Children & Medicine - FP Book1

A FocAl point leArning progrAmme
CHILDREN AND THEIR MEDICINES:

ENHANCING YOUR PRACTICE
BOOK 1
March 2012 CENTRE FOR PHARMACY
FP115/1 P O S T G R A D U AT E E D U C AT I O N
Content contributors
Brian Conn, local tutor, CPPE
focal point Children and their medicines: enhancing your practice – Book 1
Sharon Conroy, lecturer in paediatric clinical pharmacy, University of Nottingham

Nishma Khetani, pharmacist, Lloydspharmacy
Zoe Lansdowne, specialist pharmacist, child health, University Hospital Southampton NHS Foundation Trust
Bhavna Patni, pharmacy proprietor, Allens Pharmacy
Steve Tomlin, consultant pharmacist for children’s services, Evelina Children’s Hospital, Guy’s and
St Thomas’ NHS Foundation Trust
Helen Williamson, specialist research and development pharmacist, Birmingham Children’s Hospital NHS
Foundation Trust
This programme uses some of the content from NHS Education Scotland programme, Introduction to
paediatric pharmaceutical care, and the CPPE open learning programme, Child health: working with the National
Service Framework for children, young people and maternity services. CPPE recognises the contribution made by
the authors and reviewers.
CPPE programme developer

Alison Levine, learning development pharmacist
Reviewers
Emma Gilchrist, senior paediatric pharmacist, Evelina Children’s Hospital, Guy’s and St Thomas’ NHS
Foundation Trust
Steve Tomlin, consultant pharmacist for children’s services, Evelina Children’s Hospital, Guy’s and
St Thomas’ NHS Foundation Trust
CPPE reviewers
Suzanne Cutler, regional manager, North West
Karen Wragg, regional manager, South Central
Piloted by
Angela Brockbank, local tutor, CPPE
Disclaimer
We have developed this learning programme to support your practice in this topic area. We recommend that
you use it in combination with other established reference sources. If you are using it significantly after the date
of initial publication, then you should refer to current published evidence. CPPE does not accept responsibility
for any errors or omissions.
External websites
CPPE is not responsible for the content of any non-CPPE websites mentioned in this programme or for the
accuracy of any information to be found there.
All weblinks were last accessed on 15 February 2012.
Brand names and trademarks

CPPE acknowledges the following brand names and registered trademarks mentioned throughout this
programme: Clenil Modulite®, Losec® MUPS®, Serevent® and Volumatic®.
Published in March 2012 by the Centre for Pharmacy Postgraduate Education, School of Pharmacy and
Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT
http://www.cppe.ac.uk
Production
Design and artwork by Ambassador
Printed by Gemini Press Ltd
2 Printed on FSC® certified paper stocks using vegetable based inks.

Contents
Learning with CPPE 4
About CPPE focal point programmes 5
About this focal point unit on children and their medicines 5
Learning objectives 6
Checklist for planning 7
Moving into focus 8
What do you want to learn? 9
Reading, practice points and talking points 10
Directing change 45
Checklist for action 46
References 47
3
Learning with CPPE
The Centre for Pharmacy Postgraduate Education (CPPE) offers a wide range of
learning opportunities for the pharmacy workforce. We are based in the University of
Manchester’s School of Pharmacy and Pharmaceutical Sciences and are funded by
the Department of Health to provide continuing education for practising
pharmacists and pharmacy technicians providing NHS services in England. For
further information about our learning portfolio, visit http://www.cppe.ac.uk.
We recognise that people have different levels of knowledge and not every CPPE
programme is suitable for every pharmacist or pharmacy technician. We have
created three categories of learning to cater for these differing needs:
Core learning (limited expectation of prior knowledge)
Application of knowledge (assumes prior learning)
Supporting specialties (CPPE may not be the provider and will direct you
to other appropriate learning providers).
This is a learning programme and assumes that you already have some
knowledge of the topic area.
Continuing professional development (CPD) – You can use this focal point unit to
support your CPD. Consider what your learning needs are in this area. Use your
CPD record sheets to plan and record your learning.
Programme guardians – A programme guardian is a recognised expert in an area

relevant to the content of a learning programme. They will review the programme
every six months to ensure quality is maintained. We will post any alterations or
further supporting materials that are needed as an update on our website. We
recommend that you check for these updates if you are using a programme more
than six months after its initial publication date.
Feedback – We hope you find this learning programme useful for your practice.
Please help us to assess its value and effectiveness by visiting the my CPPE record
page on our website. Alternatively, please email us at feedback@cppe.ac.uk.
4
About CPPE focal point programmes
We have developed focal point to give you short, clinically focused learning sessions.
It will help you learn with your colleagues and improve the services you offer your
patients. Each unit presents information and activities that are relevant for pharmacy
professionals working in primary care and in the community. There are two types of
learning event for you to choose between when using focal point units – you can
either attend a CPPE tutor-led event or can learn as part of a CPPE ‘learning
community’. Have a look at the CPPE website (http://www.cppe.ac.uk/) for more
information about how to set up a learning community.
Reference sources for all the books, articles, reports and websites mentioned in the
text can be found at the end of the programme. References are indicated in the text
by a superscript number (like this 3).
This book gets you started. It provides key information to help you meet the
learning objectives presented overleaf, but it also encourages you to identify your
own learning needs. It then challenges you to relate what you have learnt to your
own area of practice and professional development. We have included practice points
and talking points to stimulate your thinking and we will refer to these again at the
focal point event. Make sure you have studied these activities before your event.
You will receive Book 2 when you attend the focal point event. It uses a case study
and ‘clinical vignettes’ to help you apply what you have learnt and includes a
Directing change section that offers a framework to encourage you to make changes
to improve your practice. We also include some suggested answers to the learning
activities.
About this focal point unit on

children and their medicines
In this unit we consider:
n the differences in drug handling and effects between children and adults
n the use of unlicensed and off-label medicines in children and the role of the
pharmacy team in their use
n a holistic approach to the treatment of children with long-term conditions
n appropriate and effective communication with children and their parents or carers
to ensure safe and effective use of medicines
n approaches that can be implemented to ensure safe medicines use in children
n information sources useful in dealing with paediatric patients. 5
Learning objectives
You can meet the learning objectives that we identify here by reading the
information that we provide and refer you to, undertaking the various activities that
we suggest and putting what you have learnt into practice. We have split our learning
objectives into appropriate sections. This should help you determine how to meet
them. We have also linked the learning objectives in this programme to the General
Level Framework (GLF) and the NHS Knowledge and Skills Framework (KSF)
dimensions. We have suggested some competences, but you may be able to apply
your learning to other aspects of these frameworks.
Moving into focus and Reading

Objective KSF GLF
Explain the differences in HWB 7 Cluster: Delivery of patient care

drug handling and effects Level 2 Competency: Drug specific
between children and adults issues
Discuss the licensing issues HWB 7 Cluster: Delivery of patient care

that must be considered when Level 2 Competency: Drug specific
dealing with medicines in children issues
Implement a holistic approach HWB 6 Cluster: Delivery of patient care

to the treatment of children Level 3 Competency: Monitoring drug
with long-term conditions therapy
Communicate effectively with HWB 7 Cluster: Personal competencies

children and their parents Level 1 Competency: Effective
or carers communication skills
Recognise potential ways in HWB 1 Cluster: Problem solving

which children may be harmed Level 2 Competency: Analysing
by medicines, including information
medication errors and adverse
drug reactions
List useful information sources HWB 7 Cluster: Problem solving

with respect to dealing with Level 2 Competency: Gathering
paediatric patients information
6
Practice points, talking points, case study and clinical vignettes
Objective KSF GLF
Review your current approach HWB 6 Cluster: Delivery of patient care

to supporting children and Level 3 Competency: Patient information
identify ways in which you can and education
help them
Directing change and follow-up activities

Objective KSF GLF
Reflect on how you can Service Cluster: Management and

improve your practice with improvement organisation
regards to helping children Level 3 Competency: Service
development
Checklist for planning

To meet the learning objectives you will need to carry out the activities listed in the
table below. We’ve given you this list now so that you can start to plan your learning.
Although it will only take you about two and a half hours to work through Book 1,
feedback from other users suggests that it is useful to plan your activities over a
timescale that suits you – perhaps over several days. Try to set yourself a realistic
deadline for each task.
You will need to: This will take I will do this by:
about: (Insert date)
Answer the Moving into focus 5 minutes

questions
List three learning needs 5 minutes
Read the whole book 90 minutes
Undertake the practice points 20 minutes
Make notes for the talking points 10 minutes
Work through the 20 minutes

