Heart Rhythm Disturbances Associated With Rupatadine: A Case Series From the Spanish and Portuguese Pharmacovigilance Systems

Carvajal, Alfonso; Macías, Diego; Salado, Inés; Sáinz, María; Ortega, Sara; Campo, C; Pozo, Javier García del; Arias, LH Martin; Velasco, A. M.; Gonçalves, Susana; Pombal, R; Carmona, Richard H.

doi:10.1038/clpt.2008.269

Cited by 11 publications

(4 citation statements)

References 27 publications

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“…14,15,31 In canine Purkinje fibers, no effect on the cardiac action potential was observed with concentrations of rupatadine and 3-hydroxydesloratadine exceeding 2000-fold the C max value of a 10-mg dose in humans. 25 Only some cases of QT prolongation were reported with rupatadine, 32 and 1 case was referred as torsade de pointes associated with rupatadine in postmarketing surveillance. 33 Nevertheless, in this case causation by rupatadine has not been accurately demonstrated because of the involvement of other factors such as concomitant administration of sertraline and a previous family history of prolonged QTc.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Safety of Rupatadine in a Single‐Ascending‐Dose and Multiple‐Ascending‐Dose Study in Healthy Japanese Subjects, Using Intensive Electrocardiogram Assessments—Comparison With the Previous White Caucasian Thorough QT Study

Täubel

Ferber

Fernandes³

et al. 2017

Clinical Pharm in Drug Dev

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A thorough QT/QTc study in healthy white Caucasian subjects demonstrated that rupatadine has no proarrhythmic potential and raised no cardiac safety concerns. The present phase 1 study aimed to confirm the cardiac safety of rupatadine in healthy Japanese subjects. In this randomized, double-blind, placebo-controlled study, 27 healthy Japanese subjects were administered single and multiple escalating rupatadine doses of 10, 20, and 40 mg or placebo. Triplicate electrocardiogram (ECG) recordings were performed on days −1, 1, and 5 at several points, and time-matched pharmacokinetic samples were also collected. Concentration-effect analysis based on the change in the QT interval corrected using Fridericia's formula (QTcF) from average baseline was performed. Data from the formal TQT study in white Caucasian subjects was used for a comparison analysis. The ECG data for rupatadine at doses up to 40 mg did not show an effect on the QTc interval of regulatory concern. The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a significant shortening of QTcF on days 1 and 5 four hours after a standardized meal. The data from this study exhibited no statistically significant differences in the QTc effect between Japanese and white Caucasian subjects. Keywords rupatadine, Japanese, cardiac safety, food effect, assay sensitivityThe International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline E14 recommends that the QTprolonging potential of a drug be evaluated primarily by a specific "thorough QT" (TQT) study. 1 In 2005, when the ICH was first adopted, it was not expected that the results of a TQT would be influenced by ethnic factors. However, emerging clinical experience has suggested that interethnic differences can be of particular relevance when assessing the safety of some drugs. 2 Since 2010, when the ICH E14 was fully adopted in Japan, the suitability of foreign data to provide proarrhythmic liability information concerning the Japanese population is still under assessment. Nevertheless, more efficient approaches to reduce the associated costs and alternatives to a conventional TQT study have been extensively discussed to modify the current regulatory requirements now allowing thorough QT assessments in other trials.

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Section: Discussionmentioning

confidence: 99%

Cardiac Safety of Rupatadine in a Single‐Ascending‐Dose and Multiple‐Ascending‐Dose Study in Healthy Japanese Subjects, Using Intensive Electrocardiogram Assessments—Comparison With the Previous White Caucasian Thorough QT Study

Täubel

Ferber

Fernandes³

et al. 2017

Clinical Pharm in Drug Dev

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“…There are two recent reports on the cardiac effects of rupatadine [27, 28]. In the first, the authors state that data from Spain show a statistical association between rupatadine use and heart rhythm disturbances.…”

