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 Product

Cefazolin is a first-generation cephalosporin antibiotic with bactericidal properties.¹ Administered parenterally, it is indicated for the treatment of infections caused by susceptible organisms, including respiratory tract, urogenital, skin and soft tissue, biliary tract, bone and joint infections, as well as for endocarditis, septicaemia, and perioperative prophylaxis.

To date, three products containing cefazolin are registered with the Drug Control Authority (DCA), all in injectable formulations.²

 

Overview of Safety Concern

Kounis syndrome (KS) is characterised by cardiovascular manifestations resulting from an allergic or hypersensitivity reaction.³ This response can trigger coronary artery vasospasm, which may lead to a myocardial infarction. In addition to drugs, this hypersensitive reaction can also be triggered by environmental factors, certain foods, or various conditions.⁴

Spontaneous reports and literature have identified cases of KS in patients receiving cefazolin.³ While the exact frequency of KS remains unknown, its unique clinical presentation and management challenges have led to growing medical interest.⁴ Treating KS is particularly complex, requiring clinicians to simultaneously address both cardiac dysfunction and systemic allergic reactions. For instance, although adrenaline is the standard intervention for severe anaphylaxis, it should be used with caution in patients with KS, as it carries the risk of worsening coronary vasospasms and intensifying myocardial ischaemia. 

 

Source of Safety Concern

In February 2026, the National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) regarding the risk of KS following the use of cefazolin.³

A review of regulatory data reveals that in August 2023, the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan mandated revisions to the product information for cefazolin to include warnings regarding acute coronary syndrome accompanying allergic reaction.⁵

 

Background of the Safety Issue

KS is driven by the interaction of mast cells with T lymphocytes and macrophages, which triggers the massive release of inflammatory mediators directly into cardiac tissue, coronary arteries, and atherosclerotic plaques.⁴ Clinically, the syndrome presents as a combination of systemic allergic manifestations and acute cardiac symptoms. Symptoms of KS typically have a rapid onset, with 80% of patients reacting within the first hour of exposure.⁶

Three variants of KS have been described based on a patient’s underlying cardiac status.⁴ Type I involves coronary spasms in patients without risk factors for coronary heart disease; Type II occurs in those with existing atherosclerosis; and Type III affects patients with a history of coronary stent implantation. While the syndrome can be fatal due to myocardial infarction, the prognosis depends on the specific type, the presence of complications, and the trigger involved.^4,6 Most patients can expect full recovery with appropriate management. Generally, Type I patients have the best prognosis.⁴

 

Local Adverse Drug Reaction Reports⁷

To date, the NPRA has received a total of 513 adverse drug reaction reports with a total of 891 adverse events associated with cefazolin use in Malaysia. The most frequently reported adverse events were pruritus (102), rash (79), and urticaria (79).

There are no cases of KS associated with the use of cefazolin reported to the NPRA to date.

 

Advice for Health Care Professionals

• Cefazolin may induce KS, a condition characterised by concurrent hypersensitivity and acute cardiac symptoms. In suspected cases, clinicians must simultaneously manage both the allergic and myocardial manifestations to ensure patient stabilisation.
• Monitor patients closely during and after cefazolin administration for signs and symptoms suggestive of hypersensitivity reactions and acute coronary events, especially within the first hour of exposure.
• Discontinue cefazolin immediately and initiate appropriate clinical management if KS or acute allergic symptoms are suspected.
• Exercise caution when managing anaphylaxis in patients with suspected KS, as adrenaline may worsen coronary vasospasm and intensify myocardial ischaemia.
• Report all suspected adverse events associated with cefazolin-containing products to the NPRA.

 

References:

1. National Pharmaceutical Regulatory Agency (NPRA). Cefazolin Sandoz 1g Vial. [Package Insert]. 2024 January [Cited 2026 Apr 3]. The Malaysian Product Registration Database (QUEST). Available from: https://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2026 [cited 2026 Apr 3]. Available from: https://www.npra.gov.my
3. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC) recommendations on signals. Adopted at the 12-15 January 2026 PRAC meeting [Internet]. 2026 February 9 [cited 2026 Apr 3]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-12-15-january-2026-prac-meeting_en.pdf
4. Fang W, Song L, Deng Z, Sun W, Li Z, Wang C. Analysis of Clinical Features of Kounis Syndrome Induced by Cephalosporin. Front. Cardiovasc. Med. 2022 Apr 26;9:885438. Available from: https://doi.org/10.3389/fcvm.2022.885438
5. Japan Pharmaceuticals and Medical Devices Agency (PMDA). Revision of precautions – cefazolin sodium, cefazolin sodium hydrate [Internet]. 2023 August 29 [cited 2026 Apr 3]. Available from: https://www.pmda.go.jp/files/000263941.pdf
6. Sato M, Arai T. A case of Kounis syndrome presenting as coronary artery spasm associated with cefazolin-induced anaphylaxis during general anesthesia. JA Clin Rep. 2019 Jul 31;5(1):49. Available from: https://doi.org/10.1186/s40981-019-0269-3
7. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2026 [cited 2026 Mar 5]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Wang Khee Ing    

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