Clinical Setting Influences Off-Label and Unlicensed Prescribing in a Paediatric Teaching Hospital
Clinical Setting Influences Off-Label and Unlicensed Prescribing in a Paediatric Teaching Hospital
Petra Czarniak ) 0 1 2
Lewis Bint 0 1 2
Laurent Favi 0 1 2
Richard Parsons 0 1 2
Jeff Hughes 0 1 2
Bruce Sunderland 0 1 2
0 Data Availability Statement: Interested parties will be able to obtain the data in the same manner that the authors did, even if this requires a data sharing agreement. Requests can be sent to Dr. Petra Czarniak, Curtin University, School of Pharmacy , GPO Box U1987, Perth, Western Australia 6845 ( P
1 Academic Editor: Umberto Simeoni, Centre Hospitalier Universitaire Vaudois , FRANCE
2 1 Curtin University , Bentley, Western Australia , Australia , 2 Princess Margaret Hospital , Roberts Rd, Subiaco, Western Australia , Australia , 3 Department of Pharmaceutical Sciences, Utrecht University , The Netherlands
This study confirmed off-label and unlicensed use of drugs remains common. Further, that
prevalence of both is influenced by the clinical setting, which has implications in regards to
medication misadventure, and the need to have systems in place to minimise medication
authors have completed the Unified Competing
Interest Form (available on request from the
corresponding author). These declare no support
from any organisation for the submitted work; no
financial relationships with any organisations that
might have an interest in the submitted work in the
past three years; and no other relationships or
activities that could appear to have influenced the
errors. Further, there remains a need for changes in the regulatory system in Australia to
ensure that manufacturers incorporate, as it becomes available, evidence regarding efficacy
and safety of their drugs in children in the official product information.
In Australia, it is a requirement that drugs to be marketed are licensed by the Therapeutics
Goods Administration (TGA) to ensure they meet requirements for efficacy, safety and quality
. Many medications prescribed for children have not been evaluated in this population and
dosages are often extrapolated from data obtained from adult trials. Developmental changes in
children that occur with age, including gastric acidity, the activity of hepatic drug metabolising
enzymes, renal function and drug receptor expression, influence the pharmacokinetic and
pharmacodynamic effects of drugs . These factors can render data extrapolated from clinical
studies in adults inappropriate in children.
Off-label and unlicensed prescribing is not illegal in Australia and is often clinically
appropriate. Reasons for off-label prescribing include administration to children outside the age
range for which the product is licensed, the use of doses other than those stated in the approved
Product Information, the use of alternative routes of administration or use for indications not
approved in the license . Reformulation of a registered drug (to obtain a desired dose or
make the drug easier to administer), formulations manufactured under a special license, the
use of unregistered drugs or the use of a non-pharmacological substance as a medicine are
examples of unlicensed prescribing . Unlicensed and off-label prescribing is a global
Several retrospective and prospective studies have been conducted in the United Kingdom
(UK) , France , the Netherlands , Germany [8, 9], Switzerland , Finland [11,
12], Croatia , Italy , Portugal , across Europe , United States (US) , Brazil
, Ireland , Israel , Malaysia  and Australia [1, 22, 23] in various hospital settings
that have included Emergency Department patients, outpatients or inpatients (general and
medical wards and paediatric and neonatal intensive care units). Most of the studies have been
conducted over a period of weeks or months. The extent of off-label and unlicensed prescribing
in paediatrics has been reported to range from 7 to 60%, with 28 to 100% of paediatric patients
receiving at least one off-label or unlicensed drug [2, 7, 10, 11, 15, 16, 21]. The proportion of
children that receive unlicensed or off-label drugs in the hospital setting has been shown to be
higher in intensive care units and in those with complex diseases [4, 5, 16, 24].
Data on the extent of off-label and unlicensed prescribing in paediatrics in Australia are
limited. A 10 week study that investigated the use of unlicensed and off-label drugs in a neonatal
intensive care unit at the Royal Womens Hospital, Melbourne reported its prevalence as 11%
and 47% respectively, with 80% of patients receiving at least one off-label or unlicensed drug
. A retrospective study on the use of off-label medicines on a general paediatric ward at the
Royal Hobart Hospital, Tasmania reported that 31.8% of medicines were used off-label and
57.3% of children received an off-label medicine . In Western Australia, a study conducted
in 1997 in one surgical ward and one medical ward at Princess Margaret Hospital reported a
higher incidence (17%) of off-label and unlicensed prescribing on the medical ward but found
that more children on the surgical ward (39%) received an off-label or unlicensed drug .
To improve evidence-based prescribing for children in Australia, a Paediatric Medicines
Advisory Group was formed in 2007 to provide advice to the Therapeutics Goods
Administration and Government on paediatric medicine issues. A Paediatric Medicines Dosing
Resource, the AMH Children's Dosing Companion, an initiative of the Australian Health
Ministers Advisory Council, became available in Australia in mid-2013 and provides detailed
evidence-based and peer-reviewed dosing information with monographs on 230 drugs, including
information on off-label uses . Despite this, studies of off-label and unlicensed drug use in
Australia are limited and have only investigated specific areas of paediatric hospital treatment.
This study aimed to estimate the prevalence of off-label and unlicensed prescribing from an
overall hospital perspective by randomly selecting patient records from all hospital settings
(emergency, inpatient and outpatient) over a single year of hospital patients in a major
paediatric teaching hospital in Western Australia.
A retrospective study was conducted at Princess Margaret Hospital. Medication chart records
were randomly selected from a total population of 145,550 patient encounters of which 55,591
were from Emergency Department attendances, 24,425 from inpatients and 65,534 from
outpatient admissions. The proportion of Emergency Department patients: inpatients: outpatients
was maintained to generate a list of 1200 randomly selected cases. The justification for selecting
this number of records for review was so that the 95% confidence intervals (CI) for the
prevalence estimates would be no wider than 3% (a measure of precision). Of the 1200 records,
data from 1038 medication chart records from a single year (2008) were available and analysed
for prescribing in the paediatric emergency, outpatient and inpatient departments. Each record
had a unique identifying number, the code for which was lodged with the Chief Pharmacist at
Princess Margaret Hospital. As patient medication records were de-identified prior to analysis,
written informed consent from participants was not required for the study.
An event date in 2008 was recorded for each admission record, as well as any prescribing
details (date of prescription, dosage form, dose, strength of drug, frequency of dosing), diagnosis,
and relevant patient data including sex, date of birth, weight, height, past medical history,
ceased medications and reasons for ceasing. If the event date was directly connected to another
event in 2008 (on-going care), drugs prescribed for that event were also recorded. Patient
records were accessed via the Patient Information Management Services and viewed in the Patient
Information Management Services survey room at Princess Margaret Hospital.
The patient's age was classified according to the European Medicines Agency  age
classification: newborns (zero to 27 days), infants and toddlers (28 days to 23 months), children
(two to 11 years) and adolescents (12 to 18 years).
Following data collection, all prescribed drugs were classified as licensed, off-label or
unlicensed according to the approved Product Information as shown in the 2008 edition of
Monthly Index of Medical Specialities  that was current at the time of prescribing or the
Therapeutic Goods Administration Product Information  data. Categories of off-label
prescribing were defined sequentially as follows:
1. Age/ weightadministration of a prescription drug outside the age range or weight for
which the product is licensed.
2. Indicationthe use was for indications not described in the Product Information.
3. Route of administrationthe use of alternative routes of administration other than the
approved route for that formulation in the Product Information.
4. Dosage including dose frequencythe use of doses or dose frequencies other than those
stated in the approved Product Information.
A prescription drug was considered off-label if it met at least one of the above four criteria
according to the Therapeutic Goods Administration  or Monthly Index of Medical
Specialities  Product Information.
A hierarchical approach adopted by Hsien et al  was used for this study on the basis that
an off-label prescribed drug was defined by any one classification. In keeping with Hsien et al
 all prescriptions were initially analysed for age so that drugs with no paediatric information
or those prescribed for an age group for which the drug was not licensed were classified as
offlabel for age. The next level was indication, then route of administration and finally dosage
(which included frequency of administration). Once drugs were classified into a category eg
age, they were then not considered for possible classification into any subsequent category.
Where the Therapeutic Goods Administration or Monthly Index of Medical Specialities
Product Information provided a drug dose range (eg Painstop 12 yrs [1012kg]: 56 mL), dosages
administered outside this dose range were considered off-label. However, where the dose
provided in the Therapeutic Goods Administration or Monthly Index of Medical Specialities
Product Information was prescribed on a weight basis eg paracetamol 15mg/ kg/ dose, a
variation of 10% was accepted to allow for practical dosage volumes [27, 28].
Drugs were classified as unlicensed if they were an unregistered drug, an unlicensed
formulation of a registered drug or the use of a non-pharmacological substance as a medicine. Where
a drug was classified as both off-label and unlicensed, the final classification was off-label. For
any drugs where there was an uncertainty as to whether or not it was off-label or unlicensed, a
conservative approach was adopted and it was classified as licensed. Prescribed drugs were
coded based on the Anatomical Therapeutic Chemical classification.
Prescriptions for oxygen, parenteral nutrition and drugs used in research studies, were
Simple descriptive statistics (means and standard deviations for continuous variables,
frequencies and percentages for categorical variables) were determined for patients and
prescription drugs. The Pearson Chi-square test was used to determine whether the proportion of
patients receiving licensed, unlicensed and off-label drugs differed significantly between
hospital settings. A similar analysis was used to compare proportions of drugs prescribed between
the settings. A logistic regression model was used to compare the proportions of licensed drugs
between different drug classes. Continuous variables were compared between settings using an
Analysis of Variance. A p-value of less than 0.05 was taken to indicate a statistically
This study was approved by the Princess Margaret Hospital Ethics Committee (Audit
103QP) and the Human Research Ethics Committee at Curtin University (approval number
Data were collected from a total of 1038 medication chart records which were randomly
selected from inpatients, outpatients and Emergency Department admissions. Of these, 59% were
male and 41% were female. One patient, a 19 year old, was excluded from the study due to age.
Most records (n = 403; 39%) were from the Emergency Department; 37% were outpatients
(n = 380) and 24% inpatients (n = 254) and in each setting, a majority was male (58% in the
Emergency Department, 55% outpatients, 65% inpatients). The average age (standard
deviation) of inpatients was 6.4 5.4 years, outpatients 7.8 5.2 years and Emergency Department
patients 5.6 4.8 years; with a median age in each setting of 5.4 years, 7.8 years and 4.0 years
respectively (p = 0.0003). Fig. 1 shows that most patients were in the European Medicines
Fig 1. Age distribution of inpatients, outpatients and emergency department patients.
Agency 2 to 11 year age group, with the Emergency Department having the most frequent
attendance for the 28 days to 23 months age group.
Although the gender differences and frequencies of patients prescribed no drugs, licensed,
off-label or unlicensed drugs was statistically significant (p = 0.0198) (Table 1), there was no
statistical difference between genders in the proportions of cases prescribed no drugs (32.6%
overall) or licensed drugs (31.0% overall, p = 0.1520). However, amongst the remaining 378
cases who were prescribed at least one off-label or unlicensed drug, 85.9% of the 142 females
were prescribed an off-label drug compared with the 93.6% of the 236 males (p = 0.0121).
The highest proportion of patients who were prescribed at least one off-label drug was
children (85.2%) and neonates (83.3%) as inpatients (Table 2). Higher levels of unlicensed
prescribing were observed in inpatient and outpatient infants (7.5% and 11.5% respectively).
Differences in prescribing for inpatients and outpatients were significant (p = 0.0077 and
0.0004 respectively) but not for Emergency Department patients (p = 0.2514)
A total of 2654 drugs were prescribed to 699 patients. Of the 2654 prescriptions, 1905
(71.8%; 95% CI: 70.1% to 73%) were for licensed drugs, 681 (25.7%; 95% CI: 24.0% to 27.3%)
for off-label drugs and 68 (2.6%; 95% CI: 2.0% to 3.2%) for unlicensed drugs. The number of
drugs prescribed in each setting is shown in Table 3. More drugs were prescribed to inpatients
(1494; 56.3%) than outpatients (502; 18.9%) or Emergency Department patients (658; 24.8%).
