ADR that result in revision of patient information
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| Singapore: QT prolongation and Torsades de Pointes with donepezil |
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Health Sciences Authority (HSA) announces that cases of QT prolongation and Torsades de Pointes (TdP) associated with donepezil have been reported overseas and in 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. 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.
In Jul 2021, the European Medicines Agency (EMA) assessed that donepezil may increase the risk of cardiac conduction disorders including QT prolongation and TdP. The 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.
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. 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. They may wish to consider ECG evaluation as part of the clinical monitoring of at-risk patients.
Please refer to the following website in HSA for details:
http://www.hsa.gov.sg/announcements/safety-alert/qt-prolongation-and-torsades-de-pointes-with-donepezil
In Hong Kong, there are 35 registered pharmaceutical products containing donepezil. All products are prescription-only medicines. So far, the Department of Health (DH) has not received any case of adverse drug reaction related to donepezil.
Related news was previously issued by TGA and Health Canada, and was posted on the Drug Office website on 1 Mar 2022 and 20 Jul 2022. Letters to inform local healthcare professionals were issued by the DH on 1 Mar 2022 and 20 Jul 2022. As previously reported, the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Wednesday, Aug 31, 2022
Issued at HKT 16:00
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