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www.elsevier.es/ai

ORIGINAL ARTICLE

Off-label prescribing for allergic diseases in pre-school children

M. Morais-Almeida ∗ , A.J. Cabral

Immunoallergy Department, CUF Descobertas Hospital, Lisbon, Portugal

Received 29 December 2012; accepted 2 February 2013

KEYWORDS Abstract
Asthma; Background: Several studies have demonstrated that medication is commonly used off-label
Atopic eczema; in children with allergic diseases. The aim of this study was to characterise off-label use of
Infant; prescriptions for allergic diseases in pre-school children from an allergology outpatient unit.
Off-label Methods: The clinical files of children aged ≤6 years seen in a reference allergology consultation
prescription; with asthma, allergic rhinitis, and/or atopic eczema were reviewed. A total of 500 patients were
Pre-school children; consecutively observed from January to June 2012. The data collected included gender, age,
Rhinitis diagnosis, and prescriptions with the respective daily dosage.
Results: A total of 1224 prescriptions were registered. The most prescribed medications were
oral antihistamines (34.6%), antileukotrienes (22.6%), topical nasal corticosteroids (20.3%), and
inhaled corticosteroids (17.7%). From all prescriptions, 422 (34.5%) were considered off-label
for age (62.6%), dosage (31.7%), or clinical indication (5.7%). Off-label use was more frequent
in children aged <2 years, with 73.5% prescribed for children of this age.
Conclusions: Off-label use of drugs for the treatment of paediatric allergic diseases is high.
However, these prescriptions are not necessarily wrong, and are recommended in many guide-
lines. Randomised controlled studies are limited by methodological difficulties creating the
need for more observational studies in order to further evaluate the safety and efficacy of
drugs used in children.
© 2012 SEICAP. Published by Elsevier España, S.L. All rights reserved.

Introduction off-label use, i.e. use outside the formal indications autho-
rised by the regulatory authorities, in a different age group,
Many drugs used in the treatment of allergic diseases are dose, or indication1 is common in many paediatric illnesses
not appropriately studied in the paediatric population, espe- like allergic disease. This happens because of practical and
cially in infants and younger children. Nonetheless, their ethical considerations in carrying out clinical trials in this
population.2 In general, off-label prescription rates range
from 11% to 37% in children treated in the community
∗ Corresponding author.
setting, and in up to 62% of children in paediatric hospi-
E-mail address: mmoraisalmeida@netcabo.pt tal wards.3 The major concern with this off-label use is
(M. Morais-Almeida). the increased risk of adverse drug reactions.4 Additionally,

0301-0546/$ – see front matter © 2012 SEICAP. Published by Elsevier España, S.L. All rights reserved.
http://dx.doi.org/10.1016/j.aller.2013.02.011

Please cite this article in press as: Morais-Almeida M, Cabral AJ. Off-label prescribing for allergic diseases in pre-school
children. Allergol Immunopathol (Madr). 2013. http://dx.doi.org/10.1016/j.aller.2013.02.011
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Table 1 Drugs used for treatment of asthma, allergic rhinitis, and atopic eczema, and their authorizations for use according
to age and dose.
Category Drug Minimum age Maximum dose
IC Budesonide 2 years 400 ␮g/day --- 2 to 7 years
Fluticasone 12 months 200 ␮g/day --- 1 to 4 years; 400 ␮g/day --- 4 to 16 years
NC Budesonide 6 years 400 ␮g/day
Fluticasone furoate 6 years 55 ␮g/day
Mometasone 6 years 100 ␮g/day
LABAa Salmeterol 4 years 100 ␮g/day
AH Cetirizine 2 years 5 mg/day --- 2 to 6 years; 10 mg/day --- 6 to 18 years
Levocetirizine 2 years 2.5 mg/day --- 2 to 6 years; 5 mg/day --- older than 6 years
Loratadine 2 years 5 mg/day --- 2 to 6 years; 10 mg/day --- 6 to 18 years
Desloratadine 12 months 1.25 mg/day --- 1 to 5 years; 2.5 mg/day --- 6 to 12 years
Ebastine 2 years 2.5 mg/day --- 2 to 5 years; 5 mg/day --- 6 to 11 years
Ketotifen 6 months 0.1 mg/kg/day - 6 months to 3 years; 2 mg/day --- older than 3 years
AL Montelukast 6 months 4 mg/day --- 6 months to 5 years; 5 mg/day --- 6 to 14 years
TI Pimecrolimus 2 years
Source: Infarmed, I.P.11
IC: inhaled corticoids; NC: nasal topic corticoids; LABA: long acting ␤2 agonists; AH: oral antihistamines; AL: anti-leukotriene; TI: topic
immunomodulator.
a Always used in combination with fluticasone --- authorisations identical to isolated use.

