Azithromycin and rare risk of cardiovascular death

What health professionals should do

Health professionals should be aware of this potential adverse event so they can balance the benefits of azithromycin with the rare but serious risk of sudden cardiac death. 

Consider precautionary ECG screening for patients with a high risk of a prolonged QT. 

Azithromycin

Azithromycin is available as Zithromax and Zithromax IV and a number of generic brands. 

Tablet forms are indicated for mild to moderate infections in adults, including:

• upper and lower respiratory tract infections
• uncomplicated skin and skin structure infections
• uncomplicated urethritis and cervicitis due to Chlamydia trachomatis
• acute streptococcal pharyngitis/tonsillitis.

They are also indicated for Chlamydia trachomatis conjunctivitis and trachoma in children aged 12 months or older. 

Intravenous use of azithromycin is indicated for community-acquired pneumonia involving susceptible organisms.

Background

The US Product Information was updated in November 2021 to include cardiovascular death in the ‘warnings and precautions’ and ‘adverse reactions’ section, based on advice drawing from published literature and observational studies.

Following this update, we undertook a full evaluation of the safety signal and sought expert advice from the Advisory Committee on Medicines. The Committee advised that on balance, while the evidence is currently inconsistent, an additional statement regarding the risk of cardiovascular death and requisite precautionary monitoring should be included in the PI.

See Advisory Committee on Medicines recommendations. 

Cases reported to the TGA

We have received 4 reports possibly associating azithromycin with cardiovascular death (to March 2024). The reports involved patients of both genders ranging in age from 26 to 84, with the majority aged over 60 years. In 2 of these cases, azithromycin was the only suspect medication. 

Information from these reports is de-identified and published in the Database of Adverse Event Notifications (DAEN) for medicines.

PI updates

The following updates were made to sections 4.4 and 4.8 the Australian PI.

4.4 Special warnings and precautions for use:

Cardiovascular death

Some observational studies have shown an approximately two-fold increased short-term potential rare risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. The data in these observational studies are insufficient to establish or exclude a causal relationship between acute cardiovascular death and azithromycin use. This potential risk was noted to be greater during the first 5 days of azithromycin use. In patients whose medical history and/or ongoing medical treatments place them at high risk for a prolonged QTc, consider performing a screening ECG. Consider balancing this potential risk with treatment benefits when prescribing ZITHROMAX.

4.8 Adverse effects (undesirable effects)

Post-marketing experience

Cardiovascular disorders: hypotension; palpitations and arrhythmias including ventricular tachycardia have been reported. There have been rare reports of QT prolongation, torsades de pointes and cardiovascular death.

The latest Product Information (for health professionals) and Consumer Medicine Information (for patients) for azithromycin are available on TGA eBusiness services.

Further reading

Zaroff JG, et al. Association of Azithromycin Use With Cardiovascular Mortality. JAMA Netw Open. 2020 Jun 1;3(6). doi: 10.1001/jamanetworkopen.2020.8199.

Ray WA, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012 May 17;366(20):1881-90. doi: 10.1056/NEJMoa1003833.

Rao GA, et al. Azithromycin and levofloxacin use and increased risk of cardiac arrhythmia and death. Ann Fam Med. 2014 Mar-Apr;12(2):121-7. doi: 10.1370/afm.1601.

Cheng YJ, et al. The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk. J Am Coll Cardiol. 2015 Nov 17;66(20):2173-2184. doi: 10.1016/j.jacc.2015.09.029.

What to report? You don't need to be certain, just suspicious!

We encourage the reporting of all suspected adverse reactions to medicines, including vaccines, over-the-counter medicines, herbal, traditional or alternative remedies.

We particularly request reports of:

• all suspected reactions to new medicines (look for the Black Triangle ▼ in PI and CMI documents – this symbol identifies medicines that are new or being used differently)
• all suspected medicines interactions
• suspected reactions causing death, admission to hospital or prolongation of hospitalisation, increased investigations or treatment, or birth defects.

To report a suspected side effect or for more information about reporting, go to our ‘Report problem or side effect’ webpage.

Disclaimer

Medicines Safety Update is aimed at health professionals. It is intended to provide practical information to health professionals on medicine safety, including emerging safety issues. The information in Medicines Safety Update is necessarily general and is not intended to be a substitute for a health professional's judgment in each case, taking into account the individual circumstances of their patients. Reasonable care has been taken to ensure that the information is accurate and complete at the time of publication. The Australian Government gives no warranty that the information in this document is accurate or complete and shall not be liable for any loss whatsoever due to negligence or otherwise arising from the use of or reliance on this document.

© Commonwealth of Australia 2024

This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved, and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to tga.copyright@tga.gov.au.

For the latest safety information from us, subscribe to the TGA Safety Information email list via our website.

Medicines Safety Update is written by staff from our Pharmacovigilance Branch.

Editor: Dr Megan Hickie

Deputy Editor: Aaron Hall

Contributors: Deborah Greenbaum & Dr Emma Knott