The number of drugs prescribed per patient ranged from zero to 21 (which included
licensed, off-label and unlicensed drugs). Almost one-third of patients (32.6%) were prescribed
no drugs while many received either one or two drugs (20.7% and 12.8% respectively). Seven
inpatients were prescribed 21 drugs. Few inpatients were prescribed no drugs (4.7%).
Frequently inpatients were prescribed three (11.0%), four (13.4%) or six (11.8%) drugs. The mean (SD,
median, [quartiles]) number of drugs prescribed for inpatients was 5.88 (4.35, 5.00,
[3#x2013;8]), outpatients 1.32 (1.82, 1.00, ) and Emergency Department 1.63 (2.5, 1.00,
). Many outpatients and Emergency Department patients were prescribed no drugs (38%
and 46% respectively) or one drug (29% and 21% respectively). There were statistically
Gender No Drugs LiDcreungssed Off-label Drugs UnDlicruegnssed
Patient Setting and Age No Drugs Licensed Drugs Off-label Drugs UnDlicruegnssed p
(n = 1905)
(n = 681)
(n = 68)
The p-values (Chi-square test) to assess differences between genders in each setting were: p = 0.8572
(inpatient); p = 0.0361 (outpatient); p = 0.1182 (Emergency Department).
significant differences in the proportions of drugs in each category prescribed to patients in
each setting (p < 0.0001). The number of off-label drugs prescribed to each patient ranged
from zero to 11 (inpatients), zero to five (outpatients) and zero to six (Emergency Department
Table 4 shows that the main therapeutic classes of drugs were those for the nervous system
(39.0%), alimentary tract and metabolism (15.4%) and anti-infectives for systemic use (15.1%).
When all 2654 drugs were classified into their specific Anatomical Therapeutic Chemical
classification categories (Table 4), the highest percentages of off-label prescribing was for drugs of
the cardiovascular system (40.6%), respiratory system (39.4%), genitourinary system/ sex
hormones (36.8%) and alimentary tract (34.1%). Drugs classified as off-label in the cardiovascular
system included clonidine, hydralazine and nifedipine; the respiratory system included
salbutamol and ipratropium; the genitourinary system/ sex hormones included sildenafil and
solifenacin and the alimentary tract included ondansetron, metoclopramide and omeprazole.
Within specific Anatomical Therapeutic Chemical classification categories, the highest
percentage of unlicensed prescribing was for systemic hormonal preparations excluding sex
hormones (14.3%), sensory organs (13.7%), and antineoplastics and immunomodulating agents
(11.9%). Unlicensed drugs prescribed from each of these categories included dexamethasone
(reformulated), Dilacaine (a Princess Margaret Hospital eye drop formulation) and
The 10 most commonly prescribed drugs were paracetamol, ibuprofen, ondansetron,
Painstop Day (120 mg paracetamol and 5 mg codeine phosphate per 5 mL), morphine, oxycodone,
amoxicillin, dexamethasone, salbutamol and prednisolone. The 10 most frequently prescribed
off-label drugs were ondansetron (13.8%), Painstop Day (10%), salbutamol (7.5%), oxycodone
(7.2%), paracetamol (7.1%), midazolam (4.3%), fentanyl (3.1%), Timentin (ticarcillin with
clavulanic acid) (2.8%), amoxicillin (2.6%) and flucloxacillin (2.6%).
The 10 most common off-label drugs prescribed to different age groups is shown in Table 5.
Not surprisingly, the 10 most commonly prescribed drugs overall as well as off-label drugs in
each age category were different with neonates prescribed more anti-infectives and adolescents
prescribed more analgesics or other drugs classified for the nervous system.