Directing change exercise
7
Moving into focus
Consider the following questions. Use them to focus your thoughts and stimulate
your learning. Are you confident you know the answers?
1. Can you give four examples of how drug handling in children differs from
drug handling in adults? List them here.
2. Do you have a responsibility to notify a child’s parent or carer that a drug they
have been prescribed is unlicensed?
3. What are the regulatory requirements of carrying out a medicines use review
in a child?
4. Medication errors are most commonly made when patients move between
primary and secondary care. What action can you take to reduce the risk?
5. Where could you access a patient information leaflet for a drug used off-label
in a child?
8
What do you want to learn?
Write down three things that you would like to gain from this focal point learning
unit. These will help you plan your own CPD entry. You will need to tell others
about them at the focal point event.
1.
2.
3.
Now you have completed your reflection and planning for this focal point unit, it’s
time to undertake the background reading.
9
Reading
The aim of this focal point programme is to help pharmacists and pharmacy
technicians enhance their care of children and management of their medicines.
Paediatric patients pose issues that are not commonly seen in adult patients. Issues
such as altered drug handling, use of unlicensed or off-label drugs and difficult
communication often make children a challenging patient group for community
pharmacists. This programme will help you consider how you can deal with such
issues and ultimately maximise your input into the care of children and the
management of their medicines.
1. Why children are different

There are many misconceptions about the use of medication
Children? They’re just in children and this one is particularly common. Although in
mini-adults who need the majority of cases the way in which children handle
smaller doses! medication is the same as in adults, this is not always the case.
It is important for members of the pharmacy team to be aware of
how children are different in comparison to adults (other than the
obvious: their weight!). This section provides important background
information which will underpin your understanding of these differences. For some,
these concepts will be new and for others they will be revision. However, this is an
excellent place for all to start when learning about the use of medication in children.
There are important differences in the pharmacokinetics British National Formulary

(absorption, distribution, metabolism and elimination) definitions of age
of certain drugs between adults and children which Neonate Birth to one month
Infant Up to one year
should be appreciated when considering the
Child 12 years or younger
appropriateness of doses for paediatric patients. It is also
(unless specified
important to understand why the recommended dose otherwise)
(mg/kg, mg/m2, etc.) and frequency of administration NB. A pragmatic approach must be
for many drugs differs between children and adults. applied to consider the child’s weight,
development and physiological
development.
1.1 Drug absorption
Drug absorption refers to how the drug is absorbed into the bloodstream and
applies to all routes of administration except for the intravenous route. There are two
important factors that must be considered in relation to how a drug is absorbed:
n rate of absorption
n extent of absorption.
The more rapidly a drug is absorbed, the higher the peak drug plasma concentration
10 will be and the sooner the required therapeutic effect (or side-effects) will be
experienced. The extent of absorption will determine the
Notes
level of exposure to the drug; anything that decreases
absorption will necessitate the administration of a larger dose
in order to achieve a therapeutic effect. Many routes of
absorption in children are similar to adults, but there are also
variations. Let us now look at the main differences in the
most common routes of administration.
Oral
There is some evidence to suggest that, in neonates and
young infants, gastric emptying and gastrointestinal transit
time may be prolonged (relative to adults and older
children), resulting in slower rates of absorption.1 Also,
reduced gastric acid secretion during the first few months of
life can affect the extent of absorption of some drugs.2
However, the available evidence suggests that the clinical
significance of these differences is small and that most orally
administered drugs will be absorbed into the systemic
circulation of children at a rate and extent similar to that
observed in healthy adults.
Increasing gastric acidity is the probable explanation of

improved phenobarbital absorption with increasing age
that has been demonstrated in children.3
Acute diarrhoea, which is particularly common during

childhood, may dramatically reduce the extent of drug
absorption by reducing the time that the drug remains in the
small intestine. If a child is receiving medicine for other
conditions while experiencing an attack of diarrhoea, you
should consider whether or not referral to their GP is
appropriate (for example, children taking antiepileptics or
immunosuppressants).
Rectal
The rectal route is useful when oral drug administration is
not possible (due to nausea, vomiting or seizure activity).
The longer the period for which any rectal dosage form is
retained, the greater the extent to which it is absorbed. For
this reason, solid as well as liquid preparations should be
placed well up into the rectal vault, but not so far that it
passes the absorption surface of the rectum.
11
The rate and extent of absorption of diazepam is improved when rectal solutions
rather than suppositories are used. The use of rectal solutions of diazepam is
preferred in children who have either febrile convulsions or recurrent, poorly
controlled epilepsy when immediate vascular access is not possible. However,
buccal midazolam is now generally used in preference to rectal diazepam.
Percutaneous
Percutaneous absorption of drugs occurs more readily in infants and young children
due to the immature epidermal barrier, increased skin hydration and a higher surface
area to body weight ratio.4 This has resulted in reported toxicities for a number of
compounds administered topically, including hexachlorophane, povidone-iodine,
chlorhexidine gluconate, boric acid, salicylic acid and corticosteroids.5
Liberal use of corticosteroid creams on the skin of newborn infants, especially if

they are pre-term, is generally avoided as it may lead to Cushingoid effects if
continued for more than a week, particularly if under occlusion (eg, under the
nappy).
Intramuscular
The intramuscular route of administration is usually avoided in children for several
good reasons. Firstly, it is very painful to administer intramuscularly if there is little
muscle mass (which is the case in young children). Secondly, muscle is poorly
perfused in infants and so good drug concentrations are unlikely to be reached.
This situation is used to good effect in newborn babies who are given vitamin K
immediately after birth to prevent haemorrhagic disease of the newborn.
Intramuscular administration of vitamin K provides a good depot effect for this

medicine over the first few weeks of life.
Immunisations are also administered by the intramuscular route. The thigh is the
preferred site of injection in children under one year of age.
1.2 Drug distribution

A further factor that determines the serum drug concentrations achieved following
administration of a given dose is the way in which the drug is distributed throughout
the various body fluids and tissues. This varies according to the physical
characteristics of the compound.
The composition of a newborn baby’s body is very different to that of an adult in

terms of body fat and water. The greatest changes in fat, total body water (TBW)
and extracellular water (ECW) occur during the first year of life.
12
Table 1: Extracellular fluid, TBW and fat volumes
Notes
according to age
Pre- Full- 4-6 1 Greater Adult
term term months year than
1 year
Extracellular 50% 45% 30% 25% 20-25% 20-25%

fluid volume
TBW 85% 75% 60%
Fat content 3% 12% 30% 18%
Such changes in body composition can affect the apparent

volume of distribution of a drug. For example, theophylline,
which is distributed in ECW, and the aminoglycosides that
are distributed in TBW have greater volumes of distribution
in neonates and infants. Loading doses need to be increased
to take account of this.
Another determinant of drug distribution is the extent to

which the drug is bound to protein. Binding to proteins
within the blood may be less in neonates and infants, as
serum albumin and total protein concentrations are lower.
Increased competition for binding sites from high levels of
bilirubin and the free fatty acids seen in infants and neonates
further increase the proportion of free drug.
Plasma levels of phenytoin do not need to be as high in

infancy as more of the phenytoin is unbound and thus
active to be effective (and toxic). The normal range in
neonates is 6-15 mg/L, compared to 10-20 mg/L for
children and adults.
The high level of neonatal bilirubin is mostly bound to

albumin. Administration of drugs such as sulphonamides,
which bind extensively to serum albumin, will result in
competition for the limited number of binding sites, causing
displacement of some bilirubin. This can then cross the
blood-brain barrier into the central nervous system, causing
nerve cell degeneration – a condition known as kernicterus.
Due to widespread awareness of the problem, this is now a
rare situation.
13
1.3 Drug metabolism
The final determinant of drug plasma concentrations is the ability of the child to
remove the drug from the body. This will normally involve metabolism and/or
excretion of unchanged drug in urine. The primary organ for drug metabolism is the
liver. At birth, the ability of this organ to metabolise drugs is not fully developed.
The liver metabolises drugs in a number of different ways which are classed as either
hepatic phase I reactions or hepatic phase II reactions. The capacity of the liver to
carry out these reactions is dependent on the age of the child.
Table 2: Hepatic phase I and II reactions
Types of reaction Effect of age
Hepatic phase I Oxidation, reduction, Mature over first few months of life
hydrolysis Adult levels reached at six months
Hepatic phase II Acetylation, Increase significantly over first two

glucuronidation to three months of life. Adult levels
reached at about three years of age
Sulphate conjugation, Present at birth at similar levels to

glycine conjugation those found in adults
The immaturity of this pathway in infancy can lead to significantly extended half-
lives of hydroxylated drugs, such as diazepam.
The metabolism of paracetamol

