This article reviews ocular medication use in children, providing a summary of their licensing status in Italy, the UK, and the USA and analyse the amount of available studies testing these medicines in the paediatric population. Most of the drugs listed have only recently obtained paediatric use approval and are now widely prescribed for children by a growing number of clinicians [29
]. However, for most of these drugs wide differences in the licensed age groups were found and only a few are available in all three countries. Even if the Paediatric Regulation in EU and USA specifically aims at giving children the same access to authorised medicinal products suitable for their use, the age approval and occasionally the approach towards certain therapeutic problems is under the direct responsibility of National Authorities, so differences in drug licensing procedure between countries remain. There is therefore a need for evidence-based harmonization of drug licenses in order to guarantee equal drug availability and access [30
Furthermore, many ocular medications commonly used in children still do not have paediatric dosing and safety labelling information in any country. For example, almost for all glaucoma medications (such as prostaglandin analogues and carbonic anhydrase inhibitors), paediatric use is labelled "not recommended".
At this time no paediatric RCTs were available for several ocular medications. When available, the studies were often limited to small case series and case reports, so more extensive controlled trials will be needed to confirm their safety and efficacy also in paediatric population. On the contrary, evidence on efficacy was found for drugs that were not licensed for children, such as tetracycline and bupivacaine.
In spite of the fact that no ophthalmologic drugs are found in the EMA's priority list, several drugs were recently studied in paediatric clinical trials in the European countries and the USA. In particular, the ongoing research is examining the potential use of intravitreally injected anti-VEGF drugs, such as bevacizumab, successfully used in adults with diabetic retinopathy or age-related macular degeneration (AMD), a cause of a severe vision loss among the aging population in many western countries [31
]. These drugs could now also be used in paediatric vitreoretinal diseases, as shown by recent studies on intravitreal injection of bevacizumab for the treatment of ROP, the leading cause of childhood blindness [33
Moreover, the available guidelines on the pharmacological management of eye diseases in the paediatric population often recommend the use of medications not licensed or investigated in children, especially for the management of glaucoma (such as prostagliandin analogs) or acute bacterial conjunctivitis (such as steroids and antibiotics combinations). An effort to stimulate research and clinical development is therefore needed also for them, in order to guarantee medicines that have been proven to be of benefit also in paediatric patients.
Many good ethical and economical reasons exist for limiting paediatric clinical trials, while guaranteeing appropriate conclusions. Because of the characteristics of the paediatric population, limited information is also available regarding the side effects related to ocular medication use in children [38
]. As the number and variety of ocular medications has increased and the number of clinicians involved in their prescription has grown, the risk of systemic adverse reactions may also increase [39
]. When prescribing ocular medications in children, physicians should therefore carefully consider their risk/benefit profile, referring to details of labelling for paediatric use, such as the age of the child for whom the drug is approved, and be aware of their potentially serious systemic side effects [5
Some strategies for reducing systemic absorption and toxicity should be followed whenever possible. First of all, the lowest available dosage of medication necessary to achieve a therapeutic benefit while minimizing risk should be used. Secondly, since different formulations may have different degrees of systemic absorption, formulations with lower systemic absorption, which may be more suitable for use in children, should be used. Ophthalmic gel or ointment, for example, has been found to have reduced systemic absorption compared to the ophthalmic solution [28
]. In addition, paediatric patients should be monitored closely during and after treatment for local and systemic side effects [29
The present findings suggest that access to, and rational use of, ocular medications in the paediatric population continue to present a considerable challenge. Paediatric clinical trials are important for defining how infants and children respond to medications and for identifying age-specific toxic effects [41
]. While recent legal and economic incentives in both Europe and the USA stimulate research to obtain more data regarding dosing, efficacy, and safety of medicines used in children, problems remain in obtaining adequate evidence [42
]. In this context, there is a pressing need for further clinical research to improve the quality, efficacy, and safety of ocular medications offered to paediatric patients. Clinical research must be carried out using appropriate methodologies (e.g. study design, sample size, randomization, and blinding) [38
] also (and in particular) in the paediatric ophthalmic area, where effective up-to-date treatments, and additional research and education on use in children, remain priorities [43