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Fingolimod first-dose effects in patients with relapsing multiple sclerosis concomitantly receiving selective serotonin-reuptake inhibitors
Multiple Sclerosis and Related Disorders (2015) 4, 273–280
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
CLINICAL TRIAL
Fingolimod first-dose effects in patients with relapsing multiple sclerosis concomitantly receiving selective serotonin-reuptake inhibitors R.A. Bermela,n, R. Hashmonayb, X. Mengb, S. Randhawab, P. von Rosenstielb, N. Sfikasb, D. Kantorc a
Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, USA Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA c Neurologique, Ponte Vedra, FL, USA b
Received 8 October 2014; received in revised form 6 February 2015; accepted 2 April 2015
KEYWORDS
Abstract
Fingolimod; Multiple sclerosis; Serotonin-reuptake inhibitors; Cardiac safety; Depression; Drug interactions
Selective serotonin-reuptake inhibitors (SSRIs), commonly administered for depression and anxiety in patients with multiple sclerosis, are associated with QT interval prolongation. Fingolimod (FTY720; Gilenyas, 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 6 h, 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
Abbreviations: AV, atrioventricular; AVB, atrioventricular block; ECG, electrocardiogram; FDA, US Food and Drug Administration; FDO, first-dose observation; FREEDOMS, FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; GIRK, G-protein-gated inwardly-rectifying potassium; HR, heart rate; MS, multiple sclerosis; QTc interval, QT interval corrected for heart rate; QTcB interval, QT interval corrected for heart rate using Bazett's correction method; QTcF interval, QT interval corrected for heart rate using Fridericia's correction method; S1PR, sphingosine 1-phosphate receptor; SSRI, selective serotonin-reuptake inhibitors; TRANSFORMS, Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis n Corresponding author. Tel.: +1 216 444 8600; fax: +1 216 445 6259. E-mail address: [email protected] (R.A. Bermel). http://dx.doi.org/10.1016/j.msard.2015.04.002 2211-0348/& 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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R.A. Bermel et al. 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. & 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1.
Introduction
Depression and anxiety are common in patients with multiple sclerosis (MS), with prevalences higher than those observed both in the general population and in patients with other chronic diseases (Patten et al., 2003). The annual prevalence of depression in patients with MS is estimated to be up to 14%, with a lifetime prevalence of up to 50% (Goldman Consensus Group, 2005); anxiety disorders are estimated to affect more than 30% of patients with MS (Korostil and Feinstein, 2007). Selective serotonin-reuptake inhibitors (SSRIs) are widely prescribed for the treatment of patients with depression and anxiety, including in those with MS (Koch et al., 2011). There is, however, some evidence that SSRIs are linked to QT interval prolongation (Funk and Bostwick, 2013). In particular, citalopram appears more likely to be associated with this effect than other SSRIs, and the US Food and Drug Administration (FDA) has issued revised recommendations for the use of the drug owing to a potential risk of abnormal heart rhythms when it is used at high doses (US Food and Drug Administration, 2012c). Fingolimod (FTY720; Gilenyas, Novartis Pharma AG) is a first-in-class sphingosine 1-phosphate receptor (S1PR) modulator (Brinkmann et al., 2010; Chun and Hartung, 2010), approved for relapsing forms of MS as a once-daily oral therapy at a dose of 0.5 mg (European Medicines Agency, 2011; US Food and Drug Administration, 2012b). The efficacy benefits of fingolimod over both placebo and intramuscular interferon β1a on key measures of disease activity (relapse rates, disability progression versus placebo, lesion load and brain volume loss) have been established in clinical trials (Calabresi et al., 2014; Cohen et al., 2010; Kappos et al., 2010). Fingolimod is associated with a transient, generally asymptomatic reduction in heart rate (HR) and, rarely, with generally asymptomatic atrioventricular (AV) block on treatment initiation, which are expected pharmacodynamic effects (Schmouder et al., 2006). Binding of fingolimod phosphate (the active phosphorylated compound) to S1PR subtype 1 on cardiac myocytes activates G-protein-gated inwardly-rectifying potassium (GIRK) channels (similar to the vagal stimulus), causing the transient reduction in HR. With continued administration of fingolimod, S1PRs are internalized and degraded, which leads to progressive resolution of the bradycardia over subsequent hours to days of treatment (Schmouder et al., 2006). In phase 3 clinical studies in patients with MS, the HR effect was maximal on day 1 and had recovered to baseline levels within 1 month of fingolimod initiation (DiMarco et al., 2015).
In a thorough QT interval study, fingolimod administered at 1.25 mg and 2.5 mg doses resulted in prolongation of the corrected QT interval (QTc), with the upper bound of the 90% confidence interval being an increase of 14.0 ms; although there was no consistent increase in the incidence of QTc interval outliers associated with fingolimod treatment (US Food and Drug Administration, 2012b). In the fingolimod clinical study program, clinically relevant prolongation of the QT interval was not observed at the approved fingolimod 0.5 mg dose (US Food and Drug Administration, 2012b). However, because of the effect of bradycardia on QT interval duration, the US fingolimod label guidelines currently recommend that patients receiving concurrent therapy with QT interval-prolonging drugs, with a known risk of causing torsades de pointes, should be observed overnight with continuous electrocardiogram (ECG) monitoring after their first dose of fingolimod (US Food and Drug Administration, 2012b). SSRIs are generally classified as QT interval-prolonging drugs, though only citalopram is listed by name in the fingolimod prescribing information as having a known risk of torsades de pointes (US Food and Drug Administration, 2012b). In the EU, the fingolimod Summary of Product Characteristics recommends that medicinal products that prolong the QTc interval are avoided in patients with relevant risk factors such as hypokalemia, hypomagnesemia or congenital long-QT interval syndrome (European Medicines Agency, 2011). It is important to assess whether concomitant administration of fingolimod and SSRIs results in any unexpected first-dose effects in patients with MS. Here, we analyzed safety data from over 3300 patients with relapsing MS who were enrolled in the fingolimod clinical trial program to compare cardiac outcomes during treatment initiation in patients who were or were not receiving an SSRI, including a subset of patients receiving citalopram or escitalopram.
2. 2.1.
Methods Study design and participants
These analyses included all patients randomized to receive fingolimod 0.5 mg, fingolimod 1.25 mg or placebo in the core, controlled parts of the phase 2 (ClinicalTrials.gov identifier NCT00333138) and the phase 3 FREEDOMS (NCT00289978), FREEDOMS II (NCT00355134) and TRANSFORMS (NCT00340834)
Fingolimod first-dose effects in patients with relapsing multiple sclerosis fingolimod studies in patients with relapsing MS (Calabresi et al., 2014; Cohen et al., 2010; Kappos et al., 2006; Kappos et al., 2010). The study designs, entry criteria and overall results of the phase 2, FREEDOMS, FREEDOMS II and TRANSFORMS studies have been reported elsewhere (Calabresi et al., 2014; Cohen et al., 2010; Kappos et al., 2006, 2010), and the analyses in this paper do not involve new patients. All studies adhered to the International Conference on Harmonization Guidelines for Good Clinical Practice (ICH, 1996), and were conducted in accordance with the Declaration of Helsinki (WMA, 2013). Study protocols were approved by the institutional review board at each study site. All patients provided written, informed consent before any studyrelated procedure was performed. All concomitant medications taken within 30 days prior to screening or during the course of the study were recorded. Cardiovascular exclusion criteria relevant to this report comprised: recurrent syncope of suspected cardiac origin; myocardial infarction in the 6 months before study entry or current unstable angina; baseline resting heart rate less than 55 bpm; second-degree or higher AV block (AVB); sinus node dysfunction; congestive heart failure; diabetes mellitus; coronary or peripheral arterial spasm; a corrected QTc interval greater than 440 ms; and concomitant use of Vaughan Williams class 3 antiarrhythmic drugs. Patients with controlled hypertension and those receiving therapy with either non-dihydropyridine-type calcium channel antagonists or β-blockers were not excluded.
