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Off-Label Drug Use in Pediatric Patients

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Off-Label Drug Use in Pediatric Patients
E Kimland1 and V Odlind1
INTRODUCTION
Until recently, it was considered unethical or impossible to
perform clinical trials of new medicines in children. As a con-
sequence, many medicines used for treating children are insuf-
ficiently documented with regard to dosing, efficacy, and safety.
The off-label use of drugs has been extensive in treating the pedi-
atric population. This article gives an overview of the extent and
types of off-label use of medicines in pediatric populations.
Children Are Not Small Adults
Children are defined as individuals 0–18 years of age. In pedi-
atrics, the patient may be a premature infant weighing 500 g or
a fully grown adolescent weighing as much as 100 kg.
Doses for children are often derived by scaling from adult dos-
ages after adjusting for body weight. However, it is well known
that pharmacokinetic responses to a drug, such as drug absorp-
tion, distribution, metabolism, and excretion, are substantially
different in children as compared with adults, and that these
responses change with growth and maturation. In the newborn,
especially in the preterm neonate, the elimination of drugs is
low because of insufficient drug metabolizing capacity of the
liver and immaturity of kidney function. Therefore, these infants
require doses that are even lower than the calculated weight-
adjusted doses.1 Toddlers and preschool children, however, have
higher metabolic capacity and may require doses higher than the
weight-adjusted doses.2 Also, the surface area-to-body weight
ratio in children can be up to three times higher than in adults,
and this can lead to a larger proportion of topically administered
drugs being absorbed in children.1 It is clear, therefore, that mere
scaling from adult dosages does not always give good enough
estimates of suitable dosages for children.3,4
Use of Drugs in Pediatrics
Drug therapy is widely used to treat diseases in childhood;
several prescription and drug utilization studies in primary
health-care settings have shown that children, especially infants
and preschoolers, receive considerable amounts of drugs.5–7
The average number of drugs prescribed per child per year, as
reported by these studies, varies between 0.8 and 3.2.5,6,8–9
1Medical Products Agency, Uppsala, Sweden. Correspondence: E Kimland (Elin.kimland@mpa.se)
Received 12 December 2011; accepted 6 February 2012; advance online publication 4 April 2012. doi:10.1038/clpt.2012.26
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nature publishing group
The drugs most commonly prescribed to children are antibiot-
ics for systemic use, followed by drugs for respiratory ailments,
and analgesics.5–7 Overall, however, children receive treatment
with all types of drugs.9
Pediatric patients receive considerable amounts of drugs at
hospitals where, it could be assumed, the most severely ill chil-
dren are treated. However, there have been very few large drug
utilization studies to estimate pediatric drug use in the hospital
setting.
A few small studies have reported that children receive
substantial amounts of over-the-counter drugs and natural
remedies.10–15 A recent study in Sweden estimated that chil-
dren are likely to receive at least one over-the-counter drug dur-
ing any given 3-month period and that information relating to
pediatric use is lacking with respect to several of these drugs.16
Natural health products are often regarded as harmless agents;
however, untoward effects have been documented with the use
of such products.17
Use of Inadequately Documented Drugs in the
­Pediatric Population
There has long been a lack of pediatric clinical trials, and this
has led to limited or no pediatric documentation with respect to
many approved drugs. Ethical and other considerations might
result in withholding a potentially important drug treatment
from children if the drug in question has not been adequately
tested in a pediatric population. The other option open to the cli-
nician is to resort to “off-label” use of the drug, that is, a use out-
side of its authorized product license as defined in the Summary
of Product Characteristics (SmPC). A single prescription can
be categorized as off-label use in several different categories,
of which the most common are shown in Table 1. In earlier
studies, a drug use was classified as off-label if the dose, dosing
frequency, or the age/weight of the patient was not in agreement
with the particulars in the drug labeling.18–27 In more recent
studies, the most prominent reasons for drug use being classified
as off-label were a total lack of information in the label about
pediatric use of the drug and the use of a nonapproved dose in
relation to age or weight.9,28–30
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Table 1  Off-label categories
Off-label category Description
Age Drug not recommended in the SmPC below a
certain age
Weight Drug not recommended in the SmPC for children
below a certain weight
Absence of pediatric No mention at all in the SmPC regarding pediatric
information use
Lack of pediatric clinical Stated lack of evidence of efficacy and safety in
data pediatric patients in the SmPC
Contraindication Statement in the SmPC that the drug is
contraindicated in children
Indication Drug prescribed for indications outside of those
listed in the SmPC
Route of administration Drug administered by a route not described in
the SmPC
SmPC, Summary of Product Characteristics.
Paracetamol given to a premature infant is one example of
off-label drug use (age/weight); others are diclofenac used for
abdominal pain (indication), adrenaline given through inhala-
tion rather than intravenously (route of administration), and the
administration of morphine (absence of pediatric information)
or codeine (lack of pediatric data) as an analgesic.
The definition of off-label drug use is sometimes interpreted
differently by different investigators. For example, some studies
included several off-label categories (Table 1) whereas others
used only one or a few of the categories.20–32 Such differences
in categorization make comparisons between studies difficult
or impossible.
In addition to being treated with authorized drugs used
off-label, children also receive drugs that do not have mar-
ket approval. For these latter drugs, the background docu-
mentation has not been critically assessed by a competent
authority. Extemporaneously prepared drugs (EPDs) are those
that are prepared at pharmacies and are widely used in the
pediatric population, probably because of limited or no avail-
ability of a specific drug, dosage, or formulation suitable for
children.31,32 Little information exists to support the phar-
macokinetics of EPDs, and they are rarely of assured qual-
ity. Consequently, the background documentation of EPDs is
even poorer than that of approved drugs used off-label. The
proportion of EPD use and the specific EPDs that are admin-
istered to children are other areas of study that have been
poorly investigated.
Pediatricians sometimes prescribe nonapproved drugs
because there is no available approved drug or drug strength
or formulation suitable for children. This could be the result
of a market-driven decision by the company in anticipation
of low sales of the drug for pediatric use. The list of approved
drugs differs between countries, and drugs that are approved
in one country may not be approved in another. Overall,
however, nonapproved drugs may be less well documented
than approved ones used off-label; more important, nonap-
proved drugs are not subject to the same pharmacovigilance
as approved ones.
Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 5 | may 2012
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Extent of Off-Label Drug Use and Use of
­Nonapproved and Extemporaneously Prepared
Drugs in Pediatric Treatment
Several reports on drug prescribing in the pediatric setting show
that off-label use of drugs and the use of nonapproved drugs and
EPDs is extensive in hospital as well as in outpatient care (Tables 2
and 3). It has been reported that the vast majority of pediatric
patients in hospital care are at risk of receiving at least one drug
used off-label or a nonapproved drug or an EPD (Table 2). In neo-
natal hospital care, almost all patients are exposed to at least one
off-label or nonapproved drug or an EPD (Table 2). In primary
health care, up to two-thirds of pediatric patients were reported to
have received at least one undocumented drug (Table 3).
In hospital and neonatal care studies, the proportion of off-
label use varied between 10 and 65%, whereas the proportion
of prescriptions for nonapproved drugs varied between 3 and
48% (Table 2). In outpatient care, the proportions of off-label
and nonapproved drug prescriptions varied between 11 and 31%
and between 0.3 and 17%, respectively (Table 3).
The therapeutic drug categories most commonly used off-label
in hospital care were analgesics and antibiotics.18–24,26,28–29,33
Some of the most common drugs used off-label in pediatric
hospital care were morphine, paracetamol, salbutamol, caffeine,
and heparin. Another area with a high proportion of off-label
drug use was that of cardiovascular drugs.18,24,26,29,34,35
A point prevalence study carried out in Sweden, compris-
ing all hospital-treated children, reported that even carbohy-
drates and/or electrolyte solutions were commonly used in an
off-label manner.29 In particular, glucose infusions intended
for intravenous administration were given by the oral route to
neonates and infants for pain relief. In many studies, the use of
intravenous carbohydrate, electrolyte, and other solutions was
excluded from the analysis, and therefore the true proportion
of off-label use of products may have been underestimated in
those studies.18,20,21,36–37 Although intravenous carbohydrates
and electrolytes given orally probably present a low risk, the
administration of drugs by an unintended route is associated
with the potential risk of administration errors.
In primary health care, antibiotics for systemic use were
among the most commonly prescribed drugs used off-label,
as were antiasthmatic drugs.5,6,9,30 However, in the majority of
studies, the highest proportion of off-label drug use in children
in primary health care was among topically administered drugs
such as dermatologicals and eye drops.9,25,27,30,38–41
Many studies show that young children—in particular, neonates
and infants—received the highest proportion of undocumented
drug prescriptions (off-label, nonapproved, and EPD), both in
primary health care9,25,30,40–42 and in hospital care.23,29 In a large
study in Sweden, ~70% of all drugs given to neonates in hospital
care were off-label, nonapproved drugs or EPDs, that is, drugs
insufficiently documented for the specific age group.29
Risks and Adverse Drug Reactions Associated with
Off-Label Drug Use in Children
Because physicians who treat children are well aware of the lack
of pediatric labeling, they have had to gain clinical experience in
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Table 2  Studies of drug treatment in pediatric hospital settings

Children receiving at
Drug least one drug Off-label of all Nonapproved or EPD
Setting as reported Patients (n) prescriptions (n) OL/NAP/EPD (%) prescriptions (%) of all prescriptions (%) Reference
Pediatric intensive care 166 862 70 23 14 19
Surgical and medical pediatric 609 2,013 42 18  7 20
wards
Pediatric ward 624 2,262 67 39  7 21
Pediatric emergency ward 132 222 42 26  8 22
Pediatric ward 74 237 NA 19  3 23
Pediatric ward, pediatric and 237 2,139 90 18 48 24
neonatal intensive care unit
Neonatal intensive care, 108 629 76 36 13 36
pediatric and surgical pediatric
wards
Pediatric ward 1,461 4,265 89 60 <1 26
Pediatric emergency ward 336 667 68 51 NA 28
Neonatal ward, pediatric 60 483 100 25 24 18
intensive care, surgical and
medical pediatric wards
Pediatric ward 265 1,450 83 40  6 61
All Swedish pediatric hospitals 2,947 11,294 60 34 15 29
Pediatric ward, neonatal ward, 293 1,017 92 44 34 33
pediatric intensive care unit
Neonatal intensive care 70 455 90 55 10 37
Neonatal intensive care 105 525 93 59 16 62
Neonatal intensive care 97 1,442 80 47 11 35
Neonatal intensive care 34 176 NA 51 12 63
Neonatal ward 490 1,981 100 65 22 34
Proportion of children receiving at least one off-label, nonapproved or extemporaneous drug and proportion of prescriptions of off-label, nonapproved, or extemporaneously
prepared drugs.
EPD, extemporaneously prepared drug; NA, not applicable; NAP, nonapproved; OL, off-label.

Table 3  Studies of drug treatment in pediatric primary health care

Children receiving at least Off-label of all Nonapproved/EPD of all
Children (n) Drugs (n) one drug OL/NAP/EPD (%) prescriptions (%) prescriptions (%) Reference
989 2,522 56 29 4 38
1,175 3,347 NA 11 0.3 39
357,784 575,526 NA 21 — 30
455,661 1,592,006 NA 13 — 40
19,283 68,019 NA 23 17 27
6,141 17,453 46 14 15 25
151,476 467,334 NA 31 <1 41
968,456 2,190,000 64 13.5 —  9
Proportion of children receiving at least one off-label, nonapproved, or extemporaneous drug and proportion of prescriptions of off-label, nonapproved, or extemporaneously
prepared drugs.
EPD, extemporaneously prepared drug; NA, not applicable; NAP, nonapproved; OL, off-label.

off-label drug use.43,44 Therefore, most well-supervised pediatric
patients are not normally at risk from such use. However, given
that the incidence of undocumented drug use in the pediatric
population appears to be greatest in critically ill neonates and
young children, there is an obvious need for more data, espe-
cially in those age groups.
A few studies have analyzed the potential association between
off-label use of drugs and the risk of adverse drug reactions
(ADRs).45–49 In two prospective studies, the incidence of ADRs
was higher among children treated with nonapproved drugs
or off-label use of drugs than among those receiving on-label
treatment with approved drugs.45,46 In three studies based on

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spontaneous reporting of ADRs, off-label drug use together with
other incorrect use was more often associated with ADRs than
when drugs were used in line with the product labeling.47–49
In one study, serious ADRs were more often associated with
off-label drug prescribing than with on-label drug prescrib-
ing.48 None of these studies, however, could demonstrate sta-
tistically significant differences, and therefore further studies
are needed.
The fact that only a few ADR reports concern topically admin-
istered drugs50 may be due to a lower propensity of these drugs
to cause ADRs as compared with systemically administered ones.
However, children do have a larger surface area-to-body weight
ratio than adults, and it has been observed that, for instance,
topically administered tacrolimus can give rise to high blood
concentrations of the drug in children.51 The potential risks of
specific topical drugs such as immunosuppressants need to be
further studied.
Although the use of approved drugs is monitored by phar-
macovigilance systems, there is currently no clear process for
collecting information on ADRs relating to the use of EDPs and
nonapproved drugs. Therefore, spontaneous reporting of ADRs
may be the only way to identify hazardous effects, although it is
well known that the spontaneous reporting system is character-
ized by substantial underreporting.52,53 Whether off-label use
of an authorized drug is as likely to result in an ADR report as
on-label use of the same drug remains to be studied.