Section: Discussionmentioning

confidence: 99%

“…There are two recent reports on the cardiac effects of rupatadine [27,28]. In the first, the authors state that data…”

Section: Discussionmentioning

confidence: 99%

No cardiac effects of therapeutic and supratherapeutic doses of rupatadine: results from a ‘thorough QT/QTc study’ performed according to ICH guidelines

Donado

Izquierdo²,

Pérez³

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Drug-induced prolongation of QTc interval on the ECG increases the risk of ventricular tachyarrhythmias.• This problem beset the antihistamine class of drugs in the 1990s and resulted in the withdrawal of two drugs, terfenadine and astemizole. • In 2005 the International Conference onHarmonization approved guideline E14, which has been termed a 'thorough QT/QTc study' , for the routine clinical testing of the proarrhythmic potential of pharmacotherapy. WHAT THIS PAPER ADDS• To our knowledge, this is one of the first published trials to evaluate multiple doses of antihistamine therapy using the new criteria and it confirms the cardiac safety of rupatadine, an anti-H1 compound with activity on platelet-activating factor. AIMSTo evaluate the effects of therapeutic and supratherapeutic doses of rupatadine on cardiac repolarization in line with a 'thorough QT/QTc study' protocol performed according to International Conference on Harmonization guidelines. METHODSThis was a randomized (gender-balanced), parallel-group study involving 160 healthy volunteers. Rupatadine, 10 and 100 mg day -1 , and placebo were administered single-blind for 5 days, whilst moxifloxacin 400 mg day -1 was given on days 1 and 5 in open-label fashion. ECGs were recorded over a 23-h period by continuous Holter monitoring at baseline and on treatment days 1 and 5. Three 10-s ECG samples were downloaded at regular intervals and were analysed independently. The primary analysis of QTc was based on individually corrected QT (QTcI). Treatment effects on QTcI were assessed using the largest time-matched mean difference between the drug and placebo (baseline-subtracted) for the QTcI interval. A negative 'thorough QT/QTc study' is one where the main variable is around Յ5 ms, with a one-sided 95% confidence interval that excludes an effect >10 ms. RESULTSThe validity of the trial was confirmed by the fact that the moxifloxacin-positive control group produced the expected change in QTcI duration (around 5 ms). The ECG data for rupatadine at both 10 and 100 mg showed no signal effects on the ECG, after neither single nor repeated administration. Furthermore, no pharmacokinetic/pharmacodynamic relationship, gender effects or clinically relevant changes in ECG waveform outliers were observed. No deaths or serious or unexpected adverse events were reported. CONCLUSIONSThis 'thorough QT/QTc study' confirmed previous experience with rupatadine and demonstrated that it had no proarrhythmic potential and raised no concerns regarding its cardiac safety.

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“…To the Editor: We would like to comment on some aspects of the article by Carvajal et al , “Heart Rhythm Disturbances Associated With Rupatadine: A Case Series From the Spanish and Portuguese Pharmacovigilance Systems.” 1 …”

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confidence: 99%

Rupatadine and Heart Rhythm Disturbances

Fite

Borja

2009

Clin Pharmacol Ther

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Heart Rhythm Disturbances Associated With Rupatadine: A Case Series From the Spanish and Portuguese Pharmacovigilance Systems

Cited by 11 publications

References 27 publications

Cardiac Safety of Rupatadine in a Single‐Ascending‐Dose and Multiple‐Ascending‐Dose Study in Healthy Japanese Subjects, Using Intensive Electrocardiogram Assessments—Comparison With the Previous White Caucasian Thorough QT Study

Cardiac Safety of Rupatadine in a Single‐Ascending‐Dose and Multiple‐Ascending‐Dose Study in Healthy Japanese Subjects, Using Intensive Electrocardiogram Assessments—Comparison With the Previous White Caucasian Thorough QT Study

No cardiac effects of therapeutic and supratherapeutic doses of rupatadine: results from a ‘thorough QT/QTc study’ performed according to ICH guidelines

Rupatadine and Heart Rhythm Disturbances

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