2.2. Patient monitoring during first-dose administration The initial dose of fingolimod was administered by an independent physician (supported by a nurse or other healthcare professional) not involved in the patient's MS treatment to preserve study blinding. Patients were observed in a clinical setting, and their vital signs were recorded at hourly intervals for at least 6 h. The mean change from baseline in hourly heart rate was determined. A 12-lead ECG was obtained before firstdose fingolimod administration, at 6 h post-dose and at any time when symptoms or major changes in vital signs were noted. ECG tracings were sent to a central ECG facility for analysis, ensuring consistent and accurate interpretation of all data generated across numerous study sites. Participants were eligible for discharge 6 h after the first dose if all the following criteria were met: heart rate of at least 51 bpm; heart rate greater than 80% of baseline value; heart rate not the lowest hourly value of the monitoring period; no symptoms of decreased heart rate; no treatment given for bradycardia; and an ECG tracing not showing any significant abnormalities versus the pre-dose tracing, except sinus bradycardia. The observation period was extended for patients who did not meet one or more of these criteria, and hospitalization was permitted at the discretion of the first-dose administrator. Patients whose heart rate dropped by more than 30% relative to baseline or those experiencing symptomatic bradycardia had to return to the site for the administration of the second dose and had to be monitored as they were for the first dose. Symptomatic bradycardia (bradycardia symptoms during first dosing) was noted and graded by the first-dose administrator.
2.3.
275
Outcome measures
At the time of fingolimod first-dose administration, vital signs including HR and clinical status outcomes were recorded, and then noted hourly for 6 h (the time after which patients are typically discharged from first-dose observation) in the subgroups of patients who, at the time of first dose, were (1) not receiving an SSRI; (2) receiving an SSRI (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline); or (3) specifically receiving the SSRI citalopram or its stereoisomer, escitalopram. ECGs were obtained pre-dose and 6 h post-dose.
2.4.
Analyses
Data were analyzed descriptively for each of the three patient subgroups. The QT interval was corrected for heart rate (QTc) using Bazett's (QTcB) and Fridericia's (QTcF) correction methods (Bazett, 1920; Fridericia, 1920). Consistent with standard regulatory guidance related to QT interval reporting, we present analyses of mean group QTc interval change in addition to categorical analyses of change from baseline QTc interval and absolute QTc interval. In line with current convention, change from baseline QTc interval was categorized as follows: under 30 ms change, unlikely to be of clinical significance; 30–60 ms, potentially of clinical significance; or over 60 ms, higher likelihood of clinical significance (US Food and Drug Administration, 2005). Here, we focus on the findings in patients treated with the approved fingolimod 0.5 mg dose versus placebo. Data for patients who received fingolimod 1.25 mg are included in Supplementary Tables 1–4 for completeness, together with uncorrected QT interval values.
3.
Results
The baseline patient demographics (age and sex) were generally balanced across patient subgroups (Table 1). At treatment initiation, 154/1212 (12.7%) and 108/866 (12.5%) patients were receiving concomitant SSRIs in the fingolimod 0.5 mg and placebo groups, respectively. A total of 70.8% and 79.6% of patients receiving concomitant SSRIs in the fingolimod 0.5 mg and placebo groups, respectively, had a history of depression compared with 14.5% and 17.2% of patients not receiving SSRIs. Similarly, 25.3% and 22.2% of patients receiving concomitant SSRIs in the fingolimod 0.5 mg and placebo groups, respectively, had a history of anxiety compared with 7.7% and 10.2% of patients not receiving SSRIs. This is as expected, owing to the fact that SSRIs are normally prescribed to treat depression and anxiety.
3.1.
ECG findings 6 h post-dose
In patients treated with fingolimod 0.5 mg, the mean change in QTc interval from baseline (pre-dose) to 6 h after treatment initiation was under 10 ms (both Bazett's and Fridericia's methods), with similar mean QTc interval changes recorded across all non-SSRI, SSRI and citalopram/escitalopram subgroups (Table 2). In more than 91% (Bazett) and 89% (Fridericia) of patients receiving fingolimod 0.5 mg, the maximum increase in QTc interval from baseline to 6 h was under 30 ms, irrespective of whether individuals received SSRIs, including citalopram or escitalopram specifically (Table 2). QTc interval changes of 30–
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R.A. Bermel et al.
Table 1
Baseline patient demographics and relevant medical history. Patients not receiving SSRIs at fingolimod first dose
Patients receiving SSRIs at fingolimod first dose
Placebo n= 758
Placebo n = 108
Fingolimod 0.5 mg n= 1058
Mean (SD) age, years 38.2 (8.7) 37.4 (8.9) Women, n (%) 559 (73.7) 716 (67.7) Medical history, n (%) Anxiety 77 (10.2) 81 (7.7) Cardiac disorders 66 (8.7) 71 (6.7) Depression 130 (17.2) 153 (14.5) SSRI treatment history, n (%)a Citalopramb 0 (0.0) 2 (0.2)c d c 3 (0.4) 2 (0.2)c Escitalopram e 0 (0.0) 1 (0.1)c Fluoxetine f Fluvoxamine 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Paroxetineg 2 (0.3)c 0 (0.0) Sertralineh
Fingolimod 0.5 mg Placebo n = 154 n= 42
39.7 (8.6) 40.8 (8.0) 89 (82.4) 136 (88.3) 24 (22.2) 11 (10.2) 86 (79.6)
20 22 25 1 13 28
(18.5) (20.4) (23.1) (0.93) (12.0) (25.9)
Patients receiving citalopram or escitalopram at fingolimod first dose
39 (25.3) 21 (13.6) 109 (70.8)
22 35 41 1 26 35
(14.3) (22.7) (26.6) (0.65) (16.9) (22.7)
Fingolimod 0.5 mg n= 57
37.2 (7.8) 41.8 (7.4) 36 (85.7) 49 (86.0) 14 (33.3) 5 (11.9) 34 (81.0)
15 (26.3) 9 (15.8) 43 (75.4)
20 22 0 0 0 0
22 35 0 0 0 0
(47.6) (52.4) (0.0) (0.0) (0.0) (0.0)
(38.6) (61.4) (0.0) (0.0) (0.0) (0.0)
SD, standard deviation; SSRI, selective serotonin-reuptake inhibitor. a Some patients were taking more than one SSRI. b Includes patients recorded as taking citalopram, citalopram hydrobromide or citalopram hydrochloride. c Historical treatment; was not taken at the time of fingolimod first dose. d Includes patients recorded as taking escitalopram or escitalopram oxalate. e Includes patients recorded as taking fluoxetine or fluoxetine hydrochloride. f Includes patients recorded as taking fluvoxamine maleate. g Includes patients recorded as taking paroxetine, paroxetine hydrochloride or paroxetine mesylate. h Includes patients recorded as taking sertraline or sertraline hydrochloride.
60 ms relative to baseline occurred in a slightly greater proportion of patients receiving concomitant SSRIs compared with those receiving only fingolimod 0.5 mg (QTcB interval, 8.0% versus 3.9%; QTcF interval, 10.7% versus 6.6%, respectively). Fewer than 1% of patients receiving fingolimod 0.5 mg had QTc interval changes over 60 ms relative to baseline, and fewer than 1.3% of patients receiving fingolimod had absolute QTc intervals of over 450 ms (men) or over 470 ms (women) according to Bazett's or Fridericia's correction methods, irrespective of whether or not they were receiving an SSRI; this was similar to the findings in the placebo group. Newly occurring ECG findings are presented in Table 3. In the fingolimod 0.5 mg group, new post-dose ECG findings were detected in 6.3% of patients not receiving SSRIs versus 5.3% of patients receiving SSRIs; in the placebo group, the equivalent values were 3.9% and 4.7%, respectively. In the fingolimod group, first-degree AV block was detected in 3.4% of patients not receiving SSRIs versus 4.6% of patients receiving SSRIs; in the placebo group, the equivalent values were 0.7% and 0.9%, respectively. A total of 0.2% of patients in the fingolimod group not receiving SSRIs and no patients receiving SSRIs had a Mobitz I AV block.
