Public Assessment Report for paediatric studies submitted in ...

Public Assessment Report
for paediatric studies submitted in accordance
with Article 45 of Regulation (EC) No1901/2006, as
amended
Rapporteur: AT
Carbomer
Siccapos Gel
Siccapos Gel 2
AT/W/0011/pdWS/001
Finalisation procedure (day 120): 03.07.2012
Date of finalisation of PAR 29.08.2012
Carbomer
AT/W/0011/pdWS/001 Page 1/13

TABLE OF CONTENTS
I. Executive Summary ....................................................................................................... 4
II. RecommendatioN .......................................................................................................... 6
III. INTRODUCTION ............................................................................................................. 6
SCIENTIFIC DISCUSSION ......................................................................................................... 8
III.1 Information on the pharmaceutical formulation used in the clinical study(ies) ......... 8
III.2 Non-clinical aspects ................................................................................................................... 8
III.3 Clinical aspects ............................................................................................................................ 8
IV. MEMBER STATES Overall Conclusion AND RECOMMENDATION ........................... 12
V. List of Medicinal products and marketing authorisation holders involved ............. 13
Carbomer
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ADMINISTRATIVE INFORMATION
Invented name of the medicinal
product(s):
INN (or common name) of the active
substance(s):
See section VI
Carbomer
MAH (s): See section VI
Pharmaco-therapeutic group
(ATC Code):
Pharmaceutical form(s) and
strength(s):
S01AX20
eye gel, 2,0 mg/g
Carbomer
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I. EXECUTIVE SUMMARY
Legal background
Art. 45 of Reg. 1901/2006
By January, the 26 th 2008, any paediatric studies already completed, by the date of entry into
force, in respect of products authorised in the Community shall be submitted by the marketing
authorisation holder for assessment to the competent authority.
The competent authority may update the Summary of Product Characteristics and Package
Leaflet, and may vary the marketing authorisation accordingly. Competent authorities shall
exchange information regarding the studies submitted and, as appropriate, their implications for
any marketing authorisations concerned.
The EMA shall coordinate the exchange of information.
As requested by the EMA in a letter dated 27 th July 2011 and in accordance with Article 45 of
Regulation EC No 1901/2006 as amended, the Marketing Authorization Holders submitted 5
studies/publications.
Background to dry eye
Dry eye is a widespread problem, affecting 0.39% to 33.7% of the population. It can occur in
association with a number of congenital, autoimmune, endocrine, and inflammatory disorders, or
under certain environmental and nutritional conditions.
Dry eye is a chronic condition caused by instability of the tear film covering the eye; the tear film
breaks up to leave dry spots rather than being maintained between blinks. Tears consist of a
slightly alkaline fluid that is spread across the eye by blinking and is lost via the lachrymal ducts
or by evaporation. Mucus secreted by the conjunctiva is also required to maintain tear film
stability and dry eye can result from reduced production of either tears or conjunctival mucus.
Reduced tear secretion is common in the elderly, but also occurs in some systemic disorders or
as an adverse effect of drugs such as those, like tricyclic antidepressants, that have
antimuscarinic effects. Tear film instability may also result from increased tear evaporation, for
example due to corneal exposure in thyroid disease, or from lid, corneal, or other eye disorders.
The main symptoms of dry eye are discomfort, typically with a chronic gritty sensation, visual
disturbances, and sometimes photophobia. If left untreated corneal ulceration and eventual loss
of sight may occur.
Treatment of dry eye is mainly symptomatic using 'artificial tears' preparations: eye drops
containing hypromellose or other cellulose ethers (carmellose, hyetellose, methylcellulose),
hydroxypropyl guar gum, polyvinyl alcohol, or povidone are used.
Minor SmPC and PL changes are proposed in section 4.2.
Carbomer
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Summary of outcome
No change
Change
New study data
New safety information
Paediatric information clarified
New indication
Carbomer
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II. RECOMMENDATION
Dry eye symptom does occur in the paediatric population.
But from the Clinical Assessor´s point of view, unfortunately based on the data / documentation
provided, no specific recommendation regarding the use of Carbomer in the paediatric
population can be given.
