QT prolongation and Torsades de Pointes with donepezil

Donepezil is a specific and reversible inhibitor of acetylcholinesterase registered under several brand names in Singapore since 1998.  It is indicated for the symptomatic treatment of mild to moderate and severe Alzheimer’s dementia. Cases of QT prolongation and Torsades de Pointes (TdP) associated with donepezil have been reported overseas and in published literature.

About QT prolongation and Torsades de Pointes^1-3

QT prolongation refers to a delayed interval between the onset of ventricular depolarisation to the end of ventricular repolarisation, which can predispose to arrhythmias. It can either be congenital or acquired, with the latter being more prevalent. Acquired QT prolongation is often drug-induced or a result of structural heart disease such as myocardial infarction and left ventricular hypertrophy.

Excessive QT prolongation could lead to TdP, a potentially life-threatening form of polymorphic ventricular tachycardia that may manifest as palpitations, syncope, seizure-like activity or sudden cardiac arrest. Risk factors for TdP include older age (>65 years), female gender, uncorrected electrolyte imbalances, family history of QT prolongation, pre-existing cardiovascular disease (e.g., heart failure, myocardial infarction, bradycardia), and recent cardioversion with QT-prolonging drugs.

Many drugs associated with QT prolongation and TdP inhibit potassium channels that mediate the cardiac rapid delayed rectifier current (I_kr), which in turn leads to a prolonged ventricular action potential duration and an extended repolarisation phase. These channels are encoded by KCNH2 or hERG. In preclinical safety evaluation using mammalian expression system, donepezil and its metabolites have been found to inhibit the hERG channel ionic current recorded from hERG channels. In addition to channel inhibition, donepezil also impairs channel trafficking to the cell membrane and decreases mature channel membrane density.

Findings from recent published literature

Kho et al. conducted a single-centre retrospective analysis to investigate the effect of long-term donepezil therapy on electrocardiogram (ECG) changes, in particular its effects on the QT interval.⁴ A resting 12-lead ECG obtained during the most recent acute hospital admission was compared to the ECG prior to commencing donepezil therapy. Fifty-nine patients who were on donepezil therapy for at least a year and 53 controls (matched for age, gender, ethnicity and comorbidities) were included in the study.

The study found that long-term use of donepezil (≥1 year) was associated with significantly prolonged QT intervals (393.3 ± 35.6ms at baseline vs 411.9 ± 44.6ms on donepezil; p=0.002), and the results remained consistent across the QT corrected using Bazett (QTcB), Fredericia, Framingham and Hodges formulae. Among those treated with donepezil, 16 male and 11 female patients presented with QT prolongation, defined in the study as QTcB interval ≥450ms and ≥460ms respectively, with the longest QTcB interval at 570ms. Of these patients, 11 males and five females had normal corrected QT intervals prior to starting treatment. In contrast, no cases of QT prolongation nor any significant changes to the QT intervals were noted in the control group (393.3 ± 36.1ms vs 387.4 ± 37.0ms; p=0.156). Donepezil was also found to increase the PR (177.0 ± 29.0ms vs 186.1 ± 34.2ms; p=0.04) and QRS (101.7 ± 20.3ms vs 104.7 ± 22.3ms; p=0.04) intervals, but no dose- or treatment duration-related differences were observed. Based on their findings, the authors recommended that ECG evaluation should take place before and after donepezil initiation.

Regulatory actions taken by overseas regulatory agencies

In July 2021, the European Medicines Agency (EMA) assessed that donepezil may increase the risk of cardiac conduction disorders including QT prolongation and TdP.⁵ Their review considered information from spontaneous adverse event reports and published literature. The EMA recommended for the addition of warnings on QT prolongation and TdP and interactions with other medicinal products known to prolong the QT interval to the package inserts (PIs) of donepezil products.

Similar updates on cardiac conduction disorders were made to the Australian PIs for donepezil following the Australian Therapeutic Goods Administration’s (TGA) review of evidence from published literature and domestic and international post-market adverse event data.⁶

Local situation

To date, HSA has not received any local reports of QT prolongation or TdP associated with donepezil. HSA is in the process of working with the product registrants to include warnings on QT prolongation and TdP in the local PIs of donepezil products. 

HSA’s advisory

Healthcare professionals are advised to consider the risk of QT prolongation or TdP when prescribing donepezil to patients with pre-existing or family history of QT prolongation, relevant pre-existing cardiac disease (e.g., decompensated heart failure, recent myocardial infarction, bradyarrhythmias), electrolyte disturbances (hypokalaemia, hypomagnesaemia), or taking concomitant drugs known to affect the QT interval (Table 1). They may wish to consider ECG evaluation as part of the clinical monitoring of at-risk patients.

Table 1. Common drugs known to prolong QT interval

Drug class	Examples
Class IA antiarrhythmics	Quinidine
Class III antiarrhythmics	Amiodarone, sotalol
Antidepressants	Citalopram, escitalopram, amitriptyline
Antipsychotics	Phenothiazine derivatives, sertindole, pimozide, ziprasidone
Antibiotics	Clarithromycin, erythromycin, levofloxacin, moxifloxacin

 

References

1. Postgrad Med J 2021; 97: 452-458
2. Curr Cardiol Rev 2016; 12: 141-154
3. Ther Adv Drug Saf 2020; 11: 1-14
4. Clin Toxicol 2021; 59: 208-214
5. https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-5-8-july-2021-prac-meeting_en.pdf
6. https://www.tga.gov.au/publication-issue/donepezil-and-cardiac-conduction-disorders

Published: 30 Aug 2022

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