Ocular medicines in children: the regulatory situation related to clinical research

  • Filomena Fortinguerra1Email author,

    Affiliated with

    • Antonio Clavenna1 and

      Affiliated with

      • Maurizio Bonati1

        Affiliated with

        BMC Pediatrics201212:8

        DOI: 10.1186/1471-2431-12-8

        Received: 9 May 2011

        Accepted: 20 January 2012

        Published: 20 January 2012

        Abstract

        Background

        Many ocular medications are prescribed for paediatric patients, but the evidence for their rational use is very scant. This study was planned to compare the availability and the licensing status of ocular medications marketed in Italy, the United Kingdom (UK), and the United States of America (USA) related to the amount of published and un-published RCTs testing these drugs in the paediatric population.

        Methods

        A quantitative analysis was performed to evaluate the number of ocular medications with a paediatric license in Italy, the UK, and the USA. A literature search was also performed in MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) on ophthalmic pharmacological therapy in children aged < 18 years, published up to December 2010. A search in the international clinical trial registries, the list of paediatric investigation plans (PIPs) approved by European Medicines Agency (EMA), and the table of medicines with new paediatric information approved by Food and Drug Administration (FDA) was also performed.

        Results

        In all, of 197 drugs identified, 68 (35%) single drugs are licensed for paediatric use at least in one considered country, while 23 (12%) were marketed in all three countries. More specifically, in Italy 43 single drugs (48% of those marketed) had a paediatric license, while 39 (64%) did in the UK and 22 (54%) did in the USA. Only 13 drugs were marketed with a paediatric license in all countries.

        The percentage of drugs licensed for paediatric use and for which at least one RCT had been performed ranged between 51% in Italy and 55% in the USA. No published RCTs were found for 11 (48%) drugs licensed for paediatric use in all three countries. In all, 74 (35%) of the retrieved RCTs involved mydriatic/cycloplegic medications.

        A total of 62 RCTs (56% completed) on 46 drugs were found in the international clinical trial registries. Cyclosporin and bevacizumab were being studied in many ongoing trials. Twenty-six drugs had new paediatric information approved by FDA based on new paediatric clinical trials, while only 4 PIPs were approved by EMA.

        Conclusions

        There is a pressing need for further research and clinical development in the pediatric ophthalmic area, where effective up-to-date treatments, and additional research and education on use in children, remain priorities.

        Keywords

        review ocular medicines eye diseases drug therapy paediatrics

        Background

        Many drugs on the market labelled for adult use contain no information on paediatric use because their safety and efficacy have not been well studied in paediatric patients [1]. Many widely used drugs therefore include disclaimers stating that the paediatric use is "not recommended". Despite the prevalence of eye disease in early childhood (in the United Kingdom, by 3 years of age 5.7% of children had had ≥ 1 eye condition, 0.24% of which associated with visual impairment) [2] more than in other paediatric areas, evidence for the rational use of ocular medicines in these patients is very scant.

        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.

        A study was planned to compare the availability and the licensing status of ocular medications marketed in Italy, the United Kingdom (UK), and the United States of America (USA) related to the amount of published and un-published RCTs testing these drugs in the paediatric population.

        Methods

        Ocular medications were identified and classified according to the International Anatomic-Therapeutical-Chemical classification system (ATC) [10] as S01: antibiotics, antivirals, anti-allergy drugs, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, diagnostic agents, lubricants, glaucoma medications, local anaesthetics, and vascular endothelial growth factor inhibitors (anti-VEGF drugs) and combinations. A quantitative analysis was performed to record the number of ophthalmic drugs available on the market and those approved for paediatric use in Italy, the UK, and USA. Data on the licensing status of individual drugs were obtained by consulting national formularies: Italy's Repertorio Farmaceutico Italiano (Refi) [11], the UK's British National Formulary (BNF) [12], and the USA's Physicians' Desk Reference® (PDR®) [13].

        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.

        In addition, a search for paediatric clinical trials on ocular medications in the World Health Organization's International Clinical Trials Registry Platform (ICTRP) [14], the ClinicalTrials.gov registry [15], and the International Standard Randomized Controlled Trial Number Register (ISRCTN) [16] was performed in order to find which of these drugs are under paediatric investigation. Furthermore, the list of paediatric investigation plans (PIPs) approved by EMA [17], the "List of the active substances included in the work-sharing procedure in accordance with Articles 45 and 46 of the European Paediatric Regulation [18], and the FDA's "Table of Medicines with new paediatric information", a list of drugs approved for paediatric use resulting from the paediatric clinical trials performed in response to paediatric legislative initiatives [19], and the updated priority list for studies into off-patent paediatric medicinal products [20], were also consulted in order to assess if there is a gap between research and clinical practice.

        Results

        Quantitative analysis

        A total of 197 ocular medications were reported in the 2010 ATC index, respectively, 88 (45%), 63 (31%), and 41 (21%) of which were marketed in Italy, the UK, and the USA.

