Overview

Diclofenac is a non-steroidal anti-inflammatory (NSAID) that exhibits pronounced anti-rheumatic, anti-inflammatory, analgesic, and antipyretic properties.^1-3 Its therapeutic effects are achieved through the inhibition of cyclooxygenase activity, thereby reducing the synthesis of prostaglandin, which plays an important role in inflammation, pain, and fever.

Diclofenac is approved in Malaysia for the treatment of rheumatism, acute gout attacks, painful post-traumatic and post-operative inflammation and swelling, primary dysmenorrhea, acute migraine attacks, as well as adjuvants in severe and painful inflammatory infections of the throat, nose, or ears.^1-2,4 Although diclofenac has antipyretic properties like other NSAIDs, it is not registered for the indication of fever in the general population, including children, in Malaysia.

There are currently 73 products containing diclofenac registered in Malaysia, including nine (9) products in the form of suppositories with different strengths for adults and children.⁴ Other available forms include oral tablets/ capsules/suspensions, powder for oral solutions, injections, and topical application.

Acute necrotising encephalopathy of childhood (ANEC) is a rare, fulminant type of encephalopathy that predominantly affects young children under five (5) years of age from East Asian regions such as Japan.^5-6 Its main clinical presentations include fever, followed by seizures and a rapid decline in levels of consciousness.^5-7 The prognosis of ANEC is generally poor, with high mortality and significant neurological deficits in survivors.

Background of the Safety Issue

It was brought to the National Pharmaceutical Regulatory Agency’s (NPRA) attention of suspected local cases of fatal ANEC following the off-label use of diclofenac suppository to treat fever in children.⁸

ANEC is one of the most severe central nervous system (CNS) complications in children with viral infections like influenza.⁵ The pathogenesis of ANEC is mainly attributed to systemic cytokine storms, in which excessive production of proinflammatory cytokines causes vascular endothelial injury and cell death, resulting in oedematous lesions in the brain and systemic organ damage.^5-6 In severe cases, this condition can rapidly progress to disseminated intravascular coagulation (DIC) or multiple organ failure (MOF). While there is currently no definitive recommended therapy for ANEC, early administration of corticosteroids, or combined therapy with immunoglobulin or therapeutic hypothermia, had been shown to improve neurological and survival outcomes in cases of ANEC.⁷

The precise role of diclofenac in aggravating or triggering ANEC remains poorly understood.^5-6 However, studies in Japan suggest that the use of diclofenac could significantly increase the fatality rate of influenza-associated encephalopathy (including ANEC). The hypothesised mechanism is that their inhibitory activity on cyclooxygenase may either promote thrombosis or interfere with the repair of vascular endothelial damage, contributing to the pathogenesis of ANEC.

Adverse Drug Reaction Reports⁸

To date, the NPRA has received 9,625 reports with 18,691 events following the use of diclofenac-containing products, including 110 reports with 175 events for diclofenac suppositories. Of these, there were two (2) reports of suspected ANEC potentially related to the off-label use of diclofenac suppository for treating fever in children.

Advice for Health Care Professionals

• Be aware of the safety concern associated with the use of diclofenac suppositories in children, which could potentially aggravate or trigger ANEC.
• DO NOT prescribe diclofenac, including in the form of suppositories, for the treatment of fever in children, as it is not registered for the indication. Instead, recommend appropriate doses of paracetamol along with tepid sponging and adequate fluid intake for hydration.
• It is important to carefully recognise ANEC, especially in children with suspected influenza. Consider early initiation of appropriate management for ANEC, given the potential for severe neurological sequelae and high mortality rates.
• Report all suspected adverse events following the use of diclofenac and other NSAIDs in any form to the NPRA.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). VOLTAREN (diclofenac sodium) Suppositories 12.5mg, 25mg and 50mg [Package Insert]. 2022 Mar [cited 2022 Nov 30]. The Malaysian Product Registration Database (QUEST). Available from: http://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). CATAFLAM (diclofenac potassium) Tablets 50mg [Package Insert]. 2021 Aug [cited 2022 Nov 30]. The Malaysian Product Registration Database (QUEST). Available from: http://www.npra.gov.my
3. Alfaro RA, Davis DD. Diclofenac. [Updated 2022 May 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan [cited 2022 Dec 16]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557879/
4. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2022 [cited 2022 Nov 30]. Available from: https://www.npra.gov.my
5. Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with influenza and other viral infections [Internet]. Acta Neurol Scand Suppl. 2007 [cited 2022 Dec 16];186:45-56. Available from: https://pubmed.ncbi.nlm.nih.gov/17784537/
6. Mizuguchi M. Influenza encephalopathy and related neuropsychiatric syndromes. Influenza and Other Respiratory Viruses. 2013 Nov;7 Suppl 3(Suppl 3):67-71. Available from: https://doi.org/10.1111/irv.12177
7. Lee YL, Abu Hassan H, Ismail IH. Acute necrotizing encephalopathy of childhood: A severe case with fatal outcome [Internet]. Mal J Med Health Sci. 16(2): 323-325, May 2020. [cited 2022 Nov 30]. Available from: http://psasir.upm.edu.my/id/eprint/77949/1/2020042012144646_MJMHS_0455.pdf
8. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2022 [cited 2022 Nov 25]. 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, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

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