These differences in the development of different metabolic routes are reflected in
the metabolism of paracetamol, where sulphate and glucuronide conjugates
account for the elimination of the major part of the administered dose. Children
under the age of 12 years excrete more sulphate than glucuronide conjugates in
their urine, whereas glucuronide is the major metabolite excreted in those over the
age of 12 years.
However, values for the elimination half-life of paracetamol are similar in adults
and children but lower in newborn (especially premature) babies. In paracetamol
overdose, the conjugation pathways become saturated and increased amounts of a
reactive intermediate, that covalently binds to hepatocellular macromolecules, are
formed. The result is cell damage and necrosis. Despite the differences in
paracetamol metabolism in children, the risk of paracetamol hepatotoxicity is
probably the same as in adults. There are fewer reported cases in children, but this
probably reflects the fact that children generally ingest less of the drug than adults
and are brought for treatment earlier. There is also some evidence to suggest that
hepatotoxicity in malnourished children can result from therapeutic doses
14 administered chronically to patients with reduced glutathione stores.
1.4 Drug excretion
Notes
Glomerular filtration rate at birth is highly dependent on
gestational age, but increases rapidly over the first week of
postnatal life and reaches adult values (allowing for
differences in body size) by about three months of age.
Tubular secretory and resorptive capacity appears to mature
more slowly, approaching adult values at about seven months
of age.2
Chloramphenicol, if administered in the first few weeks
of life at the high doses used in older children, will
accumulate due to inadequate glucuronyl transferase
activity. In addition, any glucuronide that is formed will
also accumulate, due to inadequate development of the
renal tubular secretion mechanism. Reduced doses must
therefore be used in these babies and serum concentrations
closely monitored.6
Elimination half-lives
The half-life is the time the body takes to clear half of the
drug from the body. The elimination half-life of a drug is
determined both by the volume in which the drug is
distributed and by the ability of the eliminating organs (eg,
the liver and kidneys) to remove it from the blood. Because
of differences in drug distribution volumes and elimination
pathways in children, the elimination half-lives of many
drugs are shorter in children than in adults and neonates.
Table 3: Examples of drug half-lives
Drug Half-life Half-life

in children in adults
Phenobarbitone 36-72 hours 100 hours
Theophylline 4-6 hours 6-12 hours
15
1.5 Pharmacodynamics
There are also differences in the pharmacodynamics (how drugs exert their effects
on the body) of some drugs in children compared to adults. It is this aspect of
variance that makes extrapolation of data from adults even less certain and
potentially dangerous.
Children are far more likely to have extrapyramidal side-effects to metoclopramide

than adults, since the treatment dose for nausea is closer to the dose that causes
side-effects.
1.6 Checking doses

The Personal Child Health Record, commonly known as the ‘red book’, is issued to
every child in England. It is a record of health and progress and can be shared with
health professionals. The child’s weight (along with other information) is recorded in
the red book, and so the record serves as a useful resource for pharmacists when
checking the appropriateness of drug dosing.
14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
13.5 GIRLS WEIGHT (kg) 3 4 5 6 7 8 9 10 11
13.5
13 0 –1 year 13
Age in weeks/ months
12.5 99.6th 12.5
12 12
11.5 98th
11.5
11 11
10.5 Some degree of weight 91st 10.5

loss is common after birth.
10 10
Calculating the percentage
75th
9.5 weight loss is a useful way 9.5
to identify babies who
9
t
9 need extra support. 50th
8.5
8
e i g h 25th
9th
8.5
8
w
7.5 7.5
Weight (kg)
7 2nd 7
6.5 0.4th 6.5

th
.6
99
6 6
th
98
5.5 5.5
st
91
5 th
5
99.6th 75
4.5 th 4.5
98th 50
91st th
4 25 4
75th
9th
50th 3.5 d 3.5
2n
25th th
3 0.4 3
9th
2nd
2.5 2.5
0.4th
2 2
1.5 1.5
Age in weeks/ months 1
1
1 2 3 4 5 6 7 8 9 10 11
0.5 0.5
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
16 Used with permission from Harlow Printing

Practice point 1
Notes
Is the prescription below, for a three-year-old (weight
16 kg) for treatment of tonic-clonic seizures, within
the licensed dose?
Carbamazapine 100 mg / 5 mL liquid – 40 mg twice

daily for five days, then 80 mg twice daily for five
days, then 80 mg three times daily thereafter.
2. Licensing issues in children

In fact, the majority of medicines used
Most drugs used in in children are licensed and used within
children are unlicensed
– it’s an unavoidable the terms of that licence. Nevertheless,
situation. a study from the UK has shown that
11 percent of children treated at home by
their GP receive at least one unlicensed or
off-label drug.7
2.1 Background
Although many unlicensed and off-label drugs are initiated in
secondary or tertiary care, many of these patients are ultimately
managed in the community. Families often have problems
getting a prescription for further supplies from their GP, as
communication from the hospital regarding the drug,
indication, dose and formulation can be slow. Some GPs are
reluctant to prescribe the medicines due to cost and a lack of
familiarity with them.
For community pharmacy teams, problems arise when a family

arrives with a prescription, having completely or almost run out
of the medicine, as they may not appreciate that the medicine is
unlikely to be on the shelf and will need ordering. 17
Other challenges for pharmacists and pharmacy technicians include how the dose can
be checked for clinical appropriateness and how/where to procure the drug in time to
satisfy the family’s requirements. Community pharmacy teams also report a lack of
communication from secondary care and also from GPs.
After a number of drug-related tragedies,

legislation was passed in the US and the
UK in the 1960s. Substantial evidence was
subsequently required to prove that a drug
is safe and effective in the proposed
conditions for use before it can be
licensed. These legislative changes in drug
approval processes led to improvements in
the safety, efficacy and quality of drugs for
adult patients, but ironically created a situation where many medicines were no
longer recommended for use in children, due to insufficient clinical evidence being
available. This situation, which led to children being described as ‘therapeutic
orphans’,8 has still not dramatically improved.
Due to the lack of appropriate clinical evidence, children are often required to take
medicines which are either unlicensed (ie, they have not been subjected to the
licensing process) or off-label (ie, they are being used outside the terms of the
licence). Many manufacturers choose to write disclaimers stating that their products
should not be used in children, or make recommendations limited to specific age
groups, indications or routes of administration.
The same safety, efficacy and quality standards are not guaranteed for unlicensed or
off-label products, as they are not supported by the reassurances that the licensing
system was introduced to provide. This does not mean that unlicensed and off-label
prescribing implies inappropriate prescribing; sometimes the evidence to support
such use is considerable. Unlicensed and off-label prescribing is needed when there
is a lack of availability of medicines licensed for use in children and, consequently, a
lack of formulations which children can take in strengths appropriate to the dose
ranges required.
Professional ethical standards for prescribers and pharmacists require a licensed

product to be prescribed and dispensed where a suitable product is available.
Spironolactone is licensed for children, in a starting dose of 3 mg/kg body weight

daily in divided doses, but is only available as tablets (lowest strength: 25 mg).
This is completely inappropriate for providing a dose to a small baby who may
weigh as little as 2 kg. An unlicensed liquid preparation of spironolactone must
therefore be provided.
18
For some drugs, there are real and proven reasons why they
Notes
are not licensed in children. Examples include aspirin being
contraindicated for management of fever due to its link with
Reyes syndrome – a very serious condition leading to
neurological impairment or death. More commonly, however,
the lack of suitable licensed products is a result of the lack of
clinical trials due to costs.
Ethical, practical and technical problems of conducting

clinical trials in children make it more difficult, expensive and
time-consuming than in adults. EU legislation now requires
the pharmaceutical industry to conduct paediatric clinical
trials in children, if the drug is likely to be beneficial, in
return for six months’ extension to the product patent.9
2.2 Legalities of licensing

If a patient suffers harm due to a defect in a licensed medicine,
used in a licensed manner, then the pharmaceutical company
producing it will be vicariously liable. However, provision is
made in law and current regulations for doctors and non-
medical prescribers to prescribe, pharmacists to dispense and
nurses to administer unlicensed and off-label drugs. The
responsibility for this prescribing will, however, lie with the
prescriber. Pharmacists are responsible for the quality and
constituents of any unlicensed medicine provided to a patient.
Where possible, Certificates of Analysis or Conformity should
be obtained when purchasing unlicensed products - ideally, it is
expected that contractors will make every reasonable effort to
obtain one.
Statements from the Royal College of Paediatrics and Child

Health (RCPCH) and the Neonatal and Paediatric Pharmacists
Group (NPPG) in the UK and similar paediatric professional
bodies in the US stress that the informed use of unlicensed and
off-label medicines is necessary in paediatric practice.10,11 They
state that those who prescribe for a child should choose the
medicine which offers the best prospect of benefit for that
child, with due regard to cost. Practice should be in accordance
with a respectable, responsible body of professional opinion
and in line with the best information available. It is now
considered that a prescriber could be subject to claims of
malpractice if they denied a patient the best potential treatment
19
just because it was unlicensed or off-label.12
Patient consent to use unlicensed medicines
Consent is often obtained before unlicensed and off-label drugs are prescribed for
an adult. However, to do so in children would be impractical due to the incidence
and nature of unlicensed and off-label prescribing in paediatrics. The RCPCH and
NPPG advise that it is not necessary to obtain consent from parents/carers/patients
to prescribe or administer such drugs, beyond the steps taken when prescribing
licensed drugs. This means that it is not necessary to specifically point out to families
that a drug is unlicensed or off-label; instead, pharmacists need only engage in a
discussion with them around which medicines they are happy to take and how,
irrespective of licence status.
2.3 Use of unlicensed and off-label medicines in children

