Treatment initiation monitoring data from FIRST and FREEDOMS II confirms the transient and generally benign effect of fingolimod on HR and rhythm. Decrease in HR is well characterized, self limited, and mostly asymptomatic; no third degree AVB was noted.