Furthermore, from the Clinical Assessor´s point of view, it is not advisable to decidedly suggest a
Non – Use of Carbomer in the paediatric population due to the lack of data provided, since
Carbomer has rather physical properties and thus might be quite suitable to moisten the eye in
this population, especially in a Benzalkonium Chloride free formulation.
Due to the poor data available for assessment and in the course of discussion with all Member
States following wording is considered appropriate to be included in the SmPC and PIL, as it
does not restrict the use of Carbomer in eye drops already licensed for use in children and
adolescents and also reflects clinical daily routine, but still does point out to the lack of study
data on safety and efficacy:
´The safety and efficacy of XXX in children and adolescents at the posology recommended in
adults has been established by clinical experience, but no clinical trial data are available`
As already mentioned above, Carbomer has no pharmacological properties and therefore, when
administered to the eye in children and adolescents, no significant safety issues are anticipated.
Proposed SPC changes
Section 4.2 Posology and method of administration
Children and adolescents aged to 18 years:
´The safety and efficacy of XXX in children and adolescents at the posology recommended in
adults has been established by clinical experience, but no clinical trial data are available`
Proposed PIL changes:
Section 2 “Take special care with /……./”
Children and adolescents aged to 18 years:
´The safety and efficacy of XXX in children and adolescents at the posology recommended in
adults has been established by clinical experience, but no clinical trial data are available`
Section 3
Children and adolescents aged to 18 years:
´The safety and efficacy of XXX in children and adolescents at the posology recommended in
adults has been established by clinical experience, but no clinical trial data are available`
III. INTRODUCTION
One MAH (Ursapharm) submitted 5 published paediatric studies/reports for carbomer, in
accordance with Article 45 of the Regulation (EC)No 1901/2006, as amended on medicinal
products for paediatric use.
Carbomer
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A very short critical expert overview has also been provided, but no relevant information could
be obtained.
The MAH stated that the submitted paediatric studies/reports do not influence the benefit risk for
carbomer and that there is no consequential regulatory action.
In addition, the following documentation has been included:
- A line listing
Carbomer
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SCIENTIFIC DISCUSSION
III.1 Information on the pharmaceutical formulation used in the clinical study(ies)
Not applicable
III.2 Non-clinical aspects
1. Introduction
No non-clinical studies were submitted.
2. Non clinical study(ies)
None
3. Discussion on non clinical aspects and conclusion
Assessor’s comment:
Not applicable
III.3 Clinical aspects
1. Introduction
The MAH Ursapharm submitted 2 published studies/reports for:
1. "Keratoconjunctivitis sicca in juvenile rheumatoid arthritis."
Akinci, A.; Cakar, N.; Uncu, N.; Kara, N.; Acaroglu, G.
Cornea 2007; 26: 941
2. "Dry eye in pediatric contact lens wearers."
Greiner, K. L.; Walline, J. J.
Eye & Contact Lens 2010; 36: 352
The MAH Ursapharm submitted 3 literature references = publications for:
1. "Dry eye in childhood: epidemiological and clinical aspects."
Alves, M.; Dias, A. C.; Rocha, E. M.
Ocul Surf 2008; 6: 44
2. "Dry eye syndrome and neurotrophic keratitis in childhood. ."
Dietrich, T.; Renner, A. B.; Helbig, H.; Oberacher-Velten, I. M.
Ophthalmologe 2010; 107: 911
3. "Augenerkrankungen im Kindesalter".
Küchle, H. J.; Busse, H.
Georg Thieme Verlag, Stuttgart/New York 1985.
Carbomer
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2. Clinical studies
A) published clinical studies
1. "Keratoconjunctivitis sicca in juvenile rheumatoid arthritis."
Akinci, A.; Cakar, N.; Uncu, N.; Kara, N.; Acaroglu, G.
Cornea 2007; 26: 941
� Methods
• Objective(s)
To compare the symptoms, signs, and results of objective tests for keratoconjunctivitis sicca
(KCS) in patients with juvenile rheumatoid arthritis (JRA) and controls.
• Study design
Prospective study. JRA group + Control Group
• Study population /Sample size
Seventy-six patients with JRA were examined. Twelve patients receiving glucocorticoids were
excluded due to glucocorticoids intake, thus 64 patients with JRA were included. 38 boys + 26
girls in both groups. The mean age was 13.2 ± 3.1 (SD) years (range, 8-17 years) in the JRA
group and 13.4 ± 3.3 years (range, 8-17 years) in the control group.
