title: Fingolimod first-dose effects in patients with relapsing multiple sclerosis concomitantly receiving selective serotonin-reuptake inhibitors.
abstract: Selective serotonin-reuptake inhibitors (SSRIs), commonly administered for depression and anxiety in patients with multiple sclerosis, are associated with QT interval prolongation. Fingolimod (FTY720; Gilenya(®), Novartis Pharma AG) is a first-in-class sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis. Fingolimod first-dose administration is associated with a transient, generally asymptomatic, slowing of heart rate, which may also prolong QT interval. This posthoc analysis compared cardiac outcomes in over 3300 patients with relapsing multiple sclerosis who were or were not receiving SSRIs during fingolimod treatment initiation, including a subset of patients receiving citalopram or escitalopram. Vital signs were recorded hourly for 6h, and electrocardiograms were obtained pre-dose and 6 h post-dose. Changes in mean hourly heart rate from baseline (pre-dose) to 6 h post-dose were similar among patients not receiving SSRIs (fingolimod 0.5 mg, -7.5 bpm; placebo, 0.0 bpm) and those receiving SSRIs (fingolimod 0.5 mg, -6.6 bpm; placebo, 0.3 bpm). In patients treated with fingolimod 0.5 mg, the mean change in corrected QT interval from baseline to 6 h after treatment initiation was under 10 ms, and few patients had absolute corrected QT intervals of over 450 ms (men) or 470 ms (women), calculated according to Bazett׳s or Fridericia׳s correction methods, irrespective of whether or not they were receiving an SSRI; similar findings were reported in the placebo group. Co-administration of SSRIs and fingolimod was not associated with an increased incidence of any electrocardiogram findings compared with fingolimod therapy alone, and the majority of patients receiving fingolimod (83-86%) were discharged from first-dose monitoring at 6 h irrespective of whether they were also receiving SSRIs. These analyses provide reassurance that concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment initiation.
authors.affiliation: Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, USA. Electronic address: BERMELR@ccf.org.
authors.forename: R A
authors.initials: RA
authors.lastname: Bermel
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: R
authors.initials: R
authors.lastname: Hashmonay
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: X
authors.initials: X
authors.lastname: Meng
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: S
authors.initials: S
authors.lastname: Randhawa
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: P
authors.initials: P
authors.lastname: von Rosenstiel
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sfikas
authors.affiliation: Neurologique, Ponte Vedra, FL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Kantor
mesh_terms: D000328:Adult; D015283:Citalopram / Q000009:adverse effects / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004359:Drug Therapy, Combination / Q000009:adverse effects; D004562:Electrocardiography; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D015283:Citalopram; D000068876:Fingolimod Hydrochloride; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Cardiac safety; Depression; Drug interactions; Fingolimod; Multiple sclerosis; Serotonin-reuptake inhibitors