        In all, 68 (35%) single drugs are licensed for paediatric use in at least one considered country, while 23 drugs (12%) were marketed in all three countries. More specifically, in Italy 43 single drugs (48% of those marketed) had a paediatric license, while 39 (64%) did in the UK and 22 (54%) did in the USA. Only 13 drugs were marketed with a paediatric license in all the countries (Table 1). Only 3 licensed drugs appear in the World Health Organization (WHO) list of paediatric essential drugs. Tetracycline as 1% eye ointment and adrenaline as 2% eye drops, considered essential drugs for children, were not licensed for paediatric use in any country.
        Table 1

        Paediatric licensing status and number of RCTs related to ocular medications

        Pharmaco-therapeutic Group

        Drug name

        Licence Status

        RCTs

          

        IT

        UK

        USA

        Published

        Non-published

        ANTI-ALLERGY MEDICATIONS

         

        14/12*

        8/8*

        11/10*

        34

        5

        Anti-histamine agent

        Azelastine

        ≥ 4 yrs

        ≥ 12 yrs

        ≥ 3 yrs

        4

        -

         

        Emedastine

        ≥ 3 yrs

        ≥ 3 yrs

        ≥ 3 yrs

        1

        -

         

        Epinastine

        ≥ 12 yrs

        ≥ 12 yrs

        ≥ 3 yrs

        -

        -

         

        Ketotifen

        ≥ 3 yrs

        ≥ 3 yrs

        ≥ 3 yrs

        5

        3

         

        Levocabastine

        all

        NA**

        NA

        6

        -

         

        Olopatadine

        ≥ 3 yrs

        ≥ 3 yrs

        ≥ 3 yrs

        4

        1

        Mast cell stabilizer

        Spaglumic acid

        all

        NA

        NA

        -

        -

         

        Lodoxamide

        all

        ≥ 4 yrs

        > 2 yrs

        1

        -

         

        Nedocromil sodium

        ≥ 6 yrs

        ≥ 6 yrs

        ≥ 3 yrs

        5

        -

         

        Sodium cromogligate

        ns**

        all

        NA

        6

        -

         

        Pemirolast

        NA

        NA

        ≥ 3 yrs

        -

        -

        Decongestant (Sympathomimetic agent)

        Naphazoline

        ≥ 10 yrs

        NA

        nl

        -

        1

         

        Oxymetazoline

        ≥ 3 yrs

        NA

        ≥ 6 yrs

        -

        -

         

        Tetryzoline

        ≥ 3 yrs

        NA

        ≥ 6 yrs

        -

        -

        ANTI-ALLERGY COMBINATIONS

         

        3/3

        1/1

        2/2

        0

        0

        Anti-histamine agent + Decongestant

        Antazoline + Xylometazoline

        NA

        ≥ 5 yrs

        NA

        -

        -

         

        Chlorpheniramine + Tetryzoline

        ≥ 3 yrs

        NA

        NA

        -

        -

         

        Pheniramine + Tetryzoline

        ≥ 3 yrs

        NA

        NA

        -

        -

        Mast cell stabilizer + Decongestant

        Cromoglicate + Tetryzoline

        ≥ 3 yrs

        NA

        NA

        -

        -

        Astringent + Decogestant

        Zinc sulfate + Tetryzoline

        NA

        NA

        ≥ 6 yrs

        -

        -

        Decogestant + Lubricants

        Tetryzoline + Povidone + Dextran 70 + Polyethylene glycol 400

        NA

        NA

        ≥ 6 yrs

        -

        -

        ANTI-GLAUCOMA MEDICATIONS

         

        23/6

        14/1

        6/1

        4

        3

        Beta-blocker

        Timolol

        > 1 m

        nl**

        nl

        4

        2

        Carbonic anhydrase inhibitor

        Dorzolamide

        all

        nl

        ns

        -

         

        Sympathomimetic agent (selective α 2 - agonist)

        Apraclonidine

        ≥ 12 yrs

        ≥ 12 yrs

        nl

        -

        -

         

        Brimonidine

        ≥ 12 yrs

        NA

        ≥ 2 yrs

        -

        1

         

        Clonidine

        ns

        NA

        NA

        -

        -

        Parasympathomimetic (colinergic) agent

        Aceclidine

        ≥ 3 yrs

        NA

        NA

        -

        -

         

        Pilocarpine

        ≥ 3 yrs

        nl

        Nl

        -

        -

        ANTI-GLAUCOMA COMBINATIONS

         

        2/1

        1/0

        2/2

        1

        0

        Beta-blocker + Carbonic anhydrase inhibitor

        Timolol + Dorzolamide

        ≥ 2 yrs

        nl

        ≥ 2 yrs

        1

        -

        Beta-blocker + Sympathomimetic agent

        Timolol + Brimonidine

        nl

        NA

        ≥ 2 yrs

        -

        -

        ANTI-INFLAMMATORY MEDICATIONS

         

        16/8

        8/5

        5/2

        16

        6

        Non-Steroidal Anti-Inflammatory Drug (NSAID)

        Diclofenac

        ≥ 3 yrs

        nl

        nl

        4

        1

         

        Indomethacin

        ≥ 3 yrs

        NA

        NA

        -

        -

         

        Ketorolac

        NA

        nl

        ≥ 3 yrs

        3

        -

        Steroid agent

        Betamethasone

        NA

        all

        NA

        -

        -

         

        Desonide

        > 1 m

        NA

        NA

        -

        -

         

        Dexamethasone

        > 1 m

        all

        nl

        6

        2

         

        Fluorometholone

        ≥ 2 yrs

        ≥ 2 yrs

        ≥ 2 yrs

        3

        1

         

        Hydrocortisone

        > 1 m

        all

        NA

        -

        -

         

        Prednisolone

        NA

        all

        nl

        -

        2

         

        Clobetasone

        >1 m

        NA

        NA

        -

        -

        Steroid agent + Decongestant

        Fluorometholone + Tetryzoline

        ≥ 2 yrs

        NA

        NA

        -

        -

         

        Clobetasone + Tetryzoline

        ns

        NA

        NA

        -

        -

        ANTI-INFECTIVE MEDICATIONS

         

        21/13

        9/9

        10/7

        27

        3

        Antibacterial agent

        Chloramphenicol

        ≥ 3 yrs

        all

        NA

        7

        -

         

        Fusidic acid

        ns

        all

        NA

        3

        -

         

        Propamidine isetionate

        NA

        all

        NA

        -

        -

        Aminoglycoside

        Gentamycin

        ≥ 3 yrs

        all

        >1yr

        2

        1

         

        Neomycin

        NA

        all

        NA

        -

        -

         

        Netilmycin

        > 1 m

        NA

        NA

        -

        -

         

        Tobramycin

        ≥ 1 yr

        NA

        nl

        3

        -

        Quinolone

        Ciprofloxacin

        all

        ≥ 1 yr

        ≥ 1 yr

        2

        -

         

        Gatifloxacin

        NA

        NA

        ≥ 1 yr

        -

         
         

        Levofloxacin

        ≥ 1 yr

        ≥ 1 yr

        ≥ 1 yr

        2

        -

         

        Lomefloxacine

        ≥ 1 yr

        NA

        NA

        -

        -

         

        Moxifloxacin

        ≥ 1 m

        nl

        ≥ 1 yr

        3

         
         

        Ofloxacin

        nl ophtalmia neonatorum

        > 1m

        ≥ 1 yr

        1

        -

        Antiviral agent

        Acyclovir

        all

        all

        nl

        -

        -

         

        Idoxuridine

        ≥ 3 yrs

        NA

        NA

        -

        -

         

        Trifluridine

        all

        NA

        ≥ 6 yrs

        -

        -

        Other anti-infective agent

        Povidone - Iodine

        > 1 m

        NA

        nl

        4

        2

        ANTIBACTERIAL COMBINATIONS

         

        9/2

        6/3

        4/1

        3

        0

        Antibacterials

        Polimyxin B + Trimethoprim

        NA

        all

        > 2 ms

        1

        -

         

        Polimyxin B + Bacitracin

        NA

        all

        nl

        1

        -

         

        Neomycin + Polymyxin B + Gramicidin

        NA

        ≥ 2 yrs

        nl

        -

        -

         

        Neomycin + Chloramphenicol

        ns

        NA

        NA

        -

        -

        Antibacterial + Steroid

        Neomycin + Polymyxin B + Dexamethasone

        nl

        all

        ≥ 2 yrs

        -

        -

         

        Neomycin + Polymyxin B + Hydrocortisone

        NA

        NA

        ns

        -

        -

         

        Neomycin + Chloramphenicol + Hydrocortisone

        ns

        NA

        NA

        -

        -

         

        Neomycin + Prednisolone

        ns

        all

        NA

        -

        -

         

        Neomycin + Fluocinolone

        ns

        NA

        NA

        -

        -

         

        Neomycin + Betamethasone

        NA

        all

        NA

        1

        -

         

        Tobramycin + Dexamethasone

        nl

        NA

        ≥ 2 yrs

        -

        -

         

        Prednisolone + Sulphacetamide

        NA

        NA

        ≥ 6 yrs

        -

        -

         

        Tobramycin + Fluorometholone

        NA

        NA

        ≥ 2 yrs

        -

        -

        Antibacterial + Steroid + Decongestant

        Neomycin + Gramicidin + Tetryzoline + Dexamethasone

        ≥ 3 yrs

        NA

        NA

        -

        -

         

        Betamethasone + Sulphacetamide + Tetryzoline

        ≥ 2 yrs

        NA

        NA

        -

        -

        MYDRIATIC/CYCLOPLEGIC MEDICATIONS

         

        7/4

        6/5

        2/1

        55

        3

        Antimuscarinic agent

        Cyclopentolate

        ≥ 3 yrs

        > 3 ms

        all

        14

        -

         

        Homatropine

        ns

        > 3 ms

        nl

        -

        -

         

        Tropicamide

        > 1 m

        all

        NA

        10

        -

         

        Atropine

        ns

        > 3 ms (nl uveitis)

        NA

        31

        3

         

        Ibopamine

        all

        NA

        NA

        -

        -

        Decongestant (Sympathomimetic agent)

        Phenylephrine

        ≥ 12 yrs

        All (nl 10% drops)

        NA

        2

        -

        PERI-OPERATIVE MEDICATIONS

         

        2/0

        4/4

        1/0

        4

        0

        Local anaesthetic

        Lidocaine

        nl

        all

        nl

        2

        -

         

        Oxybuprocaine

        ns

        all

        NA

        1

        -

         

        Proxymetacaine

        NA

        all

        NA

        -

        -

         

        Tetracaine

        NA

        all

        NA

        1

        -

        LUBRICANTS AND ASTRIGENTS

         

        5/0

        10/5

        4/0

        0

        0

        Ocular lubricant and astringent

        Polyvinyl alcohol

        Ns

        all

        NA

        -

        -

         

        Carmellose sodium

        ns

        all

        NA

        -

        -

         

        Hydroxyethylcellulose

        NA

        all

        NA

        -

        -

         

        Paraffin

        NA

        all

        NA

        -

        -

         

        Sodium hyaluronate

        ns

        all

        NA

        -

        -

         

        Hypromellose

        NA

        all

        nl

        -

        -

        LUBRICANT COMBINATIONS

         

        0/0

        2/2

        6/2

        0

        0

        Lubricants

        Hypromellose + Glycerin

        NA

        NA

        all

        -

        -

         

        Hypromellose + Dextran 70

        NA

        all

        nl

        -

        -

         

        Hypromellose + Glycerin + Polyethylene glycol 400

        NA

        NA

        ≥ 6 yrs

        -

        -

        Lubricant + Steroid agent

        Hypromellose + Dexamethasone

        NA

        all

        NA

        -

        -

        OTHER OCULAR MEDICATIONS

         

        2/1

        2/2

        2/1

        0

        0

        Hypertonic agent

        Sodium chloride

        NA

        all

        Nl

        -

        -

        Ocular diagnostic agent

        Fluorescein

        ns

        all

        NA

        -

        -

        Topical immunomodulator

        Cyclosporine 0.05%

        NA

        NA

        ≥ 16 yrs

        -

        -

        Other ocular agent

        Heparin

        > 1 m

        NA

        NA

        -

        -

        TOTAL SINGLE DRUGS

        68

        88/43

        61/39

        41/22

        140

        20

        TOTAL COMBINATIONS

        29

        16/7

        10/6

        14/7

        4

        -

        NOTE: Only drugs with a paediatric licence at least in one country are listed. The drugs in bold are listed in the WHO model list of essential medicines for children.

        * N° drugs marketed/N° drugs marketed with paediatric licence

        ** ns: not specified; nl: not licensed for paediatric use; NA: not authorised

        Fifteen single drugs and six combinations (mainly anti-infective, anti-inflammatory, and anti-allergy medications) were licensed for paediatric use only in Italy, while 16 single drugs and 8 combinations were licensed only in the UK (mainly local anaesthetics and lubricants), and 2 single drugs and 8 combinations only in the USA (mainly anti-infective medications). Almost all anti-allergy medications and combinations had a paediatric license in all three countries, while no local anaesthetics are licensed for paediatric use in Italy and USA and no NSAIDs are in the UK.

        Wide differences were found in the age groups for which the drugs were licensed and only for 6 drugs the age range is the same or similar in all countries.

        Qualitative analysis

        Bibliographic search

        The bibliographic search produced 158 RCTs on 69 single drugs and combinations, involving a total of 18,816 children (Table 2). The percentage of drugs licensed for paediatric use with at least one RCT ranged between 51% in Italy and 55% in the USA. No published RCTs were found for 11 (48%) ocular medications licensed for paediatric use in all three countries.
        Table 2

        Summary of retrieved RCTs on the use of ocular medications in the paediatric population

        Pharmaco-therapeutic Group

        Drug name

        Formulation

        N° RCTs

        N° Children

        Age range

        MYDRIATIC/CYCLOPLEGIC MEDICATIONS

         

        74 (35%)

          

        Antimuscarinic agent

        Atropine

        eye drops 1%

        31

        3530

        all

         

        Cyclopentolate

        eye drops 0.5%

        2

        28

        ≤ 13 yrs

          

        eye drops 1%

        11

        181

        ≤ 16 yrs

         

        Tropicamide

        eye drops 1%

        9

        348

        all

         

        Pirenzepine

        ophthalmic gel 1%

        3

        276

        6 - 12 yrs

         

        Cyclopentolate/Tropicamide

        eye drops 1%/1%

        6

        176

        all

        Sympathomimetic agent

        Phenylephrine

        eye drops 2.5%

        1

        10

        ≤ 1 m

        Antimuscarinic agent + Sympathomimetic agent

        Tropicamide/Phenylephrine

        eye drops 1%/2.5%

        3

        92

        ≤ 1 m

          

        eye drops 0.5%/2.5%

        2

        51

        ≤ 8 yrs

          

        eye drops 0.5%/0.5%

        1

        12

        3-11 yrs

         

        Cyclopentolate/Phenylephrine

        eye drops 1%/2.5%

        2

        30

        ≤ 6 yrs

          

        eye drops 0.2%/1%

        3

        99

        ≤ 1 m

        ANTI-INFECTIVE MEDICATIO NS

         

        51 (24%)

          

        Antibacterial agent

        Chloramphenicol

        eye drops 0.5%

        7

        1664

        ≤ 12 yrs

         

        Azithromycin

        eye drops 1%

        1

        335

        ≥ 1 yr

          

        eye drops 1.5%

        2

        542

        ≥ 1 yr

         

        Tetracycline

        eye drops 1%

        2

        518

        1- 10 yrs

          

        eye ointment 1%

        2

        218

        ≥ 6 ms

         

        Besifloxacin

        eye suspension 0.6%

        3

        1124

        ≥ 1yr

         

        Fusidic acid

        eye drops 1%

        3

        594

        ≤ 2 yrs

         

        Moxifloxacin

        eye drops 0.5%

        3

        645

        all

         

        Tobramycin

        eye drops

        3

        741

        ≤ 12 yrs

         

        Ciprofloxacin

        eye drops 0.3%

        2

        193

        ≤ 12 yrs

         

        Levofloxacin

        eye drops 0.5%

        2

        106

        1-16 yrs

         

        Gentamycin

        eye ointment

        2

        117

        ≤ 12 yrs

         

        Erythromycin

        eye drops

        1

        110

        ≤ 1 m

          

        eye ointment

        1

        24

        ≤ 1 yr

         

        Ofloxacin

        eye drops 0.3%

        1

        23

        ≥2 yrs

         

        Oxytetracycline

        eye drops 1%

        1

        450

        ≤ 1 m

         

        Sulphacetamide

        eye drops 10%

        1

        14

        ≤ 1 m

        Antibacterials combinations

        Polymixin B/Oxytetracycline

        eye ointment

        2

        132

        2-10 yrs

         

        Polymixin B/Bacitracin

        eye ointment

        1

        66

        ≥ 1 m

         

        Polymixin B/Trimethoprim

        eye drops

        1

        28

        all

        Antibacterial agent + NSAID

        Gentamycin/Diclofenac

        eye drops

        1

        12

        ≤ 12 yrs

        Antibacterial agent + Steroid agent

        Neomycin/Betamethasone

        eye drops

        1

        12

        ≤ 12 yrs

         

        Tobramycin/Dexamethasone

        eye drops

        1

        28

        4-10 yrs

        Antifungal agents

        Miconazole

        eye suspension 1%

        1

        12

        ≥ 15 yr

         

        Econazole/Miconazole

        eye suspension 1%/1%

        1

        7

        ≥ 15 yr

        Other anti-infective eye preparation

        Povidone-iodine

        eye drops 2.5%

        4

        3132

        ≤ 1 yr

         

        Silver nitrate

        eye drops 1%

        1

        450

        ≤ 1 m

        ANTI-ALLERGY MEDICATIONS

         

        31 (15%)

          

        Anti-histamine agent

        Levocabastine

        eye suspension 0.5%

        6

        174

        ≥ 3 yrs

         

        Ketotifen

        eye drops 0.025%

        5

        522

        ≥ 3 yrs

         

        Olopatadine

        eye drops 0.2%

        4

        99

        ≥ 3 yrs

         

        Azelastine

        eye drops 0.02%

        4

        132

        ≥ 4 yrs

         

        Bepotastine

        eye drops 1%

        1

        36

        ≥ 10 yrs

          

        eye drops 1.5%

        1

        36

        ≥ 10 yrs

         

        Emedastine

        eye drops 0.05%

        1

        -

        3-16 yrs

        Mast cell stabilizer

        Lodoxamide

        eye drops 0.1%

        1

        15

        ≥ 6 yrs

         

        Cromoglycate

        eye drops 2%

        4

        128

        ≥ 4 yrs

          

        eye drops 4%

        1

        30

        ≥ 16 yrs

         

        Nedocromil

        eye drops 2%

        3

        85

        ≥ 4 yrs

        ANTI-INFLAMMATORY MEDICATIONS

         

        18 (9%)

          

        Corticosteroid

        Dexamethasone

        eye drops 0.1%

        6

        159

        all

         

        Fluorometholone

        eye drops 0.1%

        3

        52

        ≤ 10 yrs

         

        Rimexolone

        eye drops 1%

        1

        22

        4 - 8 yrs

        NSAID

        Diclofenac

        eye drops 0.1%

        4

        93

        ≥ 2 yrs

         

        Ketorolac

        eye drops 0.5%

        3

        70

        ≤ 12 yrs

         

        Flurbiprofen

        eye drops

        1

        50

        ≥ 5 yrs

        ANTIGLAUCOMA MEDICATIONS

         

        10 (5%)

          

        Beta-blocker

        Timolol

        eye drops 0.25%

        2

        44

        7-13 yrs

          

        eye drops 0.5%

        1

        12

        ≥ 14 yrs

          

        gel-forming solution 0.25%

        1

        35

        ≤ 6yrs

          

        gel-forming solution 0.5%

        1

        36

        ≤ 6yrs

         

        Betaxolol

        eye suspension 0.25%

        1

        52

        ≤ 6 yrs

         

        Levobetaxolol

        eye suspension 0.5%

        1

        46

        ≤ 6 yrs

        Carbonic anhydrase inhibitor

        Brinzolamide

        eye suspension 1%

        1

        32

        ≤ 6 yrs

         

        Dorzolamide

        eye drops 2%

        1

        56

        ≤ 6 yrs

        Acetylcholinesterase inhibitor

        Echothophate iodide

        eye drops

        1

        20

        -

        PERI-OPERATIVE MEDICATIONS

         

        18 (9%)

          

        Local anaesthetic agent

        Bupivacaine

        subconjuntival infiltration

        2

        38

        5-10 yrs

          

        eye drops 0.5%

        1

        17

        3-6 yrs

         

        Proparacaine

        eye drops 0.5%

        3

        58

        ≤ 1 m

         

        Lidocaine

        eye drops 2%

        1

        10

        3 - 14 yrs

          

        ophthalmic gel 2%

        1

        24

        3-12 yrs

         

        Amethocaine

        eye drops 0.5%

        2

        45

        2 - 8 yrs

         

        Levobupivacaine

        eye drops

        1

        13

        1 - 16 yrs

         

        Oxybuprocaine

        eye drops 0.4%

        1

        20

        3-8 yrs

         

        Tetracaine

        eye drops 1%

        1

        44

        1-12 yrs

         

        Sucrose

        eye drops

        1

        11

        ≤1 m

        Chemotherapeutic agents

        Mitomicyn C

        eye drops 0.02%

        1

        10

        ≥ 6 yrs

          

        ocular injection 0.4%

        1

        7

        ≥ 6 yrs

         

        5-fluorouracil

        ocular injection

        1

        4

        ≤ 12 yrs

         

        Mitomicyn C/5-fluorouracil

        ocular injection

        1

        4

        ≤ 12 yrs

        OTHER DRUGS

         

        7 (3%)

          

        Vernal keratoconjunctivitis

        Cyclosporine

        eye drops 2%

        1

        14

        5-16 yrs

          

        eye drops 1.25%

        1

        20

        5-14 yrs

          

        eye drops 1%

        1

        32

        5-14 yrs

         

        Mipragoside

        ophthalmic gel 0.5%

        1

        12

        5-20 yrs

        ROP therapy

        Bevacizumab

        intravitreal injection

        1

        7

        ≤ 1 m

        Esotropia

        Botulinum toxin

        ocular injection

        1

        27

        6-12 yrs

        Dacryocystitis

        Herba houttuyaniae

        eye drops

        1

        268

        ≤ 1 m

        TOTAL (69 single drugs & combinations)

          

        209

        18,816

         

        NOTE: the total is higher than the sum of the RCTs (158) because some drugs were tested in more than one trial. The references to RCTs are available upon request to the corresponding author.

        In all, 74 retrieved RCTs (35%) regarded mydriatic/cycloplegic medications, mainly antimuscarinic agents. In particular, 31 RCTs involving 3,530 children belonging to all age groups studied atropine as eye drops 1%, a drug licensed for paediatric use only in the UK (≥ 3 months). In addition, 3 studies were available on pirenzepine, a drug not licensed for paediatric use in any country.

        Regarding the treatment of allergic conjunctivitis, 49 (23%) RCTs on 11 drugs were found: 22 studies involved 6 anti-histamine agents (azelastine, bepotastine, emedastine, ketotifen, levocabastine, and olopatadine) tested in children ≥ 3 years, and 9 RCTs involved 3 mast cell stabilizers, such as lodoxamide, cromoglicate, and nedocromil, in children ≥ 4 years. Bepotastine is the only drug unlicensed for paediatric use in all considered countries.

        A total of 43 RCTs (21%) concerned 20 antibacterial agents and their combinations, 8 of them (40%) not licensed for paediatric use in any country considered, such as the fluoroquinolone besifloxacin as eye suspension 2%, tested in 3 RCTs in children older than one year. Among the six combinations studied 3 were licensed for paediatric use in the UK and 2 in the USA, while none in Italy. In addition, the anti-infective agent povidone-iodine, licensed for use in children older than 1 month, was studied only in Italy in 3 RCTs.

        Among the medications commonly used in ophthalmic surgical procedures (e.g. strabismus surgery) there were 7 local anaesthetics (proparacaine, not licensed for paediatric use in any country was the drug most studied), 3 steroids (dexamethasone, fluorometholone, and rimexolone), and 3 NSAIDs (diclofenac, ketorolac, and flurbiprofen).

        Ten RCTs regarded anti-glaucoma agents: 7 were on 3 beta-blockers, 2 on carbonic anhydrase inhibitors, and the last one on an acethylcholinesterase inhibitor, echothophate iodide. The most studied drug is timolol, a beta-bloker licensed for use in children older than 1 month only in Italy, as well as the carbonic anhydrase inhibitor dorzolamide.

        Phenylephrine, the only decongestant agent studied, licensed for paediatric use in all countries considered, was involved in 11 RCTs, in which it was used in combination with a mydriatic/cyclopegic agent for eye examinations in children. In one RCT involving 10 neonates, phenylephrine was used alone.