(Exclusion criteria: for both groups consisted of receiving glucocorticoids or antihistamines
because these drugs are known to affect tear secretion, 5 presence of any other systemic
disease, use of an ocular topical treatment within the last 6 months, and previous ocular laser or
surgical treatment.
• Outcomes/endpoints
Relation between tear film breakup time (TBUT), Schirmer test results, and JRA-related variables
such as age of onset, duration, and type of JRA; presence of antinuclear antibodies (ANAs); and
history of uveitis were evaluated.
• Statistical Methods
Analysis of variance, multivariate regression analysis, Kruskall-Wallis, Student t tests, and X2
tests were used for statistical analysis.
� Results
• Among 64 children with JRA, 32 had the pauciarticular, 22 had the polyarticular, and 10 had the
systemic form of disease. ANA was positive in 24 (37.5%), and previous uveitis was detected in
15 (23.4%) children. The mean age of onset and duration of JRA were 6.1 ± 3.4 (range, 5-12) and
6.8 ± 2.8 years (range, 4-13 years), respectively.
Dry eye signs were detected in 7 children (10.9%) in the JRA group and in 1 child (1.5%) in the
control group; therefore, the prevalence of dry eye signs was significantly higher in the JRA group
(X2 test, P = 0.038).
Among 64 children with JRA, 38 were boys and 26 were girls. TB UT and Schirmer test results
were significantly lower in boys (Student t test, P = 0.023 and P 0.018, respectively).
7 (10.9%) of the 64 children with JRA had a definite diagnosis and 1 (1.5%) of 64 had a probable
diagnosis of KCS.
Among patients with JRA, boys and ones with longer duration of disease are more prone to have
lower basal tear secretion and tear-film stability.
Carbomer
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Assessor’s comment:
Although this study shows, that dry eyes symptoms are associated with JRA in children, no information
regarding the symptomatic treatment of dry eyes with Carbomer can be obtained, therefore no relevant
information or recommendation regarding the use of Carbomer in children can be given.
2. "Dry eye in pediatric contact lens wearers."
Greiner, K. L.; Walline, J. J.
Eye & Contact Lens 2010; 36: 352
� Methods
• Objective(s)
To determine whether children who wear contact lenses truly have fewer dry eye complaints than
adults do.
• Study design
Ninety-four pediatric contact lens wearers aged 8 to 14 years, were recruited from pediatric
contact lens studies conducted at both The Ohio State University College of Optometry and New
England College of Optometry and given the Contact Lens Dry Eye Questionnaire (CLDEQ) short
form. All of the subjects wore either 1 Day Acuvue or Acuvue Advance contact lenses (Vistakon;
Jacksonville, FL). and all subjects wore contact lenses for at least 3 months. The Acuvue Advance
contact lens wearers were all provided with Opti-Free Replenish multipurpose contact lens
solutions.
CLDEQ: Subjects categorize the frequency of each symptom coded as 1, never; 2, infrequently; 3,
occasionally; 4, frequently; and 5 constantly.
• Study population / Sample size
Ninety-four pediatric contact lens wearers aged 8 to 14 years. The average (±SD) age of the
sample was 11.7 ±. 1.5 years, 56.4% were female, 59.6% were white, and 19.1% were black
• Outcomes/endpoints
CLDEQ: Subjects categorize the frequency of each symptom coded as 1, never; 2, infrequently; 3,
occasionally; 4, frequently; and 5 constantly. If the subject classifies the symptom as infrequent to
constant, he or she then categorizes the intensity of the symptom within the first 2 hr of inserting
the lenses, in the middle of the day, and at the end of the day. Intensity is ranked on a scale of 1
to 5, where 1 is not at all intense, and 5 is very intense.
• Statistical Methods
� Results
• The average (±SD) age of the sample was 11.7 ± 1.5 years, 56.4% were female, 59.6% were
white, and 19.1% were black. The mean (±SD) CLDEQ composite score was 0.25 ± 0.50 (range=
-1.20 to 1.45). In the literature, the adult mean (±SD) CLDEQ composite score was 1.02 ± 0.80
(range = -0.74 to 4.50). Of the 94 surveys collected, 4.3% of children were categorized as having
dry eye compared with 56.2% of the adults who completed the CLDEQ survey in the adult study.