Improving Drug Use in Pediatric Patients: Initiatives
By Medical Authorities
To improve pediatric drug therapy, new legislation was intro-
duced both in the United States (Pediatric Research Equity Act,
2003) and in the European Union (Paediatric Regulation, 2006).
The new legislation aims to facilitate the development and avail-
ability of safe and effective medicines for children and to ensure
that those medicines are of high quality, ethically researched,
and approved appropriately. Furthermore, the legislation aims
to improve the general level of knowledge about the use of medi-
cines in children. The legislation has included some economic
incentives for the pharmaceutical industry regarding patent pro-
tection for both newly approved drugs and drugs that are already
on the market.54,55 The new legislation will also exert pressure on
national regulatory agencies as well as on research grant foun-
dations, professional organizations, and research networks to
identify unmet needs so as to make sure that pediatric clinical
trials are performed with high ethical and scientific quality.
Inadequate pediatric labeling of drugs is often attributed to
the lack of scientific documentation in children. However, it has
been shown that information outside the drug labeling is often
available in the scientific literature.41,56 As a consequence, and in
order to update the SmPC with relevant pediatric information,
the EU Paediatric Regulation states that pediatric studies that
have not previously been assessed by authorities “shall be sub-
mitted by the marketing authorisation holder for assessment to
the competent authority” (Paediatric Regulation, articles 45 and
46). The competent authority may then update the SmPC and
may vary the marketing authorization accordingly. It remains to
Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 5 | may 2012
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be shown whether those legal activities will improve pediatric
use of medicines and reduce off-label use of drugs in the pedi-
atric population.
Priority Areas For Medicines For Children
The widespread use of inadequately documented drugs in the
pediatric population strongly supports the need for medicines
suitable for children of all age groups with regard to strength,
formulation, and taste.20,22,26,42 The high proportion of undocu-
mented drugs used to treat children in hospital care underlines
the general need to improve drug use among the most severely
ill children.
Neonates and infants receive the greatest proportion of off-
label use of drugs, EPDs, and nonapproved drugs in hospital
care. Given that neonates and infants are particularly vulner-
able because of their immature renal and hepatic function,
and given the need to take their body proportions (weight
and surface area) into consideration when determining dos-
ages, the practical difficulties that may be encountered in drug
administration, and the inability of these very young patients
to express or report ADRs, further evidence of both the safety
and efficacy of many drugs is urgently needed in these age
groups.
Analgesics such as opioids and nonsteroidal anti-­inflammatory
medications such as diclofenac have been highlighted by sev-
eral authors as drug types for which clinical trials are most
needed to obtain appropriate efficacy, safety, and dosage data
for all pediatric age groups.19–21,24,29,35,37,40,57 Analgesics also
appear on the European Medicines Agency (EMA) priority list
of pediatric drugs requiring further studies.58 Cardiovascular
drugs have also been reported as severely lacking in pediatric
documentation.59,60
With the development of electronic, computerized patient
record systems, the structured documentation of off-label use
and the use of nonapproved drugs, including the clinical out-
comes of such treatments, could greatly improve the knowledge
in this area. There is also a need for improved recording of actual
drug use in children because it has been shown that drug treat-
ment is insufficiently documented in the medical records of
pediatric patients.56
Concluding Key Points
• Children have the same right as adults to receive safe and
effective drugs, i.e., well-tested drugs, in the correct dose, by
an appropriate route of administration, for the right indica-
tion, and for the right period of time, together with adequate
and correct information and medical surveillance.
• The practice of off-label prescribing of drugs for pediatric
patients is substantial, both in primary health care and in
hospital care, and must be regarded as a patient safety issue
associated with an increased risk of ADRs.
• The most vulnerable pediatric group—critically ill neonates
and infants—has the highest exposure to drugs that are
insufficiently documented with regard to efficacy, safety, and
dosage; this situation underscores the need for clinical trials
in these age groups.
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• Off-label prescribing of drugs for pediatric patients is a con-
tinuing public health concern. More clinical trials in children
are needed, as well as more focused interventions such as
careful postmarketing surveillance of drug safety in chil-
dren. It is also important that all aspects of drug treatment
in children, including the occurrence of ADRs and other
drug-related problems, should be thoroughly documented
in clinical practice.
• In addition to pediatric trials of new medicines, there is also
a need for more research on some older drugs, particularly
analgesics and cardiovascular drugs, that are commonly used
in pediatric patients.
Acknowledgments
The views presented are those of the individual authors and may not be
understood or quoted as being made on behalf of or reflecting the position
of the Medical Products Agency.
Conflict of Interest
The authors declared no conflict of interest.
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