Safe Supply of Paediatric
Unlicensed Medicines
Steve Tomlin
Consultant Paediatric Pharmacist
Honorary Clinical Reader
Every Dose Is Different
• Is dosing in adults logical?
– One size fits all – useful for tablets
• Paracetamol, ranitidine
• When does a child become an adult?
• Mg/kg
• When can doses be rounded up or down?
• Paracetamol, cefuroxime
• Is Licensing Logical?
• Aciclovir
What do children take?
Dose (mg)
30
60
120
250
500
Dosage
form?
Drops
Liquid/melt
Liquid/melt
Liquid/melt/
tablet
Tablet/
capsule
Therapeutic Orphans
• Europe - >50% of medicines used in children have
never been tested in children.
• Conroy S, Br Med J. 2000, 320:79-82
• Australia - 25% of medicines licensed in children
do not have appropriate formulations for children.
• Tan E, Med J Aust. 2003, 179(4):195-8
• 1/3 of research papers into children’s medicines
did not allow for the work to be reproduced / 51%
did not use a paediatric formulation.
• Standing J, Paediatrics. 2005, 116(4):559-562
• Pandit S, Arch Dis Child. 2010, 95:754-756
Unlicensed & Off-Label
Medication
Proportion of medicines used not licensed:
80% Neonatal Intensive Care Unit (NICU)
40% Paediatric Intensive Care (PICU)
25% general paediatric in-patients
11% children at home
 Nunn A, 2003, Arch Dis Child. 2003. 88:369-371
Policy statement
Joint RCPCH/NPPG Standing
Committee on Medicines
• ‘it is not necessary to take additional steps, beyond
those taken when prescribing licensed medicines,
to obtain the consent of parents, carers and child
patients to prescribe or administer unlicensed
medicines or licensed medicines for unlicensed
applications.’
• Treatment Should Be The Best You Can
Give!
Paediatric Patient Needs
• Age-appropriate formulations
– Type of formulation (liquid / solid)
– Dose flexibility
– Excipients and levels
• Ease of dosing and compliance
–
–
–
–
Palatability
Frequency of dosing
Ease of manipulation (by carer)
Perceptions of parent / carer?
What medicine are you getting?
•
•
•
•
•
Licensed In Some Children
Licensed Adult Medicine
Import
Special
Extemporaneously Prepared
• Product aligned to Clinical Need
Intravenous Preparations
• Hospital Neonatal Unit
– 31% of prescriptions < 1/10 vial
– 4.8% of prescriptions <1/100 vial
• Arch Dis Child. 2000; 834:92-6
• Dose calculations often involve decimal points
• Units often have to change – how to label
• Standard Concentrations
IV Formulation
– Benzyl alcohol harmful in infants
• contained in e.g. amiodarone and lorazepam injections
– Shehab N, Pediatr Crit Care Med. 2009. 10(2): 256-259
– Phenobarbital injection – 90% propylene glycol 
hyperosmolality in infants, pH 11
– Ibuprofen – lignocaine in premature babies
– Paracetamol – 10 x overdoses
– Phenytoin – need to dilute, but it precipitates
Oral Formulations
– Phenobarbital elixir BP – 38% alcohol
– Sugar or Sorbitol?
– Dispersible Tablets (aspirin and diclofenac)
– The history of nifedipine
– Tuleu C, J of Drug Delivery Science & Tech. 2005. 15(4): 319-324
– Captopril – bioequivalence?
– Mulla H, Arch Dis Child. 2007. 92:409-411
– Clobazam – what’s left in the bottle
– Glass ampoules for oral solutions?
– (vitamin K, Caffeine)
Import/export of captopril oral liquid
10578
miles each
way
BMS,
UK
No MA for children
Not bioequivalent to:
tablets
compounded liquids
BMS,
Victoria,
Australia
Changing Medicines
• Crushing tablets can change profile
165
– Increase side effects
– Decrease duration
110
55
0
0
4
8
12
16
20
24
0
4
8
12
16
20
24
165
110
55
0
Pharmaceutical Issues when Crushing,
Opening or Splitting
Oral Dosage Forms
June 2011
• Changing the way in which a dosage form is presented can
alter its absorption characteristics, result in medicines
instability, produce local irritant effects, cause failure to
reach the site of action, may produce occupational health
and safety issues, and could result in a preparation with an
unacceptable taste.
• .. In most circumstances in which no appropriate licensed
medicine is available, the prime objective should be to
provide patients with a ready-to-use unlicensed medicine.
Other Routes
• INTRANASAL
– Midazolam – why do they cry?
• TOPICAL
– Chlorhexidine – it just cleans the skin!!
• RECTAL
– Glycerine Chips
– Paracetamol / Morphine
The Future
•
•
•
•
•
Standardisation / Formulary
BP? BNF-C?
Directed Prescribing
Defined Drop down boxes
Tighter Tariff