Chloramphenicol eye drops containing borax or boric acid buffers: use in children younger than 2 years

Following a review of the available toxicological data and a calculation of daily exposure to boron from a typical dosing regimen, we have concluded that the balance between the benefits and risks of chloramphenicol eye drops containing borax or boric acid remains positive for children aged 0 to 2 years. Chloramphenicol eye drops can be safely administered to children aged 0 to 2 years where antibiotic eye drop treatment is indicated.

From:
Medicines and Healthcare products Regulatory Agency
Published
7 July 2021
Therapeutic area:
Infectious disease, Ophthalmology

Post-publication note: January 2022

In January 2022, the MHRA published the Public Assessment Report on the review of the use of chloramphenicol eye drops containing borax and boric acid buffers in children under 2 years.

Advice for healthcare professionals:

  • some licences for chloramphenicol eye drop products containing borax or boric acid buffers were recently updated to restrict use in children younger than 2 years of age to reflect warnings on maximum daily limits for boron exposure
  • we have reviewed the available evidence and sought independent expert advice to understand whether there is a risk for children aged 0 to 2 years when using these products within the licensed indication, for what is likely to be a short period of time
  • our review has concluded that the benefits of chloramphenicol eye drops containing borax or boric acid outweigh the potential risks for children, including those aged 0 to 2 years
  • a typical regimen of one drop, applied typically 3 to 4 times a day, to both eyes, would result in a daily exposure well below the safety limit for children aged 0 to 2 years (see notes on dosing schedule in section on Findings of review)
  • advise parents and caregivers that chloramphenicol eye drops remain an important medicine for children when antibiotic eye treatment is indicated and that they have been used safely for many years – see Advice to provide to parents and carers below
  • the product information for affected chloramphenicol products is being updated to reflect the revised advice and remove restrictions for use in infants – in the meantime we ask healthcare professionals to reassure parents and carers that these products can be safely given to children aged 0 to 2 years as prescribed

Advice for healthcare professionals to provide to parents and carers

  • eye infections (conjunctivitis) are very common in babies and infants and it is important they are treated properly
  • chloramphenicol eye drops are an important medicine for treating bacterial eye infections in children and have been used safely for many years
  • some eye drops contain borax or boric acid, which are sources of boron – these ingredients are included as buffers to make sure the medicine is not too acidic or alkaline and is comfortable when administered to the eye
  • although concerns have been raised about boron and a possible effect on future fertility, these products can be safely given to children younger than 2 years as advised by a doctor or other prescriber
  • experts have advised that the amount of liquid that can be absorbed through the eyes of young children and the way these products are prescribed mean that the daily exposure to children would be well below the calculated safety limits

Review of the interpretation of EU guidance on boric acid and borates as excipients

Excipient guidance

In October 2017, warnings for boric acid (and borates) were introduced into the European Commission guideline for excipients in the labelling and package leaflet of medicines containing boron.[footnote 1][footnote 2] Marketing authorisation holders were asked to update their product information (Summary of Product Characteristics and Patient information Leaflet) in line with the 2017 guidance over a period of time; and this occurred in the UK last year.

The European guidance requires the addition of strong warnings not to give children aged 0 to 2 years products if an exposure greater than 1 milligram (mg) of boron a day is exceeded due to concerns around impaired fertility.

MHRA review

With restrictions introduced on the use of some products in children younger than 2 years, concerns were raised by the Royal College of Ophthalmologists and other professional organisations regarding the applicability of these warnings and restrictions for very young children and the lack of suitable alternatives to chloramphenicol eye drops.

We therefore undertook a review of the interpretation of the EU guidance on boric acid and borates as relates to children aged 0 to 2 years. The MHRA reviewed the available quality, clinical and toxicological evidence and sought independent expert advice from the Paediatric Medicines Expert Advisory Group of the Commission on Human Medicines to understand the risk for infants when these products are used within the licensed indication for what is likely to be a short period of time.

Findings of review

The European guidance threshold for boron is based on a pregnancy-related effect (reduced fetal weights). Furthermore, the uncertainty factors used in the derivation of the permitted daily exposure (PDE) are based on toxicokinetic and bodyweight data from pregnant rats and humans. Therefore, our review concluded that the current PDE is not relevant to children aged 0 to 2 years.

Based on studies conducted in animals, the most sensitive toxicological effect potentially relevant to infants is reproductive toxicity (adverse effects on fertility). This data was generated in adult animals, not juvenile animals, therefore the relevance to the developing reproductive tract and long-term effects on fertility are unknown. There are no data indicating clinical relevance to adults and children at present, therefore the assumption of potential risk to future fertility of infants is hypothetical. In terms of the exposures associated with the use of chloramphenicol eye drops, there are adequate safety margins in place for adverse effects on fertility and for exposures associated with reduced fetal weights, an endpoint not considered relevant to infants.

Levels of boron in chloramphenicol eye drops vary by product, but around 0.12mg of boron per drop might be present (based on a boron concentration of around 3mg/ml and a drop size of about 40 microlitres (μL)). Boron exposure calculated using the full amount per drop appears to be an overestimate. Administering eye drops in young children is difficult due to lack of co-operation and potential crying during administration. Because of this, some liquid will be blinked out. Based on expert opinion, the maximum volume that can be accommodated in the conjunctival sac of a child younger than 2 years is between 10μL and 20μL. Expert advice on current clinical practice suggests a typical regimen of one drop administered, applied typically 3 to 4 times a day to both eyes, which would result in a daily exposure well below 1mg per day, even if 100% absorption is assumed.

For severe eye infections, the BNF-C states a dose of one drop, every 2 hours (with frequency reduced as the infection is controlled).[footnote 3] This would result in a daily exposure over the limit of 1mg per day threshold for infants younger than 2 years assuming the maximum dose (24 drops) is administered and 100% absorption occurs. Expert opinion is that it is unlikely that the maximum dose will be achieved as the drops will likely be only administered during waking hours and the high dose is for a short duration of a few days.

Conclusion of the review

Given the toxicological data and the calculation of daily exposure from a typical dosing regimen, it has been concluded that the benefit-risk balance of chloramphenicol eye drops containing boron or boric acid remains positive for children aged 0 to 2 years.

The product information for affected chloramphenicol products will be updated shortly to reflect the revised advice that these products can be safely administered to children aged 0 to 2 years.

We have requested the removal of restrictions and associated warnings about boron exposure in children aged 0 to 2 years from the product information (Summary of Product Characteristics and Patient Information Leaflets) for UK chloramphenicol eye drop products.

To ensure continuity of supply, we will not be recalling products that are accompanied by Patient Information Leaflets with previous warnings. As such, for a short time, we ask healthcare professionals to reassure concerned parents and caregivers that chloramphenicol eye drops can be used safely when prescribed for use in their children as long as the instructions for use are followed.

Report suspected reactions on a Yellow Card

Report suspected adverse drug reactions or adverse incidents involving chloramphenicol eye drops to the Yellow Card scheme.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.

Article citation: Drug Safety Update volume 14, issue 12: July 2021: 1.

  1. European Medicines Agency. Annex of the European Commission guideline ‘Excipients in the labelling and package leaflet of medicinal products for human use’ (EMA/CHMP/302620/2017). SANTE-2017_11668. Published 9 October 2017; updated November 2019. ↩

  2. European Medicines Agency. Questions and answers on boric acid and borates used as excipients in medicinal products for human use (EMA/CHMP/619104/2013). Published 9 October 2017. ↩

  3. BNF for Children (BNF-C). Chloramphenicol. Accessed June 2021. ↩

Published 7 July 2021
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