Eur J Clin Pharmacol (2015) 71:379–381 DOI 10.1007/s00228-014-1804-9
LETTER TO THE EDITORS
QT prolongation induced by hydroxyzine: a pharmacovigilance case report Jonathan Vigne & Joachim Alexandre & Fabienne Fobe & Paul Milliez & Magalie Loilier & Sophie Fedrizzi & Antoine Coquerel
Received: 1 December 2014 / Accepted: 29 December 2014 / Published online: 28 January 2015 # Springer-Verlag Berlin Heidelberg 2015
Background Hydroxyzine is a first-generation antihistamine, antagonist of central and peripheral H1 receptors with anticholinergic properties. Marketed in France under the name Atarax®, it has been approved in the treatment of chronic urticaria, mild forms of anxiety, second-line therapy of insomnia in the child up to 6-year-old, and in premedication prior to general anesthesia. We report a severe QT prolongation exposing to risks
J. Vigne : J. Alexandre : M. Loilier : S. Fedrizzi : A. Coquerel Department of Pharmacology and Pharmacovigilance, CHU de Caen, Caen 14032, France J. Alexandre : P. Milliez Department of Cardiology, CHU de Caen, Caen 14032, France J. Vigne : J. Alexandre : P. Milliez Université de Caen Basse-Normandie, EA 4650 Signalisation, électrophysiologie et imagerie des lésions d’ischémie-reperfusion myocardique, Caen 14032, France F. Fobe Department of Anesthesiology, CHU de Caen, Caen 14032, France P. Milliez : A. Coquerel Université de Caen Basse-Normandie, Medical School, Caen14032, France A. Coquerel Inserm, U 1075 COMETE, UFR de Médecine, Avenue de la Côte de Nacre, CS 14032, Cedex 5, Caen, France A. Coquerel (*) Department of Pharmacology and Pharmacovigilance, CHU de Caen, Avenue de la côte de nacre, 14000 Caen, France e-mail:
[email protected]
of torsades de pointe (TdP) and sudden cardiac death during a per os medication at high posology with hydroxyzine.
Case report A 72-year-old man was admitted to our emergency department (day 0) with a 3-day history of worsening pruritus without fever. Examination revealed a bile duct obstruction with a mixed increase in total and conjugated bilirubin (up to 500 and 300 μmol/L, respectively). His past medical history included diabetes, chronic pancreatitis, and ischemic cardiomyopathy; there was no renal failure (GFR = 91 mL/min/1.73 m2 , Cockcroft-Gault formula). Patient’s medication was as follows: irbesartan (150 mg.day−1), clopidogrel (75 mg.day−1), simvastatine (20 mg. day−1), and insuline. Before hydroxyzine treatment, QTc was determined at 450 ms (QT manually measured, QTc calculated with the Bazett’s formula [1]). At day 1, hydroxyzine was introduced (100 mg.day−1 then 175 mg.day−1 the next 2 days) to treat pruritus (Fig. 1). From day 4, the patient presented several syncopal events concomittant with a QTc prolongation (measured at 590 and 582 ms respectively at day 6 and 10), acute renal and liver failures, a 45/min sinus bradycardia and a hypokalemia at 3.3 mmol/L. Hydroxyzine blood levels at day 6 and 10 were 96 and 506 ng/mL, respectively (quantified by high performance liquid chromatography coupled with tandem mass spectrometry, usual therapeutic concentration: 50–100 ng/mL [2]). Torsades de pointes (TdP) have not been recorded (no ECG performed during syncope) but were highly suspected. Hydroxyzine was stop and hypokalemia corrected. QTc returned progressively to normal value without recurrence of syncope after hydroxyzine discontinuation.
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Eur J Clin Pharmacol (2015) 71:379–381
Fig. 1 a Left: represents a 12-lead ECG of the patient at day 10; QTc was measured at 582 ms. b Right: evolution of biological parameters, corrected QT interval (QTc), and heart rate (HR). QTc and hydroxyzine
blood level are represented on the right axis, the other parameters on the left axis. The two markers (up-down arrow) indicate syncope. GFR glomerular filtration rate, GPT glutamate pyruvate transaminase
Discussion
already well-known TdP risks factors (including hypokalemia and bradycardia) could induce QT prolongation and lifethreatening TdP. The present work underlines the recent addition of hydroxyzine to the list of drugs with conditional risk of TdP and drugs to be avoided by patients with congenital long QT syndrome [8]. It also reminds that recommended hydroxyzine’s posology must be respected, the risk of QT prolongation and syncope increases dramatically in case of an overdose. Finally, considering the large use of the molecule, the recurrence of hydroxyzine-induced QT prolongation is probably underestimated. Information must be given to clinician.
In the last decades, number of drugs were withdrawn due to cases of TdP [3], leading to intensify assessment of drug QT interval. In our case, hydroxyzine was identified as the only drug able to induce QTc interval prolongation in the patient’s active medication. Moreover, a hydroxyzine overdose was detected probably due to high posology, bile ducts obstruction, and liver impairment (rise in GPT). Cetirizine is the hydroxyzine’s major active metabolite; unfortunately, its blood level dosage was not performed. We suppose that combination of hydroxyzine overdose and transient renal failure could have lead to cetirizine accumulation. However, cetirizine seems to be safe regarding ventricular repolarization, even at supratherapeutic dose [4]. There’s only one published clinical case of hydroxyzine-induced QT prolongation. This case describes recurrent syncope during hydroxyzine treatment at usual posology in a 34-year-old woman presenting a hERG mutation [5]. hERG gene codes for the α subunit of a potassium channel (IKr) implicated in the ventricular repolarization. Experimentally, it was shown that hydroxyzine could be proarrhythmic by blocking hERG channels and therefore prolonging action potential duration [6], thus inducing TdP. In the French pharmacovigilance database, we found 24 cases of QT prolongation mentioning hydroxyzine with a suspected accountability assumed in 7 cases [7]. We publish here the first clinical case of hydroxyzineassociated QT prolongation with drug dosage data. The association of hydroxyzine, especially at high posology, and others
Conflicts of interest There are no competing interests to declare.
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Eur J Clin Pharmacol (2015) 71:379–381 5. Sakaguchi T, Itoh H, Ding W-G et al (2008) Hydroxyzine, a first generation H(1)-receptor antagonist, inhibits human ether-a-go-gorelated gene (HERG) current and causes syncope in a patient with the HERG mutation. J Pharmacol Sci 108:462–471 6. Lee BH, Lee SH, Chu D et al (2011) Effects of the histamine H(1) receptor antagonist hydroxyzine on hERG K(+) channels and cardiac
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