The majority of unlicensed drugs, which included cephazolin and Dilacaine eye drops,
dexamethasone, azathioprine, propranolol, tinidazole, gonadorelin and tocilizumab, were
Table 4. Frequency (percentage) of licensed, off-label and unlicensed drugs prescribed in each Anatomical Therapeutic Chemical classification
Anatomical Therapeutic Chemical classification
(n = 1905)
(n = 681)
(n = 68)
The p-values in the last column compare the proportion of licensed drugs within each ATC class against the proportion in the Nervous System ATC group
(the largest group of drugs).
reformulated due to a lack of availability of a commercial preparation. A few unlicensed and
unregistered drugs, including tocilizumab, were imported since they were not available in
The most common reasons for off-label prescribing were due to age and dosage (43.2% and
47.4% respectively; Table 6). The percentage of off-label prescribing due to dosage would
probably have been higher but once drugs were classified as off-label due to age (ie the first
hierarchical category), then further classification of that set was not considered. This indicates that
dosage was clearly the primary factor leading to off-label prescribing. The least common reason
for off-label prescribing was indication.
Reasons for off-label prescribing varied with each Anatomical Therapeutic Chemical
classification code with some therapeutic classes off-label all of the time for age, such as blood and
blood forming products, dermatologicals, systemic hormonal preparations excluding sex
hormones, drugs affecting the musculoskeletal system and antiparasitic products. Drugs affecting
the respiratory system were more commonly off-label due to dosage (85.9%) rather than age
This is the first study of its kind involving a random selection of patient records to investigate
the extent of off-label and unlicensed prescribing across all major patient settings in a
The proportion of off-label and unlicensed prescribing in this study (25.7% and 2.6%
respectively) was higher than reported in a previous Princess Margaret Hospital study conducted
more than a decade ago, in which 16.2% of drugs prescribed were off-label or unlicensed .
However, our findings were similar to a recent Australian inpatient study in Tasmania which
Drugs prescribed for 28 days
(n = 94 drugs)
(n = 533 drugs)
(n = 1302 drugs)
Drugs prescribed for 1218 years
(n = 725 drugs)
Note: Augmentin Duo (amoxicillin/ clavulanic acid); Painstop Day (paracetamol/ codeine phosphate)
reported 31.8% of drugs as off-label . The results of the current study were different to
those from a previous Australian study conducted in a neonatal intensive care unit more than
10 years ago, which reported 47% of drugs as off-label and 11% as unlicensed, with 80% of
infants prescribed either an off-label or unlicensed drug . The percentage of patients
prescribed off-label or unlicensed drugs in the current study (36.5%) was similar to a previous
Princess Margaret Hospital study but less than the 57.3% reported in a recent study in
The difference in the age of patients in O'Donnell's study  (gestational age of 22.7 to 41.4
weeks) and other Australian studies involving a wider age range of patients, such as Turner's
study  (in which the age ranged from 49 days to 18 years), Ballard's study  (in which
the age ranged from one day to 11 years) and the current study (age zero to 18.4 years), makes
a direct comparison of rates inappropriate with other Australian studies. However, in the
current study, when only inpatient neonates aged zero to 27 days were considered, despite some
being slightly older than in O'Donnell's study, the extent of off-label prescribing was 83.3%
which was considerably higher than the overall study result. Although the number of inpatients
in this group was small (n = 12), the finding suggests that by comparing specific patients
groups, including specific age groups, the extent of off-label prescribing reported is highly
variable. In addition, limiting the age range to lower age groups would give a higher likelihood of
an off-label classification, especially with respect to age. Neonates are treated on birth at
Reason for off-label prescribing
another hospital in Western Australia unless they have been discharged in which case they
would be expected to attend this hospital. This may explain the lower number in this sample.
The prevalence of off-label and unlicensed prescriptions in this study was lower than those
reported in several overseas studies in the UK (55% and 10%) , Sweden, Italy, Germany,
Netherlands (39% and 7%) , the Netherlands alone (44% and 28%) , Switzerland (25%
and 24%) , France (63% and 10%) , Israel (59% and 16%)  and Malaysia (34% and
27%) . However, the current findings were similar to a study in Germany which reported
26.3% off-label and 0.4% unlicensed prescribing . The percentage of off-label prescribing in
this study was also similar to the 30.5% reported by Hsien et al  in Germany. Other studies
that reported lower off-label or unlicensed prescribing included studies in Israel (26% and 8%)
, UK (18% and 7%)  and Croatia (12% and 13%) .