Children are often unable to swallow tablets and capsules and may be in danger of
aspiration if they are pushed to do so. Palatable liquid formulations are needed to
facilitate administration and accurate measurement of paediatric doses, but these are not
often commercially available. It may be necessary and desirable to choose a
pharmacologically alternative drug that is available in a more suitable form for
administration. Pharmacists and pharmacy technicians should be proactive in informing
and encouraging prescribers to use these where available. When this is not possible,
other means of supplying medicines must be used, possibly involving the supply of
unlicensed medicines. We will look at some of these means now.
Extemporaneously dispensed medicines

To deliver a child’s dose, products such as oral liquids, powders or capsules are often
needed. Traditionally, when these have not been available commercially, they have been
prepared extemporaneously. This often has to be done with little information to support
the bioavailability of the drug, dose uniformity and the physical, chemical and
microbiological stability of the preparation. The result is often unpleasant to take and
has a short shelf-life.
For these reasons, extemporaneous dispensing is increasingly considered to be the last

resort. Standards of extemporaneous dispensing procedures and quality of drug source
and excipients used are extremely variable.
Currently, there are no common European
regulations or guidelines to regulate
extemporaneous dispensing. It may be
performed in a highly equipped laboratory
in a licensed manufacturing unit within the
pharmaceutical industry or at an NHS
hospital. In such areas, good manufacturing
practice guidelines should be met – these are
20
enforced by regulatory authorities. This will involve trained
Notes
personnel and strict checking and documentation procedures,
suitable equipment and ingredients of a high standard. At the
other end of the spectrum, extemporaneous dispensing may be
done on the dispensary bench in a pharmacy with little
equipment and documentation available.
It has been shown that for 75 percent of extemporaneously

dispensed liquids and capsules in hospitals across Europe, there
is a suitable licensed alternative available in another European
country, North America or Australia, but not in the country in
question.13
Purchase of Specials
Unlicensed products, purchased from a ‘Specials’
pharmaceutical manufacturer or hospital/commercial
manufacturing unit, will have been prepared under
controlled manufacturing conditions. Some may have
undergone quality assurance processes. There is therefore
less risk involved than with extemporaneous dispensing.
It should also be possible to purchase the product to a

certain specification and to ask for a Certificate of Analysis
or Conformity to provide evidence that the product is what it
is supposed to be. The products are more likely to be
produced against formulae with evidence to support their
physical, chemical and microbial stability, though in many
circumstances this is still lacking.
At the moment, many formulations are used depending on

which manufacturer is chosen. The equivalence of different
formulations in terms of stability, bioavailability, dose
uniformity and efficacy is unknown. Research is required to
establish appropriate formulae and to encourage
manufacturers to use them. In the meantime, the same
manufacturer’s formulation of a product should be provided
each time (where possible) for an individual patient,
particularly for drugs with a narrow therapeutic index, in
order to ensure bioequivalence. Hospital pharmacists should
communicate with their community pharmacy colleagues to
provide them with information on the drug formulation,
supplier, strength and dose in a timely fashion when patients
are discharged from hospital on unlicensed medicines.
21
Practice point 2
Identify a pharmacist or pharmacy technician at your local paediatric

department who you could contact if you needed some advice.
The increased risk of medication errors associated with unlicensed medicines will
be discussed in Section 5.
The cost of unlicensed Specials has escalated in the UK in the past few years. On
1 November 2011, a list of 50 Specials was added to the Drug Tariff (Part VIIIB)
in order to rationalise the reimbursement price of these products to community
pharmacists. This is an attempt to improve transparency in the costs of Specials
and to reduce their significant financial impact. To learn more, read the frequently
asked questions document compiled by the Pharmaceutical Services Negotiating
Committee at http://www.psnc.org.uk/data/files/Specials_changes/Unlicensed
_specials_and_imports_FAQs.pdf and access the CPPE e-learning programme,
Safer supply and use of Specials, at http://www.cppe.ac.uk/e-learning.
Importing suitable medicines licensed in other countries

Importing licensed medicines from other countries may be a preferable alternative
to the use of extemporaneous dispensing or purchasing Specials, since these
medicines have been through the rigours of a regulatory process to ensure safety,
efficacy and quality. However, the standards in the country providing the licence
must be considered. Australia, the US and most other European countries employ
similar standards to those in the UK and so products should be of a similar and
acceptable quality. An example licensed product would be vitamin A drops, which
are used to treat biliary atresia (a condition which causes progressive destruction of
the bile ducts). This product is available in Italy but not in the UK.
There are difficulties around importation or free movement of medicines between

countries: this can be a complicated and expensive process and gaining access to
information on such product availability is not always easy.
Other issues to consider include:

n reliable and timely availability of the medicine is essential
n processes need to be established to ensure that if a product defect occurs, and the
product is subject to a recall by the manufacturer in the country in question, this
22 information gets through to the UK pharmacist
n product and patient information must be available in
Notes
English, or at least a translation provided – some
importation companies now provide an assurance to have
this information available with the product.
Further options for using unlicensed medicines
Several other options are possible in the provision of
medicines where a licensed product is unavailable.
n Solutions for injection can be given orally (off-label route
of administration). This must be done with care, as
different formulations may include different salts, with
varying bioavailability and stability; the pH of some
injection solutions can cause problems; and other
excipients must be checked to be safe. The taste of many
injections is problematic and the cost of using an expensive
injectable form orally must be considered. Sodium chloride
30 percent injection is given orally to neonates who have
low sodium due to immaturity.
n Use of tablet cutters to half or quarter-sized tablets may
help, though this is inaccurate and dose equivalence is
unlikely to be achieved.
n Soluble tablets can be dissolved in 10 mL water – giving a
proportion of the resulting solution will deliver a dose that
is a fraction of a tablet.
n Pharmaceutical companies may occasionally supply
unlicensed drugs on a ‘named-patient’ basis.
n Use of chemicals may be necessary to treat rare conditions
for which there is no licensed preparation or
pharmaceutical grade material available.
Practice point 3
You receive a phone call from a GP who wants to
prescribe a three-month-old baby (weight 6 kg)
omeprazole at a dose of 4.2 mg once daily.
She would like to know what form to prescribe. What
options are available? Which one would you advise?
23
It must be remembered that if an unlicensed medicine provided for a child in
hospital needs to be continued at home, plans should be made with and on behalf of
the family to avoid problems occurring. Depending on the shelf-life of the
preparation, the family may need to obtain a prescription from their GP quickly,
then find a community pharmacist to organise further supplies, in order to avoid
delays and breaks in treatment. Problems can be avoided if the hospital pharmacist
communicates with the patient’s community pharmacist, preferably prior to patient
discharge. By providing information on dose, formulation, ingredients and/or
product sources, seamless care for the patient can be assured. The hospital
pharmacist must be aware and proactive both to facilitate this and to make sure that
the family are aware that these products are unlikely to be available ‘off the shelf’
and must be ordered well in advance.
Off-label drug use refers to use outside the conditions of the product licence or
marketing authorisation in terms of dose, age of patient, indication, route of
administration, and contraindications, as outlined in the table below.
Table 4: Differences between off-label and licensed drug use
Potential differences Example

from licensed use
Dose Higher or lower Gentamicin doses used in neonates

are often off-label to ensure effective
therapy without toxicity
Age of Not licensed at all in Morphine and high-strength

patient children or not for beclometasone inhalers are not
children under a licensed in children
certain age
Indication Used to treat Diclofenac is licensed to treat

childhood illnesses not post-operative pain in children
covered by the licence but is also used to treat juvenile
idiopathic arthritis
Route of Alternative routes Cyclizine is sometimes given by

administration may be necessary in subcutaneous injection in children;
children however, it is not licensed for any
route
Contraindictions These may need to Aspirin is contraindicated in children

be disregarded under 16 years but used to treat
Kawasaki disease
24
Knowledge of excipients
Notes
Awareness of inappropriate excipients in some medicine
formulations (even some actually licensed for children) is
important. The problems with food colourings and ‘E’
numbers have been highlighted in the press but, if a parent
phones up to say that their child has become hyperactive two
months after discharge from hospital, would you consider a
prescribed medicine formulation as the cause? Some
excipients are undesirable in children with specific disorders.
Children with phenylketonuria must avoid aspartame as it

can lead to the accumulation of toxic metabolites in the
central nervous system.
The British Pharmacopoeia formulation of phenobarbital

elixir, which contains 38 percent alcohol, should not given
to children. It has been estimated14 that if a 5 mL (15 mg)
dose was given to a 3 kg baby, this would be equal to an
adult swallowing a couple of glasses of wine.
The European Commission has stated that benzyl-alcohol is

contraindicated in infants and young children.15 This has
implications for formulations of medicines used in children –
for example, the summary of product characteristics for
amiodarone and lorazepam injections both now state that
they contain benzyl-alcohol and are contraindicated in
infants or young children up to three years old. This poses a
dilemma when more appropriate alternatives for these
patients are not available.
The sugar content of medicines must also be considered,

particularly in the case of chronic medicines. It is, however,
unlikely to be a major issue in short-term medicines. Sorbitol
is sometimes used instead of sugar to sweeten medicines, but
it can cause diarrhoea if taken in large quantities.
Advanced formulations
More advanced formulations are becoming increasingly
available for adult patients. For example, transcutaneous
delivery systems, fast-dissolving drug formulations and
multiple unit dose systems all offer potential major
improvements.16 Generally, however, children are not
considered when these innovative products are being
developed. 25
3. Managing long-term conditions in children
The majority of children with long-term conditions are

Most children with long- managed in primary care, presenting community
term conditions are managed pharmacy with good opportunities to have significant
in secondary care – what
input into their care. Although the management of
input can I have?
long-term conditions such as asthma, epilepsy, cystic
fibrosis and diabetes involve vastly different treatments, many of the
issues faced are the same: working with patients to achieve
concordance, maximising compliance, provision of information
to patients and carers and the management of medicines in school.
3.1 Concordance, compliance and adherence

Concordance is an interesting topic within the paediatric population. People still
use the argument that compliance should be the aim with children and a
concordant relationship is not as important as with adults. However, it is also
recognised that, depending on many factors, children will either be the best or
worst patients that you will come across – and their medicines-taking is part of that
picture. It is hard to know whom you are trying to have a concordant relationship
with! Young children often take full responsibility for their medicines-taking,
especially in chronic diseases; conversely, some older teenagers may be totally
reliant on and led by their parents.
These aspects may not be made obvious in a short-contact counselling session and
truly concordant relationships can only take place with a full understanding of the
child’s background and family set-up. One thing is clear, however: it is important to
involve the child as much as possible in any discussions about medicines-taking. If
a two-year-old believes that a puffer and spacer are theirs and they must use it
twice a day, it will often be them who takes responsibility, walking into the room
with it to their lips (perhaps holding it the wrong way round, but that is another
matter) to say “it’s time for my puffer”. Children tend to like routine and the right
stickers on their spacer device may make all the difference.
Concordance is usually established between two people – professional and patient

– but the use of drugs in children usually involves a third partner: the parent(s) or
carer(s). It is therefore essential that you establish in your own mind who needs to
be involved at each stage. Children have rights, but parents have responsibilities
and both these needs must be met. It must also be remembered that the form of
interaction, the language used and the relevance of information may be totally
different for the two parties involved. Little research has been conducted to aid
practitioners in this field. However, it does seem clear and desirable that, whenever
possible, the child should be involved in conversations affecting their medicines.
26
Factors affecting compliance
Notes
Age
Adolescents may
be less compliant
than younger
children in taking
their medicines.
The compliance of
infants and
toddlers is very
much determined
by the parents, depending on factors such as their success in
administering each dose to the child (administering eye
drops to a reluctant two-year-old is no easy task!). School-
age children gradually learn to regulate their own medicines
management, with increasing influence from their peers and
social environment (which may be negative or positive).
Adolescents vary enormously in their compliance record,
although it is often poor. Life has many issues to contemplate
at this age and medicines are just one tiny part of the picture.
Palatability
Children are unlikely to be motivated to take a poor-tasting
medicine. For example, flucloxacillin liquid and prednisolone
soluble tablets are known to be especially unpleasant.
Different medicines and brands have different flavours and
acceptability to individual children. Assessment of palatability
should be a key part in the development of a medicine,
particularly where administration to children is likely. Up to
40 percent of mothers have been reported to use things such
as jam, sugar or juice to flavour medicines in order to get
some sort of compliance.17 However, parents and carers
must be advised to seek guidance from their pharmacy
before mixing medication with food to ensure that there are
no compatibility issues. Parents can also try giving liquids by
oral syringe down the side of a dummy to improve
compliance.
Length of therapy and frequency of dosing

Short courses and once or twice-daily dosing have been
shown to be more acceptable to children. Once or twice-daily
dosing is also preferable as it often avoids the need for
27
medication to be given during school hours. This should always be considered when
deciding on the treatment regimen for a child.
Generally, children under 12 years old find it difficult to understand the concept of
long-term preventative drugs, especially if they have no symptoms of being ill.
Children with asthma or cystic fibrosis seem to be exceptions to this; their degree of
autonomy in the use of drugs is often considerable.
Administration issues
The practical issues of administrating medicines may limit compliance, particularly
in neonates and young infants. Parents and carers should be counselled by the
pharmacy team on how to administer their child’s medication and how to resolve
any potential issues. This advice should be tailored to each individual child.
It is impossible to give flucloxacillin liquid on an empty stomach in a baby who is

having three-hourly feeds. Four times a day dosing should be flexible to fit with a
young baby’s nap times.
3.2 Improving concordance/compliance

Improving choice and ease of application often helps empower the patient and
increases compliance. For example:
n allowing asthmatic children a choice in their inhaler device

n prescribing of multiple inhalers which fit a single spacer device
n allowing children with eczema to pick their favourite emollient.
The best choice of drug in terms of side-effects is very important. Matching the
medicine to the patient is extremely important – especially in teenagers. A teenager,
for example, is more likely to be worried about an increase in facial hair, facial spots
or weight than they would be about hypertension.
The provision of information is integral in establishing concordance and adherence.

Providing the child and the parents with information will both empower the child
and help create a supportive family structure. Patient information leaflets (PILs)
help facilitate concordance. However, these are not usually available for patients
taking unlicensed medicines. For off-label medicines, manufacturer’s leaflets may be
confusing, cause doubt and may reduce the chance of achieving concordance – but,
legally, they must be provided with dispensed medicines. PILs for medicines use in
children can be obtained from http://www.medicinesforchildren.org.uk. This
website is discussed in more detail in Section 6.
Commercial comic books are available at http://www.medikidz.com which aim to

engage directly with children who take medicines and have medical conditions.
28
Another approach that often works well in improving
Notes
compliance and adherence is the use of reward materials,
such as sticker charts. Ways in which you can enhance your
communication with children is discussed later in the
programme.
3.3 Medicines use reviews and the new medicine

service
A medicines use review (MUR) can be conducted in any
patient who is deemed to be competent (ie, they have the
capacity to give informed consent), including children, and is
able to fully engage in discussion with the pharmacist.
Competent children are also suitable to receive the new
medicine service (NMS) if they fit the eligibility criteria.18,19
Under the current regulatory framework it is not appropriate
to conduct an MUR with the guardian of a person who is
not competent.
MURs and the NMS are useful methods through which

compliance can be improved in children taking long-term
medication. For more information on MURs and the NMS,
you may like to access the following CPPE programmes:
n MUR accreditation (guide)

n Targeting your MURs more effectively (guide)
n New medicine service (open learning and video wall).
Practice point 4
Make a list of child patient groups who could
potentially benefit from an MUR or inclusion in the
NMS.
29
3.3 Medicines in schools
Administering medicines in schools poses many problems and policies will vary
considerably between individual schools. There are problems in who will give the
medicine, where to store it and who takes responsibility for ensuring that the child
takes the correct dose.
Most teachers are not trained in medicines administration and do not have a legal
duty to administer medicine; this is a voluntary role. Pharmacists may be in a
position to help train teachers, either directly or by assisting school nurses with this
task. Pharmacies may also help by dispensing school medicines separately, labelled
with appropriate directions, to avoid midday doses being taken to school in
unlabelled bottles or envelopes.
The Department for Education and Skills and the Department of Health issued a
good practice guide in 2005 called Managing Medicines in Schools and Early Years
Settings,20 which states that education authorities, schools and governing bodies must
formulate their own policies for managing medicines.
A school policy needs to be clear to all parents and pupils, and might include
issues such as:
n whether the head teacher accepts responsibility, in principle, for school staff
giving or supervising children taking prescribed medicine during the school day
n the circumstances when non-prescription medicine may be taken (eg,
painkillers)
n the school’s policy on long-term conditions or complex medical needs
n the need for prior written agreement from parents or guardians for any
medicine, prescribed or non-prescribed, to be given to a child
n the policy on pupils carrying and taking their medicines themselves
n staff training in dealing with medical needs
n record-keeping
n storage and access to medicines
n the school’s emergency procedures.
Once or twice-daily dosing can help to avoid the problem of children having to take
medicines during the school day. For example, clarithromycin and erythromycin can
both be given to treat respiratory infections. In a school-age child, clarithromycin
would be preferable due to its twice-daily dosing, as opposed to four times a day
with erythromycin. Modified-release preparations may also avoid the need for the
administration during school hours. In some situations, taking medicines three times
daily – before school, after school and before bedtime – may be appropriate.
30
If medication must be administered at school, it is reasonable
Notes
to ask for a second prescription so that dual dispensing can
take place, allowing for medicine to be kept at school and at
home.
Some schools will often only allow medicines to be used that

have official dispensing labels on them. Thus over-the-
counter (OTC) medicines may not be allowed, unless a label
can be created or a prescription can be obtained for
dispensing. It is advisable to contact the school for advice
regarding this issue, as their medicines policy should cover
the administration of non-prescription medication. The issues
concerning schools are so complex and difficult that the
government has issued comprehensive guidance for them.21
3.4 Improving continuity of care

For those patients who are regularly in and out of hospital,
you may find that building a relationship with the specialist
paediatric pharmacist in secondary care is extremely
beneficial. Good communication across the primary-
secondary care interface will help reduce the risk of
medication error and help improve your understanding of
the patient’s condition. Asking the parent if you could see a
copy of the discharge letter is another way of obtaining
information from secondary care.
If possible, parents and carers of children with long-term

conditions should be made aware of the benefits of using the
same community pharmacy each time they collect
medication:
n risk of medication errors be will reduced

n consistent supply of medication (eg, same
manufacturer/brand, strength) will be ensured
n the pharmacy team will be able to have greater input to the
care of the child if they know about their condition and
their medication.
31
4. Communicating with children and their
parents/carers
As a pharmacist or pharmacy technician, you do not need
If the parent is reminding of the importance of adequate
administering a medicine,
communication with patients as an essential element of
they are the person I need
to speak to. your role. Indeed, you may be a parent (or a
grandparent) and will be aware that, when communicating
with children, a number of barriers need to be overcome in order to
get your message across. To avoid dealing with these barriers,
pharmacists and pharmacy technicians may consider talking
directly to a child’s parent or carer. Although in some circumstances this may be
appropriate (eg, in a very sick child), in the majority of cases the child should be
included in any discussion relating to them and/or their medications. The pharmacy
team should always try to engage with a child, irrespective of their age.
Children are creatures of habit. They like routine and familiarity, and so every
opportunity should be taken to speak to them. Once you become a familiar face to a
child, you will find that getting your message across to them will become much
easier. There are numerous opportunities for you to start building a relationship with
your paediatric patients. Such opportunities include MURs, provision of NMS,
OTC advice and counselling on prescription items. Errors have been known to
occur when a patient moves from primary to secondary care. Time should therefore
be taken to speak with patients (and their parents/carers) who have recently been
discharged from hospital to reduce the risk of harm.
Communication will often be verbal, but it could also be in a written format. Younger
children may respond well to adherence tools such as sticker charts. Such charts can
be used when counselling on a new medicine to help explain how it should be taken
and will help improve compliance when the child is at home.
Building a rapport with paediatric patients is especially important for those with
long-term conditions. In Section 3.2, we talked about establishing compliance to
ensure that children gain the maximum benefit from their medication. Excellent
communication skills are needed if a child is to understand:
n what their medicine is for

n how it should be taken
n what the benefits are of taking it
n what the consequences are of not taking it.
When speaking to a child on these matters, put it into a context that is relevant to
them and remember that their priorities will differ from those of their parent(s).
32
Your task may be further complicated by the need to aid
Notes
communication with the school – as discussed earlier,
systems will vary between schools. If written information is
available to support your discussion, you may have to
consider providing duplicates for the child’s school or for a
second parent.
Here are some tips from our child health experts and
community pharmacists:
If I do an MUR with a
child, I always make Try and crouch down to
sure they sit in the their level. It’s very
consulting room chair so intimidating if you’re
that they feel important. standing over them.
Do anything to make
it fun for the child. A Nothing will work for
sticker (it can be any every child. Be prepared
sticker) will usually get to adapt and try a
their attention. different approach if
what you are doing
isn’t working.
Remember that your

non-verbal
communication is Consider what is
very important – important to the child
always smile! when deciding how to
approach a problem.
Talking point A
What is your ‘top tip’ to help engage with children?
33
5. Medication safety issues in children
The safety of medicines is a consideration for all

If the dose is licensed, patients, but children are much more
it is clinically susceptible to harm from medication than adults.
appropriate.
The pharmacy team must appreciate how harm can
occur and understand what can be done to minimise the
risk of it occurring.
5.1 Medication errors

It is important to appreciate the increased potential for medication errors to occur in
children and also to be aware of the types of errors that occur most commonly.
Unfortunately, most of the research into medication errors in children has been
conducted in secondary care and there is little available on the incidence of errors in
primary care. Errors commonly occur (in patients of all ages) when moving between
primary and secondary care, when patients are discharged from hospital or following
outpatient appointments.
Errors are more likely to occur when dealing with unfamiliar drugs or those
prescribed in unfamiliar doses. If you have any doubts about the clinical
appropriateness of a medicine prescribed for a child, you should query this with the
prescriber. Specialist paediatric pharmacists and pharmacy technicians in secondary
care are a useful source of information for children who are known to that hospital.
Doses expressed as a volume of liquid may not appear at first glance to be out of the
ordinary. However, when the dose is calculated in milligrams or milligrams per
kilogram, the appropriateness of the dose is far more apparent. When dealing with
medicines in a liquid form, it is good practice to check with the patient or carer what
strength the child was previously taking. When labelling a liquid, the directions
should express the required dose in millilitres and milligrams (ie, ‘give 5 mL (50 mg)
once daily’).
Errors have resulted when patients are provided with different strengths of liquid
medicines without them realising. Parents tend to be familiar with the volume of
medicine which they need to administer to their child, but not necessarily the
strength of the preparation. If they are prescribed a different strength, they may not
realise this unless it is carefully explained to them. Consequently, they may continue
to administer the same volume, with potentially serious consequences. This may
occur due to lack of communication at the interface between primary, secondary
and/or tertiary care, or due to errors when a GP tries to prescribe an unlicensed
product which is not on his computerised prescribing system.
34
Children taking tacrolimus suspension, provided as an
Notes
unlicensed Special following liver transplantation, have
required readmission to hospital with graft rejection, due to
inadvertent prescribing of lower concentrations of the liquid
and continued administration of the same volume.
The administration of the medicine is another potential

source of error. Time should be taken to clearly explain to
parents, carers and children (if appropriate) how a medicine
should be administered. Specially designed medicine spoons
and oral syringes are widely available and should always be
supplied with liquid medicines. Parents and carers should be
counselled on how to administer liquid medicines (ie, how
many spoons to give or how to use an oral syringe) and
made aware that a kitchen teaspoon is not a suitable
substitute for a medication spoon.
Talking point B
Review the case of Abbie Jones on the Telegraph website at
http://www.telegraph.co.uk/news/uknews/7457772/
Baby-died-after-GP-surgery-issued-wrong-
prescription.html (this article has not been critiqued for
accuracy).
The findings of the subsequent General Pharmaceutical

Council’s fitness to practise hearing can be found on pages
18 to 19 of the November 2011 issue of Regulate at
http://pharmacyregulation.org/resources/corporate-
publications/regulae/regulate-nov-2011.
At what points could this tragedy have been prevented?
35
5.2 Adverse drug reactions in children
Unfortunately, children are especially susceptible to adverse drug reactions (ADRs).

To help identify children suffering with an ADR, pharmacists need to appreciate the
precipitating risk factors and be aware of the drugs which are associated with an
increased risk of side-effects in children.
In general, these are the essential features of an ADR:
n There is some evidence that at least one medicine is responsible.

n The effect is unintended.
n It is harmful, or potentially harmful.
n The reaction is seen at normal doses used clinically (to distinguish ADRs from
‘toxicity’, which is used to describe the symptoms of overdose or poisoning).
In studies that have investigated the characteristics of ADRs specifically in children,
the reported incidence has varied considerably. This, in part, reflects the limited
amount of high-quality research in children, but also the wide variations in study
setting, patient group and definition of adverse reaction used.
Incidence in children
A study22 published on the incidence of
ADRs in children in different healthcare
settings found that:
n in hospitalised children, the overall

incidence of ADRs was 9.5 percent –
severe reactions accounted for 12.3
percent of the total
n the overall rate of paediatric admissions
due to ADRs was 2.1 percent and 39.3 percent of these were life-threatening
reactions
n for children seen as outpatients, the overall incidence of ADRs was 1.5 percent.
These rates are broadly similar to studies focusing on adults (though the rate of
medication-induced hospital admissions is somewhat lower than in adult studies).
However, the high proportion of ADRs in the hospital setting that were severe in
nature raises concern, as this is higher than corresponding figures in adult studies.
Another study has suggested that the risk of ADRs associated with the use of
unlicensed or off-label drugs may be greater than that for licensed medicines.23 This
highlights the critical importance of reporting all suspected ADRs in children. As in
adults, polypharmacy was found to be a consistent risk factor for ADRs.23
36
Fatal outcomes
Notes
A review was published in 2002 of all yellow-card reports of
suspected ADRs with a fatal outcome in children received by
the Committee on Safety of Medicines (CSM) from 1964 to
2000.24 There were 331 deaths relating to 390 suspected
medicines among children aged under 16. The yellow card
scheme depends on voluntary reporting and is not a
complete dataset of ADRs.
The study has its limitations but nevertheless provides a

useful insight into the drugs suspected of having caused
deaths in children. The nature of the reported ADRs was
diverse, with hepatic failure the most frequent. The classes of
medicines most frequently associated with fatalities were:
n antibiotics
n anticonvulsants
n cytotoxic agents
n anaesthetic gases.
A more recent study, carried out at Alder Hey Children’s
Healthcare Hospital, implicated the following drugs in
admissions attributable to ADRs:25
n cytotoxic agents
n immunosuppressants (prednisolone, tacrolimus,
myophenolate, ciclosporin)
n anti-infectives (cefaclor, amoxicillin, mefloquine)
n vaccines
n analgesics
n antiemetics.
Clinical presentation of ADRs in children

