QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of fingolimod and abarelix. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for fingolimod, when combined with abarelix (100%). We do not expect any change in exposure for abarelix, when combined with fingolimod (100%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
The bioavailability of fingolimod is unknown. Protein binding [ Pb ] is not known. The metabolism does not take place via the common cytochromes.
The bioavailability of abarelix is unknown. The terminal half-life [ t12 ] is rather long at 316.8 hours and constant plasma levels [ Css ] are only reached after more than 1267.2 hours. The protein binding [ Pb ] is 97.5% strong. The metabolism via cytochromes is currently still being worked on.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither fingolimod nor abarelix increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither fingolimod nor abarelix increase anticholinergic activity.
QT time prolongation
Rating: In combination, fingolimod and abarelix can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||fin||aba|
|Abdominal pain||11.0 %||11.0||n.a.|
|Atrioventricular block||4.7 %||4.7||n.a.|
|Malignant melanoma||0.7 %||0.7||n.a.|
Progressive multifocal leukoencephalopathy: fingolimod
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: Fingolimod, a sphingosine 1-phosphate (S1P) receptor subtype 1, 3, 4 and 5 modulator, has been used for the treatment of patients with relapsing forms of multiple sclerosis, but atrioventricular conduction block and/or QT-interval prolongation have been reported in some patients after the first dose. In this study, we directly compared the electropharmacological profiles of fingolimod with those of siponimod, a modulator of sphingosine 1-phosphate receptor subtype 1 and 5, using in vivo guinea-pig model and in vitro human ether-a-go-go-related gene (hERG) assay to better understand the onset mechanisms of the clinically observed adverse events. Fingolimod (0.01 and 0.1mg/kg) or siponimod (0.001 and 0.01mg/kg) was intravenously infused over 10min to the halothane-anaesthetized guinea pigs (n=4), whereas the effects of fingolimod (1μmol/L) and siponimod (1μmol/L) on hERG current were examined (n=3). The high doses of fingolimod and siponimod induced atrioventricular conduction block, whereas the low dose of siponimod prolonged PR interval, which was not observed by that of fingolimod. The high dose of fingolimod prolonged QT interval, which was not observed by either dose of siponimod. Meanwhile, fingolimod significantly inhibited hERG current, which was not observed by siponimod. These results suggest that S1P receptor subtype 1 in the heart could be one of the candidates for fingolimod- and siponimod-induced atrioventricular conduction block since S1P receptor subtype 5 is localized at the brain, and that direct IKr inhibition may play a key role in fingolimod-induced QT-interval prolongation.
Abstract: BACKGROUND AND PURPOSE: The aim of this study was to investigate the correlation between the duration of the QTc interval and the brain lesion load at the level of the structures involved in superior autonomic control (insula, cingulate cortex and amygdala-hippocampus) in multiple sclerosis (MS) patients. METHODS: Thirty-one consecutive patients with relapsing-remitting MS were recruited. The QT interval was measured manually in all 12 leads by a single blinded observer, with the longest QT value adjusted for heart rate by using the Bazett's formula. All patients performed a brain magnetic resonance imaging (MRI) scan including three-dimensional double inversion recovery and three volumetric fast-field echo sequences. The following MRI measures were obtained: (i) global and regional cortical thickness (CTh); (ii) white matter lesion load volume; (iii) cortical damage blindly assessed by a trained observer who assigned, on the basis of the number of cortical lesions, a score from 0 to 5 for each of the brain areas analysed. RESULTS: In all, 16% of the patients had an increased QTc interval. The QTc interval was correlated with disease duration, cortical insular lesion volume and grey matter lesion volume in the three examined areas and inversely correlated with global and insular CTh. CONCLUSIONS: An increased QTc interval in patients with MS may have a cerebral origin possibly driven by involvement of the insular cortex. With the recent introduction in clinical practice of treatments with potential cardiac effects such as fingolimod, the recognition of a long QTc interval could be clinically crucial and should encourage appropriate electrocardiographic monitoring in order to prevent the risk of malignant ventricular pro-arrhythmia and iatrogenic sudden death.
Abstract: Cardiac arrhythmias and ECG abnormalities including bradycardia, prolongation of the QT interval, and atrioventricular (AV) conduction blocks have been extensively observed with fingolimod, the first marketed oral drug for treating the relapsing-remitting form of multiple sclerosis. This study was aiming to further elucidate the effects of fingolimod on cardiac electrophysiology at three different levels: (i) in vitro, (ii) ex vivo, and (iii) in vivo. (i) Patch-clamp experiments in whole cell configuration were performed on Ca1.2-transfected tsA201 cells exposed to fingolimod-phosphate 100 or 500 nmol/L (n = 27 cells, total) to measure drug effect on L-type calcium current (I). (ii) Langendorff perfusion experiments were undertaken on male Hartley guinea-pigs isolated hearts (n = 4) exposed to fingolimod 10 and 100 nmol/L to evaluate drug-induced effects on monophasic action potential duration measured at 90% repolarization (MAPD). (iii) Implanted cardiac telemeters were used to record ECGs in guinea-pigs (n = 7) treated with a single dose of fingolimod 0.0625 mg/kg suspension, administered as an oral gavage. (i) In vitro cellular experiments showed that fingolimod-phosphate causes a concentration-dependent reduction in I. (ii) Ex vivo Langendorff experiments revealed that fingolimod had no significant effect on MAPD. (iii) Fingolimod caused significant prolongations of the RR, PR, QT, and QTcintervals in vivo. Reversible AV blocks were also observed in 7/7 animals. Fingolimod possesses I-blocking properties, further contributing to its AV conduction-slowing effects. These properties are also consistent with its mitigated effect on the QT interval in humans, despite previously shown HERG-blocking effect.