More prominent warnings about serious side effects for fluoroquinolone antibiotics

Summary

Fluoroquinolones, including ciprofloxacin, norfloxacin and moxifloxacin, are broad-spectrum antibiotics used against susceptible infections and are usually reserved for patients who have no other treatment options.

More prominent warnings are being added to the product information (PI) and consumer medicine information (CMI) for all oral and injectable (systemic) fluoroquinolones to strengthen existing warnings about serious side effects. These include:

• central nervous system stimulation leading to transient tremor, restlessness, light-headedness, confusion, and very rarely to hallucinations or seizures
• tendonitis and tendon ruptures 
• psychiatric reactions. 

Although rare, these side effects can be disabling and potentially irreversible. They can occur in patients of any age without pre-existing risk factors and have been reported simultaneously in the same patient. The nervous system and psychiatric reactions can occur after the first dose.

These updated warnings do not apply to fluoroquinolone eye or ear drops.

What health professionals should do

Health professionals should:

• be aware of these potential serious side effects and are reminded to use fluoroquinolones judiciously in line with Australian antibiotic prescribing guidelines
• warn patients to be alert to any unusual symptoms following treatment with fluoroquinolones and to seek health advice
• promptly discontinue fluoroquinolones in the event of an adverse reaction and consider prescribing alternative treatment.

Fluoroquinolones

Fluoroquinolones are broad-spectrum antibiotics that are active against a wide range of bacteria, including gram-negative and some gram-positive organisms. 

Oral and intravenous fluoroquinolone antibiotics marketed in Australia include:

• ciprofloxacin
• norfloxacin
• moxifloxacin.

There are more than 80 fluoroquinolone products on the market in Australia. Many are subsidised by the Pharmaceutical Benefits Scheme with restrictions on use to reduce the spread of antibiotic resistance.

Background

A 2023 review by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) into the serious side effects associated with fluoroquinolones found that regulatory changes taken by the MHRA to restrict use in 2019 had not appeared to reduce prescribing rates.¹ These regulatory changes stated that fluoroquinolones should not be prescribed for non-severe or self-limiting conditions, or non-bacterial conditions, for example non-bacterial prostatitis. As a result, the MHRA review recommended several updates to the safety information to highlight the risks of these side effects. They also recommended the updates should be communicated directly to health professionals. 

After investigating this issue, we are introducing ‘boxed warnings’ to the Australian PIs and CMIs to raise awareness of these serious side effects in line with warnings from other international regulators.

Boxed warnings are included on the first page of PIs and CMIs to highlight significant medicine safety risks.

Adverse events reported to us

A search of our publicly available Database of Adverse Event Notifications (DAEN) on 20 December 2024 for ciprofloxacin, norfloxacin and moxifloxacin returned 128 adverse event reports involving the musculoskeletal system that were reported as serious. These include management of the adverse event by a GP, a hospital admission or a hospital emergency visit. The most common included inflammation of a tendon (tendonitis), joint pain (arthralgia) and muscle pain (myalgia).

Adverse events reported for ciprofloxacin, norfloxacin and moxifloxacin and the nervous system returned 152 considered serious by the reporter. The most common included weakness, numbness or pain in the hands and feet (peripheral neuropathy), headache and pins and needles (paraesthesia). 

There were 59 psychiatric adverse events reported for ciprofloxacin, norfloxacin and moxifloxacin considered serious by the reporter. The most common were confusional state, anxiety and depression.  

‌Importantly, inclusion in the DAEN does not mean that the details of the reported event have been confirmed, or that the event has been determined to be related to a medicine.‌

Warnings in the PI 

The boxed warning will be included in the Australian PIs for oral and injectable ciprofloxacin - external site, norfloxacin - external site and moxifloxacin - external site products and relates to existing information in Section 4.4 Special warnings and precautions.

Health professionals should refer to the PI of the relevant product for more detailed information as the wording in section 4.4 differs between products.

The boxed warning text (ciprofloxacin is given as the example):

WARNING

Serious disabling and potentially irreversible adverse reactions

Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions involving different body systems that have occurred together in the same patient. Patients of any age or without pre-existing risk factors have experienced these adverse reactions. These include but are not limited to serious adverse reactions involving the nervous system (see section 4.4 Effects on the CNS), musculoskeletal system (see section 4.4 Tendonitis and tendon rupture) and psychiatric effects (see section 4.4 Psychiatric reactions).

References

1. Ly NF et al. Impact of European Union Label Changes for Fluoroquinolone-Containing Medicinal Products for Systemic and Inhalation Use: Post-Referral Prescribing Trends - external site. Drug Saf. 2023 Apr;46(4):405-416.

Further reading

Baggio D and Ananda-Rajah MR. Fluoroquinolone antibiotics and adverse events - external site. Aust Prescr. 2021 Oct;44(5):161-164. doi: 10.18773/austprescr.2021.035. Epub 2021 Oct 1. PMID: 34728881; PMCID: PMC8542490.

What to report? You don't need to be certain, just suspicious!

We encourage the reporting of all suspected adverse reactions to medicines, including vaccines, over-the-counter medicines, and herbal, traditional or alternative remedies.

We particularly request reports of:

• all suspected reactions to new medicines (look for the Black Triangle ▼ in PI and CMI documents – this symbol identifies medicines that are new or being used differently)
• all suspected medicine interactions
• suspected reactions causing death, admission to hospital or prolongation of hospitalisation, increased investigations or treatment, or birth defects.

To report a suspected side effect or for more information about reporting, go to our ‘Report problem or side effect’ webpage or contact our Pharmacovigilance Branch at: ADR.Reports@health.gov.au.

Disclaimer

Medicines Safety Update is aimed at health professionals. It is intended to provide practical information to health professionals on medicine safety, including emerging safety issues. The information in Medicines Safety Update is necessarily general and is not intended to be a substitute for a health professional's judgment in each case, that takes into account the individual circumstances of their patients. Reasonable care has been taken to ensure that the information is accurate and complete at the time of publication. The Australian Government gives no warranty that the information in this document is accurate or complete, and shall not be liable for any loss whatsoever due to negligence or otherwise arising from the use of or reliance on this document.

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For correspondence or further information about Medicines Safety Update, contact our Pharmacovigilance Branch at ADR.Reports@health.gov.au.

Medicines Safety Update is written by staff from our Pharmacovigilance Branch.

Editor: Dr Megan Hickie

Deputy Editor: Aaron Hall

Contributors: Renae Mura and Steph Cheung