Analyses of Adverse Drug Reactions to Fluoroquinolones in Spontaneous Reports Before and After the Referral and in Clinical Routine Cases.

Introduction: In November 2018, the European Medicines Agency (EMA) restricted the use of fluoroquinolones (used by mouth, injections or inhalation) in the context of a referral due to long-lasting and potentially irreversible adverse drug reactions (ADRs). Fluoroquinolones should no longer be used to treat mild or moderate bacterial infections unless other antibacterials cannot be used.
Objectives: The first aim of our study was to analyze whether in the period before compared with after the referral the characteristics of spontaneous ADR reports related to fluoroquinolones differed and whether specific ADRs were more frequently reported for fluoroquinolones compared with cotrimoxazole. Secondly, we analyzed whether the ADR profile differed between individual fluoroquinolones. Finally, the number of fluoroquinolone reports was considered in relation to the number of outpatient drug prescriptions.
Methods: All spontaneous ADR reports from Germany received before the referral (01/2014-12/2019) and after the referral (01/2020-12/2022) for adults in which fluoroquinolones (n = 2575; n = 967) or cotrimoxazole (n = 299, n = 275) were reported as suspected/interacting were identified in the European ADR database, EudraVigilance. The ADR reports were descriptively analyzed concerning the reported characteristics. Odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated by logistic regression analyses, which were performed to investigate whether aortic aneurysms, retinal detachments, cardiac arrhythmias, peripheral polyneuropathies, nervous system disorders, toxic liver diseases and non-traumatic injuries of muscles, tendons and synovialis were more frequently reported for fluoroquinolones compared with cotrimoxazole. Stratified analyses between fluoroquinolones were conducted by calculating ORs and their 95% CIs by using two-by-two tables. Reporting rates were calculated by dividing the number of fluoroquinolone reports by the number of fluoroquinolone prescriptions.
Results: Reporting rates of fluoroquinolones clearly increased until 2019 and decreased afterward. Only minor differences in the characteristics of fluoroquinolone reports (e.g., regarding the indications) were observed in reports received before and after the referral. In both periods, peripheral neuropathies, nervous system, and muscle and tendon disorders were more often reported for fluoroquinolones than cotrimoxazole. In the pooled fluoroquinolone-stratified analyses, (i) peripheral neuropathies and nervous system disorders were more frequently reported for ciprofloxacin, (ii) non-traumatic injuries of muscle, tendon, and synovialis were more often reported for levofloxacin, and (iii) cardiac arrhythmias and toxic liver diseases were more frequently reported for moxifloxacin compared with the other fluoroquinolones.
Conclusion: In accordance with a reminder sent by the EMA referring to prescribing trends for fluoroquinolones, our study showed that the characteristics of spontaneous ADR reports for fluoroquinolones after the referral were similar to those before the referral, underlining the importance of adhering to the recommended restrictions issued by the EMA. In addition, we observed individual differences between ciprofloxacin, levofloxacin, and moxifloxacin with regard to their ADR profile. Further studies are needed to confirm our results.
Competing Interests: Declarations. Funding: ANKA is funded by own resources from the German Federal Institute for Drugs and Medical Devices’ (BfArM) and the Institute for Medical Biometry, Informatics, and Epidemiology (IMBIE), University Hospital Bonn, Germany (V-2020.2/68502/2020-2024). The data provisioning services provided by the data integration center (DIC) Bonn were created with and/or are currently supported, in part, via funding by the Federal Ministry of Education and Science (BMBF) under grant numbers (FKZ): 01ZZ1602C, 01ZZ1803Q, 01ZZ2303G, and 01KX2121. Competing interests: DD and MS are supported by the ANKA project, which is founded by the Federal Institute for Drugs and Medical Devices and the Institute for Medical Biometry, Informatics and Epidemiology at the University Hospital Bonn. Ethics approval: The ethics committee of the Medical Faculty of Bonn waved the need for approval since this is not required for retrospective analyses based on pseudonymized spontaneous reports from EudraVigilance and clinical routine data from the University Hospital Bonn and stated that fthere are no ethical concerns (file no. 458/20 and 100/21). Thus, consent to participate is not required and was not obtained. Consent to participate: Not applicable. Consent for publication: Not applicable. Availability of data and materials: The pseudonymized ADR reports from EudraVigilance are not publicly accessible due to data protection requirements. Distinct levels of access are provided for various stakeholders ( https://www.ema.europa.eu/en/human-regulatory/research-development/pharmacovigilance/eudravigilance/access-eudravigilance-data ). Being one of the competent authorities in Germany, the highest level of access is granted to the Federal Institute for Drugs and Medical Devices (BfArM). Nevertheless, even with the lowest access level, researchers can perform the same analysis in EudraVigilance (EV) with aggregated data (public access: http://www.adrreports.eu/en/index.html ). For further information regarding processing personal data in the context of the operation of EudraVigilance Human we refer to the European Medicines Agency’s Data Protection Notice for EudraVigilance Human. Code availability: Not applicable. Author's contributions: DD, JW, BH, and BS contributed to the conception and design of the study. DD selected the statistical methods, performed the analysis and created all tables and figures. The results were discussed by all authors. The first draft of the manuscript was written by DD. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
(© 2024. The Author(s).)