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

Overview

Amoxicillin is a beta-lactam antibiotic used for the treatment of bacterial infections and for surgical antimicrobial prophylaxis.^1-2 Currently, there are 71 products containing amoxicillin for use in human registered with the Drug Control Authority (DCA), available as single active ingredient products, in combination with clavulanic acid, or as part of a kit containing amoxicillin, clarithromycin and a proton pump inhibitor.³ These amoxicillin-containing products come in various dosage forms, including tablets, capsules, syrups, oral suspensions, granules for oral suspensions, and injections.

Aseptic meningitis is an inflammation of the linings of the brain and spinal cord without evidence of an infectious cause.^1,4-5 It is characterised by neurological symptoms, including fever, headache, and altered mental status, as well as cytological abnormalities in the cerebrospinal fluid (CSF).^4-5 Drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), antimicrobials, intravenous immunoglobulin, and antiepileptic drugs, have been identified as potential causes of aseptic meningitis.

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received safety information from Health Canada regarding the risk of aseptic meningitis linked to amoxicillin-containing products.¹ Following a review of available information from both local and international pharmacovigilance databases, as well as published case reports, Health Canada concluded that there might be a link between amoxicillin-containing products and the risk of aseptic meningitis.

The exact pathogenesis of drug-induced aseptic meningitis remains unclear, but two main mechanisms may be involved—direct drug toxicity and immune hypersensitivity.^4-5 However, there is growing evidence suggesting that amoxicillin-induced aseptic meningitis (AIAM) may be a type IV delayed hypersensitivity reaction mediated by T cells.

The reported time-to-onset of AIAM ranged from 3 hours to 13 days after amoxicillin administration, with a high incidence of recurrent episodes.^4-5  Fever and headache were reported as the most common symptoms.⁴ Typical CSF findings included leukocytosis with lymphocytic predominance, elevated CSF protein, normal CSF glucose (unlike low CSF glucose in bacterial meningitis), and negative culture. Symptoms generally resolved within 1 to 4 days after discontinuation of amoxicillin-containing products (i.e., positive dechallenge), while some cases demonstrated positive rechallenges of AIAM.^4-5  

Men may be at higher risk for AIAM than women, as evidenced by a higher-than-expected number of AIAM reports received from males and growing evidence of the sex differences in immune responses.^4-5

Adverse Drug Reaction Reports⁶

The NPRA has received a total of 16,137 reports with 28,175 adverse events suspected to be related to amoxicillin-containing products. However, there have been no local reports specifically of aseptic meningitis.

Advice for Healthcare Professionals

• Be aware of the very rare risk of aseptic meningitis following the administration of amoxicillin-containing products, especially in male patients.
• Advise patients to be vigilant and seek immediate medical attention if they experience any signs and symptoms of aseptic meningitis, such as fever, headache, nausea, vomiting and neck stiffness, while undergoing treatment with amoxicillin-containing products.
• If suspected of having aseptic meningitis, after ruling out other infectious or disease-related causes, obtain a comprehensive medication history and consider the possibility of AIAM in patients prescribed amoxicillin-containing products.
• AIAM is reversible after drug withdrawal and generally resolves without the need for further treatment. Prompt recognition of AIAM can prevent aggressive diagnostic procedures, prolonged treatments, and the risk of recurrent episodes related to future amoxicillin use.
• Please report all suspected adverse events associated with the use of amoxicillin-containing products to the NPRA.

References:

1. Health Canada. Summary Safety Review - Amoxicillin-containing Products - Assessing the Potential Risk of Aseptic Meningitis [Internet]. 2021 Dec [cited 2024 May 21]. Available from: https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00276.
2. Ministry of Health (MOH) Malaysia. National Antimicrobial Guideline (NAG) 2019, 3rd Edition [Internet]. 2023 Oct [cited 2024 May 20]. Available from: https://pharmacy.moh.gov.my/en/documents/national-antimicrobial-guideline-nag-2019-3rd-edition.html
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST 3+ system [Internet]. 2024 [cited 2024 Apr 17]. Available from: https://www.npra.gov.my/index.php/en/consumers/information/products-search.html
4. Fan Z, He Y, Sun W, Li Z, Ye C, Wang C. Amoxicillin-induced aseptic meningitis: clinical features, diagnosis and management. Eur J Med Res. 2023 Aug 27;28(1):301. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464253/
5. Chandler RE. Increased risk for aseptic meningitis after amoxicillin or amoxicillin-clavulanic acid in males: A signal revealed by subset disproportionality analysis within a global database of suspected adverse drug reactions. Pharmacoepidemiol Drug Saf. 2019 Mar;28(3):389-395. Available from: https://doi.org/10.1002%2Fpds.4707
6. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 May 20]. Available from: https://www.npra.gov.my (access restricted).

Written by: Nafiza Mohd. Ismail
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali