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, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

Overview of Products

Amiodarone is a class III antiarrhythmic agent commonly used to suppress life-threatening arrhythmias such as ventricular tachyarrhythmia, particularly among end-stage heart failure patients.^1,2 It is also indicated for the treatment of atrial and nodal rhythm disorders, among others.³

In Malaysia, there are currently seven (7) products containing amiodarone registered with the Drug Control Authority (DCA), available in either oral or injectable forms.⁴

 

Overview of Safety Concern

Primary graft dysfunction (PGD) is defined as dysfunction of the left, right or both ventricles that occurs within 24 hours after heart transplantation, which cannot be explained by other causes such as hyperacute rejection, pulmonary hypertension, or severe intraoperative bleeding.^5,6 PGD is the primary cause of early mortality following heart transplantation, with the highest risk of death observed in patients with severe PGD, requiring mechanical circulatory support.^2,6,7

 

Source of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from Health Canada regarding the risk of PGD post-heart transplantation associated with pre-transplant amiodarone use.⁸ The safety review was initiated after a labelling update in the United Kingdom. Health Canada conducted an assessment based on data provided by manufacturers, reports from the Canada Vigilance database and published scientific literature.

The review concluded that there is sufficient evidence to support an increased risk of PGD in patients who received amiodarone prior to heart transplantation. Consequently, Health Canada has required updates to the product information for amiodarone-containing medicines to include this identified risk.

 

Background of the Safety Issue

The mechanism by which pre-transplant amiodarone use may result in PGD remains unclear.¹ Due to its long half-life, tissue concentrations of amiodarone may remain high after heart transplantation, allowing the drug to enter the cardiac graft, where it may exert negative chronotropic and inotropic effects, potentially impairing early graft function.⁹

Several studies have reported a 1.3- to 3.7-fold increased risk of PGD in patients treated with amiodarone before heart transplantation.^1,2,7,10 Evidence also suggests that higher amiodarone doses may elevate the risk of severe PGD.^9,10 Therefore, healthcare professionals should carefully evaluate the need to reduce or discontinue amiodarone therapy in patients awaiting heart transplantation.¹ This approach is supported by findings indicating that lowering the dose or stopping amiodarone use may decrease the likelihood of PGD post-transplant.

 

Local Adverse Drug Reaction Reports¹¹

To date, the NPRA has received 496 reports with 878 adverse events suspected to be related to amiodarone-containing products. The most frequently reported adverse events were an increase in alanine aminotransferase (156), aspartate aminotransferase (68) and hepatic enzymes in general (65). No reports of PGD post-heart transplantation following use of amiodarone have been received locally.

 

Regulatory Actions

The NPRA has completed a review of the potential risk of PGD with amiodarone. On 7 October 2025, a directive [Ruj. Kami: NPRA.600-1/9/13 (69) Jld. 1] has been issued for all registration holders of products containing amiodarone to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

 

Advice for Healthcare Professionals

• Be aware that PGD can occur following pre-transplant use of amiodarone, with studies showing up to almost four-fold increased risk of PGD.
• For patients on the heart transplant waiting list, consider an alternative antiarrhythmic drug as early as possible.
• If the use of amiodarone is deemed necessary, dose reduction should be considered, as evidence suggests that lowering the dose may mitigate the risk of PGD following heart transplantation.
• Any dose reduction or discontinuation should be undertaken with caution due to the potential recurrence of life-threatening tachyarrhythmias.
• Report all adverse events suspected to be related to the use of amiodarone-containing products to the NPRA.

 

References:

1. Jennings DL, Vaishnavi Gadela N, Jaiswal A, Touch A, Baker WL. Pre-transplant amiodarone use does not affect long-term heart transplant survival. Pharmacotherapy. 2021 Dec;41(12):1024-1032. Available from: https://doi.org/10.1002/phar.2533
2. Hoemann B, Takayama H, Jennings DL, Han J, Ando M, Restaino S, Colombo P, Farr M, Naka Y, Takeda K. Discontinuing amiodarone treatment prior to heart transplantation lowers incidence of severe primary graft dysfunction. Clin Transplant. 2020 Feb;34(2):e13779. Available from: https://doi.org/10.1111/ctr.13779
3. National Pharmaceutical Regulatory Agency (NPRA). CORDARONE (amiodarone) [Package Insert]. QUEST3+ Product Search. 2020 Dec [cited 2025 Oct 7]. Available from: http://www.npra.gov.my.
4. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2025 [cited 2025 July 24]. Available from: https://www.npra.gov.my
5. Smith NF, Salehi Omran S, Genuardi MV, Horn ET, Kilic A, Sciortino CM, Keebler ME, Kormos RL, Hickey GW. Primary Graft Dysfunction in Heart Transplant Recipients-Risk Factors and Longitudinal Outcomes. ASAIO J. 2022 Mar 1;68(3):394-401. Available from: https://doi.org/10.1097/mat.0000000000001469
6. Benck L, Kransdorf EP, Emerson DA, Rushakoff J, Kittleson MM, Klapper EB, Megna DJ, Esmailian F, Halprin C, Trento A, Ramzy D, Czer LSC, Chang DH, Ebinger JE, Kobashigawa JA, Patel JK. Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant. J Heart Lung Transplant. 2021 Sep;40(9):970-980. Available from: https://doi.org/10.1016/j.healun.2021.06.002
7. Buchan TA, Moayedi Y, Truby LK, Guyatt G, Posada JD, Ross HJ, Khush KK, Alba AC, Foroutan F. Incidence and impact of primary graft dysfunction in adult heart transplant recipients: A systematic review and meta-analysis. J Heart Lung Transplant. 2021 Jul;40(7):642-651. Available from: https://doi.org/10.1016/j.healun.2021.03.015
8. Health Canada. Summary Safety Review – Amiodarone- Assessing the Potential Risk of Primary Graft Dysfunction Following Heart Transplantation [Internet]. 2024 Apr 30 [cited 2025 Oct 7]. Available from: https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SSR1706035839788
9. Wright M, Takeda K, Mauro C, Jennings D, Kurlansky P, Han J, Truby L, Stein S, Topkara V, Garan AR, Yuzefpolskaya M, Colombo P, Naka Y, Farr M, Takayama H. Dose-dependent association between amiodarone and severe primary graft dysfunction in orthotopic heart transplantation. J Heart Lung Transplant. 2017 Nov;36(11):1226-1233. Available from: https://doi.org/10.1016/j.healun.2017.05.025
10. Chinnadurai T, Patel SR, Saeed O, Hanif W, Rivas-Lasarte M, Farooq M, Castillo C, Taveras M, Fauvel D, Shin JJ, Sims D, Murthy S, Vukelic S, Chavez P, Forest S, Goldstein D, Jorde UP. The Interaction of Amiodarone and Continuous-flow Left Ventricular Assist Device Use in Risk of Severe Primary Graft Dysfunction Following Heart Transplantation. Transplant Direct. 2022 Jan 13;8(2):e1281. Available from: https://doi.org/10.1097/txd.0000000000001281
11. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 July 24]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Wo Wee Kee
Reviewed/Edited by: Lim Sze Gee, Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali