其 他 安 全 警 示
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| The United Kingdom: Chloramphenicol eye drops containing borax or boric acid buffers: use in children younger than 2 years (English only) |
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Medicines and Healthcare products Regulatory Agency (MHRA) announces that chloramphenicol eye drops can be safely administered to children aged 0 to 2 years where antibiotic eye drop treatment is indicated.
In Oct 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. 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 United Kingdom 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.
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. The MHRA therefore undertook a review of the interpretation of the European 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.
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, the MHRA’s 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 British National Formulary for Children (BNF-C) states a dose of one drop, every 2 hours (with frequency reduced as the infection is controlled). 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.
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. The MHRA has requested the removal of restrictions and associated warnings about boron exposure in children aged 0 to 2 years from the product information for United Kingdom chloramphenicol eye drop products.
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.
- The MHRA has 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.
- The MHRA’s 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.
- 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.
- 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 the MHRA asks healthcare professionals to reassure parents and carers that these products can be safely given to children aged 0 to 2 years as prescribed.
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/chloramphenicol-eye-drops-containing-borax-or-boric-acid-buffers-use-in-children-younger-than-2-years
In Hong Kong, there are 23 registered pharmaceutical products which are chloramphenicol-containing eye drops. All products are prescription-only medicines. Four of these products are indicated for children aged 2 years or above. For the remaining 19 products, they contain boric acid and related excipients. So far, the Department of Health (DH) has not received any case of adverse drug reaction related to chloramphenicol. Healthcare professionals are advised to balance the risk of possible adverse effects against the benefit of treatment. The DH will remain vigilant on safety update of the drug issued by other overseas drug regulatory authorities.
Ends/Thursday, Jul 8, 2021
Issued at HKT 17:00
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