younger children and infants have a considerably increased by allergy specialists at a reference allergology consulta-
risk of prescription errors, especially dosage errors.5 tion.
However, off-label prescriptions are not necessarily
incorrect,6 and may even be appropriate in certain clini-
cal situations provided there is no alternative treatment, Methods
and when the likely benefits outweigh the potential risks,7
such as when conventional treatments are unable to achieve The clinical files of children aged ≤6 years followed in our
control of the disease. The potential advantages of off-label allergology consultation who were diagnosed with current
prescribing, apart from the probable benefit to the indi- asthma, allergic rhinitis, and/or atopic eczema phenotypes,
vidual patient, are that new therapeutic uses may be with predominantly moderate to severe clinical presenta-
described, and data on the efficacy and safety of the drug tions, were systematically reviewed. Consecutive medical
being used in new settings may be collected.8 With off- visits were analysed from the beginning of January 2012 until
label prescriptions, the physician must act as an enlightened the inclusion of a total of 500 patients (June 2012).
intermediary. On the one hand, managing the regulatory The data collected included gender, age, diagnosis, and
data aimed at ensuring the effectiveness and safety of the drugs prescribed for the control of allergic diseases that
prescription, and on the other hand, putting all his or her were used for a minimum period of two weeks, as well
knowledge into serving the interests of the patient. as the respective dosages. Drugs used for acute treatment
Several studies have consistently shown that off-label were not considered. The drugs included were classified as
use in children is common. A population-based cohort study follows: (1) inhaled corticosteroids (IC); (2) nasal topical
carried out in primary care units in Holland assessed the corticosteroids (NC); (3) long acting ␤2 agonists (LABA); (4)
prescribing of respiratory drugs in 2502 children, showing oral antihistamines (AH); (5) oral antileukotrienes (AL); (6)
that almost 37% were off-label, and 39% in this group were topical immunomodulators (TI).
prescriptions for asthma.9 The TEDDY study, comparing the The formal indications for each drug were available from
use of anti-asthmatic drugs in children in Holland, Italy, Infarmed --- Autoridade Nacional do Medicamento e Pro-
and the United Kingdom, established that off-label use of dutos, I.P. (Infarmed),11 the national authority on drug
␤2-agonists and inhaled corticosteroids is frequent, inclu- control and authorisation, and were confirmed by the phar-
ding up to 80% of the inhaled budesonide prescriptions in maceutical companies responsible for their production and
Italy.10 distribution; these indications were systematically com-
In Portugal, few studies exist concerning off-label use pared by the authors, who found no discrepancies (Table 1).
of drugs in paediatric populations, and none are speci- The age groups were classified according to the paedi-
fically related to drugs for the treatment of aller- atric age definitions provided by the European Medicines
gic disease. This study aimed to characterise off-label Agency (EMA).12 As such, the sample was divided as follows:
prescribing of drugs used in the treatment and con- age < 2 years, and age 2---6 years. Although EMA considers an
trol of asthma, allergic rhinitis, and atopic eczema in a age group for newborns ‘‘younger than one month old’’, the
significant sample of pre-school aged children followed sample did not include any patients in this age group.

Please cite this article in press as: Morais-Almeida M, Cabral AJ. Off-label prescribing for allergic diseases in pre-school
children. Allergol Immunopathol (Madr). 2013. http://dx.doi.org/10.1016/j.aller.2013.02.011
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by antileukotrienes (22.6%), nasal topical corticosteroids

Table 2 Characterisation of the study population.
(20.3%), inhaled corticosteroids (17.7%), association of
Total (%) inhaled corticosteroids and LABA (4.6%), and, finally, topic
Gender
immunomodulators (0.2%). The most often used drugs were
Female 195 (61)
montelukast (22.6%), levocetirizine (17.1%), mometasone
Male 305 (39)
(17.1%), and fluticasone (17.0%) (Table 3).
Of all the prescriptions, 802 (65.5%) were authorised for
Age use in children and were used according to the formally
<2 years 80 (16) approved indication. The remaining 422 (34.5%) drugs were
2---6 years 420 (84) used off-label, outside the approvals for age (62.6%), dosage
Diagnosis (31.7%), or clinical indication (5.7%). Mometasone, flutica-
Asthma 238 sone, and levocetirizine were the drugs most frequently
Allergic rhinitis 350 prescribed in this fashion (Table 3). In Portugal, as in sev-
Atopic eczema 35 eral other European countries, mometasone is authorised
solely for children aged >6 years and is therefore frequently
used off-label. The same occurs with levocetirizine, which
The study was approved by the ethical committee of the is authorised only for children aged >2 years. As for fluti-
institution. casone, its off-label use was related to prescribing doses
greater than the approved dosage. Only montelukast was
prescribed outside of its clinical indication since, in Portu-
Statistical analysis
gal as in other countries, it can only be used as adjunctive
therapy in the preventive treatment of asthma in children
Statistical comparisons (chi-square) were performed using age <2 years, being not authorised as a single therapy,11 with
the statistical program IBM SPSS Statistics version 19.0.0 the exception if it is not possible to use inhaled steroids as
(2010, Chicago, IL, USA), and p < 0.05 was considered sta- controller medication.
tistically significant. Dividing the prescriptions into categories, we highlight
the off-label use of nasal topical corticoids in over 75% of the
Results total prescription (Table 4), which was always due to the age
limitation. We also note the off-label use of pimecrolimus
A total of 500 patient files were verified (Table 2), due to age in cases of severe atopic eczema, despite its
corresponding to 1224 prescriptions used to control reduced prescribing in three patients aged 8, 10, and 12
the previously mentioned pathologies. The most pre- months, respectively.
scribed drugs were oral antihistamines (34.6%), followed

Table 3 Total number of prescriptions studied.

Category Drug Prescriptions

Total Off-label

Total % Age Dose Indication

IC Budesonide 9 1 11.1 1 --- ---
Fluticasone 208 94 45.2 --- 94 ---
NC Budesonide 11 9 81.8 9 --- ---
Fluticasone furoate 28 12 42.9 12 --- ---
Mometasone 209 168 80.4 168 --- ---
LABA Salmeterol 56 17 30.4 17 --- ---
AH Cetirizine 115 16 13.9 6 10 ---
Levocetirizine 209 52 24.9 48 4 ---
Loratadine 3 0 0 --- --- ---
Desloratadine 53 19 35.8 --- 19 ---
Ebastine 5 5 100.0 --- 5 ---
Ketotifen 38 1 2.6 --- 1 ---
AL Montelukast 277 25 9.0 --- 1 24
TI Pimecrolimus 3 3 100.0 3 --- ---
Totals 1224 422 34.5 264 (62.6%) 134 (31.7%) 24 (5.7%)
Results in n, except when pointed out. IC: inhaled corticoids; NC: nasal topic corticoids; LABA: long acting ␤2 agonist; AH: oral
antihistamines; AL: anti-leukotriene; TI: topic immunomodulator.

Please cite this article in press as: Morais-Almeida M, Cabral AJ. Off-label prescribing for allergic diseases in pre-school
children. Allergol Immunopathol (Madr). 2013. http://dx.doi.org/10.1016/j.aller.2013.02.011
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Table 4 Prescriptions according to age and drug category.

Total Authorised Off-label

Total % Total % Age Dose Indication

Age group (years)
<2 181 48 26.5 133 73.5* 68 41 24
2---6 1043 754 72.5 289 27.5* 195 94 ---
Drug category
IC 217 122 56.2 95 43.8 1 94 ---
NC 248 59 23.8 189 76.2 189 --- ---
IC + LABA 56 39 69.6 17 30.4 17 --- ---
AH 423 330 78.0 93 22.0 54 39 ---
AL 277 252 91.0 25 9.0 --- 1 24
TI 3 --- --- 3 100 3 --- ---
Results in n, except when pointed out. IC: inhaled corticoids; NC: nasal topic corticoids; LABA: long acting ␤2 agonist; AH: oral
antihistamines; AL: anti-leukotriene; TI: topic immunomodulator.
* p < 0.001.

Although the overall prescribing for children aged <2 The clinical investigation of drugs in the paediatric
years was lower than in older children, off-label use was population is regulated by international standards (ICH E11),
relatively much more frequent. Up to 73.5% of prescriptions including European (EC no. 1902/2006), which set out spe-
in this age group were off-label compared with 27.7% in cific requirements for the protection of children in clinical
the oldest age group (Table 4). This difference was statisti- trials.15,16 However, the current EMA regulations encourage
cally significant (p <0.001). Note that, with one exception, research and development of drugs in the paediatric popu-
all children aged <2 years received at least one off-label lation to improve the available information on these drugs,
prescription. by assigning benefits to the pharmaceutical industry like
extending the period of patent exclusivity.17,18
Nonetheless, most drugs available on the market are not
Discussion specifically tested in children, particularly younger children.
In Portugal, Infarmed has specialised committees, namely
This study provides detailed and original information about the Committee for the Evaluation of Medicinal Products,
national off-label prescribing for the allergic diseases which is responsible for issuing opinions on the quality,
asthma, allergic rhinitis, and atopic eczema in the paedi- safety, and efficacy of drugs within their marketing authori-
atric population. sations (AIM). They have the responsibility for reviewing and
We found that, in pre-school children, the use of drugs approving the Summaries of Product Characteristics (RCM).
for these conditions in moderate to severe forms is frequent However, the use of drugs outside their authorised RCM is
(34.5%), particularly in children aged <2 years, with more not the concern of authorities and is the sole responsibility
than 73% of prescriptions made for this group. This is proba- of the prescriber.19
bly due to the absence of data on the safety and efficacy of This study showed a great number of off-label
drugs at this age group, owing to the lack of clinical trials.1---4 prescriptions, although it can be overestimated related with
The lack of clinical research in the paediatric popula- the severity of the clinical manifestations of the included
tion, mainly in infants, results from a combination of factors children; these values must be interpreted with caution,
that can contribute to this age group being the last to however, as they may suggest inadequate or inappropriate
benefit from medical progress.2,13 Pharmaceutical compa- use. Off-label prescribing is not necessarily incorrect6 and is
nies, which can never promote or recommend off-label use contemplated in several therapeutic guidelines that include
of their drugs, apparently view the approval of drugs in chil- paediatric populations, but remarkably with no indication
dren as a market that would bring small financial benefit, that some of the drugs are being recommended for unli-
with only a few drugs representing a large enough economic censed and off-label use.20 In fact, indications for drug use in
interest. As such, it is not surprising that the drugs that have therapeutic guidelines do not clinically or legally authorise
been adequately studied in children are anti-infectious vac- their use, even if the guidelines support it.
cines and some antibiotics. Specific medical techniques and Off-label prescribing is frequently necessary, but should
appropriate equipment are also necessary for clinical inves- be evaluated according to clinical indications, therapeutic
tigation in the paediatric population; technical procedures alternatives, and risk-benefit considerations, and off-label
that seem simple in adults, such as drawing blood, among use implies obtaining informed consent from the patient or
other minimally invasive interventions, can be difficult to guardian. However, if off-label use of drugs does not require
execute or even authorise in children. Lastly, the ethical a signed informed consent by the patient or his or her legal
implications in children are more complex, with potential representative, is oral consent enough? In the prescriptions
risks associated with the intervention, and significantly hin- studied, off-label drug use was systematically indicated and
der clinical trials in this population.14 justified to the parents or caretakers as well as the clinical

