Fluoroquinolones and potential risk of retinal detachment

HSA would like to highlight the potential risk of retinal detachment associated with the use of oral fluoroquinolones.

Fluoroquinolones are broad-spectrum antibiotics that are used to treat a wide range of indications such as the infections of the urinary tract, respiratory tract, skin and soft tissue, bones and joints, and abdominal cavity. Oral fluoroquinolones licensed locally include ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, pefloxacin, ofloxacin, and lomefloxacin.

Background

The association between oral fluoroquinolones intake and occurrence of retinal detachment has been investigated in several epidemiological studies. Two large cohort studies² have found a statistically significant increased risk of retinal detachment with use of oral fluoroquinolones³.

The first study was a nested case-control study involving a cohort of patients in British Columbia, Canada, who had visited an ophthalmologist between January 2000 and December 2007. Out of 989,591 patients, 4,384 cases of retinal detachment and 43,840 controls were identified. This study found the current use of oral fluoroquinolones to be associated with a higher risk of developing a retinal detachment (3.3% of cases vs 0.6% of controls; adjusted rate ratio (ARR), 4.50 (95% confidence interval [CI], 3.56-5.70).  For current users, the mean number of days from the first fluoroquinolone prescription to the first event of a retinal detachment was 4.8 ± 4.8 days. No risk was observed among recent users (ARR, 0.92; 95% CI, 0.45-1.87) or past users (ARR, 1.03; 95% CI, 0.89-1.19).

The second study was a retrospective population-based cohort study conducted with data extracted from the Taiwan National Health Insurance Research Database from 1998 to 2010. The rate of rhegmatogenous retinal detachment (RRD) in adults treated with an oral fluoroquinolone (n=178,179 prescriptions) was compared with adults treated with oral amoxicillin (n = 178,179 prescriptions). The overall adjusted hazard ratio for fluoroquinolones use and RRD was 2.07 (95% CI, 1.45-2.96). The interval between use of oral fluoroquinoloness and onset of RRD was 35.5 days (interquartile range, 14-57 days).

This increased risk of retinal detachment was not confirmed in other published studies^4,5,6,7,8 as well as in a study conducted by the European Medicines Agency (EMA).⁹ However, in most of these studies, confidence intervals were relatively wide and thus a small increase in risk cannot be excluded.

Plausible mechanism for retinal detachment2

The exact mechanism of retinal detachment with fluoroquinolones is unknown. The retina is a delicate structure within the eye attached to the cortical vitreous by a complex matrix of collagen fibers. Vitreous liquefaction, a normal aging change of the vitreous, can result in retinal traction, which in turn can lead to retinal tears and subsequently retinal detachment. Conditions that interfere with connective tissue and collagen formation also increase vitreous liquefaction and have been shown to increase the risk of retinal detachment. Isolated animal studies have shown that fluoroquinolones interfere with collagen synthesis¹⁰ and disrupt the extracellular matrix outside the retina, including the corneal matrix.¹¹Hence it is postulated that fluoroquinolones could damage connective tissue including that of the vitreous and vitreous cortex through the aforementioned mechanisms observed in animals, potentially leading to retinal detachment.

International regulatory actions

The EMA and Health Canada (HC)¹² have reviewed this safety concern. Both agencies concluded that a causal relationship between fluoroquinolones intake and retinal detachment cannot be excluded based on the available data. Given the seriousness of retinal detachment with possible sequelae and the need for immediate intervention by an ophthalmologist in the event when this occurs, both EMA and HC have recommended the package inserts of fluoroquinolones to highlight the urgency to consult a healthcare professional if patients experienced vision problems during or following oral fluoroquinolones administration.

HSA’s actions and advisory

HSA has not received any reports of retinal detachment associated with the use of fluoroquinolones although we have received several reports describing visual disturbances such as blurred vision, eye redness, itching and conjunctivitis.

HSA has been working with the companies to update the package inserts of fluoroquinolone-containing products registered in Singapore to warn of this potential risk and to highlight the need to seek medical attention in the event of visual impairment and disturbances. In view of the fact that retinal detachment is serious and that its association with oral fluoroquinolones use cannot be ruled out, healthcare professionals are advised to consider this potential risk when prescribing and dispensing fluoroquinolones to patients.  Healthcare professionals are also encouraged to report any cases of retinal detachment associated with the use of fluoroquinolones to HSA. 

References

1. http://www.snec.com.sg/eye-conditions-and-treatments/common-eye-conditions-and-procedures/Pages/retinal-detachment.aspx ↗ (opens in new tab)

2. JAMA 2012; 307: 1414-19

3. Clin Infect Dis 2014; 58: 197-203

4. Pharmacoepidemiol Drug Saf 2014; 23: 745-52

5. J Antimicrob Chemother 2014; 69: 2563-67

6. Drug Saf 2014; 37:171-82

7. Ophthalmology 2014; 121: 1269-73

8. JAMA 2013; 310: 2184-90

9. http://www.ema.europa.eu/docs/en_GB/document_library/ ↗ (opens in new tab)
   PRAC_recommendation_on_signal/2014/07/WC500169486.pdf ↗ (opens in new tab)

10. J Orthop Res 2011; 29(1): 67-73

11. BMC Opthalmol. 2003; 6: 3-10

12. http://hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/fluoroquinolones-eng.php ↗ (opens in new tab)