Open Access

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

  • Filomena Fortinguerra1Email author,
  • Antonio Clavenna1 and
  • Maurizio Bonati1
BMC PediatricsBMC series ¿ open, inclusive and trusted201212:8

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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Copyright

© Fortinguerra et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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