3.2.
HR at 6 h post-dose
At baseline (pre-dose), mean sitting HR was similar in patients not receiving and those receiving SSRIs. The changes in mean
hourly HR from baseline (pre-dose) to 6 h post-dose in each treatment group were similar among patients not receiving SSRIs (fingolimod, –7.5 bpm; placebo, 0.0 bpm) and those receiving SSRIs (fingolimod, –6.6 bpm; placebo, 0.3 bpm). The majority of patients maintained a HR above 55 bpm in all subgroups regardless of treatment. HR remained above 55 bpm in 80.6% of patients treated with fingolimod and 95.0% of those receiving placebo in the subgroup not receiving SSRIs, compared with 79.9% and 92.6%, respectively, in the SSRI subgroup. No individual had a HR below 40 bpm during the first 6 h of treatment, irrespective of treatment group or whether patients were receiving SSRIs.
3.3.
Clinical experience
Most individuals who underwent extended observation were discharged on the same day. In the fingolimod group, 82.6% of patients not receiving SSRIs versus 85.7% of those receiving SSRIs were discharged at 6 h (Table 4); in the placebo group, the equivalent proportions were 90.7% and 92.8%, respectively (percentages are based on the number of patients from whom clinical experience data were collected). No bradycardia symptoms were recorded in the SSRI or citalopram/escitalopram subgroups. In the non-SSRI subgroup, 0.7% of patients receiving fingolimod and 0.1% of patients receiving placebo had symptoms of bradycardia; all were categorized as being mild or moderate in severity.
Fingolimod first-dose effects in patients with relapsing multiple sclerosis
Table 2
277
QTc interval changes 6 h after initiation of fingolimod treatment.
QT interval values available Bazett's correctiona Mean (SD) QTc interval change, ms Maximum QT interval change, ms o30 30–60 460 QTc interval 4450 ms (men) or 4470 ms (women) QTc interval 4500 ms (men) or 4520 ms (women) Fridericia's correctiona Mean (SD) QTc interval change, ms Maximum QT interval change, ms o30 30–60 460 QTc interval 4450 ms (men) or 4470 ms (women) QTc interval 4500 ms (men) or 4520 ms (women)
Patients not receiving SSRIs Patients receiving SSRIs at at fingolimod first dose fingolimod first dose
Patients receiving citalopram or escitalopram at fingolimod first dose
Placebo n= 758
Placebo n= 42
Fingolimod 0.5 mg n= 1058
Placebo n= 108
Fingolimod 0.5 mg n= 154
747 (98.5) 1029 (97.3)
106 (98.1) 150 (97.4)
1.8 (18.1) –1.2 (17.8)
6.2 (17.8) 1.1 (19.0)
701 44 2 9
(93.8) (5.9) (0.3) (1.2)
988 40 1 5
(96.0) (3.9) (0.1) (0.5)
98 7 1 3
(92.5) 137 (91.3) (6.6) 12 (8.0) (0.9) 1 (0.7) (2.8) 2 (1.3)
0 (0.0)
0 (0.0)
2.5 (14.0)
8.2 (14.6)
6.6 (14.9) 9.5 (15.6)
721 26 0 2
960 68 1 3
104 1 1 1
(96.5) (3.5) (0.0) (0.3)
0 (0.0)
(93.3) (6.6) (0.1) (0.3)
0 (0.0)
1 (0.9)
0 (0.0)
(98.1) 134 (89.3) (0.9) 16 (10.7) (0.9) 0 (0.0) (0.9) 1 (0.7)
1 (0.9)
0 (0.0)
42 (100.0) 7.6 (19.6)
38 3 1 2
(90.5) (7.1) (2.4) (4.8)
Fingolimod 0.5 mg n = 57 56 (98.2) –3.6 (17.6)
52 4 0 0
(92.9) (7.1) (0.0) (0.0)
1 (2.4)
0 (0.0)
8.0 (16.2)
6.6 (12.9)
40 1 1 0
(95.2) (2.4) (2.4) (0.0)
1 (2.4)
53 3 0 0
(94.6) (5.4) (0.0) (0.0)
0 (0.0)
Data are presented as the number (%) of patients unless otherwise specified. QTc, QT interval corrected for heart rate; SD, standard deviation; SSRI, selective serotonin-reuptake inhibitor. a Percentage calculated based on the number of patients with a QT interval value.
4.
Discussion
The results of this large pooled analysis of fingolimod clinical trial data from over 3300 patients with relapsing MS indicate that the well-characterized, transient nature of fingolimod first-dose effects on HR and AV conduction are largely unaffected by concomitant use of SSRIs. Fingolimod 0.5 mg therapy in patients receiving SSRIs was not associated with additional risk of ECG or clinical events compared with those who were not receiving SSRIs. Serotonin–norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine, are also utilized by patients with MS, though less commonly than SSRIs (Perez et al., 2015). The impact of SNRIs on the QT interval is not as well understood as that of SSRIs. Venlafaxine can be associated with QT prolongation in overdose, though duloxetine is thought to actually shorten the QT interval (US Food and Drug Administration, 2012a, 2014). Our study did not assess the effect of SNRIs on cardiac outcomes. This was the first analysis to assess the influence of SSRI coadministration on QT interval in patients with MS who initiated fingolimod therapy. There were differences in the precise values obtained using Bazett's and Fridericia's correction
methods, and this might be explained by the transient bradycardia associated with fingolimod treatment initiation and the known under-correction of QT interval values by Bazett's method at HRs below 60 bpm (Fermini and Fossa, 2003). In this regard, the FDA has deemed Fridericia's correction as more accurate than Bazett's correction in patients with such altered HRs (US Food and Drug Administration, 2005). Regardless, the categorical analysis of QTc interval data was similar for both correction methods. Our data suggest that fingolimod 0.5 mg treatment may influence the QT interval to a small extent, typically with QTc interval changes under 30 ms occurring 6 h after treatment initiation, comparable to natural QTc interval variability in the absence of a medication effect (Morganroth et al., 1991). QTc interval changes of 30–60 ms relative to baseline occurred in a slightly greater proportion of patients receiving concomitant SSRIs compared with those receiving only fingolimod 0.5 mg. In both the group receiving only fingolimod 0.5 mg and the group receiving concomitant SSRIs, QTc interval changes of more than 60 ms relative to baseline were rare and isolated events. The clinical relevance of QTc interval change for these categories is unknown; thus, it is helpful to view the results in the context of true QTc interval values exceeding a defined threshold. Very
278
Table 3
R.A. Bermel et al. New findings in patients who had a post-dose ECG at 6 ha. ECG analysis population Patients not receiving SSRIs at fingolimod first dose
Patients receiving SSRIs at fingolimod first dose
Placebo n= 758
Fingolimod 0.5 mg n= 1058
Placebo n= 108
Fingolimod 0.5 mg Placebo n = 154 n = 42
Fingolimod 0.5 mg n = 57
1041 (98.4)
107 (99.1)
152 (98.7)
56 (98.2)
Patients who had a post- 748 (98.7) dose ECG New abnormalitiesb,c 29 (3.9) First-degree AV block 5 (0.7) AV Mobitz I 0 (0.0) Prolonged QTc 0 (0.0) interval Left anterior 4 (0.5) hemiblock Ventricular premature 1 (0.1) complex Sinus bradycardia 1 (0.1) Other abnormal 0 (0.0) rhythm Depressed ST segment 1 (0.1) Flat T waves 5 (0.7) Inverted T waves 8 (1.1) Biphasic T waves 4 (0.5) Abnormal U waves 0 (0.0)
66 35 2 0
(6.3) (3.4) (0.2) (0.0)
5 1 0 1
(4.7) (0.9) (0.0) (0.9)
8 7 0 0
(5.3) (4.6) (0.0) (0.0)
Patients receiving citalopram or escitalopram at fingolimod first dose
42 (100.0) 3 1 0 1
(7.1) (2.4) (0.0) (2.4)
3 3 0 0
(5.4) (5.4) (0.0) (0.0)
3 (0.3)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (0.1)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
7 (0.7) 1 (0.1)
1 (0.9) 0 (0.0)
1 (0.7) 0 (0.0)
1 (2.4) 0 (0.0)
0 (0.0) 0 (0.0)
1 7 6 1 0
0 2 1 0 0
0 1 0 0 0
0 0 1 0 0
0 0 0 0 0
(0.1) (0.7) (0.6) (0.1) (0.0)
(0.0) (1.9) (0.9) (0.0) (0.0)
(0.0) (0.7) (0.0) (0.0) (0.0)
(0.0) (0.0) (2.4) (0.0) (0.0)
(0.0) (0.0) (0.0) (0.0) (0.0)
Data are presented as the number (%) of patients. AV, atrioventricular; ECG, electrocardiogram; SSRI, selective serotonin-reuptake inhibitor. a Abnormal ECGs reported in 0.5% of patients or more in any treatment group. b Multiple findings of the same abnormality within the same patient were counted only once. c Percentage calculated based on the number of patients who received a post-dose ECG.