• Conclusion: Pediatric contact lens wearers have fewer complaints about dry eyes than do adult
contact lens wearers, which may be because of improved tear film, differences in reporting of
symptoms, or modality of contact lens wear.
Carbomer
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Assessor’s comment:
No information about Carbomer can be obtained from this paper. Therefore no evaluable information
regarding safety, efficacy and posology can be drawn from this publication.
B) literature references = publications
1. "Dry eye in childhood: epidemiological and clinical aspects."
Alves, M.; Dias, A. C.; Rocha, E. M.
Ocul Surf 2008; 6: 44
This paper provides an overview about the possible causes of dry eye in childhood.
Dry eye can occur in association with a number of congenital, autoimmune, endocrine, and inflammatory
disorders, or under certain environmental and nutritional conditions.
Assessor`s comment:
No information about Carbomer can be obtained from this paper. Therefore no evaluable information
regarding safety, efficacy and posology can be drawn from this publication.
2. "Dry eye syndrome and neurotrophic keratitis in childhood."
Dietrich, T.; Renner, A. B.; Helbig, H.; Oberacher-Velten, I. M.
Ophthalmologe 2010; 107: 911
This reference is a literature overview of the pathogenesis of dry eye syndrome and neurotrophic keratitis.
Clinical cases from paediatric ophthalmology office are presented as well as therapeutic strategies.
Assessor`s comment:
No information about Carbomer can be obtained from this paper. Therefore no evaluable information
regarding safety, efficacy and posology can be drawn from this publication.
3. "Augenerkrankungen im Kindesalter".
Küchle, H. J.; Busse, H.
Georg Thieme Verlag, Stuttgart/New York 1985.
This is an abstract from a book in German language about eye diseases in children. Unfortunately the
relevant pages about diseases of the lacrimal apparatus are missing.
Assessor`s comment:
No conclusion about Carbomer regarding safety, efficacy and posology can be drawn from this
publication.
Carbomer
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IV. MEMBER STATES OVERALL CONCLUSION AND
RECOMMENDATION
� Overall conclusion
Dry eye symptom does occur in the paediatric population.
But from the Clinical Assessor´s point of view, unfortunately based on the data / documentation
provided, no specific recommendation regarding the use of Carbomer in the paediatric
population can be given.
Furthermore, from the Clinical Assessor´s point of view, it is not advisable to decidedly suggest a
Non – Use of Carbomer in the paediatric population due to the lack of data provided, since
Carbomer has rather physical properties and thus might be quite suitable to moisten the eye in
this population, especially in a Benzalkonium Chloride free formulation.
Due to the poor data available for assessment and in the course of discussion with all Member
States following wording is considered appropriate to be included in the SmPC and PiL, as it
does not restrict the use of Carbomer in eye drops already licensed for use in children and
adolescents and also reflects clinical daily routine, but still does point out to the lack of study
data on safety and efficacy:
´The safety and efficacy of XXX in children and adolescents at the posology recommended in
adults has been established by clinical experience, but no clinical trial data are available`
As already mentioned above, Carbomer has no pharmacological properties and therefore, when
administered to the eye in children and adolescents, no significant safety issues are anticipated.
� Recommendation
Proposed SPC changes
Section 4.2 Posology and method of administration
Children and adolescents aged to 18 years:
´The safety and efficacy of XXX in children and adolescents at the posology recommended in
adults has been established by clinical experience, but no clinical trial data are available`
Proposed PIL changes:
Section 2 “Take special care with /……./”
Children and adolescents aged to 18 years:
´The safety and efficacy of XXX in children and adolescents at the posology recommended in
adults has been established by clinical experience, but no clinical trial data are available`
Section 3
Children and adolescents aged to 18 years:
´The safety and efficacy of XXX in children and adolescents at the posology recommended in
adults has been established by clinical experience, but no clinical trial data are available`
Carbomer
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V. LIST OF MEDICINAL PRODUCTS AND MARKETING
AUTHORISATION HOLDERS INVOLVED
URSAPHARM
Arzneimittel GmbH
URSAPHARM
Arzneimittel GmbH
Siccapos Gel 2,0 mg/g eye gel
Siccapos Gel 2 2,0 mg/g eye gel
Carbomer
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