Please cite this article in press as: Morais-Almeida M, Cabral AJ. Off-label prescribing for allergic diseases in pre-school
children. Allergol Immunopathol (Madr). 2013. http://dx.doi.org/10.1016/j.aller.2013.02.011
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necessity for the drug’s use, which was invariably authorised of moderate to severe allergic diseases is high. With few
after the requested clarifications, increasing the compli- studies of long-term safety, the implications inherent in this
ance to the indicated treatments. This type of information type of use become evident. The Paediatric Committee of
is very important for patient and caregiver adherence, but the EMA has issued a list of drugs currently administered
it is often omitted. A survey conducted in the UK found to children for which information on pharmacokinetics,
that most paediatricians did not obtain informed consent, efficacy, and safety are urgently needed; fluticasone and
or inform the children’s parents that the drug’s use was montelukast, among others, were included.29 The standard
off-label, which could indicate poor medical practice.21 method consists of performing randomised controlled tri-
From the prescriptions studies, we note the very frequent als, which are limited by methodological difficulties, hence
off-label use of a very safe topical nasal corticosteroid, the need to develop sufficiently extensive post-marketing
mometasone. The reason for off-label use was entirely due observational studies in order to obtain sufficient data to
to its use outside the authorised age group, as it is only evaluate the safety and efficacy of drugs used in paediatric
approved for children aged ≥6 years. This imposition is made populations.
by EMA, whereas the U.S. Food and Drug Administration In some emerging diseases in our area of expertise the
(FDA) already allows the use of this drug in younger children, majority of drugs available that provide the best results are
i.e. those aged >2 years.22 Despite the discrepancy in per- used off-label regardless of age.30
missions, the fact that the FDA, which is responsible for the The presence of complete and updated records with
regulation of drugs in the United States, has already autho- detailed information on the drugs used, dosages, routes
rised broader use of this drug offers additional security for of administration, and adverse effects are important in
prescribing it off-label in Europe. If the authorisations were obtaining reliable data essential for further evaluation of the
identical, off-label use of mometasone would be only 4.3%. safety and efficacy of drugs in which more complex studies
The same can be said of the use of some antihistamines, in children are not feasible for practical and/or ethical
in particular levocetirizine, whose off-label use was reasons. As with other populations with unique character-
approximately 25%, and almost entirely due to its use in istics, such as pregnant women and the elderly, publication
children aged under the authorised age. As of 2009, the FDA and distribution of this information by the scientific com-
approved prescribing this drug for children and infants from munity is critical for the acquisition of new safety data,
six months of age22 after publication of long-term trials allowing the approval of new dosages, clinical indications,
that demonstrated its safety and efficacy in this paediatric and/or prescribing for younger children, reducing off-label
population.23 In our pharmaceutical market, levocetirizine drug use that, although often appropriate, is not without
is still only approved for children aged >2 years.11 As in the risks.
above-mentioned case, if the indications were the same Finally, this study should increase clinicians’ awareness
on both continents, off-label prescribing of this drug would of prescribing drugs off-label such that they are available at
have been irrelevant. any time to discuss use of the drugs with patients and their
Regarding topical immunomodulators, pimecrolimus was families, as well as provide the motives that justify their
prescribed for only three cases of atopic eczema, but always use, valuing benefits versus risks, increasing compliance and
off-label for age, despite its use being justified by clini- contributing to achieve better outcomes.
cal severity. This pathology appears in over 60% of patients
before the age of 12 months;24 however, these drugs are
only approved for children aged >2 years by both the FDA Ethical disclosures
and EMA.11,22,25 This limitation was imposed because there
are no current studies of long-term safety that are deemed Protection of human subjects and animals in research.
sufficient for approval in younger children. The concerns of The authors declare that no experiments were performed
the regulatory authorities are based on the theoretical risk on humans or animals for this investigation.
of systemic immunosuppression derived from the use of oral
calcineurin inhibitors such as pimecrolimus or tacrolimus in
transplant recipients, and the existence of rare instances of Patients’ data protection. Confidentiality of data. The
malignancy associated with their use.26 However, pharma- authors declare that no patient data appear in this article.
cokinetic data obtained from clinical trials in children aged
<2 years did not suggest concentrations high enough to cause
systemic immunosuppression, unlike oral administration, or Right to privacy and informed consent. The authors
demonstrate a correlation between systemic concentrations declare that no patient data appear in this article.
and percentage body surface area treated or the duration of
treatment.27 Likewise, there was no interference with the
development of normal immune responses to vaccinations.28
Besides demonstrating extreme efficacy, these trials demon-
Funding
strate safety data for IT use in atopic eczema, but more
extensive surveillance is needed to determine long-term None to declare.
safety. Nonetheless, since its introduction on the market in
2001, no definite causal relationship between the use of IT
and malignancy has been established.26 Conflict of interest
In this study, we confirmed that the off-label use of anti-
allergic drugs in pre-school-aged children for the treatment None to declare.

Please cite this article in press as: Morais-Almeida M, Cabral AJ. Off-label prescribing for allergic diseases in pre-school
children. Allergol Immunopathol (Madr). 2013. http://dx.doi.org/10.1016/j.aller.2013.02.011
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