Regulatory advice from the EMA
Due to an associated future risk of impaired fertility, the European Medicines Agency (EMA) has published an update to The European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’. They state that all preparations containing boric acid or borates above a threshold level must include a warning in their package leaflet.
EMA threshold levels for children under 2 years
A warning in the packaging leaflet should be included for any product with potential to result in exposure to more than:
- 1mg daily of boron; or
- 5.7mg daily of boric acid
Implications for use
Any product that would result in exposure to more than 1mg daily of boron, should not be used in children under 2 years.
Chloramphenicol eye drops
Most UK manufacturers of chloramphenicol eye drop preparations have now updated their Summary of Product Characteristics to include a warning contraindicating use in children less than 2 years old, due to boron content.
Chloramphenicol eye ointment
Chloramphenicol eye ointment preparations do not contain boric acid or borates and so can be prescribed for children less than 2 years old.
Pharmacy-only (P) preparations of chloramphenicol are not licensed for sale or supply to children under 2 over the counter, but they are not contraindicated.
Advice from the Royal College of Ophthalmologists
The Royal College of Ophthalmologists has published a safety alert statement highlighting the following points for consideration:
- Chloramphenicol eye preparations have been widely used in children of all ages for many years with no documented adverse effects on fertility. To our knowledge there is no new scientific data from human studies to support this change to the product licence.
- There are circumstances where chloramphenicol eye drops are required in preference to eye ointment and no suitable alternative product exists. Other antibiotic eye drops may also contain boron e.g. gentamicin. Commonly available non-boron containing products suitable for young children, such as fusidic acid and azithromycin, have a much narrower spectrum of activity compared to chloramphenicol, and may not be a suitable replacement in some cases. Use of quinolone or broad-spectrum cephalosporin drops (some of which contain no boron) should be reserved for severe eye infections such as keratitis and endophthalmitis to maintain their effectiveness and not used routinely for simple bacterial conjunctivitis.
- Most manufacturers do not list boron content for their products but those that do give a range of 1.1mg/ml-2.9mg/ml. Given that the maximum volume that can be accommodated in the conjunctival sac is between 10-20µL, a typical regime of one drop to either eye four times daily would result in a daily exposure well below 1mg/day, even if 100% absorption is assumed.
- It is unlikely that formulations of boron-containing eye drops will be changed to remove boron in the near future.
- Antibiotic stewardship remains of primary importance to the College. There is a risk that avoiding all use of antibiotic eye drops with boron-containing excipients in children will result in increased prescribing of second or third-line antibiotics and encourage the development of microbial resistance.
- Implications for use section added to cover differences in boron content between eye drops and ointment
- Title changed to clarify that covers all chloramphenicol eye products