Overview of Products

Azithromycin is a macrolide antibiotic commonly used for treating bacterial infections.^1,2 The oral formulation may be used to treat respiratory, skin, ear, and sexually transmitted infections,  while injectable formulations are indicated for conditions like community-acquired pneumonia (CAP) and pelvic inflammatory disease (PID) caused by susceptible organisms. In Malaysia, there are 45 products containing azithromycin currently registered with the Drug Control Authority (DCA).³

 

Overview of Safety Concern

Cardiovascular death refers to death with an underlying cardiovascular cause such as myocardial infarction, heart failure, arrhythmia, or stroke.⁴ Sudden cardiac death (SCD), a subset of cardiovascular death, describes the unexpected death that occurs within one hour from symptom onset when death is witnessed, and within 24 hours of last being seen alive and well if unwitnessed.⁵ Most deaths meeting this definition are caused by cardiac arrhythmias, which may be associated with risk factors such as QT prolongation.

QT prolongation signals an abnormally delayed ventricular repolarisation.⁶ The QT interval on an electrocardiogram (ECG) represents the interval between the onset of ventricular depolarisation and the end of ventricular repolarisation. Macrolides, including azithromycin, may prolong the QT interval by blocking the rapid delayed rectifier potassium current (I_Kr) conducted by human ether-a-go-go gene (hERG)-encoded potassium channel, which can lead to torsades de pointes (TdP) that may result in potentially fatal cardiac arrhythmias^1,7,8

 

Background of Safety Concern

In 2024, the National Pharmaceutical Regulatory Agency (NPRA) received updates from the Australian Therapeutic Goods Administration (TGA) regarding the rare risk of cardiovascular death linked to azithromycin use.⁹

The TGA conducted a full evaluation of the cardiovascular death risk, reviewed local cases, and sought expert advice from the Advisory Committee on Medicines.⁹ This review followed the United States Food and Drug Administration (U.S. FDA)'s update to azithromycin product information in 2021 to include the risk of cardiovascular death, based on published literature and observational studies.^9,10

Cumulative findings from observational studies suggest an approximately two-fold increase in the rare short-term risk of acute cardiovascular death in adults treated with azithromycin, particularly within the first 5 days of use, compared to other antibiotics, including amoxicillin. ^4,8,9-13 However, inconsistencies across studies make the evidence insufficient to establish or exclude a causal relationship between azithromycin use and acute cardiovascular death.^9,10  Despite this, the TGA has decided to update the product information to include a statement about the potential risk of cardiovascular death and the need for precautionary monitoring in patients at risk of QT prolongation.⁹

Previously, in 2013, the U.S. FDA had issued a drug safety communication to inform updates to the product information regarding the risk of potentially fatal QT interval prolongation and torsades de pointes associated with azithromycin.¹⁴ This safety update was based on two key studies:

• A study by Ray et al. (2012), which reported a higher risk of cardiovascular death and all-cause death in patients treated with a 5-day course of azithromycin compared to those receiving amoxicillin, ciprofloxacin, or no drug.^11,14 The duration of the elevated risk of all-cause mortality and of cardiovascular death corresponded with the duration of azithromycin therapy, while the excess risk of cardiovascular death, especially of sudden cardiovascular death, was consistent with arrhythmias from drug-related QT prolongation.
• A clinical study by the manufacturer, which indicated that azithromycin prolonged the QT interval.¹⁴

A warning regarding the risk of QT prolongation and the associated risk of arrhythmias, including ventricular tachycardia, has already been included in the product information for azithromycin products in Australia and Malaysia.^1,3,9

 

Local Adverse Drug Reaction Reports¹⁵

To date, the NPRA has received 1,254 reports involving 2,190 suspected adverse events related to azithromycin-containing products.  While no cases of cardiac death or sudden cardiac death have been reported, there have been 45 reports of cardiac-related adverse events, including ventricular tachycardia, with 7 cases reporting a fatal outcome.

However, it is important to note that some of these fatalities were attributed to non-cardiovascular causes (e.g., sepsis), while the cause of death in most cases remained unknown. In cases where a cardiovascular cause was suspected, the available information was insufficient to establish or exclude a causal association with azithromycin. Contributing factors such as underlying cardiovascular disease, existing comorbidities, concurrent pharmacotherapy, or other confounding variables may have influenced the observed outcomes.

The NPRA has reviewed these reports and continues to closely monitor the safety profile of azithromycin-containing products to assess and respond to any emerging safety concerns.

