An evaluation of reports of ciprofloxacin, levofloxacin, and moxifloxacin-association neuropsychiatric toxicities, long-term disability, and aortic aneurysms/dissections disseminated by the Food and Drug Administration and the European Medicines Agency

ABSTRACT

Introduction: Ciprofloxacin, levofloxacin, and moxifloxacin belong to the fluoroquinolone class of antibiotics and are amongst the most commonly prescribed antibiotics. In 2018 and 2019, Food and Drug Administration (FDA) and the European Medicine Agency (EMA) requested that manufacturers harmonize FQ safety information related to neuropsychiatric, aortic dissection, and long-term disability. The authors hypothesize that FDA and EMA epidemiologists support a strong association between these drugs and the three toxicities.

Areas covered: Studies of FQ-associated neuropsychiatric toxicity, long-term disability, and aortic ruptures/dissections. Clinical sources include FDA Advisory Committee documents, a 2014 Citizen Petition filed with the FDA requesting safety information additions to FQ labels for neuropsychiatric toxicities (partially granted in 2018), an under-review Citizen Petition under review by the FDA requesting a FQ Risk Evaluation and Mitigation Strategy, and safety notifications from the EMA.

Expert opinion: FDA and the EMA report state that neuropsychiatric toxicity, long-term disability, and aortic dissections//aneurysms occur with all FQs. Disability and neuropsychiatric toxicity can occur after one dose or several months after FQs. United States’ and European’ regulators warn physicians not to prescribe FQs for uncomplicated acute urinary tract infection, sinusitis, or bronchitis, unless other possible choices are tried first, as risks outweigh benefits in these settings.

KEYWORDS:

• Fluoroquinolones
• adverse events
• neuropsychiatric toxicity
• restricted distribution
• REMS (Risk Evaluation and Mitigation Strategy)

Article highlights

• Three fluoroquinolones, ciprofloxacin, levofloxacin, and moxifloxacin, have been identified by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as being strongly associated with neuropsychiatric toxicity including suicide, aortic dissections/aneurysms, and long-term disability.

• These associations have been reported at Advisory Committee meetings held in 2013, 2015, and 2018 by the FDA and by one Advisory Committee held by the EMA in 2018

• Safety warnings describing these toxicities have been disseminated by the FDA, EMA, Canada Health, the Therapeutic Goods Administration in Australia and the manufacturers of ciprofloxacin, levofloxacin, and ciprofloxacin between 2013 and 2019.

• The most recent safety announcements on ciprofloxacin, levofloxacin, and moxifloxacin from the FDA, EMA, Canada Health, and the Therapeutic Goods Administration in Australia now state that these agents should not be considered as first-line therapies for acute sinusitis, bacterial infections among persons with chronic obstructive pulmonary disease, or urinary tract infections as the risks outweigh the benefits in these settings.

• Antimicrobial stewardship programs are ideal change agents to ensure that the most recent safety advisories are implemented in practice.

• If clinically meaningful changes in the use of these three FQs do not occur, consideration should be given to implementing a Risk Evaluation and Mitigation Strategy that includes registration of patients and providers.

This box summarizes key points contained in the article.

Box 1. Drug summary box.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have been a speaker for Bayer (moxifloxacin) and Menarini (delafloxacin). All other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was supported by funding from a grant from the National Cancer Institute [R01CA165609] the Centers for Economic Excellence program of the state of South Carolina and the Doris Levkoff Meddin Center for Medication Safety.