Adverse reactions in children typically occur at lower doses
than in adults and symptoms may be atypical. Children are
at particular risk from ADRs that affect growth and
development.
Examples of reactions of particular importance are shown in

Table 5.
37
Table 5: Examples of drug reactions
Drug/class Reaction Notes
Sodium valproate Hepatotoxity Major risk factors:

n Aged under three years
n Concomitant use of other
anticonvulsants
n Developmental delay
Aspirin Reye’s syndrome Contraindicated in children
(symptoms: drowsiness, under 16 years unless used
coma, hypoglycaemia, as an antiplatelet drug or to
seizures, liver failure) treat Kawasaki disease
Lamotrigine Serious skin reactions Major risk factors:

(Stevens-Johnson syndrome, n Concomitant use of toxic
epidermal necrolysis) sodium valproate
n Initial dose higher than
recommended
n Rapid dose escalation
Corticosteroids Growth suppression, Seen in long-term
adrenal suppression corticosteroid treatment
Sedating Sleep apnoea Should not be given to

antihistamines children under two years
except on specialist advice
Morphine Sedation Neonates – particularly if

preterm – may be more
susceptible to respiratory
depression
Tetracyclines Tooth discolouration, Contraindicated in children

enamel hypoplasia seen in under 12 years, except
children up to eight years doxycycline can be used for
and after exposure in utero the treatment and post-
exposure prophylaxis of
anthrax when an alternative
antibiotic cannot be given
(unlicensed use)
38
Some ADRs occur less frequently in children. These include:
Notes
n cholestatic jaundice due to erythromycin
n gastrointestinal bleeds with non-steroidal
anti-inflammatory drugs
n hepatotoxicity with flucloxacillin
n severe skin reactions with trimethoprim/sulfamethoxazole.
Remember that an ADR may not always be caused by a

drug; it may be due to an excipient in the medicine.
5.3 The role of the pharmacy team in dealing

with ADRs
The pharmacy team have an integral role to play in the
prevention and early detection of ADRs. Be alert to the
possibility of ADRs in all patients. Children or their parents
may ask about symptoms experienced since taking a newly
prescribed medicine and whether or not these are side-effects.
Your observations in linking signs or symptoms to current or
previous drug therapy are vital. Remember to consider the
use of OTC medicines and herbal remedies. Reporting of
suspected ADRs can be achieved through two routes:
pharmacovigilance and the CSM yellow card scheme.
Pharmacovigilance is the process of:
n monitoring the use of medicines to identify previously

unrecognised adverse effects or changes in the pattern of
such effects
n assessing the risks and benefits of medicines
n providing information to optimise safe and effective use of
medicines
n monitoring the impact of any action taken.
The clinical trials carried out before drugs are licensed test
them in a relatively small number of patients (1500 on
average) in very strict conditions. It is important to bear in
mind that children are often excluded from these trials, due
to the issues discussed in Section 2. However, in practice,
millions of patients, including children, may take these
medicines.
39
These patients may vary in their rates of distribution and excretion, in their
metabolism and in the other medications they are taking.
For these reasons, although clinical trials will identify the more common and
predictable side-effects of medicines, rarer side-effects will only be seen when the
medicine is used in larger numbers. This is why pharmacovigilance (also referred to
as post-marketing surveillance) of licensed medicines is so important.
Vigilance for suspected medicine side-effects in children is vital because:
n the action of a medicine and its

disposition in children (especially the
very young) may be different from
that in adults
n medicines are less intensively tested
in children
n many medicines are not specifically
licensed for use in children and are
used off-label
n suitable formulations may not be available to allow precise dosing for children
n the nature and course of illness and ADRs may differ between adults and children.
The CSM has an expert working group on paediatric medicines. Its remit is to
improve the availability of medicines for children within the regulatory framework
and to advise on the safety issues relating to specific medicines used in children.
The CSM requests that all suspected ADRs in children should be reported, even if it
is an established drug and regardless of whether the medicine is licensed for use in
children. If a baby is born with a congenital abnormality, or if a pregnancy results in
a malformed aborted foetus, the CSM asks health professionals to consider if this
should be reported.
Further details on what to report can be found in the British National Formulary
(BNF) or on the CSM website. Further information on the yellow card scheme and
how to report an ADR can be found at http://yellowcard.mhra.gov.uk. Yellow
cards can be submitted electronically.
Side-effects
There is very little published research on children’s need for information about their
medicines. Ideally, the risks and benefits of taking a drug should be fully explained
to a patient, but doing so is very difficult in children.
40
Alternatively, this discussion should be had with the parents,
Notes
who should also be made aware both of the common side-
effects when their children start a new drug and of what
action to take if those side-effects occur.
If side-effects do develop, children are less well equipped

than adults to tolerate them and are less likely to understand
why they are happening. If it is appropriate to continue the
drug, parents and the pharmacy team should work with
children to maintain compliance.
6. Sources of information
There is, unfortunately, much less
information for healthcare
professionals relating to paediatric
treatments than to those for adults.
It can be very difficult to find the
information you need when handed
a prescription for an unlicensed
drug. It is therefore important to be
aware of what resources are
available to you.
Over the past two decades, tremendous progress has been

made in the understanding of health and diseases in children.
Advances in molecular biology, genetics and immunology
have led to the improved diagnosis of diseases and to new
approaches in the management of many disorders. This has
resulted in a significant improvement in patient care. At the
same time, awareness of the problems of prescribing for
children has increased.
The most useful resource available to you is the child’s

parent(s) or carer(s). They should be your first port of call
when trying to obtain information. In addition to information
about their child’s condition and medication, they may be
able to give you the details of useful contacts, for example,
healthcare professionals in secondary care.
Medicines for Children (http://www.medicinesforchildren.

org.uk) is an extremely useful resource for health
professionals and parents.
41
It provides information and videos on the administration of different dosage forms
and has a section on the use of unlicensed medicines in children. Leaflets on specific
drugs can be downloaded which (among other things) explain what the medicines are
used to treat, possible side-effects and what to do if a dose is missed.
Other useful resources are listed in Table 6.
Table 6: Useful information sources
Source Use
BNF for Children Dosage, some information regarding

unlicensed/off-label use, pregnancy,
breastfeeding
NHS Choices website Information on childhood infectious

http://www.nhs.uk/pages/ diseases (symptoms, treatment,
homepage.aspx infectious periods) and coughs and colds
Immunisation against infectious diseases Latest information on vaccines and

('green book') accessible via vaccination procedures for vaccine-
http://www.dh.gov.uk preventable diseases that may occur in
the UK
Personal Child Health Record Up-to-date records of child’s weight

(‘red book’) (and other measurements) and
vaccinations. Parents may also record
details of accidents, illnesses and
medication
Martindale: The Complete Drug May provide information on unlicensed

Reference drugs
electronic Medicines Compendium Dosage, side-effects, cautions,

http://www.emc.medicines.org.uk contraindications, pharmacokinetics
Neonatal Formulary Dosage information for neonates
Regional UK Medicines Information Breastfeeding (Good Hope / Trent),

centres. Phone numbers available in pregnancy (Newcastle), paediatrics
BNF (Alder Hey)
Drug Tariff Part VIIIB Amount that will be reimbursed for the
supply of Specials
Medicines for Children Research Supports clinical trials in children

