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 judgement. 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.

Overview

Rivastigmine is a brain-selective, dual acetyl- and butyryl-cholinesterase inhibitor indicated for the treatment of dementia associated with Alzheimer’s and Parkinson’s disease.^1-2 It helps slow down the degradation of acetylcholine and facilitate cholinergic neurotransmission, which is involved in attention, learning, memory and other cognitive processes. In Malaysia, there are currently 17 products containing rivastigmine registered with the Drug Control Authority (DCA).³

The QT interval on an electrocardiogram (ECG) represents the interval between the onset of ventricular depolarisation and the end of ventricular repolarisation.⁴ QT prolongation usually signals an abnormally delayed ventricular repolarisation.^4,5 Excessive QT prolongation may predispose patients to develop Torsade de Pointes (TdP), a type of life-threatening ventricular tachycardia that can worsen to ventricular fibrillation and lead to cardiac arrest.⁵

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) learned through its global safety signal monitoring activity that the Japan Pharmaceuticals and Medical Devices Agency (PMDA) had requested all product registration holders for rivastigmine-containing products to update package inserts with the risks of QT prolongation and TdP.⁶ Following a review of post-marketing adverse reaction reports in Japan and globally, the PMDA considered that there is at least a reasonably possible causal relationship between rivastigmine and QT interval prolongation.⁷

QT prolongation and TdP have been reported in patients treated with certain cholinesterase inhibitor products, including rivastigmine. One of the common underlying mechanisms involves inhibition of acetylcholinesterase, resulting in elevated acetylcholine levels. Subsequently, stimulation of voltage-gated calcium channels occurs, raising intracellular calcium levels and leading to prolongation of QT interval.^5,8 Another mechanism relates to bradycardia-associated QT prolongation, which arises from increased vagal tone caused by elevated acetylcholine levels.^5,9 Bradycardia,  a known side effect of all acetylcholinesterase inhibitors, is identified as a risk factor for TdP in patients with QT prolongation and certain underlying risks.^1-2,5

Adverse Drug Reaction Reports¹⁰

Till date, the NPRA had received 120 reports with 211 adverse events suspected to be related to rivastigmine-containing products. The most reported adverse events were pruritus (22 reports), followed by vomiting (14) and dizziness (13). Thus far, no report of QT prolongation nor TdP has been received. However, there were locally reported events of bradycardia (4) and atrioventricular block complete (1).

Advice for Healthcare Professionals

• Be aware of the risks of QT prolongation and TdP associated with certain cholinesterase inhibitor products including rivastigmine.
• Prescribe rivastigmine with caution in patients with underlying risks of QT prolongation and TdP:
  • pre-existing or family history of QT prolongation;
  • concomitant use of drugs known to affect the QT interval (e.g., certain antiarrhythmics, antidepressants, antipsychotics, and antibiotics);
  • relevant pre-existing cardiac diseases (e.g., uncompensated heart failure, recent myocardial infarction, and bradyarrhythmias); or
  • significant electrolyte disturbances (e.g., hypokalaemia and hypomagnesaemia).

   If possible, correct modifiable risk factors (e.g., electrolyte disturbances or interacting drugs) before prescribing rivastigmine.

• Consider electrocardiogram (ECG) evaluation before and after rivastigmine initiation, and as part of the clinical monitoring of at-risk patients.
• Counsel patients to immediately tell the doctor if they develop signs and symptoms of QT prolongation and TdP such as fast, irregular heart beat or fainting.
• When QT prolongation and TdP are suspected, consider discontinuing rivastigmine or managing the use of potentially interacting drugs.
• Report all suspected adverse events associated with rivastigmine-containing products to the NPRA.

Regulatory Actions

NPRA had completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (34) Jld.1] had been issued for all registration holders of products containing rivastigmine to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

A similar safety alert on donepezil and the risks of QT prolongation & torsade de pointes was published on 16^th January 2023.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). Exelon 1.5mg, 3mg, 4.5mg and 6mg Capsule [Package Insert]. 2023 Jan. [Cited 2023 Nov 29]. The Malaysian Product Registration Database (QUEST). Available from: https://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). Exelon Patch 5, 10 and 15 [Package Insert]. 2023 Jan. [Cited 2023 Nov 29]. The Malaysian Product Registration Database (QUEST). Available from: https://www.npra.gov.my
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2023 [Cited 2023 Oct 24]. Available from: https://www.npra.gov.my
4. 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
5. 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
6. Japan Pharmaceuticals and Medical Devices Agency (PMDA). Revision of Precautions – Rivastigmine [Internet]. 2023 Aug 29 [cited 2023 Nov 29]. Available from: https://www.pmda.go.jp/files/000263937.pdf
7. Japan Pharmaceuticals and Medical Devices Agency (PMDA). Summary of investigation results – Rivastigmine [internet]. 2023 Aug 29 [cited 2023 Nov 29]. Available from: https://www.pmda.go.jp/files/000263942.pdf
8. Torres-Yaghi Y, Carwin A, Carolan J, Nakano S, Amjad F, Pagan F. QTc Interval Prolongation with Therapies Used to Treat Patients with Parkinson's Disease Psychosis: A Narrative Review. Neuropsychiatr Dis Treat. 2021 Dec 24;17:3791-3818. Available from: https://doi.org/10.2147/ndt.s324145
9. 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
10. 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)

Written by: Wang Khee Ing
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali