Eur J Pediatr (2005) 164: 552–558
DOI 10.1007/s00431-005-1698-8
O R I GI N A L P A P E R
Chiara Pandolfini Æ Maurizio Bonati
A literature review on off-label drug use in children
Received: 25 November 2004 / Accepted: 12 April 2005 / Published online: 24 May 2005

Springer-Verlag 2005
Abstract The aim was to compare results of studies
performed in different settings worldwide and identify
common therapeutic areas to allow for focused inter-
ventions, because off-label drug use can be a measure of
the lack of knowledge concerning paediatric treatments.
A secondary objective was to provide a brief review of
efforts to date. A literature review of articles on off-label
and unlicensed drug use in children involving general
prescription samples was performed using Medline and
Embase. In all, 30 studies from 1985–2004 were in-
cluded. Eleven involved paediatric hospital wards, seven
neonatal hospital wards, and 12 the community setting.
The off-label and unlicensed classification methods
varied, making results difficult to compare. In general,
off-label/unlicensed prescription rates ranged from
11%–80%, and higher rates were found in younger
versus older patients and in the hospital versus com-
munity settings. On the paediatric hospital wards, off-
label/unlicensed prescriptions ranged from 16%–62%
and most often concerned acetaminophen, cisapride,
chloral hydrate, and salbutamol. In the neonatal wards,
rates ranged from 55%–80% and often involved caf-
feine. In the community setting, rates ranged from 11%–
37% and the most commonly implicated drugs were
salbutamol and amoxicillin. Conclusion: A lack of
harmonisation between the evidence, the information
available to doctors, and its use in clinical practice exists
and this is part of the reason off-label therapies are so
common. Attempts have been made to improve knowl-
edge concerning paediatric treatments, but more focused
interventions are needed, also taking into consideration
this lack of harmonisation.
C. Pandolfini (&) Æ M. Bonati
Laboratory for Mother and Child Health,
‘‘Mario Negri’’ Institute for Pharmacological Research,
Via Eritrea 62, Milan, Italy
E-mail: pandolfini@marionegri.it
Tel.: +39-02-390144511
Fax: +39-02-3550924
Keywords Drug Æ Drug labelling Æ Legislation Æ
Paediatrics Æ Prescriptions
Introduction
The issue of the underprivileged position of children
with respect to optimal drug therapies was raised years
ago, but the situation remains inadequate. Children are
routinely given drugs that lack specific paediatric
information because of the difficulties in carrying out
clinical trials in this population, such as practical diffi-
culties and ethical considerations arising from the
involvement of children [11]. Those who administer
drugs to children are forced to deviate from the estab-
lished labelling indications, for example by manipulating
a drug’s formulation to obtain a ‘‘paediatric’’ dose (e.g.
splitting tablets into pieces), or by changing the indi-
cated route of administration (e.g. to avoid intramus-
cular injections in young patients) [19]. This is also
known as off-label drug use. More generally, off-label
drug usage is that in which drugs are prescribed outside
their licensed indications with respect to dosage, age,
indication, or route, and unlicensed drugs are those
whose formulation is modified, that are prepared as
extemporaneous preparations, that are imported or used
before a license is granted, or that are chemicals used for
therapeutic purposes.
Several initiatives aimed at increasing the number of
required paediatric studies have been taken in the last
few years, with the United States at the forefront and
Europe beginning to follow [15]. Other countries, for
example Israel [3, 30, 42,43], Australia [52, 71,75], and
Canada [40] are beginning to show interest as well (see
appendix).
Studies carried out in different settings, therapeutic
areas, and age ranges [33,63] have revealed high off-label
drug use rates everywhere, especially in neonates. Off-
label prescriptions often represent the most rational,
evidence based therapies [58] so the problem is not
inappropriate drug use by physicians, but an inadequate

evaluation and registration process [14]. However, off-
label and unlicensed uses can be considered uncontrolled
experiments that do not capture information useful to
understanding a drug’s effects and in which patients are
unknowingly being enrolled. Furthermore, little is
known about the possible harm and side-effects inherent
in this type of prescribing, with risks such as errors in
adjusting adult doses and formulations to ones suitable
for children as well as in preparing extemporaneous
preparations [47,51]. Studies examining this aspect [16,
17, 32, 36, 50, 78, 79,81] have found differing results,
many suggesting a greater adverse drug reaction risk
associated with off-label and unlicensed drug use.
This review aims to give an updated overview [53] of
the worldwide situation of off-label and unlicensed drug
use in different settings, attempting to compare the rates
found in the different studies, with a brief summary of
the related legislation and a discussion of the possible
solutions for obtaining better medicines for children.
