Sean Tumer, Research Pharmacist
Anthony J Nunn, Director of Pharmacy
lmti Choonara, Senior Lecturer in Paediatric Clinical Pharmacology
The pupose of licensing is to ensure that medicines are examined for safety, efficacy and quality. In the United Kingdom (UK) most medicines administered to adults have a product licence that outlines the particular indication, dose and route of administration for a drug. However, many medicines used for children are not licensed for use in children or are used outside the terms of the product licence ('off label'). This means that the risks or benefits of using a drug in that particular situation have not been examined by the licensing authority.
This is an area of concern for health care professionals working in neonatology and paediatrics1-8. In the UK interest increased following the loss of 'crown immunity' whaich altered the legal implications for medical, nursing and pharmacy personnel using unlicensed drugs and for their employing NHS Trusts.
This review considers the operation of the licensing system and the use of unlicensed and off-label drugs in children.
The Medicines Act 1968 requires that all medicines manufactured or marketed in the UK must have been authorised by the Licensing Authority, which is the Health Minister acting through the MCA, an executive agency of the Department of Health. As previously stated the licensing system is designed to ensure that medicines are examined for efficay, safety and quality. Pharmaceutical companies apply for a product license (PL) for a particular drug and in their submission include the indication, dose, route of administration and age group of patient for which this applies. When first submitted for licensing the amount of information on paediatric use may be limited or absent, leading to statements in thedata sheet such as 'contraindicated in children' or 'insufficient information to recommend use in children'.
Recent European legislation allows a license application in one EU country to apply to all of the member states and replaces product licenses with 'marketing authorisations' (MA) an the data sheet with a 'summary of product characteristics'.
Licensing arrangements constrain pharmaceutical companies but not prescribers. The Medicines Act 1968 and European legislation makes provision for doctors to use medicines that do not have a PL or MA (unlicensed) and for purposes other than those stated in the PL or MA (off-label).
'Off-Label' is an Americanisation (or short hand term) describing the use of licensed medicines outside the terms of their PL or MA. Use of a medicine may be 'off-label' for one of several reasons:
Medicines may be given at doses other than those stated in the PL or MA.
Example: ipratropium bromide nebules (Atrovent ®) are licensed to be given upto three times daily but in hospital practice are used more frequently than this.
Medicines may be used for indications other than those stated in the PL or MA.
Example: epoprostenol (Flolan ®) is licensed as an alternative to heparin during dialysis. It is used as a vasodilator in primary pulmonary hypertensions of the newborn and for its antiplatelet action in the treatment of diseminated intravasular coagulopathy.
Medicines may be used outside their licensed age range. Some medicines are 'not
recommended in children'.
Example: the PL for omeprazole (Losec ®) states 'there is no experience of the use of Losec ® in children' although it is frequently used in this age group.
Other medicines are licensed for use in children but only at a specific age range.
Example: salbutamol syrup is not licensed for children less than two years of age, yet is frequently used in this age group.
Many medicines are given by an unlicensed route.
Example: vitamin K injection is often administered orraly to newborns to prevent haemorrhagic disease because there is no suitable licensed preparation.
Many medicines are contrindicated for use in children.
Example: aspirin is not recommended for use in children because of its association with Reyes syndrome. However, aspirin is used for its antiplatlet action in the treatment of Kawasaki disease and in some cardiac patients.
Other examples of off-lable medicines used in infants and children are shown in table 1.
|Indication||Dinoprostone (Prostin E2®) is licensed as an oxytocic agent but is used in
paediatric cardiac patients to maintain a patent ductus arteriosus.
Immunoglobulin (Sandoglobulin ®) is licensed for the treatment of idiopathic thrombocytopenic purpura and hypogammaglobulinaemia but is also used in the treatment of Kawasaki disease and epilepsy.
|Dose||Dalivit ® multivitamin drops are licensed for infants less than one year in a dose of
0.3 ml daily. In cystic fibrosis patients, 1 ml daily is given.
Salbutamol (Ventolin ®) nebules are licensed in adults for doses of upto 40 mg daily. In practice older children may receive upto 60 mg daily.
|Age||Diazapam (Stesolid ®) rectal solution is not licensed for children less than
Fluticasone (Flixotide ®) inhalers are not recommended under the age of four years.
Amiloride (Midamor ®) tablets are not recommended for use in children
All these drugs are used outside the licensed age range
|Route||Adrenaline injection is nebulised to treat croup
Potassium Chloride 15% injection is given orally as a potassium supplement.
Lorazepam (Ativan ®) injection is used rectally to treat status epilepticus.
|Contraindicated||Ciprofloxacin (Ciproxin ®) is not recommended in children because it has been
linked to arthropathy in weight bearing joints of immature animals.
Tetracycline is not recommended in children because it is selectively taken up in developing bones and teeth and may lead to dental staining and enamel hypoplasia.
The use of medicines without a PL or MA can be classified as follows:
The PL specifies the form, appearance and packaging of a medicine and any changes to
these characteristics renders a medicine unlicensed. This includes extemporaneous
dispensing - the common practice of taking and 'adult' dose form and turning it into a
preparation suitable for a child such as an oral liquid.
Examples: preparation of ciprofloxacin suspension from tablets and the preparation of unit dose injections by a pharmacy Central Intravenous Additive Service.
This may be because the adult preparation is not suitable for use in children and there
is a need for a smaller dosage form.
Example: Digoxin paediatric injection (100 microgrammes per ml).
In other cases there may be no suitable licensed dosage form. Example: Flecainide suspension.
These may be novel medicines which are not commercially viable for a manufacturer to
take through the licensing process (the so-called 'orphan drugs).
