Response to “Rupatadine and Heart Rhythm Disturbances”

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 The authors state that data from Spain show a statistical association between rupatadine use and heart rhythm disturbances. Such an assertion is confusing because the lower limit of their 95% confidence interval for the reporting odds ratio (ROR) of rupatadine contains the value 1. We have recalculated the 95% confidence interval for the rupatadine ROR and found it to be 0.97–10.48. The RORs for levocetirizine, desloratadine, loratadine, and ebastine are indeed statistically significant, and those of the first two are higher than that for rupatadine. The ROR, as a disproportionality measure, is only one way of selecting drug–adverse drug reaction combinations that may be of interest for clinical review, particularly when it relates to a small number of cases2; more important, ROR alone does not indicate a causal relationship. The assertion by the authors that heart rhythm disturbances can have similar consequences is erroneous: atrial extrasystoles and ventricular extrasystoles in patients without heart disease have a good prognosis, whereas patients with long QT intervals or torsade de pointes may develop syncope, ventricular fibrillation, and sudden cardiac death.3 Among the Spanish patients, patient 1 had coronary ischemia, a well-known cause of ventricular tachycardia,3 which has a 1-year induction period. In this patient, periodic clinical and Holter monitoring should have been performed in order to study the case properly. Patient 2 had prolonged QT intervals and syncope before treatment with rupatadine. Moreover, he received concomitant treatment with sertraline, which is associated with QT prolongation and ventricular arrhythmias including torsade de pointes. For these reasons, the researchers ruled out a causal relationship with rupatadine.4 Patient 3 had tachycardia, an imprecise term, and palpitations, a symptom that may or may not be caused by cardiac arrhythmia. The highest therapeutic dose of rupatadine is 10 mg/day—not 20 mg/day, as the authors state. The peak plasma concentration in healthy volunteers after 10 mg/day of rupatadine, per the authors’ reference (13), is 2.3 ng/ml (4.32 nmol/l).5 This concentration is not <1/400 of the KD but <1/500. Finally, both the title and the abstract are misleading in that they refer only to rupatadine when, in fact, the study concerns several antihistamine drugs. In conclusion, the results of the Carvajal study do not suggest a causal relationship between rupatadine and cardiotoxicity. Uriach is committed to a continual monitoring of their products for safety.