A contributing factor to the lower percentages of off-label and unlicensed prescribing
reported in this study is that data were collected across all settings at Princess Margaret Hospital.
To the best of our knowledge, no previous study has investigated off-label and unlicensed
prescribing collectively in inpatients, outpatients and Emergency Department patients. Most
studies, including those in Australia, have been conducted in a selected setting e.g. Emergency
Department patients, medical or surgical wards or Intensive care units or outpatients and some
have included only neonates or children of specific age groups.
Although the overall extent of off-label and unlicensed prescribing in this study was lower
than many published studies, by selecting only specific groups of patients such as inpatients, it
was found that off-label and unlicensed prescribing occurred to a greater extent in this group
than in any of the other settings, with 77.3% of females and 77.8% of males prescribed one or
more off-label or unlicensed drugs. The percentages were much lower for Emergency
Department patients (29.2% of males and 26.4% of females) and outpatients (18.7% of males and
16.8% of females). The differences in the proportions of patients prescribed off-label and
unlicensed drugs in the different settings was statistically significant (p < 0.0001). More off-label
and unlicensed drugs were prescribed to inpatients (30.7%) compared to outpatients (20.7%)
and Emergency Department patients (28.5%) (Table 3).
When specific age groups were analysed, off-label and unlicensed prescribing was more
prevalent in neonates (n = 12; 60.0%) with 55% prescribed off-label drugs and 5% prescribed
both off-label and unlicensed drugs. However, the sample size (20 patients) was small and the
majority of neonates (60.0%) were inpatients. A high percentage of off-label and unlicensed
drugs were also prescribed to infants (n = 108; 38.8%) and children (38.2%) (n = 200; 38.2%)
compared to adolescents (n = 58; 27.0%). These differences were statistically significant overall
(p = 0.0080), with the difference being entirely attributable to the lower rate in adolescents
(infants vs adolescents p = 0.0059; children vs adolescents p = 0.0039, infants vs children
p = 0.8503). This analysis confirms that children under 12 years of age are less likely to be
included in the license specifications than adolescents (1218 years of age).
Inpatients were prescribed between zero and 21 drugs, Emergency Department patients
between zero and 16 drugs and outpatients between zero and 12 drugs. The median number of
drugs prescribed was one drug for both Emergency Department patients and outpatients and
five drugs for inpatients (overall study median was one drug). One reason for a higher median
number of drugs for inpatients was that very few inpatients were prescribed no drugs (4.7%)
compared to Emergency Department patients (38.0%) and outpatients (45.5%). This was
similar to findings reported from an inpatient study in Tasmania, in which only 20 of 300 patients
(6.7%) were prescribed no drugs . The difference in the number of drugs prescribed in each
setting was significant (p < 0.0001). There is variable reporting of patients who receive
offlabel or unlicensed drugs because some studies include patients that receive no drugs and
others omit them from the calculation.
The overall median number of drugs prescribed in this study was lower than the median of
four drugs reported by Turner . However, Turner's study was conducted on inpatients and
in this study, when only inpatients were considered, the median number of drugs (five) was
slightly higher than reported by Turner (four). A contributing factor to these differences may
be that Turner's study involved only two wards (a surgical and a medical ward) whereas in this
study, patients were randomly selected from all inpatient wards at Princess Margaret Hospital.
Furthermore, a recent study in Finland comparing prescribing trends in 2001 and 2011 also
reported an increase in the median number of prescriptions after 10 years .
Overall, the most common Anatomical Therapeutic Chemical classification categories were
the nervous system, alimentary tract and metabolism and anti-infectives for systemic use. Of
the 10 most commonly prescribed drugs, half were analgesics/ antipyretics from the nervous
system category (paracetamol, ibuprofen, Painstop Day, morphine and oxycodone). Several of
these drugs, including paracetamol, ibuprofen, oxycodone and morphine, have been reported
as commonly prescribed drugs in other studies [7, 10, 15, 17, 19, 23, 29]. In a previous study at
Princess Margaret Hospital, Turner reported that paracetamol and morphine were commonly
The most common reasons for off-label prescribing were dosage (47.4%) and age (43.2%).
Many other researchers have also reported that the most common reason for off-label
prescribing was dose and/ or dose frequency [5, 7, 15, 16, 1820, 23, 3032]. The percentage of off-label
prescribing in this study due to dosage may have been higher but since the hierarchical
classification by Hsien et al.  was used, once drugs were classified into a category above dosage (i.e.
age, indication and route of administration) they were then not considered for
Differences in study design and the variations in definition of the term "off-label" and
"unlicensed" can make a direct comparison between studies inappropriate. For example, Santos
et al.  reported that the most frequent reason for unlicensed medications was that ''safety
and efficacy have not been established in children''. Most other researchers classified this
situation as off-label rather than unlicensed  .
Approximately 35% of current prescribing to inpatient children and 28% for all categories
of patients are prescribed drugs outside of the license requirements and therefore the efficacy
and safety data associated with the use of these drugs in these populations is limited or
non-existent It is notable that most of the drugs identified as off-label or unlicensed have been
available for many years. The Therapeutics Goods Administration in Australia and regulatory
authorities in many other countries require the sponsor to seek amendments to the Product
Information data. This requirement therefore discourages any changes being submitted for
changes to the registration details when off-label prescribing for such an indication enables
patient access to the drug. A new approach could involve the establishment of an expert group to
assess clinical trials reported for indications, dosages, age and route of administration. If data
was assessed as efficacious and safe it should then be included in the Product Information.
Some registration authorities are encouraging trials in paediatric groups for new drugs.
However, currently long standing drugs are responsible for most of the current problematic situation.
These studies could be distributed around the harmonised government agencies and
potentially contribute to paediatric public health.
Limitations of This Study
There were several limitations to this study. This study involved only a single centre which was
a tertiary care centre. It is possible that in a tertiary care paediatric hospital (with a great
proportion of complex cases) the rate of off-label prescribing is higher than in a community/
regional hospital. Further, there were few neonates as they were initially treated at another
hospital. Therefore, this group is under-represented in the sample, so that conclusions regarding
the small number of study patients in this group should be interpreted with caution.
Not all charts were available during the study period although every effort was made to
access the charts. It was also expected that more patients would be prescribed psychotherapeutic
drugs than found in the sample. A reason might be that some of these may have been child
protection cases or they may have been on the ward at the time of data collection, in which case
their medical record would not have been available for the study.
There were limitations with the hierarchical classification system because in a number of
cases, if a hierarchical approach had not been used, the proportion of drugs classified as
offlabel due to indication, route of administration or dose would have been higher. The
classification system may have led to a lower proportion of unlicensed drugs being reported. In some
categories there are very low levels of unlicensed prescribing and hence an even larger sample
would be necessary to provide more confidence in these estimates.
The use of off-label and unlicensed prescribing was found to be high at Princess Margaret
Hospital with an overall prevalence of 28.3%. The percentage of patients prescribed at least one
offlabel or unlicensed drug was 36.5% with a high percentage of off-label prescribing associated
with nervous system drugs. The highest percentage of unlicensed prescribing was with systemic
hormonal preparations excluding sex hormones.
This study provides the first data on the prevalence of off-label and unlicensed prescribing
across all three main hospital settings.
These findings indicate that more than one-third of patients are being exposed to medicines
for which prescribing information is not licensed in the Product Information. Children are
considered a vulnerable group of patients and governments around the world need to be aware
of the potential public health risk from these findings.
It is recommended that a government sponsored group of experts should rigorously
consolidate and evaluate the quality of evidence for the prescribing of the common off-label drugs
identified in this study. Where there are notable deficiencies studies are recommended to
provide an adequate evidence-base for their prescribing so that they can be provided in a legally
sanctioned manner or the licensed Product Information amended accordingly.
The assistance of Vandana Chandini with some of the data collection from Princess Margaret
Hospital is gratefully acknowledged.
Conceived and designed the experiments: PC BS LB. Performed the experiments: LF PC.
Analyzed the data: RP PC. Contributed reagents/materials/analysis tools: LB LF PC. Wrote the
paper: PC RP JH BS.
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