Overview

Donepezil is a reversible acetylcholinesterase inhibitor that enhances acetylcholine levels in the brain.¹ Donepezil is indicated for the treatment of dementia in Alzheimer’s disease. In Malaysia, there are currently 21 products containing donepezil registered with the Drug Control Authority (DCA).²

The QT interval on an electrocardiogram (ECG) represents the interval between the onset of ventricular depolarisation to the end of ventricular repolarisation.³  QT prolongation usually signals an abnormally delayed ventricular repolarisation.^3-4 Excessive QT prolongation may predispose patients to develop Torsade de Pointes (TdP), a type of life-threatening ventricular tachycardia that may worsen to ventricular fibrillation and lead to cardiac arrest.⁴

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) learned through its global safety signal monitoring activity that the European Medicines Agency (EMA) had requested all product registration holders for donepezil-containing products to update package inserts with the risk of QT prolongation and TdP.⁵ Following a review of the literature and post-marketing adverse drug reaction reports, EMA considered that there is at least a reasonably possible causal relationship between donepezil and QT interval prolongation and TdP.

There are a few explanations provided for the mechanisms underlying donepezil-induced QT prolongation and TdP. As in most drug-induced instances, it is considered to be due to the inhibition of hERG-encoded potassium channels that mediate the cardiac rapid delayed rectifier current (I_kr) for cardiac repolarisation.^3-4,6-7 Apart from inhibiting hERG channels in preclinical safety studies, donepezil has also been shown to impair hERG channel trafficking and expression in the plasma membrane.^6-7 Another proposed mechanism is that increased acetylcholine levels as a result of donepezil’s acetylcholinesterase inhibition may promote the activation of voltage gated calcium channels.⁸ The subsequent elevated intracellular calcium levels may in turn prolong phase 2 of the cardiac action potential cycle, thereby increasing the risk of ventricular arrhythmias.

Kho et al. (2021) reported long-term use of donepezil (for more than a year) and concomitant use of tricyclic antidepressants were associated with significant QT prolongation.⁹ The majority of post-marketing cases recorded in VigiBase (the World Health Organisation (WHO) Global ICSR Database) reported outcomes of recovering or recovered after the withdrawal of donepezil.¹⁰ All seven (7) published cases of QT prolongation/TdP reviewed by Malik et al. (2019) showed reduced QT interval following interventions, of which six (6) reported withdrawal of donepezil and one (1) reported a switch to amlodipine from benidipine, which was thought to potentially interact with donepezil.⁸

Adverse Drug Reaction Reports¹¹

To date, the NPRA had received 69 reports with 116 adverse events suspected to be related to donepezil-containing products. The most frequently reported adverse events were from System Organ Class (SOC) Gastrointestinal Disorders, which include vomiting (14 events), followed by diarrhoea (10), and nausea (9). No reports of QT prolongation nor TdP received locally thus far. However, there were locally reported events of bradycardia (5), first-degree heart block (1), sinoatrial block (1), electrocardiogram PR prolongation (1), and syncope (2).

Advice for Healthcare Professionals

• Be aware of the risk of QT prolongation and TdP associated with donepezil.
• Prescribe donepezil with caution in patients with underlying risk factors for QT prolongation and TdP:
  • pre-existing or family history of QT prolongation;
  • relevant pre-existing cardiac diseases (e.g., heart failure, myocardial infarction, and bradycardia);
  • concomitant use of drugs known to affect the QT interval (e.g., certain antiarrhythmics, antidepressants, antipsychotics, and antibiotics);
  • significant electrolyte disturbances (e.g., hypocalcaemia, hypokalaemia, and hypomagnesaemia).

If required, correct modifiable risk factors (e.g., electrolyte disturbances or interacting drugs) as far as possible before prescribing donepezil.

• Consider ECG evaluation before and after donepezil initiation, and as part of the clinical monitoring of at-risk patients.
• Educate patients to seek immediate medical attention if they exhibit signs and symptoms of QT prolongation and TdP, such as fast, irregular heartbeat or fainting.
• When QT prolongation and TdP are suspected, consider discontinuing donepezil or managing the use of potentially interacting drugs.
• Report all suspected adverse events associated with donepezil-containing products to the NPRA.

NPRA had completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (18) Jld.1] had been issued for all registration holders of products containing donepezil to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). Aricept Evess 5mg, 10mg Orodispersible Tablet [Package Insert]. 2022 Nov [cited 2022 Nov 14]. The Malaysian Product Registration Database (QUEST). Available from: https://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2022 [cited 2022 Nov 14]. Available from: https://www.npra.gov.my
3. Khatib R, Sabir FRN, Omari C, Pepper C, Tayebjee MH. Managing drug-induced QT prolongation in clinical practice. Postgrad Med J. 2021 Jul;97(1149):452-458. Available from: https://doi.org/10.1136/postgradmedj-2020-138661
4. Huang Y, Alsabbagh MW. Comparative risk of cardiac arrhythmias associated with acetylcholinesterase inhibitors used in treatment of dementias - A narrative review. Pharmacol Res Perspect. 2020 Aug;8(4):e00622. Available from: https://doi.org/10.1002/prp2.622
5. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC) Recommendations on signals. Adopted at the 5-8 July 2021 PRAC meeting [Internet]. 2021 Aug 2 [cited 2022 Nov 14]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-5-8-july-2021-prac-meeting_en.pdf
6. Malone K, Hancox JC. QT interval prolongation and Torsades de Pointes with donepezil, rivastigmine and galantamine. Ther Adv Drug Saf. 2020 Aug 17;11:2042098620942416. Available from: https://doi.org/10.1177/2042098620942416
7. Health Sciences Authority. QT prolongation and Torsades de Pointes with donepezil [Internet]. 2022 [cited 2022 Nov 14]. Available from: https://www.hsa.gov.sg/announcements/safety-alert/qt-prolongation-and-torsades-de-pointes-with-donepezil
8. Malik, B. H., Hamid, P., Khan, S., Gupta, D., & Islam, M. (2019). Correlation Between Donepezil and QTc Prolongation and Torsades de Pointes: A Very Rare Phenomenon. Cureus, 11(12), e6451. Available from: https://doi.org/10.7759%2Fcureus.6451
9. Kho J, Ioannou A, Mandal AKJ, Cox A, Nasim A, Metaxa S, Missouris CG. Long term use of donepezil and QTc prolongation. Clin Toxicol (Phila). 2021 Mar;59(3):208-214. Available from: https://doi.org/10.1080/15563650.2020.1788054
10. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2022 [cited 2022 Nov 8]. Available from: https://www.vigilyze.who-umc.org (access restricted)
11. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2022 [cited on 2022 Nov 8]. Available from: https://www.npra.gov.my (access restricted)

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgment. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Written by: Wang Khee Ing
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr. Azuana Ramli