Every patient should get an electrocardiogram prior to and 6 hours after the first dose of fingolimod, and hourly blood pressure and heart rate measurements in between, to assess for bradycardia, according to revised labeling released by the Food and Drug Administration on May 9.
Patients with prolonged QTc intervals during the observation period should be observed overnight with continuous ECG monitoring, labeling now states.
The revisions come after more than a dozen reports of sudden or unexplained deaths in the United States and Europe following the drug’s 2010 approval for relapsing forms of multiple sclerosis, and months-long talks between the FDA and Novartis, the maker of fingolimod (Gilenya). Previous labeling recommended baseline ECGs only "in those at higher risk of bradyarrhythmia."
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Novartis noted in a press release that fingolimod has been used in more than 36,000 patients.
Labeling also now calls for overnight, continuous ECG monitoring in a medical facility for patients with preexisting heart conditions, cerebrovascular disease, recurrent syncope, or severe untreated sleep apnea; patients on beta-blockers or other drugs that slow heart rate or atrioventricular (AV) conduction; and patients with prolonged QTc intervals, whether due to drugs or medical conditions. ECG monitoring is also warranted, in some cases, for patients restarting the drug after a pause.
"Isolated delayed onset events, including transient asystole and unexplained death, have occurred within 24 hours of the first dose," the revised labeling notes, although the relationship with fingolimod is "uncertain."
The new label contraindicates the drug in patients who, in the last 6 months, have had a heart attack, unstable angina, stroke, transient ischemic attack, second- or third-degree AV block, decompensated heart failure requiring hospitalization, sick sinus syndrome with no pacemaker, baseline QTc interval of 500 ms or longer, and treatment with class Ia or class III antiarrhythmic drugs. Previous labeling had no contraindications.
Those and other changes come shortly after the annual meeting of the American Academy of Neurology, where Novartis released the results of its recent 2-year, double-blind, placebo-controlled, multicenter, phase III trial of fingolimod in 1,083 patients with relapsing-remitting multiple sclerosis.
At month 24, 0.5 mg of fingolimod once daily significantly reduced patients’ annualized relapse rates by 48% versus placebo. Fingolimod patients also had a statistically significant reduction in brain volume loss.
Those results are consistent with previous trials of the drug (N. Engl. J. Med. 2010;362:387-401; N. Engl. J. Med. 2006;355:1124-40). But in contrast to those studies, fingolimod did not show a statistically significant benefit over placebo on 2-year EDSS (Expanded Disability Status Scale) disability progression.
Overall, "there were probably not any new [safety] signals" in the recent trial, "but some of the old signals came back," said lead investigator Dr. Peter Calabresi, professor of neurology at Johns Hopkins University in Baltimore.
"There were some second-degree AV blocks in a small proportion of patients," 1-3%, he said. There were also dose-dependent, mostly reversible increases in liver function test results during treatment.
"Hypertension was more frequent in this study," as well, Dr. Calabresi said, perhaps because patients had a higher body mass index than in previous trials. The drug’s new labeling notes that about 5% of patients have an approximately 2 mm Hg rise in systolic pressure and 1 mm Hg rise in diastolic pressure after the first month of treatment.
Basal cell carcinoma, macular edema, and herpes zoster and lower respiratory infections were also slightly more frequent in fingolimod patients. Although two patients died in previous trials, there were no deaths in the most recent trial.
It’s "an individual conversation between the doctor and the patient" whether or not to use the drug. "Hopefully the doctor knows that patient well. If you already have hypertension or a history of MI or stroke, you shouldn’t go on this drug. The drug’s known to cause bradycardia and, in some cases, first- and second-degree AV block," Dr. Calabresi said.
Dr. Calabresi reported that he has received personal compensation for activities with Teva, Biogen Idec, Novartis, Genzyme, Johnson & Johnson, Vertex, Abbott, Genentech, and Merck Serono, and that he has received research support from Biogen Idec, Teva, EMD Serono, Vertex, Genentech, Abbott, and Bayer.