few patients had absolute QTc intervals of over 450 ms (men) or over 470 ms (women) – which may be considered prolonged (Morganroth, 1991) – irrespective of whether or not they were receiving an SSRI, including citalopram. Findings in the placebo group were similar, although interestingly, the incidence of QTc intervals of over 450 ms (men) or over 470 ms (women) was typically higher in patients receiving placebo than in those receiving fingolimod 0.5 mg. Most importantly, when assessing clinical outcomes, coadministration of SSRIs and fingolimod was not associated with an increased incidence of any first-dose effects on HR and AV conduction compared with fingolimod therapy alone, and the majority of patients in the fingolimod group (83– 86%) were discharged from first-dose monitoring at 6 h irrespective of whether they were also receiving SSRIs. While this large pooled analysis of clinical trial data provides reassuring safety information on the concomitant use of SSRIs when initiating fingolimod therapy, it should be noted that the study population excluded patients with certain pre-existing cardiac conditions (defined in Section 2). Therefore, these data cannot be extrapolated to patient populations with these comorbidities, and guidelines contained within the full prescribing information should be adhered to (European Medicines Agency, 2011; US Food and Drug Administration, 2012b). We cannot rule out the possibility that any patient may have
chosen not to take their SSRI on the day of fingolimod administration without informing the fingolimod administrator. Furthermore, though ECG data, including QT interval data, were collected prospectively in each trial, the trials were not prospectively powered to assess the influence of concomitant use of SSRIs on QT interval when initiating fingolimod therapy, and treatment comparisons are descriptive. Nevertheless, these analyses suggest that patients with MS taking SSRIs, including citalopram, who are undergoing fingolimod treatment initiation are not at any higher risk of first-dose effects on HR and AV conduction than those not taking SSRIs. These data also suggest that standard firstdose observation (FDO) procedures for fingolimod in accordance with prescribing information (European Medicines Agency, 2011; US Food and Drug Administration, 2012b) are suitable for patients taking SSRIs (European Medicines Agency, 2011; US Food and Drug Administration, 2012b).
5.
Conclusion
Administration of SSRIs for depression and anxiety is common in patients with MS. These analyses provide reassurance that concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment initiation during FDO.
Fingolimod first-dose effects in patients with relapsing multiple sclerosis
Table 4
279
Clinical experience at initiation of fingolimod treatmenta.
Discharged at 6 h Required extended monitoring after 6 h as per protocol Hospitalized Required day 2 monitoring Study drug/placebo permanently discontinued Bradycardia symptomsb Mild Moderate Severe
Patients not receiving SSRIs at fingolimod first dose
Patients receiving SSRIs at Patients receiving fingolimod first dose citalopram or escitalopram at fingolimod first dose
Placebo n = 676
Placebo n = 97
Fingolimod 0.5 mg n= 1058
613 (90.7) 874 (82.6) 18 (2.7) 138 (13.0) 0 (0.0) 5 (0.7) 1 (0.1) 1 1 0 0
(0.1) (0.1) (0.0) (0.0)
12 (1.1) 28 (2.6) 2 (0.2) 7 5 2 0
(0.7) (0.5) (0.2) (0.0)
Fingolimod 0.5 mg n= 154
90 (92.8) 132 (85.7) 4 (4.1) 19 (12.3)
Placebo n= 41
Fingolimod 0.5 mg n = 57
39 (95.1) 48 (84.2) 2 (4.9) 8 (14.0)
0 (0.0) 1 (1.0) 1 (1.0)
3 (1.9) 4 (2.6) 1 (0.6)
0 (0.0) 1 (2.4) 1 (2.4)
0 (0.0) 2 (3.5) 0 (0.0)
0 0 0 0
0 0 0 0
0 0 0 0
0 0 0 0
(0.0) (0.0) (0.0) (0.0)
(0.0) (0.0) (0.0) (0.0)
(0.0) (0.0) (0.0) (0.0)
(0.0) (0.0) (0.0) (0.0)
Data are presented as the number (%) of patients. SSRI, selective serotonin-reuptake inhibitor. a Data from the phase 2 clinical trial were not collected and are not included in this summary. b Bradycardia symptoms reported are regardless of study drug relationship. Among patients not taking SSRIs, the most common symptom of bradycardia was dizziness (0.1% in the placebo group, 0.6% in the fingolimod 0.5 mg group).
Conflicts of interest R. Bermel has received consulting fees, research support or speaker's honoraria from Genzyme Novartis, Questcor Teva and Biogen Idec. D. Kantor has received consulting fees, research support and speaker's honoraria from Novartis. R. Hashmonay, X. Meng and S. Randhawa are employees of Novartis Pharmaceuticals Corporation. P. von Rosenstiel and N. Sfikas are employees of Novartis Pharma AG.
Acknowledgments The authors wish to thank Adam Rosenbluth, M.D., who serves as a clinical instructor in cardiovascular medicine at the Mount Sinai School of Medicine, New York, USA, for his valuable comments and suggestions provided during the development of this manuscript. This study was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Editorial support was provided by Oxford PharmaGenesis Ltd, Oxford, UK, and funded by Novartis Pharmaceuticals Corporation.
Appendix A.
Supporting information
Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/ j.msard.2015.04.002.
