ORLANDO—The first-dose cardiovascular effects of fingolimod 0.5 mg may be transient in most patients with multiple sclerosis (MS). The effects begin to resolve within six hours after administration, according to analyses of two phase III trials and interim results of a phase IV study.
The analyses, which were presented at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS, confirmed that the initiation of treatment with fingolimod is associated with a decrease in heart rate and a slowing of atrioventricular conduction, especially in the first four to six hours. Previously reported cases of bradycardia and atrioventricular block have been mostly transient and self-limited, said the investigators.
All patients who receive fingolimod “should be observed and receive hourly pulse and blood pressure measurement for at least six hours after first dose and undergo ECG predose and after the six-hour observation,” according to the drug’s current prescribing information. The label for fingolimod was revised in May 2012 following reports of sudden or unexplained deaths in the United States and Europe after the drug’s 2010 approval for relapsing forms of MS.
Fingolimod Reduced Heart Rate at Five Hours
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 six months. No patients had taken fingolimod previously, and all received at least one dose of the therapy. Subjects had received continuous treatment with a single standard-of-care DMT for six months or more. Patients’ mean age was 46, and most were white (82%) and female (76%). The mean duration of their MS symptoms was 12 years.
Patients’ mean sitting heart rate decreased from 74.1 bpm at baseline to 65.6 bpm at five hours after administration of fingolimod, said Bruce L. Hughes, MD, Director of Ruan MS Center in Des Moines, Iowa, and his colleagues. Heart rate began to recover by the sixth hour.
Most patients (98.6%) were discharged at six hours after treatment. Ten subjects required extended observations after the sixth hour, and three required a second day of observation and were subsequently discharged.
Twelve patients (1.5%) had bradycardia during the first-dose observation period. Of these patients, eight were symptomatic, four were asymptomatic, and none required treatment, according to the researchers. The mean heart rate in this group decreased to 56.3 ± 8.53 bpm and ranged from 38 to 64 bpm during bradycardia events. The patients recovered to 62.6 ± 9.46 bpm, ranging from 52 to 80 bpm, after the symptoms resolved.
Nearly 18% of the patients (137 of 783) underwent ECG at six hours postdose. In 28 subjects, the second ECG differed from the baseline ECG, and the most common new findings were first-degree atrioventricular block (11 patients) and sinus bradycardia (10 patients). There were no second-degree atrioventricular blocks. Other findings included late anterior hemiblock (one patient), atrial premature complex (two patients), and biphasic T waves (one patient).
Heart-Rate Decrease Was Greater for Patients Without Cardiac Factors
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 four-month, open-label, phase IIIb study of 2,417 patients with relapsing MS, and the FREEDOMS II trial was a two-year, double-blind, placebo-controlled, phase III study of 1,083 patients.
In the FIRST trial, the lowest heart rate occurred at four to five hours postdose. The mean decrease was 7.4 bpm in patients without cardiac factors and 6.5 bpm in those with cardiac factors, said the researchers. The cardiac factors included beta-blocker or calcium channel blocker use (120 patients), resting heart rate of 45 to 54 bpm, Mobitz type I second-degree atrioventricular block, positive tilt test, and recurrent symptomatic bradycardia.
Simrat Randhawa, MD, from Novartis Pharmaceuticals, and her colleagues reported that the mean decrease in heart rate was 7.2 and 7.3 bpm in patients without and with concomitant beta-blocker or calcium channel blocker use, respectively. One patient had a greater than three-second pause in screening and postdose ECG results. One patient discontinued the study drug because of second-degree atrioventricular block, the authors reported.
In the FREEDOMS II trial, the clinician-observed mean maximal decrease in heart rate was 8.5 bpm among patients who received fingolimod. The incidence of Mobitz I second-degree atrioventricular block with fingolimod was 3.7%, compared with 2.0% for placebo. In addition, 2:1 atrioventricular block occurred in 2% of patients taking fingolimod and in no control patients.