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

Fluoroquinolones are extensively utilised for their broad spectrum of antibacterial activity against both Gram-positive and Gram-negative bacteria.^1,2 They function by inhibiting enzymes known as DNA gyrase and topoisomerase IV, thereby stopping bacterial replication. In Malaysia, there are six (6) types of fluoroquinolones registered with the Drug Control Authority (DCA) for systemic use, encompassing both oral and injectable forms. Specifically, there are a total of 71 products registered for ciprofloxacin, moxifloxacin, levofloxacin, and ofloxacin.³

Suicidal behaviours, which include suicidal ideation, suicidal attempt, and completed suicide, have been continually reported globally, raising concerns pertaining to the use of fluoroquinolones.² Suicidal behaviour is a complex and multifaceted phenomenon, influenced by intricate interactions among biological, psychological, and social factors. While suicide is recognised as a distinct condition rather than solely a consequence of other psychiatric disorders, the existence of a psychiatric disorder, especially depression and psychosis, remains a significant risk factor for suicide.

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) became aware, through its global safety signal monitoring activity, that the United Kingdom Medicines and Healthcare products Regulatory Agency (UK MHRA) issued a reminder to all healthcare professionals regarding the potential risk of psychiatric reactions including suicidal thoughts and behaviours associated with fluoroquinolones.⁴ This alert was prompted by a reported case of suicide involving a patient who had received ciprofloxacin, despite having no history of psychiatric illness.

Various hypotheses have been proposed to explain the mechanism by which fluoroquinolones induce suicidal behaviours.^2,5 Given that the neurobiology of suicide may be partially distinct from other psychiatric disorders, questions arise whether fluoroquinolone-induced suicidal behaviour occurs independently or as a secondary effect within a broader psychopathological context.² Fluoroquinolones have been suggested to disrupt the inhibitory (GABAergic) and excitatory (glutamatergic) neurotransmission balance in the brain. Another potential mechanisms suggests the chelation of Mg²⁺ ions induced by fluoroquinolones, which lead to N-methyl-d-aspartate (NMDA) receptor activation, thus influencing excitatory processes. Additionally, decreased brain serotonin levels that could induce depression and aggression, augmented oxidative stress, and alterations of various microRNAs, could also contribute to the development of suicidal behaviours.^2,5

According to literature reviews and post-marketing reports, suicidal behaviours induced by fluoroquinolone administration may occur at any time—from as early as after the first dose to several years later.^2,6,7 At least 40% of the reported events occurred within the first two weeks of treatment.⁷

Notably, studies and case reports in global pharmacovigilance databases have primarily linked suicidal behaviours to certain fluoroquinolones, such as moxifloxacin, ciprofloxacin, levofloxacin, and ofloxacin.^2,6,7 As of the NPRA's current review, evidence remains insufficient to establish a causal association between suicidal behaviours and other fluoroquinolones for systemic use registered in Malaysia, such as gemifloxacin and norfloxacin, as well as fluoroquinolones for topical and eye preparations. Furthermore, this information has not been reflected in the product information in other Malaysia’s reference countries.

Adverse Drug Reaction Reports⁸

Till date, the NPRA has received 2,230 reports with 4,136 adverse events suspected to be related to ciprofloxacin, moxifloxacin, levofloxacin, and ofloxacin. The most frequently reported adverse events are vomiting (84), injection site pruritus (58), and dizziness (55). Among the 25 psychiatric cases reported, there was one case of depression and suicidal ideation in a patient following the administration of moxifloxacin tablets.

Advice for Healthcare Professionals

• Be aware that the use of fluoroquinolones, especially oral and injections, have been associated with psychiatric adverse events that can lead to suicidal behaviours, such as depression and psychosis, even in patient with no history of psychiatric illness.
• Exercise caution if fluoroquinolones are to be used in patients with a history of psychiatric disorder as fluoroquinolones can exacerbate existing conditions.
• Advise patients and caregivers to monitor for mood changes and suicidal thoughts throughout treatment and to seek immediate medical advice if these symptoms occur.
• Discontinue fluoroquinolones at the onset of any new or aggravated depression or psychosis.
• Consider the recent treatment history when assessing patients with suicidal behaviours.
• Report all suspected adverse events associated with fluoroquinolones-containing products to the NPRA.

Regulatory Actions

The NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13(39) Jld.1] had been issued for all registration holders of products containing ciprofloxacin, moxifloxacin, levofloxacin, and ofloxacin to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information. Previously, the NPRA had issued a directive [Ruj. Kami: (12) dlm. BPFK/PPP/07/25 Jld.3] concerning fluoroquinolones and central nervous system/neuropsychiatric effects. The new directive serves as supplementary information to the existing one for ciprofloxacin, moxifloxacin, levofloxacin, and ofloxacin. Read also the article in MADRAC Bulletin 01/2018 titled 'Recent Safety Issues with Fluoroquinolones'.

References:

1. Wierzbiński P, Hubska J, Henzler M, Kucharski B, Bieś R, Krzystanek M. Depressive and other adverse CNS effects of fluoroquinolones. Pharmaceuticals. 2023 Aug 4;16(8):1105. Available from: https://doi.org/10.3390/ph16081105
2. Samyde J, Petit P, Hillaire-Buys D, Faillie J-L. Quinolone antibiotics and suicidal behavior: Analysis of the World Health Organization’s Adverse Drug Reactions Database and discussion of potential mechanisms. Psychopharmacology. 2016 Apr 26;233(13):2503–11. Available from: https://doi:10.1007/s00213-016-4300-3
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Feb 9]. Available from: https://www.npra.gov.my
4. Medicines and Healthcare products Regulatory Agency. Fluoroquinolone antibiotics: Suicidal thoughts and behaviour [Internet]. GOV.UK; 2023 [cited 2024 Feb 9]. Available from:https://www.gov.uk/drug-safety-update/fluoroquinolone-antibiotics-suicidal-thoughts-and-behaviour
5. Wang J, Gagne JJ, Kattinakere-Sreedhara S, Fischer MA, Bykov K. Association between initiation of fluoroquinolones and hospital admission or emergency department visit for Suicidality: Population Based Cohort Study. BMJ. 2022 Oct 4; Available from: https://doi.org/10.1136/bmj-2021-069931
6. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2024 [cited 2022 Feb 9]. Available from: https://www.vigilyze.who-umc.org (access restricted)
7. Kommalapati A, Wallam S, Tella SH, Qureshi ZP, Bennett CL. Fluoroquinolone-associated suicide. European Journal of Internal Medicine. 2018 Sept;55. Available from: https://doi.org/10.1016/j.ejim.2018.07.012
8. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2024 [cited on 2024 Feb 7]. Available from: https://www.npra.gov.my (access restricted)

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