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Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 2010;9:883–97. Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a doubleblind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol 2014;13:545–56. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 2010;33:91–101. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402–15. DiMarco J, O’Connor P, Cohen JA, Reder AT, Zhang-Auberson L, Tang D, et al. First-dose effects of fingolimod: pooled safety data from three phase 3 studies. Mult Scler Relat Disord 2015;3:629–38. European Medicines Agency. Annex I. Summary of product characteristics. Gilenya (fingolimod), 〈http://www.ema.europa.eu/ docs/en_GB/document_library/EPAR_-_Product_Information/ human/002202/WC500104528.pdf〉; 2011 [accessed 27.08.14]. Fermini B, Fossa AA. The impact of drug-induced QT interval prolongation on drug discovery and development. Nat Rev Drug Discov 2003;2:439–47. Fridericia LS. Die systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken. Acta Med Scand 1920;53:469. Funk KA, Bostwick JR. A comparison of the risk of QT prolongation among SSRIs. Ann Pharmacother 2013;47:1330–41. Goldman Consensus Group. The Goldman consensus statement on depression in multiple sclerosis. Mult Scler 2005;11:328–37. ICH. ICH harmonised tripartite guidelines for good clinical practice E6 (R1). In: Proceedings of the international conference on harmonization of technical requirements for registration of pharmaceuticals for human use. Geneva, 〈http://www.ich.org/fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/ E6_R1__Guideline.pdf〉; 1996 [accessed 27.08.14].
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CLINICAL TRIAL
Fingolimod first-dose effects in patients with relapsing multiple sclerosis concomitantly receiving selective serotonin-reuptake inhibitors R.A. Bermela,n, R. Hashmonayb, X. Mengb, S. Randhawab, P. von Rosenstielb, N. Sfikasb, D. Kantorc a
Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, USA Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA c Neurologique, Ponte Vedra, FL, USA b
Received 8 October 2014; received in revised form 6 February 2015; accepted 2 April 2015
KEYWORDS
Abstract
Fingolimod; Multiple sclerosis; Serotonin-reuptake inhibitors; Cardiac safety; Depression; Drug interactions
Selective serotonin-reuptake inhibitors (SSRIs), commonly administered for depression and anxiety in patients with multiple sclerosis, are associated with QT interval prolongation. Fingolimod (FTY720; Gilenyas, 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 6 h, 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
Abbreviations: AV, atrioventricular; AVB, atrioventricular block; ECG, electrocardiogram; FDA, US Food and Drug Administration; FDO, first-dose observation; FREEDOMS, FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; GIRK, G-protein-gated inwardly-rectifying potassium; HR, heart rate; MS, multiple sclerosis; QTc interval, QT interval corrected for heart rate; QTcB interval, QT interval corrected for heart rate using Bazett's correction method; QTcF interval, QT interval corrected for heart rate using Fridericia's correction method; S1PR, sphingosine 1-phosphate receptor; SSRI, selective serotonin-reuptake inhibitors; TRANSFORMS, Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis n Corresponding author. Tel.: +1 216 444 8600; fax: +1 216 445 6259. E-mail address: [email protected] (R.A. Bermel). http://dx.doi.org/10.1016/j.msard.2015.04.002 2211-0348/& 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
274
R.A. Bermel et al. 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. & 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1.
Introduction
Depression and anxiety are common in patients with multiple sclerosis (MS), with prevalences higher than those observed both in the general population and in patients with other chronic diseases (Patten et al., 2003). The annual prevalence of depression in patients with MS is estimated to be up to 14%, with a lifetime prevalence of up to 50% (Goldman Consensus Group, 2005); anxiety disorders are estimated to affect more than 30% of patients with MS (Korostil and Feinstein, 2007). Selective serotonin-reuptake inhibitors (SSRIs) are widely prescribed for the treatment of patients with depression and anxiety, including in those with MS (Koch et al., 2011). There is, however, some evidence that SSRIs are linked to QT interval prolongation (Funk and Bostwick, 2013). In particular, citalopram appears more likely to be associated with this effect than other SSRIs, and the US Food and Drug Administration (FDA) has issued revised recommendations for the use of the drug owing to a potential risk of abnormal heart rhythms when it is used at high doses (US Food and Drug Administration, 2012c). Fingolimod (FTY720; Gilenyas, Novartis Pharma AG) is a first-in-class sphingosine 1-phosphate receptor (S1PR) modulator (Brinkmann et al., 2010; Chun and Hartung, 2010), approved for relapsing forms of MS as a once-daily oral therapy at a dose of 0.5 mg (European Medicines Agency, 2011; US Food and Drug Administration, 2012b). The efficacy benefits of fingolimod over both placebo and intramuscular interferon β1a on key measures of disease activity (relapse rates, disability progression versus placebo, lesion load and brain volume loss) have been established in clinical trials (Calabresi et al., 2014; Cohen et al., 2010; Kappos et al., 2010). Fingolimod is associated with a transient, generally asymptomatic reduction in heart rate (HR) and, rarely, with generally asymptomatic atrioventricular (AV) block on treatment initiation, which are expected pharmacodynamic effects (Schmouder et al., 2006). Binding of fingolimod phosphate (the active phosphorylated compound) to S1PR subtype 1 on cardiac myocytes activates G-protein-gated inwardly-rectifying potassium (GIRK) channels (similar to the vagal stimulus), causing the transient reduction in HR. With continued administration of fingolimod, S1PRs are internalized and degraded, which leads to progressive resolution of the bradycardia over subsequent hours to days of treatment (Schmouder et al., 2006). In phase 3 clinical studies in patients with MS, the HR effect was maximal on day 1 and had recovered to baseline levels within 1 month of fingolimod initiation (DiMarco et al., 2015).
In a thorough QT interval study, fingolimod administered at 1.25 mg and 2.5 mg doses resulted in prolongation of the corrected QT interval (QTc), with the upper bound of the 90% confidence interval being an increase of 14.0 ms; although there was no consistent increase in the incidence of QTc interval outliers associated with fingolimod treatment (US Food and Drug Administration, 2012b). In the fingolimod clinical study program, clinically relevant prolongation of the QT interval was not observed at the approved fingolimod 0.5 mg dose (US Food and Drug Administration, 2012b). However, because of the effect of bradycardia on QT interval duration, the US fingolimod label guidelines currently recommend that patients receiving concurrent therapy with QT interval-prolonging drugs, with a known risk of causing torsades de pointes, should be observed overnight with continuous electrocardiogram (ECG) monitoring after their first dose of fingolimod (US Food and Drug Administration, 2012b). SSRIs are generally classified as QT interval-prolonging drugs, though only citalopram is listed by name in the fingolimod prescribing information as having a known risk of torsades de pointes (US Food and Drug Administration, 2012b). In the EU, the fingolimod Summary of Product Characteristics recommends that medicinal products that prolong the QTc interval are avoided in patients with relevant risk factors such as hypokalemia, hypomagnesemia or congenital long-QT interval syndrome (European Medicines Agency, 2011). It is important to assess whether concomitant administration of fingolimod and SSRIs results in any unexpected first-dose effects in patients with MS. Here, we analyzed safety data from over 3300 patients with relapsing MS who were enrolled in the fingolimod clinical trial program to compare cardiac outcomes during treatment initiation in patients who were or were not receiving an SSRI, including a subset of patients receiving citalopram or escitalopram.
2. 2.1.
Methods Study design and participants
These analyses included all patients randomized to receive fingolimod 0.5 mg, fingolimod 1.25 mg or placebo in the core, controlled parts of the phase 2 (ClinicalTrials.gov identifier NCT00333138) and the phase 3 FREEDOMS (NCT00289978), FREEDOMS II (NCT00355134) and TRANSFORMS (NCT00340834)
Fingolimod first-dose effects in patients with relapsing multiple sclerosis fingolimod studies in patients with relapsing MS (Calabresi et al., 2014; Cohen et al., 2010; Kappos et al., 2006; Kappos et al., 2010). The study designs, entry criteria and overall results of the phase 2, FREEDOMS, FREEDOMS II and TRANSFORMS studies have been reported elsewhere (Calabresi et al., 2014; Cohen et al., 2010; Kappos et al., 2006, 2010), and the analyses in this paper do not involve new patients. All studies adhered to the International Conference on Harmonization Guidelines for Good Clinical Practice (ICH, 1996), and were conducted in accordance with the Declaration of Helsinki (WMA, 2013). Study protocols were approved by the institutional review board at each study site. All patients provided written, informed consent before any studyrelated procedure was performed. All concomitant medications taken within 30 days prior to screening or during the course of the study were recorded. Cardiovascular exclusion criteria relevant to this report comprised: recurrent syncope of suspected cardiac origin; myocardial infarction in the 6 months before study entry or current unstable angina; baseline resting heart rate less than 55 bpm; second-degree or higher AV block (AVB); sinus node dysfunction; congestive heart failure; diabetes mellitus; coronary or peripheral arterial spasm; a corrected QTc interval greater than 440 ms; and concomitant use of Vaughan Williams class 3 antiarrhythmic drugs. Patients with controlled hypertension and those receiving therapy with either non-dihydropyridine-type calcium channel antagonists or β-blockers were not excluded.