Examples: Caffeine injection for apnoea of prematurity and sodium phenylbutyrate injection for the treatment of hyperammonaemia.
The 'special's manufacturing license is granted to suitable NHS or commercial manufacturers and is concerned with the quality assurance of the manufacturing process. It does not include the assessment of safety, quality or efficacy of the manufactured medicine provided by the PL or MA application or scrutiny.
In some paediatric diseases, particularly rare metabolic disorders, there may be a need
to use chemicals as medicines because there are no licensed medicines available and no
pharmaceutical material of recognised standard.
Example: the chemical betaine is used to treat homocystinuria.
These may be medicines for which a PL is awaited ( named 'patent' medicines).
Example: capropil 2 mg tablets.
Medicines may be licensed in other countries but do not have a product license in the
Example: hydrocortisone suspension is licensed in the United States and has to be imported.
Further examples of unlicensed drug use are given in table 2.
|Modification to licensed medicine.
(eg: extemporaneous preparation, cytotxic recontruction or preparation by a Central Intravenous Additive Service)
|Medicines which are licensed but the particular formulation is manufactured under a 'Specials' licence||Frusemide 10 mg/ml suspension
Hydralazine 12.5 mg tablets
Propanolol solution 5 mg/5 ml
|Chemicals used as medicines||Betaine powder
|Novel medicines available as 'specials'||Caffeine injection
Nitric oxide gas
|Imported medicines||Chlorothiazide (Diuril ®) suspension (USA)
Phenazopyridine (Pyridium ®) tablets (USA)
Taurolidine (Taurolin ®) irrigation (Switzerland)
The product licence for a drug is not actually published, but the product data sheet acts as a summary of the product licence. Unfortunately many data sheets are ambiguyous in their statements for use in children, making it difficult for health professionals to make informed decisions on the risk : benefits of using a medicine for a particular indication and often whether or not it is licensed in children. There is a need to improve the provision of paediatric information within the data sheets. Prescribing an unlicensed or 'off-lable' medicine is not illegal, but it is a risk management issue that needs to be addressed.
In 1968 H. Shirkey, an American pharmacologist, used the term 'therapeutic orphans' to describe the exclusion of infants and children from approved indications for most drugs approved by the Food and Drug Administration (FDA) 9. There has been no improvement over the last 30 years with approximately 80% of the drugs approved by the FDA having a disclaimer for use in children (10-11.
The reasons for a drug being unlicensed in children are many. It is often because the drug has not been tested in children. This may be due to financial constraints or because of the apparent difficulties with trial design and ethics of testing drugs in children. This is unacceptable as children desrve the same safeguards as adults.
There has only been one published study that has looked at the extent of unlicensed/off-label drug us in the UK1. This was undertaken on a paediatric intensive care unit and found that 35% of all drugs prescribed were unlicensed or used off-label. 70% of all patients received one or more unlicensed or off-label drugs. There is clearly a need for further research to quantify the extent of the problem in other areas, both in hospital and in the community.
In the US unlicensed and off-label drug use has been recognised as an important issue and severtal intiatives have been instigated by the FDA and National Institute of Child Health and Human Development that promise to increase the number of drugs studied and labelled for children6, 12, 13. Similar schemes have been set up in Australia and Canada4.
In the Uk a joint working party of the British Paediatric Association (now the Royal College of Paediatrics and Child Health) and the Association of the British Pharmaceutical Industry have produced a report on 'the licensing of medicines for children'14. This report has made recommendations that the MCA should be keen to support and will encourage pharmaceutical companies to seek product licences for the many medicines used in children.
The recognition of the importance of studying drugs for use in children and the establishment of the various initiatives is to be applauded.
1 Turner S, Gill A, Nunn M, Hewitt B, Choonara I.
Use of 'Off-Label' and Unlicensed drugs in Paediatric Intensive Care Unit. Lancett 1996; 347-549-50.
2 Prescribing unlicensed drugs or using drugs for unlicensed indications. Drug Ther Bull 1992; 35:97-9
3 Risk:Benefit analysis of drugs in practice. Drug Ther Bull 1995; 33:33-5
4 Gervais A. Comment: medications unlabelled for use in children. Ann Pharmocother 1995; 29:1052
5 Committee on Drugs. Guidelines for the ethical conduct of studies to evaluate drugs in paediatric populations.Pediatrics 1995; 95:286-94.
6 Kaufmann RE Status of drug approval processes and regulation of medications for children. Curr Op Pediatr 1995; 7:195-8
7 Nahata RE Need for conducting research on medications unlabelled for use in pediatric patients. Ann Pharmacother 1994; 28: 1103-4
8 Zenk K Challenges in providing pharmaceutical care to paediatric patients. Am J Hosp Pharm 1994; 51:688-94
9 Shirkey HC Editorial comment: Therapeutic Orphans. J Pediatr 1968; 72:119-120
10 Gilman IJ, Gal P Pharmacokinetic and pharmacodynamic data collection in children and neonates. Clin Pharmacokinet. 1992; 23:1-9
11 Wilson TJ Pragmatic assessment of medicines available for young children and pregnant or breast-feeding women. Morselli PL, Garattini S, Sereni F eds. Basic and Therapeutic Aspects of Perinatal Pharmacology. New York, NY, Raven Press; 1975: 41 1-21.
12 Coté CJ, Kaufmann RE, Troedle CJ, Lambert GH Is the 'therapeutic orphan' about to be adopted? Pediatrics 1996; 98: 118-23.
13 Committee on Drugs. Unapproved uses of approved drugs; the physicians; the package insert and the Food and Drug Administration; Subject Review. Pediatrics 1996; 98:143-5.
14 Licensing medicines for children. British Paediatric Association 1996. London
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