Methods
A literature review of articles on the off-label or unli-
censed use of drugs in children was performed using the
Medline and Embase databases, which date back to
1966 and 1974, respectively. Medical subject headings
and free text searches were used, involving the terms
‘‘drug utilisation’’, ‘‘drug use’’, ‘‘drug approval’’, ‘‘drug
labelling’’, ‘‘off-label’’, and ‘‘unlicensed’’, combined with
the terms ‘‘child’’, ‘‘paediatrics’’, ‘‘infant’’, ‘‘adolescent’’,
and ‘‘newborn’’, and taking into consideration the fact
that some of the terms used by the individual databases
varied. The resulting article titles or abstracts were
scanned for relevance, those regarding studies on the off-
label/unlicensed use of drugs in children were obtained
and included in the review, and the bibliographies of all
the studies identified were searched for additional, rele-
Table 1 Synopsis of the studies on the off-label and unlicensed use of drugs on the neonatal and paediatric hospital wards and community
settings carried out so far. (P prospective, R retrospective)
Country (n) Period Methodology Patients
studied (n)
Paediatric hospital studies
UK (3), USA (2), 1985–1999 3 R, 8 P 74–1461
Australia, Europe,
Ireland, Italy, Israel,
The Netherlands
Neonatal hospital studies
UK (2), Australia, 1998–2002 7 P 40–143
France, Israel, Italy,
The Netherlands
Pediatric studies in the community
France (2), Israel (2), 1978–2001 6 R, 6 P 132–455661 0 days–18 years 16–56
UK (2), The Netherlands
(2), Germany, Italy,
Sweden, United States
553
vant studies. Two studies performed by the authors of
this paper that were presented at international con-
gresses and published as abstracts, were also included in
the review since all original data were available [7,55].
The search process was repeated in March 2005 in order
to include any articles published while the review was in
progress.
Of the resulting studies, only those involving general
prescription samples (all medications ordered and given
to the patients), and not subsets, were included in the
review. Four studies evaluated specific subgroups of
prescriptions, such as antibiotics or newly marketed
medicines, and were therefore excluded [44, 62, 67,83].
Another study [70] was excluded because it evaluated
possible determinants for drug prescriptions to patients
below the licensed age. Finally, two further studies were
excluded because they were only present in abstract form
[31,74].
Results
In all, 30 studies, performed between 1985 and 2004,
were included in the review (Table 1). Eleven involved
paediatric hospital wards [22, 23, 42, 48, 54, 66, 72, 75,
76, 76, 77], seven involved neonatal hospital wards [2, 3,
21, 52, 55, 66,78] and 12 the community setting [7, 10,
14, 26, 27, 30, 36, 43, 46, 61, 68, 80]. The number of
patients ranged from 40 to 455,661, with an average of
33,116. Most of the studies (21/30) were prospective
studies. The overall rates of prescriptions considered off-
label or unlicensed ranged from 11% to 80% (Table 1),
the most common reason for off-label use was dosage,
and the most common off-label/unlicensed drugs cited in
the studies were salbutamol (six studies), acetaminophen
(five studies), and caffeine and morphine (three each).
The off-label categories taken into consideration in
assigning off-label status varied significantly between
Patient Patients with ‡1 Prescriptions Prescriptions
age range unlicensed unlicensed off-label (%)
or off-label or off-label (%)
drug (%)
1 day–20 years 36–92 16–62 7–60
0–183 days 80–97 55–80 14–63
11–37 9–33
554
studies; some only considered one type of off-label use,
while others considered up to six. The most frequent
category was age (27 studies), followed by dose (23),
indication (22), route (21), formulation (7), contraindi-
cation (5), and lack of paediatric license, use in children
not mentioned, or inadvisable co-prescription (5 studies
total). The definitions of off-label and unlicensed pre-
scriptions also varied between studies.
Paediatric hospital wards
The 11 paediatric hospital ward studies involved general
paediatrics, intensive, and surgical intensive care wards.
The off-label or unlicensed drug use rates resulting from
these studies ranged from 36% to 92% of children
(receiving at least one off-label or unlicensed drug)
(Table 1) and from 16% to 62% of prescriptions. The
classification strategies used in the studies varied, yield-
ing different usage rates. However, when off-label and
unlicensed prescriptions were considered together, the
rates were more comparable because some authors
considered off-label certain uses while others considered
them unlicensed. An example is paediatric license: Craig
et al. [23] considered drugs with no paediatric license
unlicensed (for a rate of 1% of prescriptions analysed in
their study), while Pandolfini et al. [54] considered them
off-label (7% of prescriptions).
