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Change in vital signs after fingolimod initiation in patients with multiple sclerosis: the possible need for 24 h monitoring

2015; Wiley; Volume: 80; Issue: 3 Linguagem: Inglês

10.1111/bcp.12697

1365-2125

Tomohiko Uchida, Masahiro Mori, Akiyuki Uzawa, Saeko Masuda, Mayumi Mutho, Hiroki Masuda, Satoshi Kuwabara,

Inflammasome and immune disorders

Fingolimod is an oral sphingosine-1-phosphate receptor modulator that reduces relapse frequency and prevents disability progression in relapsing-remitting MS (RRMS). The first dose of fingolimod can cause bradycardia that is mostly transient, does not require treatment and typically resolves spontaneously within 24 h. However, the US Food and Drug Administration (FDA) reported that a patient with MS had died within 24 h of taking the first dose of fingolimod in December 2011, (http://www.fda.gov/Drugs/DrugSafety/ucm284240.htm). Furthermore, how fingolimod effects the cardiovascular system is not fully understood. Heart rate (HR) and blood pressure (BP) reductions often occur at night following circadian rhythm, but the effect of fingolimod on circadian rhythms is not well known. We monitored ambulatory HR and BP before and after administering the first dose of fingolimod to 12 patients with RRMS (nine females, three men; aged 18–54 years). Patients were diagnosed according to the 2005 McDonald criteria. The patients showed no evidence of anti-aquaporin-4 antibody in their sera. In addition, the patients had no history of cardiac conditions and were not previously treated with HR-lowering drugs. There were no patients with prolonged QTc intervals. We monitored HR and BP using a 24 h ambulatory blood pressure monitoring device (TM-2431, AND, Tokyo, Japan) the day before (day 0) and after (day 1) fingolimod administration. Vital signs including systolic BP (SBP), diastolic BP (DBP) and HR were measured every 15 min during the day and every 30 min at night. All patients were admitted on day 0 and administered 0.5 mg fingolimod at 10.00 h on day 1. The patients wake and bedtimes were 07.00 h and 21.00 h, respectively. All patients provided informed consent and the Ethics Committee of Chiba University Hospital approved this study. Figure 1 shows the longitudinal changes in SBP (Figure 1A), DBP (Figure 1B), and HR (Figure 1C) during the 24 h pre- and post-dose periods. These data demonstrate circadian rhythm during both the pre- and post-dose periods. We compared the means of each vital sign measured at hourly intervals during the 24 h pre- and post-fingolimod dose periods by Student's t-test and observed marked differences in SBP at 14.00 h and 15.00 h, in DBP at 16.00 h and 09.00 h and in HR at 13.00 h–21.00 h, 0.00 h and 06.00 h. By the two-way repeated measure ANOVA, fingolimod showed marked differences on SBP (0.040 ± 0.70 mmHg) (mean ± SE), DBP (1.78 ± 0.55 mmHg), and HR (5.17 ± 1.24 min−1). We then compared the means of each vital sign measurement at 10.00 h and the hourly measurements after 10.00 h during the post-dose period by the Dunnett test. We observed marked differences in HR at 17.00 h and 23.00 h–05.00 h. HR showed greater decreases at night during sleep than during the day. Bradycardia less than 50 beats min–1 was observed in the post-dose period during the day in one patient and in four patients at night. HR was reduced during sleep at night, and this reduction was increased with fingolimod administration. Fingolimod's effect on HR is due to its agonistic actions on sphingosine-1-phosphate receptors on the sinus node and atrial cells of the heart. Fingolimod induced a transient, dose-dependent bradycardia at a maximum of 4–5 h after the first dose 1. Therefore, observing for signs and symptoms of bradycardia with hourly HR and BP measurements for at least 6 h after the first dose is administered is indicated in the prescription information for GILENYA ™ 2. However, our results showed that HR peaked 7 h after the first dose. A pharmacokinetic study of a single dose of fingolimod in healthy volunteers showed a decrease in HR at 4 h, and a second significant decrease also occurred at 20 h 3. Moreover, a 20-year-old man suffered asystole 21 h after taking his first dose of fingolimod. He showed no abnormality during the 6 h monitoring period that followed the first dose 4. In this case, monitoring HR for only 6 h after fingolimod administration was insufficient, and a longer and more careful monitoring may be needed for at least 24 h after administration. It may not be necessary to worry about bradycardia due to fingolimod too much, since we have not seen more problems due to night time bradycardia with more than 100 000 MS patients on fingolimod, and genetic differences between Asian and Caucasian patients may contribute to the night time bradycardia. However, to enhance the safety of fingolimod, we recommend that HR and BP should be very carefully monitored, at least during the 24 h after fingolimod initiation with special attention to the night time measurements. All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.