S H O R T R E S E A R C H R E P O R T

Unlicensed and off-label use of medicines in children admitted
to the intensive care units of a hospital in Malaysia

Jian Lynn Lee

•

Adyani Md Redzuan

•

Noraida Mohamed Shah

Received: 14 May 2013 / Accepted: 27 August 2013 / Published online: 11 September 2013
 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2013

Abstract

Background Unlicensed and off-label use of

medicines in paediatrics is widespread. However, the
incidence of this practice in Malaysia has not been repor-
ted. Objective To determine the extent of unlicensed and
off-label use of medicines in hospitalised children in the
intensive care units of a tertiary care teaching hospital.
Methods A prospective, observational exploratory study
was conducted on medicines prescribed to children
admitted to the 3 intensive care units of Universiti Ke-
bangsaan Malaysia Medical Centre (UKMMC). Results A
total of 194 patients were admitted to UKMMC, 168 of
them received one or more drugs. Of 1,295 prescriptions,
353 (27.3 %) were unlicensed and 442 (34.1 %) were for
off-label use. Forty-four percent of patients received at
least one medicine for unlicensed use and 82.1 % received
at least one medicine off-label. Preterm infants, children
aged 28 days to 23 months, patients with hospital stays of
more than 2 weeks, and those prescribed increasing num-
bers of medicines were more likely to receive medicines
for unlicensed use. Term neonates and patients prescribed
increasing numbers of medicines had increased risk of
receiving medicines for off-label use. Conclusion Pre-
scribing of medicines in an unlicensed or off-label fashion
to the children in the intensive care units of UKMMC was
common. Further detailed studies are necessary to ensure
the delivery of safe and effective medicines to children.

Keywords

Drug information

Hospitalised

children

Intensive care unit
Malaysia
Off-label

prescribing

Unlicensed prescribing

Impacts on practice

•

Almost half of the children in the paediatric and neo-
natal intensive care units at a tertiary care teaching
hospital in Malaysia received at least one medicine that
is not licensed for them.

•

A vast majority of the children in the paediatric and
neonatal intensive care units at a tertiary care teaching
hospital in Malaysia received at least one medicine in
an off-label manner.

•

The common use of unlicensed and off-label medicines
in the paediatric and neonatal intensive care units at a
tertiary care teaching hospital in Malaysia, highlights the
need for well-designed clinical trials to ensure availabil-
ity of safe and effective medicines for use in that setting.

Introduction

Hospitalised children are exposed to many types of medi-
cations. However, many of these are often either not
licensed or are used in an off-label manner. According to
Turner et al. [

1

], the definition of unlicensed drug use is the

use of medicines without a product license or marketing
authorisation, whereas off-label drug use is defined as the
use of licensed medicines outside of the terms of their
product license or marketing authorisation with regards to
the dose, indication, age, and route of administration, as
well as contraindicated drug use. This manner of pre-
scribing was not a serious concern until evidence started to
show that the physiological response of children to many
drugs differed significantly from that of adults. For exam-
ple, after the use of chloramphenicol in neonates, grey baby
syndrome may occur [

2

]. Also, there is a high incidence of

kernicterus among premature neonates after receiving

J. L. Lee

A. Md Redzuan
N. Mohamed Shah (

&)

Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan
Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
e-mail: [e-mail]

123

Int J Clin Pharm (2013) 35:1025–1029

DOI 10.1007/s11096-013-9846-0

sulphonamide antibiotics [

3

]. Both of these disorders are

not observed in adults taking the same medications.
Although there have been major advancements in paedi-
atric clinical pharmacology, information on the pharma-
cokinetics and pharmacodynamics of therapeutics in
children is still lacking [

4

]. The lack of evidence-based

medicine in children results in uncertainty in determining
the optimal dose, hence leading to potentially reduced
efficacy of treatment and unexpected adverse drug reac-
tions (ADRs). In general, it is currently not illegal to pre-
scribe an unlicensed or off-label medicine to children, and
in some cases it may be entirely appropriate; however, it
does bypass the drug regulatory process and places a
greater responsibility on the prescriber [

4

].

The extent of unlicensed and off-label use of medicines

in paediatrics has been quantified in studies from the
United States [

5

], United Kingdom [

1

–

6

], Europe [

7

–

10

],

South Asia [

11

], Australia [

12

], and the Middle East [

13

].