 

Advice for Healthcare Professionals

• Be reminded of the potential risk of QT prolongation and cardiac arrhythmias associated with azithromycin use, and be aware of the rare risk of sudden cardiac death.
• When prescribing azithromycin, consider balancing the potential serious risks against the treatment benefits.
  • Carefully assess the patient’s medical history and/or ongoing medical treatments for risk factors related to QT prolongation.
  • Consider performing a screening electrocardiogram (ECG) in patients at high risk of QT prolongation.
• Monitor patients closely during the first five days of azithromycin therapy, when the risk of cardiovascular events is highest.
• Educate patients and caregivers to recognise signs and symptoms of serious heart rhythm changes that can be life threatening, including a fast or irregular heartbeat, dizziness, and fainting, and to seek medical attention immediately if these occur.
• Report all suspected adverse effects associated with azithromycin to the NPRA.

 

References:

1. National Pharmaceutical Regulatory Agency (NPRA). ZITHROMAX POWDER FOR ORAL SUSPENSION (azithromycin) [Package Insert]. QUEST3+ Product Search. 2022 Nov [cited 2024 Oct 10].Available from: http://www.npra.gov.my.
2. Azithromycin [Internet]. DrugBank online; 2024 [cited 2024 Nov 18]. Available from: https://go.drugbank.com/drugs/DB00207
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Oct 10]. Available from: https://www.npra.gov.my
4. Zaroff JG, Cheetham TC, Palmetto N, Almers L, Quesenberry C, Schneider J, Gatto N, Corley DA. Association of Azithromycin Use With Cardiovascular Mortality. JAMA Network Open. 2020; 3(6):e208199. Available from: https://doi.org/10.1001/jamanetworkopen.2020.8199
5. Adabag AS, Luepker RV, Roger VL, Gersh BJ. Sudden cardiac death: epidemiology and risk factors. Nat Rev Cardiol. 2010 Apr;7(4):216-25. Available from: https://doi.org/10.1038/nrcardio.2010.3
6. 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
7. Giudicessi JR, Ackerman MJ. Azithromycin and risk of sudden cardiac death: guilty as charged or falsely accused? Cleve Clin J Med. 2013 Sep;80(9):539-44. Available from: https://doi.org/10.3949/ccjm.80a.13077
8. Al-Jazairi AS, Alotaibi HS. Possible Azithromycin-Induced Life-Threatening Arrhythmia Requiring Extracorporeal Membrane Oxygenation Support: A Case Report. Am J Case Rep. 2020: 21: e926951. Available from: https://doi.org/10.12659/ajcr.926951
9. Therapeutic Goods Administration (TGA). Medicines Safety Update: Azithromycin and rare risk of cardiovascular death [Internet]. 2024 Aug 1 [cited 2024 Oct 7]. Available from: https://www.tga.gov.au/news/safety-updates/azithromycin-and-rare-risk-cardiovascular-death#:~:text=Some%20observational%20studies%20have%20shown,other%20antibacterial%20drugs%2C%20including%20amoxicillin
10. United States Food and Drug Administration (US FDA). ZITHROMAX (azithromycin) tablets / oral suspension [Package Insert]. Drugs@FDA. 2021 Nov [cited 2024 Oct 10]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/
    050670s036,050710s051,050784s037,050711s050lbl.pdf
11. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the Risk of Cardiovascular Death. N Engl J Med. 2021 Mar 17: 366;20. Available from: https://doi.org/10.1056/NEJMoa1003833
12. Rao GA, Mann JR, Shoaibi A, Bennett CL, Nahhas G, Sutton SS, Jacob S, Strayer SM. Azithromycin and Levofloxacin Use and Increased Risk of Cardiac Arrhythmia and Death. Annals of Family Medicine. 2014: 12: 121-127. Available from: https://doi.org/10.1370/afm.1601
13. Cheng Y-J, Nie X-Y, Chen X-M, Lin X-X, Tang K, Zeng W-T, Mei W-Y,Liu L-J, Long M, Yao F-J, Liu J, Liao X-X, Du Z-M, Dong Y-G, Ma H, Xiao H-P, Wu S-H. The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk. Journal of the American College of Cardiology. 2015: Vol. 66, No. 20. Available from: http://dx.doi.org/10.1016/j.jacc.2015.09.029
14. United States Food and Drug Administration (US FDA). Drug Safety Communications: FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms [Internet]. 2013 Mar 12 [cited 2024 Nov 18]. Available from: https://www.fda.gov/media/85787/download
15. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Oct 9]. Available from: https://www.npra.gov.my (access restricted)

 

DISCLAIMER

This publication is intended for healthcare professionals. The information provided aims to update on medication safety issues and should not substitute 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 arising from the use of or reliance on this publication.

 

Written by: Nafiza Mohd. Ismail

Reviewed/Edited by: Choo Sim Mei, Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali