Overview

Ceftriaxone is a third-generation cephalosporin antibiotic with a broad spectrum of activity against gram-negative and gram-positive micro-organisms.¹

Encephalopathy is a term for any diffuse disease of the brain that disrupts the function or structure of the brain.² Common neurological symptoms include loss of memory/cognitive ability, inability to concentrate, subtle personality changes, lethargy, and progressive loss of consciousness. Other neurological symptoms of encephalopathy may include myoclonus, nystagmus, seizure, tremor, muscle weakness, dementia, and loss of ability to speak or swallow.

Background of the safety issue

In December 2020, the National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) on the risk of encephalopathy that was associated with ceftriaxone.³

The signal of encephalopathy associated with ceftriaxone use was initially identified by France, based on an analysis by Lacroix et al. on all serious central nervous system (CNS) adverse drug reaction (ADR) reports of cephalosporins in the French Pharmacovigilance Database.⁴ The results of the analysis showed that encephalopathy is the most reported serious CNS adverse effect of cephalosporins and that ceftriaxone is the major contributor, after cefepime.⁵ For cefepime, the risk of encephalopathy has been identified and documented in the product information (PI), but not for ceftriaxone.⁶

There are several proposed mechanisms of ceftriaxone-induced serious CNS adverse effects such as encephalopathy.⁷ The main postulated mechanism suggested that cephalosporin neurotoxicity includes the reduction of γ-aminobutyric acid (GABA) released from nerve terminals, which leads to an increase of excitatory neurotransmission as well as cytokine release. Other postulated mechanisms for cephalosporin neurotoxicity also include induction of endotoxins.

While the pathophysiological mechanism is not fully elucidated, post-marketing reports seen in a literature study have shown that the onset of serious CNS adverse effects is in the range of one (1) to 10 days following ceftriaxone administration, and resolves in one (1) to 12 days following discontinuation.⁸

Based on the available evidence and plausible biological mechanisms, EMA concluded that there is sufficient strength for a causal relationship of encephalopathy with ceftriaxone, therefore a PI update is warranted to include safety information on encephalopathy for all products containing ceftriaxone.³

In February 2021, the Canadian Health Regulatory Agency also reviewed this safety issue and after considering all information available, concluded that there is a possible link between ceftriaxone use and the risk of encephalopathy. Canadian PI for ceftriaxone-containing products are to be updated with information on the risk of encephalopathy.⁹

Adverse Drug Reaction (ADR) Reports

To date, the NPRA has received 2,507 reports with 4,540 adverse events suspected to be related to ceftriaxone.¹⁰ The most frequently reported adverse events are pruritus, rash, urticaria, maculo-papular rash and dyspnoea. No encephalopathy case suspected to be related to ceftriaxone has been reported to NPRA. However, there are seven (7) reports of seizure/convulsion.

Advice for Healthcare Professionals:

• Encephalopathy has been reported with the use of ceftriaxone, especially in elderly patients with severe renal impairment or previous CNS diseases.
• If ceftriaxone-associated encephalopathy is suspected, with symptoms such as decreased level of consciousness, altered mental state, myoclonus, and convulsions, discontinuation of ceftriaxone should be considered.
• Please report all suspected adverse events associated with ceftriaxone-containing products to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (24)] has been issued for registration holders of ceftriaxone-containing products to update the local package inserts with this new safety information.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). Malaysian Product Registration Database (Quest 3+). Ceftriaxone local package insert [Internet]. Last revision date: 2020 September [Cited 2021 March 5]. Available from http://www.npra.gov.my
2. National Institute of Neurological Disorders and Stroke. Encephalopathy Information Page [Internet]. 2019 [Cited 2021 February 5]. Available from: https://www.ninds.nih.gov/Disorders/All-Disorders/Encephalopathy-Information Page#:~:text=,alters%20brain%20function%20or%20structure
3. Pharmacovigilance Risk Assessment Committee (PRAC). PRAC recommendations on signals: European Medicines Agency (EMA) [Internet]. 23 November 2020 [Cited 2021 February 5]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-26-29-october-2020-prac-meeting_en.pdf.
4. Pharmacovigilance Risk Assessment Committee (PRAC). Minutes of PRAC meeting on 28-31 October 2019: European Medicines Agency (EMA) [Internet]. 28 November 2019 [Cited 2021 February 5]. Available from:https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-28-31-october 2019_en.pdf.
5. Lacroix C, Kheloufia F, Montastruc F, Bennis Y, Pizzoglio V, Micallef J. Serious central nervous system side effects of cephalosporins: A national analysis of serious reports registered in the French Pharmacovigilance Database. Journal of Neurological Sciences [Internet]. 2019 [Cited 2021 February 5]; 398:196-201. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0022510X19300188.
6. Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM). Base de données publique des medicaments [Internet]. 2021 [Cited 2021 February 5]. Availabe from: https://www.ansm.sante.fr/
7. Grill MF, Maganti R. Cephalosporin-Induced neurotoxicity: clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring. The Annals of Pharmacotherapy [Internet]. 2008. [Cited 2021 February 5]; 42: 1843-1849. Available from: https://journals.sagepub.com/doi/10.1345/aph.1L307.
8. Inoue Y, Doi Y, Arisato T, Sugioka S, Koga K, Nishioka K, Sugawara A. Three cases of hemodialysis patients receiving high-dose ceftriaxone: serum concentrations and its neurotoxicity. Kidney International Reports [Internet]. 2017 [Cited 2021 February 5]; 2: 984-987. Available from: https://www.kireports.org/article/S2468-0249(17)30063-3/abstract.
9. Health Canada. Summary safety review - ceftriaxone-containing products - assessing the potential risk of encephalopathy [Internet]. 3 February 2021 [Cited 2021 February 8]. Available from: https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00257.
10. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2021 [Cited 2021 March 5]. Available from: https://www.npra.gov.my.

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.