Majority of these studies showed a high percentage of
unlicensed and off-label drug use, with the situation
varying between countries. This is probably due to national
differences in the licensing status of drugs, reference
sources used, and clinical practices. To date, the incidence
of this practice in Malaysia has not been reported.

Aim of the study

To collect detailed information on prescribed drugs in the
intensive care units, in order to estimate the use of off-label
and unlicensed medication among hospitalised children
and to identify factors associated with unlicensed and off-
label prescribing.

Methods

Data regarding medicines prescribed to children admitted to
the paediatric intensive care unit (PICU), paediatric high
dependency unit (PHDU; aged 28 days to 18 years), and
neonatal intensive care unit (NICU; preterm neonates, ges-
tational age \37 weeks and term neonates, gestational age
C37 weeks; ages 0–27 days) of Universiti Kebangsaan
Malaysia Medical Centre (UKMMC) from April 16 to June
10, 2012 were collected. Patients who did not receive any
prescriptions were excluded from the analysis. Prescriptions
solely for total parenteral nutrition (TPN), blood products,
standard intravenous fluids, plasma substitutes, oxygen
therapy, eye drops, ear drops, nasal preparations, gargles,
and topical creams and ointments were also excluded. This
was in keeping with most of the published work in this area.

Using a structured data collection form, patient demo-

graphics (gender, race, weight, height, date of birth, age,

gestational age), diagnosis, admission and discharge dates,
and details of drugs prescribed (name, dose, frequency,
route of administration, indication) were recorded. All data
were collected from the patients’ medical records and
medication charts. Any uncertainty in the indication of the
drugs prescribed was clarified with the medical officer.

For each patient, all medicines prescribed during the

study period were checked against their approved use,
which was determined using the Pharmacy Information
System (PHIS) of UKMMC and the database of the
National Pharmaceutical Control Bureau (NPCB), Ministry
of Health (MOH) [

14

]. Any discrepancies were clarified

with the drug information pharmacist at UKMMC. The
database of NPCB consists of the list of drugs registered by
the Drug Control Authority, Ministry of Health Malaysia.

All medicines were analysed for off-label use with ref-

erence to the prescribing information of the specific brand
of the medicine as stated in the Master Index of Medical
Specialities (MIMS) Drug Information System (DIS)
Malaysia [

15

]. If no information was available on the

specific generic brand, prescribing information of the drug
was obtained from the package insert of other generic
pharmaceutical companies listed in the MIMS. In general,
drug information between the generic companies is the
same or may only have minor differences to have an effect
on the categorisation of off-label.

All information recorded in the data collection form was

analysed using statistical software (SPSS



version 16.0) for

descriptive analysis to determine the extent of unlicensed
and off-label use of medicines. Binary logistic regression
analysis to predict the odds of a child receiving an unli-
censed or off-label prescription with several possible risk
predictors was performed. Risk factors investigated were
age, length of hospital stay, and number of medications
prescribed. This study was approved by the Research Ethics
Committee of UKMMC (UKM 1.5.3.5/244/NF-003-2012).

Results

During the 8-week study period, a total of 194 paediatric
patients were admitted to the 3 ICUs at UKMMC, 168
received at least one drug. The median age of the study
population was 2 years, with 60.1 % boys. A summary of
other patients’ background information is presented in
Table

1

.

A total of 1,295 drug prescriptions for 119 different drugs

were prescribed during the study period. The median number
of medicines prescribed per child was 4 (range 1–52). Out of
the 1,295 prescriptions, 353 (27.3 %) were unlicensed and
442 (34.1 %) were off-label. Based on the number of patients
who received one or more medicines, 155 (92.4 %) received
at least one unlicensed or off-label medicine, 74 (44.0 %)

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Int J Clin Pharm (2013) 35:1025–1029

123

received at least one unlicensed medicine, 138 (82.1 %)
received at least one off-label medicine, and 57 (33.9 %)
received both unlicensed and off-label medicines.

There were only 2 categories of unlicensed medicine

used, in which a total of 353 prescriptions were identified.
The most frequently prescribed category of unlicensed
medicines was extemporaneously prepared medicines
(75.6 %), followed by imported medicines not licensed in
Malaysia (24.4 %). A total of 442 prescriptions were
identified as being prescribed off-label. Medicines pre-
scribed outside the licensed age range was the most com-
mon reason for off-label prescribing (37.1 %), followed by
prescriptions that were for doses higher than the licensed
dose (21.3 %) and unlicensed indications (19.9 %).

Preterm neonates (ages 0–27 days) and infants and toddlers

(ages 28 days to 23 months) were more likely to receive an
unlicensed prescription (OR 14.00; 95 % CI 2.08–94.40;
p = 0.007 and OR 7.70; 95 % CI 1.47–40.22; p = 0.016,
respectively). A longer stay in the hospital increased the

likelihood of receiving at least one unlicensed medicine;
patients staying more than 14 days were approximately 8
times more likely to receive an unlicensed prescription (OR
7.78; 95 % CI 1.72–35.31; p = 0.008). Analysis also showed
that there was an 84 % increase in the odds of receiving an
unlicensed medicine (OR 1.84; 95 % CI 1.41–2.40;
p

\ 0.001) with every unit increase in the number of medi-

cines prescribed. In the present study, term neonates were more
likely to receive an off-label medicine than preterm neonates
(OR 11.78; 95 % CI 2.16–64.30; p = 0.004). Similarly, the
likelihood of a child receiving an off-label prescription
increased with the increasing number of medicines prescribed
(OR 1.29; 95 % CI 1.08–1.53; p = 0.004; Table

2

).

Discussion

In this present survey, 27.3 and 34.1 % of prescriptions
were found to be unlicensed and off-label, respectively.

Table 1

Patient demographics and unlicensed and off-label prescribing pattern according to wards

PICU

PHDU

NICU

No. of patients, n

27

55

86

Male

18

35

48

Female

9

20

37

Ambiguous

–

–

1

Age range

2 months–16 years

1 months–13 years

1–28 days

Median age

3 years

1.5 years

1 day

Common diagnoses

Diseases of the respiratory

system (30.0 %)

Diseases of the respiratory

system (31.7 %)

Certain conditions

originating in the
perinatal period
(86.3 %)

No. of prescriptions

268 (20.7)

345 (26.6)

682 (52.7)

No. of unlicensed prescriptions (%)

40 (14.9)

77 (22.3)

236 (34.6)

Extemporaneous preparation (%)

36 (90.0)

63 (81.8)

168 (71.2)

Unregistered product (%)

4 (10.0)

14 (18.2)

68 (28.8)

No. of off-label prescriptions (%)

85 (31.7)

105 (30.4)

252 (37.0)

No. information in children (%)

19 (22.4)

5 (4.8)

13 (5.2)

Unlicensed indication (%)

19 (22.4)

15 (14.3)

54 (21.4)

Unlicensed age range (%)

32 (37.6)

46 (43.8)

86 (34.1)

Unlicensed route of administration (%)

1 (1.2)

1 (1.0)

–

Lower than licensed dose (%)

3 (3.5)

17 (16.2)

21 (8.3)

Higher than licensed dose (%)

5 (5.9)

13 (12.4)

76 (30.2)

Less frequent than licensed frequency (%)

2 (2.4)

–

–

More frequent than licensed frequency (%)

4 (4.7)

8 (7.6)

2 (0.8)

No. of admissions with at least 1 unlicensed

medicine prescribed (%)

13 (48.1)

22 (40.0)

39 (45.3)

No. of admissions with at least 1 off-label

medicine prescribed (%)

20 (74.1)

40 (72.7)

78 (90.7)

Three most common unlicensed prescriptions

Ferric ammonium citrate [ caffeine anhydrous solution [ folic acid syrup

Three most common off-label prescriptions

Gentamicin injection [ paracetamol syrup [ glycerine suppository

Int J Clin Pharm (2013) 35:1025–1029

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123

These proportions were within the ranges that have been
reported in the literature for other countries (6.9–48 and
18–70.6 % for unlicensed and off-label uses, respectively)
[

1

,

6

–

13

].

More than three quarter of the unlicensed medicines

used in the present study were extemporaneously prepared.
Such practice is inevitable due to the lack of liquid prep-
aration suitable for administration to children unable to
take solid dosage forms. However, this may lead to the risk
of sub-optimal dosing and may jeopardise the child’s safety
due to reduced quality of the formulation, uncertain sta-
bility and modified bioavailability [

16

]. The present study

highlighted the need to develop suitable liquid preparation
for ferric ammonium citrate and folic acid to be adminis-
tered in children, as these medicines were found to be
commonly prepared extemporaneously (see Table

1

).

The most common category of off-label prescribing was

the use of medicines outside of their licensed age range

(37.1 %), followed by the use of medicines at higher doses
than the licensed dose (21.3 %) and unlicensed indications
(19.9 %). These reasons were similar to the findings of
other studies [

1

,

7

]. Injection of gentamicin, a drug rou-

tinely prescribed in the NICU, was the most frequently
prescribed off-label medicine (13.1 %) because the dose
prescribed was higher than the licensed dose. Similar
findings were reported by Conroy et al. [

6

] and Dessi et al.

[

9

], where gentamicin was used off-label due to the higher

than licensed dose and prescribed at a lower than the
licensed frequency.

The results of the current survey showed that children

younger than 2 years of age were more likely to receive
an unlicensed medication when compared to older
children. This finding was similar to the study by
Khdour et al. [

13

], which showed that infants aged

0–1 year are at risk of receiving unlicensed or off-label
medicine.

Table 2

Predictors for receiving at least one unlicensed and off-label medicine

Parameter

B

SE

p value

Odds ratio (OR)

95 % CI for OR

Upper

Lower

Predictors for receiving an unlicensed prescription

Age

Preterm 0–27 days

2.639

0.974

0.007*

14.001

2.077

94.395

Term 0–27 days

1.438

1.017

0.158

4.213

0.573

30.948

28 days–23 months

2.041

0.843

0.016*

7.701

1.474

40.223

12–18 years

0.037

1.426

0.979

1.038

0.063

16.991

2–11 years (reference)

Length of hospital stay (days)

1–3 (reference)

4–7

-0.136

0.664

0.838

0.873

0.237

3.209

8–14

0.326

0.812

0.688

1.386

0.282

6.812

15 and above

2.052

0.772

0.008*

7.782

1.715

35.313

Number of medicines prescribed

0.609

0.136

\0.001*

1.839

1.409

2.401

Predictors for receiving an off-label prescription

Age

Preterm 0–27 days

1.221

0.710

0.085

3.390

0.844

13.624

Term 0–27 days

2.466

0.866

0.004*

11.775

2.156

64.302

28 days–23 months

0.102

0.573

0.859

1.107

0.360

3.403

12–18 years

-0.381

1.182

0.747

0.683

0.067

6.925

2–11 years (reference)

Length of hospital stay (days)

1–3 (reference)

4–7

0.175

0.576

0.762

1.191

0.385

3.680

8–14

0.963

1.155

0.404

2.619

0.272

25.188

15 and above

-0.681

0.689

0.323

0.506

0.131

1.952

Number of medicines prescribed

0.252

0.087

0.004*

1.287

1.084

1.527

* Statistically significant result, p \ 0.05

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123

Among the limitations of this study included the fact

that the current study was only carried out in 3 paediatric/
neonatal intensive care units at one institution (UKMMC).
Hence, these findings may not necessarily be generalised to
paediatric populations at other hospitals in Malaysia.

Conclusion

The use of unlicensed medicine and the off-label use of
medicines in hospitalised children at the intensive care units
of UKMMC is widespread. Age (i.e., preterm neonates,
infants, and toddlers ages less than 2 years old), length of
hospital stay, and number of medicines prescribed were risk
factors for receiving unlicensed and/or off-label prescrip-
tions. In our population, this practise was common among
paediatric patients admitted to intensive care units. Further
studies are required to quantify the extent of unlicensed and
off-label drug use in the more routine settings of general
paediatric wards and the community. This information
should then be used to increase the awareness of this issue
and to advocate to the Malaysian regulatory body the needs
to develop strategies to improve the range of available
paediatric formulations.

Acknowledgments

The authors would like to thank Dr. Juriza Is-

mail, paediatrician at the UKMMC for her assistance in this research.
Special thanks to the staff of the PICU, PHDU and NICU, UKMMC
for the support throughout the research.

Funding

No funding was received for this research.

Conflicts of interest

No conflicts of interest to declare.

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