Many ocular medications are used in children to treat common bacterial and viral infections, inflammation and allergy, uveitis and glaucoma, as well as other conditions including myopia, amblyopia, and strabismus [3], even if data regarding their safety and effectiveness in the paediatric population are sparse. In 2000, a review of the 98 most commonly used or prescribed topical ophthalmic drugs found that only 51% provided information on paediatric use [4]. Without adequate paediatric labelling information, practitioners treating eye disease in children may be forced to prescribe ocular medications in an "off-label" manner, placing their paediatric patients at risk for serious adverse reactions [5,6].

Children are not small adults. Statements regarding paediatric drug use must be age-specific to indicate for which group a drug has been studied: newborns, infants, pre-school children, school-age children, and adolescents. These groups differ not only in size and body weight but in physiology and metabolism as well [7]. Children, in particular infants and neonates who have thin eye membranes, may be particularly vulnerable to systemic effects of topical ophthalmic drugs as the doses used are often not weight-adjusted and are similar to doses used in adults. Systemic absorption may have a greater impact in children than in adults due to their lower body mass, altered metabolic capacity, and an immature blood brain barrier, leading to potentially higher plasma levels for a longer period of time and to a much greater risk of serious systemic side effects [8].

In addition to these differences, other characteristics unique to the paediatric population include the lack of commercially available dosage forms and concentrations appropriate for paediatric patients and the lack of published research on the pharmacokinetics and clinical use of new drugs [9]. The result is the high frequency of serious medication errors.

In order to collect randomized controlled trials (RCTs) on safety and efficacy of ophthalmic drugs in the paediatric population, a bibliographic search for ophthalmological therapy in children aged up to 18 years in the MEDLINE (1967 - December 2010), EMBASE (1975 - December 2010), and Cochrane Central Register of Controlled Trials (1967 - December 2010) databases was performed. The MeSH search terms and additional keywords used in the search strategy were: child/infant/newborn/adolescent, ophthalmology, drug therapy, and randomized controlled trials, limiting the results to human. To make the search more complete, the terms were searched for both in the database dictionaries and through the free text search option that covered the articles' titles and abstracts. All the references retrieved were collected and analyzed using the software program Reference Manager, version 11 (Institute for Scientific Information, Berkeley, California). The titles and abstracts were screened independently by two reviewers (FF and AC) to assess the relevance of the studies. Contrasting results were reviewed by a third person (MB).

We also searched for guidelines concerning paediatric ophthalmology management in MEDLINE and EMBASE, in the National Guidance Clearinghouse, National Library of Guidelines Specialist Library, National Institute for Clinical Excellence (NICE), Australian National Health and Medical Research Council, Canadian Medical Association InfoBase and New Zealand Guidelines Group databases, and on the American Academy of Pediatrics, Canadian Pediatric Society, and Royal College of Pediatrics websites.

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 [31,32]. 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 [33-37].

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 [39,40]. 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].