        Guidelines

        Eight guidelines on pharmacological management of eye diseases in children were found: they addressed acute bacterial conjunctivitis [21], amblyopia [22, 23], strabismus [24], glaucoma [25], retinopathy of prematurity (ROP) [26, 27], and prophylaxis of neonatal ophthalmia [28] (Table 3). Those concerning screening methods for diagnosing eye diseases in the paediatric population without drug use were not reported.
        Table 3

        Summary of guidelines on pharmacological therapy of ocular disease in the paediatric population

        Ref.

        Organisation

        Title

        Disease

        Quality of evidence

        Treatment (Licensing status)

        Country

        Year

        [41]

        National Guideline Clearinghause (NGC)

        Guidelines for the treatment and management of acute bacterial conjunctivitis in children and adults.

        Acute bacterial conjunctivitis

        I

        Topical antibiotic therapy:

        • Norfloxacin 0.3% (nl)

        • Ciprofloxacin 0.3%

        • Ofloxacin 0.3%

        • Levofloxacin 0.5% (nl UK, nl USA)

        • Lomefloxacin 0.3%

        • Moxifloxacin 0.5% (nl UK)

        • Gatifloxacin 0.3% (nl IT, nl UK)

        • Chloramphenicol 0.5% (nl USA)

        • Sulfacetamide Sodium 10% (nl)

        • Erythromycin 0.5% (nl)

        • Gentamicin Sulfate 0.3% (nl)

        • Trimethoprim Sulfate/Polymyxin B 10000 U/1 mg/mL (nl IT)

        • Fusidic acid 0.1% (nl IT, nl USA)

        • Tobramycin 0.3% (nl UK, nl USA)

        • Povidone-iodine 1.25% (nl UK, nl USA)

        • Bacitracin (nl)

        Ocular steroids and steroid-antibiotic:

        • Prednisolone (nl IT, nl USA)

        • Fluorometholone 0.1%/sulfacetamide sodium 10% (nl)

        • Fluorometholone 0.1%

        • Neomycin/polymyxin B/dexamethasone 0.1% (nl IT)

        • Gentamicin 0.3%/prednisolone acetate 0.1% (nl)

        • Tobramycin 0.3%/dexamethasone 0.1% (nl)

        USA

        2005

        [34]

        Canadian Paediatric Society

        Recommendations for the prevention of neonatal ophthalmia

        Prophylaxis to prevent neonatal ophthalmia due to N gonorrhoeae

        III

        • Silver nitrate 1% eye drops (nl)

        • Erythromycin 0.5% ointment (nl)

        • Tetracycline 1% ointment (nl)

        Canada

        2002 (Rev. 2009)

        [29]

        Moore W. and Nischal K.K.

        Pharmacologic management of glaucoma in childhood

        Glaucoma

        I

        • Β-Blockers: Betaxolol 0.25% (nl)

        • Carbonic Anhydrase Inhibitors: Dorzolamide 2% (nl UK, nl USA)

        • Prostaglandin Analogs: Latanoprost (nl), Travoprost (nl), Bimatoprost (nl)

        • Adrenoceptor Agonists: Brimonidine (nl UK), Apraclonidine (nl)

        • Parasympathomimetics: Pilocarpine (nl UK, nl USA)

        UK

        2007

        [39]

        Royal College of Ophthalmologists

        Guidelines for the management of amblyopia

        Ambliopia

        III

        • Refractive correction (glasses)

        • Patching: from 2 to 6 hours per day

        • Atropine (nl IT, nl USA)

        UK

        2006

        [6]

        National Guideline Clearinghause (NGC)

        Best evidence statement (BESt). Treatment of amblyopia in children.

        Amblyopia

        I

        • Refractive correction (glasses)

        • Atropine: 1 drop/day, 2 - 7 days per week (nl IT, nl USA)

        • Patching: from 2 to 6 hours per day

        USA

        2007

        [38]

        Royal College of Ophthalmologists

        Guidelines for the management of strabismus in childhood

        Strabismus

        III

        • Surgical interventions

        • Refractive correction (glasses)

        • Miotics (not specified)

        UK

        2007

        [46]

        The Brazilian Society of Pediatrics, Brazilian Council of Ophthalmology, Brazilian Society of Pediatric Ophthalmology

        Brazilian guidelines proposal for screening and treatment of retinopathy of prematurity (ROP)

        Retinopathy of prematurity (ROP)

        III

        Surgical interventions+post surgical treatment with topical steroids/antibiotics (not specified)

        Brazil

        2007

        [40]

        Royal College of Ophthalmologists, Royal College of Paediatrics and Child Health, British Association of Perinatal Medicine & BLISS

        Guideline for the Screening and Treatment of Retinopathy of Prematurity

        Retinopathy of prematurity (ROP)

        III

        Screening examination with Cyclopentolate 0.5%/Phenylephrine 2.5% combination: 1drop each in 2 to 3 doses, each 5 minutes apart, 1 hour prior to examination (nl)

        UK

        2008

        NOTE: nl: not licensed for paediatric use; IT: Italy; UK: United Kingdom; USA: United States of America

        Five guidelines (2 regarding ROP, 2 regarding amblyopia, and 1 regarding strabismus) recommended drug use only for screening or post-surgical therapy, and not for the pharmacological management of the disease in childhood.

