cardiac dysrhythmias after fingo”>Case Report

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American Journal of Emergency Medicine

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American Journal of Emergency Medicine 33 (2015) 987.e1-987.e3

Delayed cardiac dysrhythmias after fingolimod administration?,??,?,??

Abstract

A 51-year-old woman with relapsing-remitting Multiple sclerosis was initiated on fingolimod. She developed a Mobitz Type I (Wenckebach) second-degree atrioventricular (AV) heart block during the initial 6-hour monitoring. She was transferred to the emergency department for further monitoring, where she went into a junctional tachycardia then went back into a Mobitz Type I AV block. The patient was symp- tomatic with a heart rate nadir of 38 beats per minute and treated with atropine. Junctional tachycardia has not been previously reported with fingolimod use. Patients may require extended cardiac monitoring after fingolimod administration.

Fingolimod (Gilenya) is an oral sphingosine-1-phosphate receptor modulator shown to effectively reduce relapse rates in patients with multiple sclerosis (MS) [1,2]. It acts through sphingosine-1-phosphate signaling pathways to modulate chemotactic responses and lympho- cyte trafficking [3]. Fingolimod is approved by the US Food and Drug Administration for the treatment of relapsing-remitting MS. In clinical trials, a transient decrease in heart rate was observed within 1 hour of the first dose of fingolimod [1,2]. This was a dose-related effect that attenuated by 6 hours and was completely resolved in 24 hours [1,2]. The manufacturer recommends observing all patients for signs and symptoms of bradycardia for 6 hours after the initial dose of fingolimod and longer in patients who develop bradycardia or electro- cardiographic (ECG) changes [4]. We report a patient who experienced junctional tachycardia, a previously unreported fingolimod-associated dysrhythmia and Symptomatic bradycardia with second-degree atrio- ventricular (AV) block, after the 6-hour manufacturer recommended monitoring window.

The patient is a 51-year-old woman with an established diagnosis of relapsing-remitting MS who was started on disease-modifying therapy with fingolimod.

Her baseline ECG before medication administration showed a normal

sinus rhythm with cardiac intervals within reference ranges and a resting heart rate between 58 and 68 beats per minute (see Figure A). After receiving the first dose of fingolimod 0.5 mg, the patient underwent the recommended 6-hour cardiac monitoring.

During monitoring, the patient experienced palpitations without associated chest pain, shortness of breath, or dizziness. The patient developed a Mobitz Type I (Wenckebach) second degree AV block with

? No grant or support was used in preparation of this case report.

?? No conflicts of interest with any of the authors.

? This case report was exempted from institutional review board approval.

?? The authors have no financial arrangements to disclose.

a ventricular rate between 43 and 68 beats per minute that continued to the end of the 6-hour monitoring. The patient was transferred to the emergency department (ED) for further evaluation.

The patient’s palpitations continued in the ED; vitals showed a pulse of 85 beats per minute, 19 breaths per minute, blood pressure of 121/72 mm Hg, and a pulse oxygenation of 95% on room air. The ECG showed that the patient was in a junctional tachycardia at a rate of 83 beats per minute (see Figure B). Electrolytes and Liver enzymes were within normal limits, her glomerular filtration rate was calculated at more than 60 mL/min per 1.73 m². While in the ED, her heart rate slowed, and a repeat ECG was obtained showing a Mobitz Type I AV block with a ventricular rate of 63 beats per minute (see Figure C).

The patient was admitted to the observation unit for further moni- toring. Approximately 11.5 hours after the fingolimod dose, the pa- tient complained of worsening palpitations now associated with lightheadedness, dizziness, and a feeling of near syncope. Cardiac monitoring showed a continued Mobitz Type I AV block but with a ventricular rate of 38 beats per minute.

For symptomatic bradycardia, the patient was administered atropine resulting in symptom resolution. A repeat ECG revealed a sinus rhythm at 56 beats per minute without AV block. There were no further events during observation. The following day, a repeat ECG showed a sinus rhythm at 54 beats per minute and a first-degree AV block with a PR interval of 328 milliseconds (see Figure D). As a result of improvement in symptoms and stable vital signs, the patient was discharged to follow up with neurology and cardiology.

The most common serious adverse event observed in clinical trials with fingolimod was symptomatic bradycardia [1,2,4,5]. Modulation of cardiac sphingosine receptors by fingolimod has a dose dependent reduction in heart rate on average of 10 beats per minute [6]. In clinical trials with fingolimod, first- and second-degree block occurred up to 1.2% and 0.7%, respectively, along with a case report of a prolonged sinus pause in postmarket reports [1,2,7]. Dose-dependent transient decreases in heart rate were observed within 1 to 2 hours after initial dose and attenuated within 6 hours in phase III clinical trials [1,2].

Although most bradyarrythmias occurred within the recommended 6-hour monitoring period and were self-limited, our patient experienced persistent ECG changes that required treatment and extended moni- toring. A junctional tachycardia has not been reported thus far in the literature. In pharmacokinetic studies, a single oral dose of fingolimod caused a dramatic rise in plasma concentrations over the first 6 hours followed by slower plasma elevations, which peaked in 12 to 36 hours with a median of 28 hours [8]. Data reported in this pharmacokinetic study may explain why our patient experienced delayed and Persistent symptoms. Our patient had both normal Liver and kidney function making it unlikely that these factors contributed to the development of heart block.

0735-6757/(C) 2014

987.e2 J.M. Rosini et al. / American Journal of Emergency Medicine 33 (2015) 987.e1-987.e3

Figure. Electrocardiograms.

We report a patient who after her first dose of fingolimod developed junctional tachycardia and Mobitz Type I block beyond the manufacturer recommended 6-hour monitoring period. Delayed cardiac dysrhythmias are known to occur after first doses, which may be due to the prolonged time to peak plasma concentrations. Extended monitoring may need to be considered in select patients.

Jamie M. Rosini, PharmD

Department of Pharmacy, Christiana Care Health System

4755 Ogletown-Stanton Road Newark, DE 19718 USA

Corresponding author. 4755 Ogletown-Stanton Road LE15 Pharmacy Administration, Newark, DE 19718

Tel.: +1 302 733 5059

E-mail address: [email protected]

Suraj Rajasimhan, PharmD Shawn E. Fellows, PharmD

Department of Pharmacy, Christiana Care Health System 4755 Ogletown-Stanton Road, Newark, DE, 19718 USA

E-mail addresses: [email protected]; [email protected]

Jason T. Nomura, MD

Department of Emergency Medicine, Christiana Care Health System, 4755

Ogletown-Stanton Road, Newark, DE, 19718 USA E-mail address: [email protected]

http://dx.doi.org/10.1016/j.ajem.2014.12.037

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