Network http://www.mcrn.org.uk
42
We acknowledge that not all community pharmacies have full
Notes
internet access. However, you should be able to request
access to useful websites.
Practice point 5
Spend some time looking at the resources in this
section and then consider which information
source(s) you would access in the following situations.
Situation Source(s)
A lady wants to know

what vaccinations her
two-year-old daughter
should have received.
A three-year-old girl,
newly diagnosed with
epilepsy, has been
prescribed sodium
valproate and buccal
midazolam. Her mum
would like some written
information about these
medicines to pass on to
the school.
A lady wants to know if

she can continue
breastfeeding while taking
a five-day course of
trimethoprim.
A father asks you: how

long should a child with
measles be kept out
of school?
43
Summary
Children can present the pharmacy team with a number of challenges that often
make them a tricky group of patients. However, a greater understanding of children
and their medicines will enable pharmacists and pharmacy technicians to enhance
their input into their care.
The differences in the ways in which children handle drugs must be appreciated
when considering the appropriateness of drug doses. Effective communication with
the child, parents and carers, as well as with colleagues in secondary care, is
absolutely essential in reducing the risk of medication-related errors (especially with
unlicensed preparations) and optimising treatment. When providing information to
children, parents, carers and schools, it is important to be aware of the helpful
information resources that are available to you.
44
Directing change
Here we give you the opportunity to reflect and consider how you could improve
your practice in this area.
At the focal point event we would like you to share with your colleagues an
experience that you have had regarding the care of a child. Take some time to make
some notes to support you on the evening.
You should include the following information:
n The age of the child.

n Pre-existing conditions and regular medications.
n Issues that you encountered and how you resolved them.
45
Checklist for action
At this point in the learning programme you will have carried out the following.
I completed this on:
I have answered the Moving into focus questions
I have listed three learning needs
I have read the whole book
I have undertaken the practice points
I have made notes for the talking points ready to

share at the event
I have made notes on my own Directing change scenario
Signed:
Date:
Take this book with you to your focal point event. Make sure that you know when
and where it is and what time it starts. Enjoy your learning.
46
References
1. Heimann G. Enteral absorption and bioavailability in children in relation to age.
European Journal of Clinical Pharmacology 1980;18: 43-50.
2. Ritschel WA, Kearns GL. Paediatric Pharmacokinetics. In: Handbook of Basic

Phamacokinetics. 5th ed. Washington DC: American Pharmaceutical Association;
1999. 304-321.
3. Morselli PL et al. Clinical pharmacokinetics in newborns and infants. Age related

differences and therapeutic implications. Clinical Pharmacokinetics 1980;5(6):
485-527.
4. Fluhr JW et al. Direct comparison of skin physiology in children and adults with
bioengineering methods. Paediatric Dermatology 2000;17(6): 436-439.
5. West DP et al. Pharmacology and toxicology of infant skin. Journal of

Investigative Dermatology 1981;76(3): 147-150.
6. Weiss CF et al. Chloramphenicol in the new born infant: A physiological

explanation of its toxicity when given in excessive doses. The New England
Journal of Medicine 1960;262: 787-94.
7. McIntyre J et al. Unlicensed and off label prescribing of drugs in general

practice. Archives of Disease in Childhood 2000;83(6): 498-501.
8. Shirkey H. Therapeutic orphans. Journal of Pediatrics 1968;72(1): 119-20.
9. European Parliament and the Council of the European Union. Regulation (EC)
No 1901/2006 of the European Parliament and of the Council on medicinal
products for paediatric use. Official Journal of the European Union 2006;49:
L378/1-L378/19.
10. Joint RCPCH/NPPG Standing Committee on Medicines. The use of unlicensed

medicines or licensed medicines for unlicensed applications in paediatric practice.
Policy statement. London: Royal College of Paediatrics and Child Health; 2000.
11. Coté CJ et al. Is the ‘‘therapeutic orphan’’ about to be adopted? Pediatrics

1996;98(1): 118-23.
12. Bendall C. The prescription and supply of drugs in children from a legal
viewpoint. Paediatric and Perinatal Drug Therapy 1999;3: 49-54.
13. Brion F et al. Extemporaneous (magistral) preparation of oral medicines for

children in European hospitals. Acta Paediatrica 2003;92(4): 486-490.
47
14. Jevon P et al (eds.). Medicines Management: A Guide for Nurses. Oxford: Wiley-
Blackwell; 2010.
15. European Commission. ENTR/F2/BL D(2003). Medicinal products for human use
– Safety, environment and information: Excipients in the label and package leaflet of
medicinal products for human use. Brussels: EC; 2003.
16. Cram A et al. Challenges of developing palatable oral paediatric formulations.

International Journal of Pharmaceutics 2009;365(1-2): 1-3.
17. Higa SK et al. Oral antibiotic suspension: do adult taste tests predict compliance
in infants and young children? Journal of International Pediatric Pharmacy
Practice 1997;2(5): 265-270.
18. Pharmaceutical Services Negotiating Committee. MURs: the basics.

http://www.psnc.org.uk/pages/murs_the_basics.html.
19. Pharmaceutical Services Negotiating Committee. NMS Frequently Asked

Questions (FAQ).
http://www.psnc.org.uk/pages/nms_frequently_asked_questions_faq.html.
20. Department of Health and Department for Education and Skills. Managing
Medicines in Schools and Early Years Settings. London: DH and DfES; 2005.
21. Department of Health and Department for Education and Skills. National
Service Framework for Children,Young People and Maternity Services: Medicines for
Children and Young People. London: DH and DfES; 2004.
22. Impicciatore P et al. Incidence of adverse drug reactions in paediatric in/out-

patients: a systematic review and meta-analysis of prospective studies. British
Journal of Clinical Pharmacology 2001;52(1): 77-83.
23. Turner S et al. Adverse drug reactions to unlicensed and off label drugs on
paediatric wards: a prospective study. Acta Paediatrica 1999;88(9): 965-968.
24. Clarkson A, Choonara I. Surveillance for fatal suspected adverse drug reactions
in the UK. Archives of Diseases in Childhood 2002;87: 462-466.
25. Gallagher RM et al. Adverse drug reactions causing admission to a paediatric

hospital: a pilot study. Journal of Clinical Pharmacology and Therapeutics
2011;36(2): 194-199.
48
49
Notes
Notes
50
51
Notes
For information on your orders or bookings, or any Supported by:
general enquiries, please contact us by email, telephone,
fax or post. A member of our customer services team
will be happy to help you with your enquiry.
Email: info@cppe.ac.uk
Telephone: 0161 778 4000
Fax: 0161 778 4030
Website: http://www.cppe.ac.uk
Address:
Centre for Pharmacy Postgraduate Education
School of Pharmacy and Pharmaceutical Sciences
1st Floor, Stopford Building
The University of Manchester
Oxford Road
Manchester M13 9PT
Do you have any comments on your focal point learning

experience? Email: feedback@cppe.ac.uk
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A FocAl point leArning progrAmme

CHILDREN AND THEIR MEDICINES:

Sharon Conroy, lecturer in paediatric clinical pharmacy, University of Nottingham

CPPE programme developer

Karen Wragg, regional manager, South Central

All weblinks were last accessed on 15 February 2012.

Brand names and trademarks

2 Printed on FSC® certified paper stocks using vegetable based inks.

About CPPE focal point programmes 5

About this focal point unit on children and their medicines 5

Checklist for planning 7

Moving into focus 8

What do you want to learn? 9

Reading, practice points and talking points 10

Checklist for action 46

Core learning (limited expectation of prior knowledge)

Application of knowledge (assumes prior learning)

Programme guardians – A programme guardian is a recognised expert in an area

About this focal point unit on

Moving into focus and Reading

Explain the differences in HWB 7 Cluster: Delivery of patient care

Discuss the licensing issues HWB 7 Cluster: Delivery of patient care

Implement a holistic approach HWB 6 Cluster: Delivery of patient care

Communicate effectively with HWB 7 Cluster: Personal competencies

Recognise potential ways in HWB 1 Cluster: Problem solving

List useful information sources HWB 7 Cluster: Problem solving

Review your current approach HWB 6 Cluster: Delivery of patient care

Directing change and follow-up activities

Reflect on how you can Service Cluster: Management and

Checklist for planning

Answer the Moving into focus 5 minutes

List three learning needs 5 minutes

Read the whole book 90 minutes

Undertake the practice points 20 minutes

Make notes for the talking points 10 minutes

Work through the 20 minutes

1. Why children are different

There are important differences in the pharmacokinetics British National Formulary

Increasing gastric acidity is the probable explanation of

Acute diarrhoea, which is particularly common during

Liberal use of corticosteroid creams on the skin of newborn infants, especially if

Intramuscular administration of vitamin K provides a good depot effect for this

1.2 Drug distribution

The composition of a newborn baby’s body is very different to that of an adult in

Extracellular 50% 45% 30% 25% 20-25% 20-25%

TBW 85% 75% 60%

Fat content 3% 12% 30% 18%

Such changes in body composition can affect the apparent

Another determinant of drug distribution is the extent to

Plasma levels of phenytoin do not need to be as high in

The high level of neonatal bilirubin is mostly bound to

Types of reaction Effect of age

Hepatic phase II Acetylation, Increase significantly over first two

Sulphate conjugation, Present at birth at similar levels to

The metabolism of paracetamol

Table 3: Examples of drug half-lives

Drug Half-life Half-life

Phenobarbitone 36-72 hours 100 hours

Theophylline 4-6 hours 6-12 hours

Children are far more likely to have extrapyramidal side-effects to metoclopramide

1.6 Checking doses

10.5 Some degree of weight 91st 10.5

6.5 0.4th 6.5