ORLANDO – The first-dose cardiovascular effects of fingolimod 0.5 mg were transient in most patients with multiple sclerosis and began to resolve within 6 hours after administration, according to analyses of two phase III trials and interim results of a phase IV study sponsored by the drug maker.
The analyses, which were presented in two posters at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research in Multiple Sclerosis, confirm that the initiation of treatment with fingolimod (Gilenya) is associated with a drop in heart rate (HR) and slowing of atrioventricular conduction, especially in the first 4-6 hours. Previously reported cases of bradycardia and atrioventricular blockhave been mostly transient and self-limited, the authors noted.
Fingolimod’s current prescribing information says that "All patients should be observed and receive hourly pulse and blood pressure measurement for at least 6 hours after first dose and undergo ECG predose and after the 6-hour observation." Its label was revised in May of last year following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.
In the phase IV EPOC (Evaluate Patient Outcomes, Safety, and Tolerability of Fingolimod) study, 783 patients in the United States and Canada were randomized 3:1 to open-label treatment with once-daily fingolimod 0.5 mg or standard-of-care disease-modifying therapy (DMT) for 6 months.
All patients were fingolimod naive and received at least one dose of the therapy. They had received continual treatment of a single standard-of-care DMT for 6 months or more. The patients’ mean age was 46 years, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.
Lead investigator Dr. Bruce L. Hughes of Ruan Multiple Sclerosis Center, Des Moines, Iowa, and his colleagues reported that the patients’ mean sitting HR at predose assessment dropped from a mean of 74.1 beats per minute at baseline to a nadir of 65.6 bpm, 5 hours after the therapy’s administration. HR began to recover by the 6th hour.
Most patients (98.6%) were discharged at 6 hours after treatment. Ten required extended observations after the 6th hour; three required a second day of observation and were discharged.
A total of 12 patients (1.5%) had bradycardia during the first-dose observation period. Eight were symptomatic, and four were asymptomatic. None required treatment, the researchers reported. The mean HR in this group decreased to 56.3 plus or minus 8.53 bpm, ranging from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 plus or minus 9.46 bpm, ranging from 52 to 80 bpm after the symptoms resolved.
Nearly 18% of the patients (137 of 783) had electrocardiography (ECG) performed at 6 hours post dose. In 28, the ECG differed from baseline, and the most common new findings were first-degree atrioventricular block (n = 11), and sinus bradycardia (n = 10). There were no second-degree AV blocks. Other findings included late anterior hemiblock (n = 1), atrial premature complex (n = 2), and biphasic T waves (n = 1).
The two other studies reported at the meeting also analyzed the first-dose cardiovascular effects of fingolimod 0.5 mg. The FIRST trial was a 4-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a 2-year, double-blind, placebo-controlled, phase III study of 1,083 patients.
In the FIRST trial, the nadir HR occurred 4-5 hours post dose, and the mean decrease was 7.4 in patients without cardiac factors and 6.5 bpm in those with cardiac factors, the authors reported. The cardiac factors included beta-blocker and/or calcium channel blocker use (n = 120), resting HR of 45-54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, or recurrent symptomatic bradycardia.
Dr. Simrat Randhawa and her colleagues at Novartis Pharmaceuticals reported that the mean decrease in HR was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker and/or calcium channel blocker use, respectively. One patient had a greater than 3-second pause in both screening and post dose ECG results. One patient discontinued the study drug because of second-degree AV block, the authors reported.
In the FREEDOMS II trial, the clinician-observed mean maximal decrease in HR was 8.5 bpm in the fingolimod group. The incidence of Mobitz I second-degree AV block with fingolimod was 3.7%, compared with 2.0% in placebo, while 2:1 AV block occurred in 2% of patients taking fingolimod patients and 0% taking placebo.
Most first-occurrence second-degree AV blocks were observed less than 6 hours after the first dose, the authors reported.