Summary Safety Review - Amiodarone - Assessing the Potential Risk of Primary Graft Dysfunction Following Heart Transplantation

Amiodarone-containing products

Primary graft dysfunction (PGD) following heart transplantation, impaired function of the heart occurring within 24 hours after transplantation

• Health Canada’s safety review found a possible link between the risk of PGD following heart transplantation and the pre-transplant use of amiodarone.

• Health Canada reviewed the potential risk of PGD with the pre-heart transplant use of amiodarone, a prescription drug authorized for the treatment of certain life-threatening abnormal heart rhythms (arrhythmias) in adults when other medicines did not work. The safety review was triggered by a labelling update in the United Kingdom (UK).

• Health Canada will work with the manufacturers to update the product safety information in the Canadian product monograph (CPM) for amiodarone-containing products to include the risk of PGD following heart transplantation.

Health Canada reviewed the potential risk of PGD following heart transplantation with the pre-transplant use of amiodarone. The safety review was triggered by a labelling update in the UK.

• Amiodarone is authorized for sale in Canada for the treatment of certain life-threatening arrhythmias in adults when other medicines did not work well.

• Amiodarone has been marketed in Canada since 1986. It is currently available as an oral tablet or a solution for infusion into a vein (intravenous). Various generic amiodarone products are available in Canada.

• Amiodarone is widely used in clinical practice and was the most prescribed antiarrhythmic drug in Canada in 2022.

• Health Canada reviewed information provided by the manufacturers, and from searches of the Canada Vigilance database^a and the scientific literature.

• At the time of the review, Health Canada had not received any Canadian reports of PGD related to the pre-heart transplant use of amiodarone.

• Health Canada reviewed 7 international cases of PGD in patients taking amiodarone before heart transplantation. In all 7 cases, the role of amiodarone could not be determined due to insufficient clinical information about factors that could have contributed to the risk of PGD, such as the use of other medications and patient medical conditions.

• Health Canada also reviewed 6 articles published in the scientific literature^1-6. While these studies had a number of weaknesses, including the presence of confounders (other factors that may have contributed to the occurrence of PGD) and bias (conscious or unconscious influencing of a study and its results), overall the evidence reviewed was sufficient to support an increased risk of PGD in patients taking amiodarone before heart transplantation.

• Health Canada’s review found a possible link between the pre-heart transplant use of amiodarone and the risk of PGD.

• Health Canada will work with the manufacturers to update the CPM of amiodarone-containing products to include the risk of PGD following heart transplantation.

• Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of amiodarone, and other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information involving amiodarone, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should new health risks be identified.

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information, and what is known about the use of amiodarone both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

1. Chinnadurai, T., Patel, S. R., Saeed, O., Hanif, W., Rivas-Lasarte, M., Farooq, M., Castillo, C., Taveras, M., Fauvel, D., Shin, J. J., Sims, D., Murthy, S., Vukelic, S., Chavez, P., Forest, S., Goldstein, D., & Jorde, U. P. (2022). The Interaction of Amiodarone and Continuous-flow Left Ventricular Assist Device Use in Risk of Severe Primary Graft Dysfunction Following Heart Transplantation. Transplantation direct, 8(2), e1281. https://doi.org/10.1097/TXD.0000000000001281

2. Jennings, D. L., Vaishnavi Gadela, N., Jaiswal, A., Touch, A., & Baker, W. L. (2021). Pre-transplant amiodarone use does not affect long-term heart transplant survival. Pharmacotherapy, 41(12), 1024–1032. https://doi.org/10.1002/phar.2533

3. Wright, M., Takeda, K., Mauro, C., Jennings, D., Kurlansky, P., Han, J., Truby, L., Stein, S., Topkara, V., Garan, A. R., Yuzefpolskaya, M., Colombo, P., Naka, Y., Farr, M., & Takayama, H. (2017). Dose-dependent association between amiodarone and severe primary graft dysfunction in orthotopic heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 36(11), 1226–1233. https://doi.org/10.1016/j.healun.2017.05.025

4. Benck, L., Kransdorf, E. P., Emerson, D. A., Rushakoff, J., Kittleson, M. M., Klapper, E. B., Megna, D. J., Esmailian, F., Halprin, C., Trento, A., Ramzy, D., Czer, L. S. C., Chang, D. H., Ebinger, J. E., Kobashigawa, J. A., & Patel, J. K. (2021). Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 40(9), 970–980. https://doi.org/10.1016/j.healun.2021.06.002

5. Smith, N. F., Salehi Omran, S., Genuardi, M. V., Horn, E. T., Kilic, A., Sciortino, C. M., Keebler, M. E., Kormos, R. L., & Hickey, G. W. (2022). Primary Graft Dysfunction in Heart Transplant Recipients-Risk Factors and Longitudinal Outcomes. ASAIO journal (American Society for Artificial Internal Organs: 1992), 68(3), 394–401. https://doi.org/10.1097/MAT.0000000000001469

6. Buchan, T. A., Moayedi, Y., Truby, L. K., Guyatt, G., Posada, J. D., Ross, H. J., Khush, K. K., Alba, A. C., & Foroutan, F. (2021). Incidence and impact of primary graft dysfunction in adult heart transplant recipients: A systematic review and meta-analysis. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 40(7), 642–651. https://doi.org/10.1016/j.healun.2021.03.015

1. Canadian reports can be accessed through the Canada Vigilance Online Database.