2.2. Patient monitoring during first-dose administration The initial dose of fingolimod was administered by an independent physician (supported by a nurse or other healthcare professional) not involved in the patient's MS treatment to preserve study blinding. Patients were observed in a clinical setting, and their vital signs were recorded at hourly intervals for at least 6 h. The mean change from baseline in hourly heart rate was determined. A 12-lead ECG was obtained before firstdose fingolimod administration, at 6 h post-dose and at any time when symptoms or major changes in vital signs were noted. ECG tracings were sent to a central ECG facility for analysis, ensuring consistent and accurate interpretation of all data generated across numerous study sites. Participants were eligible for discharge 6 h after the first dose if all the following criteria were met: heart rate of at least 51 bpm; heart rate greater than 80% of baseline value; heart rate not the lowest hourly value of the monitoring period; no symptoms of decreased heart rate; no treatment given for bradycardia; and an ECG tracing not showing any significant abnormalities versus the pre-dose tracing, except sinus bradycardia. The observation period was extended for patients who did not meet one or more of these criteria, and hospitalization was permitted at the discretion of the first-dose administrator. Patients whose heart rate dropped by more than 30% relative to baseline or those experiencing symptomatic bradycardia had to return to the site for the administration of the second dose and had to be monitored as they were for the first dose. Symptomatic bradycardia (bradycardia symptoms during first dosing) was noted and graded by the first-dose administrator.
2.3.
275
Outcome measures
At the time of fingolimod first-dose administration, vital signs including HR and clinical status outcomes were recorded, and then noted hourly for 6 h (the time after which patients are typically discharged from first-dose observation) in the subgroups of patients who, at the time of first dose, were (1) not receiving an SSRI; (2) receiving an SSRI (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline); or (3) specifically receiving the SSRI citalopram or its stereoisomer, escitalopram. ECGs were obtained pre-dose and 6 h post-dose.
2.4.
Analyses
Data were analyzed descriptively for each of the three patient subgroups. The QT interval was corrected for heart rate (QTc) using Bazett's (QTcB) and Fridericia's (QTcF) correction methods (Bazett, 1920; Fridericia, 1920). Consistent with standard regulatory guidance related to QT interval reporting, we present analyses of mean group QTc interval change in addition to categorical analyses of change from baseline QTc interval and absolute QTc interval. In line with current convention, change from baseline QTc interval was categorized as follows: under 30 ms change, unlikely to be of clinical significance; 30–60 ms, potentially of clinical significance; or over 60 ms, higher likelihood of clinical significance (US Food and Drug Administration, 2005). Here, we focus on the findings in patients treated with the approved fingolimod 0.5 mg dose versus placebo. Data for patients who received fingolimod 1.25 mg are included in Supplementary Tables 1–4 for completeness, together with uncorrected QT interval values.
3.
Results
The baseline patient demographics (age and sex) were generally balanced across patient subgroups (Table 1). At treatment initiation, 154/1212 (12.7%) and 108/866 (12.5%) patients were receiving concomitant SSRIs in the fingolimod 0.5 mg and placebo groups, respectively. A total of 70.8% and 79.6% of patients receiving concomitant SSRIs in the fingolimod 0.5 mg and placebo groups, respectively, had a history of depression compared with 14.5% and 17.2% of patients not receiving SSRIs. Similarly, 25.3% and 22.2% of patients receiving concomitant SSRIs in the fingolimod 0.5 mg and placebo groups, respectively, had a history of anxiety compared with 7.7% and 10.2% of patients not receiving SSRIs. This is as expected, owing to the fact that SSRIs are normally prescribed to treat depression and anxiety.
3.1.
ECG findings 6 h post-dose
In patients treated with fingolimod 0.5 mg, the mean change in QTc interval from baseline (pre-dose) to 6 h after treatment initiation was under 10 ms (both Bazett's and Fridericia's methods), with similar mean QTc interval changes recorded across all non-SSRI, SSRI and citalopram/escitalopram subgroups (Table 2). In more than 91% (Bazett) and 89% (Fridericia) of patients receiving fingolimod 0.5 mg, the maximum increase in QTc interval from baseline to 6 h was under 30 ms, irrespective of whether individuals received SSRIs, including citalopram or escitalopram specifically (Table 2). QTc interval changes of 30–
276
R.A. Bermel et al.
Table 1
Baseline patient demographics and relevant medical history. Patients not receiving SSRIs at fingolimod first dose
Patients receiving SSRIs at fingolimod first dose
Placebo n= 758
Placebo n = 108
Fingolimod 0.5 mg n= 1058
Mean (SD) age, years 38.2 (8.7) 37.4 (8.9) Women, n (%) 559 (73.7) 716 (67.7) Medical history, n (%) Anxiety 77 (10.2) 81 (7.7) Cardiac disorders 66 (8.7) 71 (6.7) Depression 130 (17.2) 153 (14.5) SSRI treatment history, n (%)a Citalopramb 0 (0.0) 2 (0.2)c d c 3 (0.4) 2 (0.2)c Escitalopram e 0 (0.0) 1 (0.1)c Fluoxetine f Fluvoxamine 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Paroxetineg 2 (0.3)c 0 (0.0) Sertralineh
Fingolimod 0.5 mg Placebo n = 154 n= 42
39.7 (8.6) 40.8 (8.0) 89 (82.4) 136 (88.3) 24 (22.2) 11 (10.2) 86 (79.6)
20 22 25 1 13 28
(18.5) (20.4) (23.1) (0.93) (12.0) (25.9)
Patients receiving citalopram or escitalopram at fingolimod first dose
39 (25.3) 21 (13.6) 109 (70.8)
22 35 41 1 26 35
(14.3) (22.7) (26.6) (0.65) (16.9) (22.7)
Fingolimod 0.5 mg n= 57
37.2 (7.8) 41.8 (7.4) 36 (85.7) 49 (86.0) 14 (33.3) 5 (11.9) 34 (81.0)
15 (26.3) 9 (15.8) 43 (75.4)
20 22 0 0 0 0
22 35 0 0 0 0
(47.6) (52.4) (0.0) (0.0) (0.0) (0.0)
(38.6) (61.4) (0.0) (0.0) (0.0) (0.0)
SD, standard deviation; SSRI, selective serotonin-reuptake inhibitor. a Some patients were taking more than one SSRI. b Includes patients recorded as taking citalopram, citalopram hydrobromide or citalopram hydrochloride. c Historical treatment; was not taken at the time of fingolimod first dose. d Includes patients recorded as taking escitalopram or escitalopram oxalate. e Includes patients recorded as taking fluoxetine or fluoxetine hydrochloride. f Includes patients recorded as taking fluvoxamine maleate. g Includes patients recorded as taking paroxetine, paroxetine hydrochloride or paroxetine mesylate. h Includes patients recorded as taking sertraline or sertraline hydrochloride.
60 ms relative to baseline occurred in a slightly greater proportion of patients receiving concomitant SSRIs compared with those receiving only fingolimod 0.5 mg (QTcB interval, 8.0% versus 3.9%; QTcF interval, 10.7% versus 6.6%, respectively). Fewer than 1% of patients receiving fingolimod 0.5 mg had QTc interval changes over 60 ms relative to baseline, and fewer than 1.3% of patients receiving fingolimod had absolute QTc intervals of over 450 ms (men) or over 470 ms (women) according to Bazett's or Fridericia's correction methods, irrespective of whether or not they were receiving an SSRI; this was similar to the findings in the placebo group. Newly occurring ECG findings are presented in Table 3. In the fingolimod 0.5 mg group, new post-dose ECG findings were detected in 6.3% of patients not receiving SSRIs versus 5.3% of patients receiving SSRIs; in the placebo group, the equivalent values were 3.9% and 4.7%, respectively. In the fingolimod group, first-degree AV block was detected in 3.4% of patients not receiving SSRIs versus 4.6% of patients receiving SSRIs; in the placebo group, the equivalent values were 0.7% and 0.9%, respectively. A total of 0.2% of patients in the fingolimod group not receiving SSRIs and no patients receiving SSRIs had a Mobitz I AV block.
3.2.
HR at 6 h post-dose
At baseline (pre-dose), mean sitting HR was similar in patients not receiving and those receiving SSRIs. The changes in mean
hourly HR from baseline (pre-dose) to 6 h post-dose in each treatment group were similar among patients not receiving SSRIs (fingolimod, –7.5 bpm; placebo, 0.0 bpm) and those receiving SSRIs (fingolimod, –6.6 bpm; placebo, 0.3 bpm). The majority of patients maintained a HR above 55 bpm in all subgroups regardless of treatment. HR remained above 55 bpm in 80.6% of patients treated with fingolimod and 95.0% of those receiving placebo in the subgroup not receiving SSRIs, compared with 79.9% and 92.6%, respectively, in the SSRI subgroup. No individual had a HR below 40 bpm during the first 6 h of treatment, irrespective of treatment group or whether patients were receiving SSRIs.
3.3.
Clinical experience
Most individuals who underwent extended observation were discharged on the same day. In the fingolimod group, 82.6% of patients not receiving SSRIs versus 85.7% of those receiving SSRIs were discharged at 6 h (Table 4); in the placebo group, the equivalent proportions were 90.7% and 92.8%, respectively (percentages are based on the number of patients from whom clinical experience data were collected). No bradycardia symptoms were recorded in the SSRI or citalopram/escitalopram subgroups. In the non-SSRI subgroup, 0.7% of patients receiving fingolimod and 0.1% of patients receiving placebo had symptoms of bradycardia; all were categorized as being mild or moderate in severity.
Fingolimod first-dose effects in patients with relapsing multiple sclerosis
Table 2
277
QTc interval changes 6 h after initiation of fingolimod treatment.
QT interval values available Bazett's correctiona Mean (SD) QTc interval change, ms Maximum QT interval change, ms o30 30–60 460 QTc interval 4450 ms (men) or 4470 ms (women) QTc interval 4500 ms (men) or 4520 ms (women) Fridericia's correctiona Mean (SD) QTc interval change, ms Maximum QT interval change, ms o30 30–60 460 QTc interval 4450 ms (men) or 4470 ms (women) QTc interval 4500 ms (men) or 4520 ms (women)
Patients not receiving SSRIs Patients receiving SSRIs at at fingolimod first dose fingolimod first dose
Patients receiving citalopram or escitalopram at fingolimod first dose
Placebo n= 758
Placebo n= 42
Fingolimod 0.5 mg n= 1058
Placebo n= 108
Fingolimod 0.5 mg n= 154
747 (98.5) 1029 (97.3)
106 (98.1) 150 (97.4)
1.8 (18.1) –1.2 (17.8)
6.2 (17.8) 1.1 (19.0)
701 44 2 9
(93.8) (5.9) (0.3) (1.2)
988 40 1 5
(96.0) (3.9) (0.1) (0.5)
98 7 1 3
(92.5) 137 (91.3) (6.6) 12 (8.0) (0.9) 1 (0.7) (2.8) 2 (1.3)
0 (0.0)
0 (0.0)
2.5 (14.0)
8.2 (14.6)
6.6 (14.9) 9.5 (15.6)
721 26 0 2
960 68 1 3
104 1 1 1
(96.5) (3.5) (0.0) (0.3)
0 (0.0)
(93.3) (6.6) (0.1) (0.3)
0 (0.0)
1 (0.9)
0 (0.0)
(98.1) 134 (89.3) (0.9) 16 (10.7) (0.9) 0 (0.0) (0.9) 1 (0.7)
1 (0.9)
0 (0.0)
42 (100.0) 7.6 (19.6)
38 3 1 2
(90.5) (7.1) (2.4) (4.8)
Fingolimod 0.5 mg n = 57 56 (98.2) –3.6 (17.6)
52 4 0 0
(92.9) (7.1) (0.0) (0.0)
1 (2.4)
0 (0.0)
8.0 (16.2)
6.6 (12.9)
40 1 1 0
(95.2) (2.4) (2.4) (0.0)
1 (2.4)
53 3 0 0
(94.6) (5.4) (0.0) (0.0)
0 (0.0)
Data are presented as the number (%) of patients unless otherwise specified. QTc, QT interval corrected for heart rate; SD, standard deviation; SSRI, selective serotonin-reuptake inhibitor. a Percentage calculated based on the number of patients with a QT interval value.
4.
Discussion
The results of this large pooled analysis of fingolimod clinical trial data from over 3300 patients with relapsing MS indicate that the well-characterized, transient nature of fingolimod first-dose effects on HR and AV conduction are largely unaffected by concomitant use of SSRIs. Fingolimod 0.5 mg therapy in patients receiving SSRIs was not associated with additional risk of ECG or clinical events compared with those who were not receiving SSRIs. Serotonin–norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine, are also utilized by patients with MS, though less commonly than SSRIs (Perez et al., 2015). The impact of SNRIs on the QT interval is not as well understood as that of SSRIs. Venlafaxine can be associated with QT prolongation in overdose, though duloxetine is thought to actually shorten the QT interval (US Food and Drug Administration, 2012a, 2014). Our study did not assess the effect of SNRIs on cardiac outcomes. This was the first analysis to assess the influence of SSRI coadministration on QT interval in patients with MS who initiated fingolimod therapy. There were differences in the precise values obtained using Bazett's and Fridericia's correction
methods, and this might be explained by the transient bradycardia associated with fingolimod treatment initiation and the known under-correction of QT interval values by Bazett's method at HRs below 60 bpm (Fermini and Fossa, 2003). In this regard, the FDA has deemed Fridericia's correction as more accurate than Bazett's correction in patients with such altered HRs (US Food and Drug Administration, 2005). Regardless, the categorical analysis of QTc interval data was similar for both correction methods. Our data suggest that fingolimod 0.5 mg treatment may influence the QT interval to a small extent, typically with QTc interval changes under 30 ms occurring 6 h after treatment initiation, comparable to natural QTc interval variability in the absence of a medication effect (Morganroth et al., 1991). QTc interval changes of 30–60 ms relative to baseline occurred in a slightly greater proportion of patients receiving concomitant SSRIs compared with those receiving only fingolimod 0.5 mg. In both the group receiving only fingolimod 0.5 mg and the group receiving concomitant SSRIs, QTc interval changes of more than 60 ms relative to baseline were rare and isolated events. The clinical relevance of QTc interval change for these categories is unknown; thus, it is helpful to view the results in the context of true QTc interval values exceeding a defined threshold. Very
278
Table 3
R.A. Bermel et al. New findings in patients who had a post-dose ECG at 6 ha. ECG analysis population Patients not receiving SSRIs at fingolimod first dose
Patients receiving SSRIs at fingolimod first dose
Placebo n= 758
Fingolimod 0.5 mg n= 1058
Placebo n= 108
Fingolimod 0.5 mg Placebo n = 154 n = 42
Fingolimod 0.5 mg n = 57
1041 (98.4)
107 (99.1)
152 (98.7)
56 (98.2)
Patients who had a post- 748 (98.7) dose ECG New abnormalitiesb,c 29 (3.9) First-degree AV block 5 (0.7) AV Mobitz I 0 (0.0) Prolonged QTc 0 (0.0) interval Left anterior 4 (0.5) hemiblock Ventricular premature 1 (0.1) complex Sinus bradycardia 1 (0.1) Other abnormal 0 (0.0) rhythm Depressed ST segment 1 (0.1) Flat T waves 5 (0.7) Inverted T waves 8 (1.1) Biphasic T waves 4 (0.5) Abnormal U waves 0 (0.0)
66 35 2 0
(6.3) (3.4) (0.2) (0.0)
5 1 0 1
(4.7) (0.9) (0.0) (0.9)
8 7 0 0
(5.3) (4.6) (0.0) (0.0)
Patients receiving citalopram or escitalopram at fingolimod first dose
42 (100.0) 3 1 0 1
(7.1) (2.4) (0.0) (2.4)
3 3 0 0
(5.4) (5.4) (0.0) (0.0)
3 (0.3)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (0.1)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
7 (0.7) 1 (0.1)
1 (0.9) 0 (0.0)
1 (0.7) 0 (0.0)
1 (2.4) 0 (0.0)
0 (0.0) 0 (0.0)
1 7 6 1 0
0 2 1 0 0
0 1 0 0 0
0 0 1 0 0
0 0 0 0 0
(0.1) (0.7) (0.6) (0.1) (0.0)
(0.0) (1.9) (0.9) (0.0) (0.0)
(0.0) (0.7) (0.0) (0.0) (0.0)
(0.0) (0.0) (2.4) (0.0) (0.0)
(0.0) (0.0) (0.0) (0.0) (0.0)
Data are presented as the number (%) of patients. AV, atrioventricular; ECG, electrocardiogram; SSRI, selective serotonin-reuptake inhibitor. a Abnormal ECGs reported in 0.5% of patients or more in any treatment group. b Multiple findings of the same abnormality within the same patient were counted only once. c Percentage calculated based on the number of patients who received a post-dose ECG.
few patients had absolute QTc intervals of over 450 ms (men) or over 470 ms (women) – which may be considered prolonged (Morganroth, 1991) – irrespective of whether or not they were receiving an SSRI, including citalopram. Findings in the placebo group were similar, although interestingly, the incidence of QTc intervals of over 450 ms (men) or over 470 ms (women) was typically higher in patients receiving placebo than in those receiving fingolimod 0.5 mg. Most importantly, when assessing clinical outcomes, coadministration of SSRIs and fingolimod was not associated with an increased incidence of any first-dose effects on HR and AV conduction compared with fingolimod therapy alone, and the majority of patients in the fingolimod group (83– 86%) were discharged from first-dose monitoring at 6 h irrespective of whether they were also receiving SSRIs. While this large pooled analysis of clinical trial data provides reassuring safety information on the concomitant use of SSRIs when initiating fingolimod therapy, it should be noted that the study population excluded patients with certain pre-existing cardiac conditions (defined in Section 2). Therefore, these data cannot be extrapolated to patient populations with these comorbidities, and guidelines contained within the full prescribing information should be adhered to (European Medicines Agency, 2011; US Food and Drug Administration, 2012b). We cannot rule out the possibility that any patient may have
chosen not to take their SSRI on the day of fingolimod administration without informing the fingolimod administrator. Furthermore, though ECG data, including QT interval data, were collected prospectively in each trial, the trials were not prospectively powered to assess the influence of concomitant use of SSRIs on QT interval when initiating fingolimod therapy, and treatment comparisons are descriptive. Nevertheless, these analyses suggest that patients with MS taking SSRIs, including citalopram, who are undergoing fingolimod treatment initiation are not at any higher risk of first-dose effects on HR and AV conduction than those not taking SSRIs. These data also suggest that standard firstdose observation (FDO) procedures for fingolimod in accordance with prescribing information (European Medicines Agency, 2011; US Food and Drug Administration, 2012b) are suitable for patients taking SSRIs (European Medicines Agency, 2011; US Food and Drug Administration, 2012b).
5.
Conclusion
Administration of SSRIs for depression and anxiety is common in patients with MS. These analyses provide reassurance that concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment initiation during FDO.
Fingolimod first-dose effects in patients with relapsing multiple sclerosis
Table 4
279
Clinical experience at initiation of fingolimod treatmenta.
Discharged at 6 h Required extended monitoring after 6 h as per protocol Hospitalized Required day 2 monitoring Study drug/placebo permanently discontinued Bradycardia symptomsb Mild Moderate Severe
Patients not receiving SSRIs at fingolimod first dose
Patients receiving SSRIs at Patients receiving fingolimod first dose citalopram or escitalopram at fingolimod first dose
Placebo n = 676
Placebo n = 97
Fingolimod 0.5 mg n= 1058
613 (90.7) 874 (82.6) 18 (2.7) 138 (13.0) 0 (0.0) 5 (0.7) 1 (0.1) 1 1 0 0
(0.1) (0.1) (0.0) (0.0)
12 (1.1) 28 (2.6) 2 (0.2) 7 5 2 0
(0.7) (0.5) (0.2) (0.0)
Fingolimod 0.5 mg n= 154
90 (92.8) 132 (85.7) 4 (4.1) 19 (12.3)
Placebo n= 41
Fingolimod 0.5 mg n = 57
39 (95.1) 48 (84.2) 2 (4.9) 8 (14.0)
0 (0.0) 1 (1.0) 1 (1.0)
3 (1.9) 4 (2.6) 1 (0.6)
0 (0.0) 1 (2.4) 1 (2.4)
0 (0.0) 2 (3.5) 0 (0.0)
0 0 0 0
0 0 0 0
0 0 0 0
0 0 0 0
(0.0) (0.0) (0.0) (0.0)
(0.0) (0.0) (0.0) (0.0)
(0.0) (0.0) (0.0) (0.0)
(0.0) (0.0) (0.0) (0.0)
Data are presented as the number (%) of patients. SSRI, selective serotonin-reuptake inhibitor. a Data from the phase 2 clinical trial were not collected and are not included in this summary. b Bradycardia symptoms reported are regardless of study drug relationship. Among patients not taking SSRIs, the most common symptom of bradycardia was dizziness (0.1% in the placebo group, 0.6% in the fingolimod 0.5 mg group).
Conflicts of interest R. Bermel has received consulting fees, research support or speaker's honoraria from Genzyme Novartis, Questcor Teva and Biogen Idec. D. Kantor has received consulting fees, research support and speaker's honoraria from Novartis. R. Hashmonay, X. Meng and S. Randhawa are employees of Novartis Pharmaceuticals Corporation. P. von Rosenstiel and N. Sfikas are employees of Novartis Pharma AG.
Acknowledgments The authors wish to thank Adam Rosenbluth, M.D., who serves as a clinical instructor in cardiovascular medicine at the Mount Sinai School of Medicine, New York, USA, for his valuable comments and suggestions provided during the development of this manuscript. This study was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Editorial support was provided by Oxford PharmaGenesis Ltd, Oxford, UK, and funded by Novartis Pharmaceuticals Corporation.
Appendix A.
Supporting information
Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/ j.msard.2015.04.002.
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