Two of these studies used significantly different clas-
sifications from the rest. In one [72], only off-label use
for indication was evaluated, in the other [48], only off-
label use for age was evaluated.
The most common reasons for off-label prescribing
were dosage and patient’s age, followed by indication.
The drugs most often listed among the more common
off-label/unlicensed drugs were acetaminophen, cisa-
pride, chloral hydrate, and salbutamol.
Neonatal hospital wards
These seven studies involved general, surgical, and
intensive care wards. The proportion of patients
receiving at least one off-label or unlicensed drug on the
neonatal wards was much higher than on the paediatric
wards and ranged from 80% to 97%, and the rates of
off-label or unlicensed prescriptions from 55% to 80%.
The study by Avenel et al. [2] also evaluated the differ-
ence in rates between neonates and premature babies
and found a higher rate of unlicensed use in the latter.
The study by ‘t Jong et al. [66], which compared different
types of wards, found a higher rate of unlicensed use on
the neonatal ward (62% compared to 39%, 40%, and
52%, on the surgical intensive care unit, the medium
care unit, and the paediatric intensive care unit, respec-
tively), due mostly to the unlicensed use of caffeine. The
same study also found a lower rate of off-label pre-
scriptions on the neonatal ward (14% compared to 29%,
19%, and 16%). Turner et al. [78] also evaluated the
difference in rates between different paediatric specialties
and found higher off-label/unlicensed drug use rates on
the neonatal surgical unit (55% of prescriptions) com-
pared to the other units (25% on the medical and sur-
gical units, 40% on the general paediatric intensive care
unit, and 44% on the cardiac intensive care unit). The
most common reasons for off-label or unlicensed drug
use were dose, followed by indication, and the drugs
appearing more frequently among the most common off-
label/unlicensed drugs were caffeine, ampicillin, dopa-
mine, phenobarbital, morphine, sodium chloride, the-
ophylline, and vitamins K and E.
Community setting
The 12 community setting studies evaluated data from
paediatric and family practice clinics, paediatrician’s
offices, and databases. The studies were characterised by
greater variation in classification schemes and were
therefore more difficult to compare. When all studies
were considered, the off-label/unlicensed prescription
rates ranged from 11% to 37%. However, Erickson
et al. [27] evaluated off-label use with respect to indica-
tion only, Bucheler et al. [10] did not look at individual
prescriptions, but evaluated whether information on the
drug, its dose unit or its formulation was available for
the age range to which the drug was prescribed, Horen
et al. [36] assigned only one off-label category to each
prescription, giving priority to contraindication and
indication, and Ekins-Daukes et al. [26] only evaluated
the 160 most prescribed drugs. The drugs appearing
most often among the more common off-label/unli-
censed drugs were salbutamol and amoxicillin and the
most common reason for off-label use was dosage, fol-
lowed by age.
Three of the studies evaluated off-label and unli-
censed drug prescription rates specifically with respect to
age range. Two found that the younger the age of the
children, the higher the rates [14,43] whereas one found
no difference [26].
Discussion
This review revealed that the methods used to assess off-
label and unlicensed drug use varied widely between
studies, making a direct comparison difficult. The re-
sults, however, show that this type of use is common to
all settings. In general, it can be noted that higher off-
label/unlicensed rates exist for neonatal versus paediat-
ric wards and for hospital versus community settings.
Concerning age, two [14,43] of three [26] community
setting studies evaluating differences found higher rates
in younger children.
The most common type of off-label drug use emerg-
ing from the review was dosage. This was expected be-
cause dose adjustments are necessary even for drugs with
paediatric labelling, since there are significant differences

in drug metabolism between narrow age ranges in chil-
dren. Acetaminophen is an example of a drug often
administered at dosages both higher and lower than
those listed in the product license, despite its well-doc-
umented use in children. Unfortunately, dose adjust-
ments can be a direct source of prescribing error [19].
The National Institutes of Health have created a list
of highest-priority drugs whose use in children needs to
be studied to ensure safety and efficacy (http://
www.fda.gov). It is interesting to note that of these
commonly-prescribed drugs listed, only one, metoclo-
pramide, appears among the most common off-label/
unlicensed drugs in the studies included in the review,
and only in one study [75] where it was used off-label for
dose as an anti-emetic on a paediatric surgery ward. This
highlights the fact that although efforts are being made
to improve knowledge on the drugs with the greatest
impact on the paediatric population, the task is a diffi-
cult one and the list should probably be expanded.
It is important to highlight the fact that off-label is
not synonymous with incorrect. Several researchers
investigated the relationship between off-label and
unlicensed drug uses and recommendations from evi-
dence-based drug therapy sources [25, 34, 43, 58, 72,
73,80] and found that they generally correspond, indi-
cating that the quality of drug therapies is not neces-
sarily related to drug license status.
Existing information on optimal drug use in children
should be made readily available to those who care for
young patients directly on the product leaflet, but this is
often not the case. A study [73] found that the official
information for paediatric anti-cancer drug therapies
was scarce, despite the availability of clinical and phar-
macological studies in the literature. The problem be-
hind the large extent of off-label and unlicensed use is
therefore also due to a lack of harmonisation between
the evidence and drug licenses [26,45]. Formularies re-
main an important source of prescribing information for
physicians because they attempt to fill this knowledge
gap. In 1999, an important pediatric formulary, Medi-
cines for Children [60], was created in the United
Kingdom. It was later translated and adapted to the
Italian situation in an effort to make essential paediatric
information available elsewhere as well [49]. Although
the creation of a worldwide paediatric formulary would
be an important milestone since it would lead to a
standard, acknowledged approach to therapy, at least
for the most frequent paediatric clinical needs [6] for-
mularies should only be temporary, supplementary
information sources because drug licenses should be
updated with all available evidence.
Several suggestions for improving paediatric drug
therapies have been proposed [37,69] but clinical trials
[12,64] are the most valid means of obtaining funda-
mental data. Furthermore, they do so in a closely
monitored, controlled environment and avoid subjecting
young patients to ‘‘trial and error’’ procedures unnec-
essarily [4,59]. It is therefore important that the number
of paediatric trials increases and that the resulting
555
information be collected, analysed, and made available
[8, 35,65].
Many studies on the off-label/unlicensed use of drugs
in children have been performed, but with different
methodologies and in different contexts. In order to be
able to fully compare off-label use rates and investigate
the differing therapeutic needs of children in different
countries, a single, international study, based on com-
mon evaluation criteria, should be carried out. Measures
to fulfill the resulting needs could then be taken in view
of all aspects of rational drug therapy, from requiring
increased information on specific drugs to producing
suitable formulations where lacking [9,20]. The Euro-
pean Community’s recent enlargement could facilitate
the inclusion of countries for which no off-label data
exists as well. Until such a study becomes feasible, sin-
gle, prospective studies analysing chosen sets of impor-
tant, but less studied drugs or indications are useful for
monitoring children’s needs more closely.
Acknowledgements Chiara Pandolfini is grateful for a Monzino
fellowship.
Appendix
Legislation concerning off-label drug use in children
In the United States, a series of regulatory measures
have been introduced to increase knowledge of drugs in
children and to change the labelling to provide better
prescribing information on appropriate dose, use and
safety of drugs [1]. The first FDA regulations on drug
use in children involved the introduction of a paediatric
section in the package insert in 1979 [41]. In 1994, the
FDA’s ‘‘Pediatric Rule’’ [24] allowed adult efficacy data
to be used, in some cases, to demonstrate drug safety
and effectiveness in children. The results were not suffi-
cient, however, and other measures followed. In 1997,
the FDA created the Pediatric Exclusivity provision in
the 1997 Modernization Act [82], in 1998 the ‘‘Pediatric
Final Rule’’ [57] was created, and in 2002, the Best
Pharmaceuticals for Children Act [5] was established.
Paediatric research grew as a result of the effective
incentives for the pharmaceutical industry. From 1998
to December 2004, 87 products underwent paediatric
information labelling changes (http://www.fda.gov/cder/
Pediatric/labelchange.htm). Although the results were
positive, the Rule was challenged on the grounds that
the FDA did not have the authority to impose paediatric
research requirements on drug companies. This led to a
legal battle and to the ‘‘Pediatric Research Equity Act of
2003’’ in December 2003 [56] which gave the FDA the
power to require drug makers to conduct paediatric
tests.
In Europe, the European Medicines Agency’s
(EMEA) Committee for Proprietary Medicinal Products
created the ‘‘Note for guidance on clinical investigation
556
of medicinal products in the paediatric population’’ in
1997 [18] describing when and how drugs should be
tested in children. However, no significant difference in
the resulting situation was found [13, 38, 69,83].
In 2001, the International Conference on Harmoni-
sation’s (ICH) Guidance for Industry: Clinical Investi-
gation of Medicinal Products in the Pediatric Population
[39] went into effect in the United States, Europe, and
Japan. In 2002, the European Commission published a
consultation document ‘‘Better Medicines for Children’’
[28] highlighting the need for suitable paediatric medi-
cines. Recently, the European Commission adopted a
proposal entitled Regulation of the European Parlia-
ment and Council on medicinal products for paediatric
use [29] which would require paediatric studies for drugs
of possible use to children.
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