        Almost all of the drugs listed in the guidelines are not licensed for use in children in any country considered, especially for prophylaxis of neonatal ophthalmia (no drug licensed), for the medical management of childhood glaucoma (5 out of 8 drugs are unlicensed) and acute bacterial conjunctivitis (8 out of 22 drugs are unlicensed). The authors indicated that all these drugs are generally used in a off label manner and that the majority of data on these medications are from adult studies.

        Finally, no guidelines on the pharmacological treatment of allergic conjunctivitis were found.

        Search for the paediatric RCTs in registries

        A search performed in the World Health Organization's International Clinical Trials Registry Platform (ICTRP), the ClinicalTrials.gov registry, and the International Standard Randomized Controlled Trial Number Register (ISRCTN) found 46 ocular medications currently under paediatric investigation in 62 RCTs (56% of which completed). Cyclosporin, an immunosuppressant agent, and bevacizumab, a humanized monoclonal antibody, were the drugs involved in the most studies: 7 RCTs testing cyclosporine in the treatment of keratoconjunctivitis (4), dry eye syndrome (2), and pterygia (1), and 4 RCTs on bevacizumab in the treatment of neovascular glaucoma in children > 3 years (all 3 completed) and in ROP in neonates > 5 months (1 ongoing RCT).

        Among the drugs that had the most ongoing studies were also two anti-hystamine drugs, ketotifen and bepotastine, and the antibacterial moxifloxacin: these were tested in 3 RCTs each for the treatment of allergic or bacterial conjunctivitis in children.

        EMA/FDA viewpoint

        Although no ophthalmologic drugs are found in the EMA's priority list for studies into off-patent paediatric medicinal products at this time, the EMA Paediatric Committee (PDCO) adopted opinions on PIPs for 12 ocular medications, with the aim to generate the necessary quality, safety, and efficacy data to support the authorization of these medicines for use in children.

        Four drugs, cysteamine, latanoprost, voclosporin and the recombinant human monoclonal antibody to human interleukin 17A received a go-ahead for a PIP, while one, travoprost/brinzolamide, was refused it. In four cases, one involving the anti-inflammatory agent bromfenac, one a new drug, ocriplasmin, for the treatment of symptomatic focal vitreomacular adhesion, and two the vascular endothelial growth factor inhibitors, ranimizumab and pegaptanib, a waiver was granted in all age groups on the grounds that the specific medicinal product does not represent a significant therapeutic benefit or because the disease or condition for which the product is intended does not occur in the specified paediatric subset(s). Finally, 2 steroid drugs, dexamethasone and triamcinolone, were refused the granting of a product-specific waiver on the grounds that the clinical studies cannot fulfil a therapeutic need of the paediatric population.

        By consulting the "List of the active substances included in the work-sharing procedure in accordance with Articles 45 and 46 of the European Paediatric Regulation, no additional data or information on their use in the paediatric population resulted to be submitted or requested to authorise the paediatric use of any ocular medicinal product.

        Twenty-six ocular medications were found in the Food and Drug Administration (FDA)'s "Table of Medicines with New Paediatric Information", a list of drugs approved for use in the paediatric population resulting from the paediatric clinical trials performed in response to paediatric legislative initiatives. Ten (38%) were anti-allergy medications, 8 (31%) were anti-glaucoma medications (6 of which were not yet licensed for paediatric use in the USA), and 5 were antibacterials and combinations. The last three agents were triamcinolone (steroid agent), lidocaine (local anaesthetic agent), and a hypromellose combination (lubricant). These drugs included approved information on use in the paediatric population resulting from the paediatric clinical trials performed in response to paediatric legislative initiatives.

        Discussion

        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, 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 [3337].

        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].

        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].

        Conclusion

        European and American legislation has established that children should have the same rights as adults to receive medicines that have been proven to be of benefit and that are unlikely to cause serious toxicity [44]. Even if the legislative initiatives in both Europe and the USA emphasizes the importance of large clinical trial in children, prioritizing the medicines to be studied on the basis of children's needs [45], differences between countries in drug licensing procedures, and occasionally in the approach towards certain therapeutic problems, may be quite significant [30]. A formulary containing common "paediatric" evidence-based safety and efficacy information could be a useful tool for improving the rational use of drugs in children and adolescents, harmonizing inter-country drug regulations and availability [46].

        In addition, recommendations from high quality RCTs and systematic reviews, and effective knowledge translation strategies are essential to clinicians and policy makers in planning changes in practice that could ultimately improve patient- and system-related outcomes. All such considerations are priorities for an area, such as ophthalmic drug therapy in children, that is lacking evidence.

        Declarations

        Acknowledgements

        Dr. Filomena Fortinguerra holds an educational fellowship granted by Boerhinger Ingelheim Italia, which had no role in the design or conduct of this research.

        Financial support: None

        Authors’ Affiliations

        (1)
        Laboratory for Mother and Child Health, Department of Public Health, Mario Negri Institute for Pharmacological Research

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        47. Pre-publication history

          1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1471-2431/​12/​8/​prepub

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        © Fortinguerra et al; licensee BioMed Central Ltd. 2012