1. Top of page
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Background : Use of unlicensed and off-label medications is common in hospital based paediatric practice. Whilst inpatient prescription can be closely monitored within the hospital setting, it is subspecialties like paediatric gastroenterology, caring for chronically ill children on an outpatient basis that require administration of regular medications in the community. Local practitioners rely on available paediatric formularies or information provided by the tertiary unit for monitoring and dispensing further prescriptions.

Aim : To assess the proportion of unlicensed and off-label medications prescribed in a paediatric gastroenterology unit to children discharged to the community and assess adequacy of information about these medications in commonly used British formularies.

Methods : All prescriptions prescribed over a six-month period (Jan–Jul 2002) either in the paediatric gastroenterology outpatient department or for children discharged home after an inpatient stay, were retrieved from the pharmacy database. The main outcome measures were to assess the proportion of medications prescribed for unlicensed or off-label use.

Results : 308 patients received 777 prescriptions of which 384 (49%) were for unlicensed or off-label use. Of these 291 (76%) were off-label; 208 in relation to indication and 83 to child's age. 93 of the prescribed medications were unlicensed; 37 were due to manipulation of formulation. Of the commonly used formularies in the UK, only ‘Medication for Children®’ contained dosage information on more than half (9/13) of the most often prescribed off-label/unlicensed medications in paediatric gastroenterology.

Conclusions : Use of unlicensed and off-label medications remains a problem in paediatric practice. Until licensing laws change and more drugs are licensed in children, paediatric gastroenterologists remain responsible for provision of information to families, local practitioners, nurses and pharmacists. Of the commonly used formularies, ‘Medicines for Children’ is the most detailed and comprehensive, and should be available to all general practitioners and pharmacists in the UK. Clear communication between specialist units and local practitioners is imperative to ensure safe and effective prescribing to children.


  1. Top of page
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Drug licensing is important to ensure the use of safe, effective and high-quality medication. Growing children have a constantly changing physiology; therefore, it is important to ensure the administration of a safe and effective dose for all age groups. Although a few medications used by children have been subjected to clinical trials, many medications prescribed to children remain unlicensed or off-label.

Licensed medications prescribed outside their licence are used ‘off-label’.1–4 This may include administration by a different route, use outside a defined age range, use of a higher or more frequent dose and prescription for a different indication. Categories of ‘unlicensed’ use include: modifications to licensed medications (such as the dispensing of a medication in a different formulation, e.g. crushing tablets to prepare a suspension); new medications available under a special manufacturing licence; use of chemicals as medications; medications used before a licence is granted; and imported, but still unlicensed, medications.

More than 30% of medications prescribed and dispensed for paediatric wards in the UK are either off-label or unlicensed.5 General practitioners also commonly prescribe off-label and unlicensed medications to children.6 The prescribing of unlicensed and off-label medications is not illegal, but remains the responsibility of the prescribing clinician.7 Therefore, easy access to information about these medications is essential.

In hospitals, access to drug information is readily available, and several individuals check a prescription before it is finally dispensed. A trainee in paediatrics who has access to commonly used formularies usually writes the first prescription. In many hospitals, a paediatric pharmacist checks this before a different hospital pharmacist dispenses it. Finally, a paediatric nurse checks the dose before the patient receives the drug. Hospital drug information services can provide great detail about the majority of commonly used medicines in children, specialist drug information may not be readily available outside the hospital setting. Although there are no data to suggest an increased risk in prescribing unlicensed/off-label medications outside hospital, the availability of support staff and access to information are likely to be less predictable. In the absence of widely available good quality information for all prescribers for children, clear communication between paediatric units and community practitioners remains crucial for the safe use of unlicensed/off-label drugs.

In order to provide better information to general practitioners and referring physicians, we assessed what proportion of prescriptions from our paediatric gastroenterology unit were for unlicensed and off-label medications. We also assessed the quality of information available on these medications in the most widely used formularies.


  1. Top of page
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Prescription records of all children under the care of three paediatric gastroenterologists were retrieved from a pharmacy database over a 6-month period (January to June 2002). We reviewed all prescriptions prescribed either in the paediatric gastroenterology out-patient department or for children discharged home following an in-patient stay.

Data collected included the date of birth, diagnosis, medication prescribed and dose and route of administration. The following items were not included in the study: standard intravenous replacement solutions, flushes for intravenous lines, blood products, topical anaesthetic creams, medications used for hydrogen and urea breath tests and medications used in clinical trials.

AD and FM assessed all the administered medications for their unlicensed or off-label use, using a previously described classification system.5 NAA, RH and SK created a database in SPSS v10.1, data were entered by AD, FM and SB, and then re-checked by SK and NAA.

The Association of the British Pharmaceutical Industry's Data Sheet Compendium 2000–2001 was used as the primary reference source.8 If a medication was not included in the compendium, the British National Formulary was consulted.9 The manufacturer was contacted in cases of inadequate information.

Four commonly used formularies in the UK are the British National Formulary,9Guy's Hospital Paediatric Formulary,10Alder Hey Book of Children's Doses11 and Medicines for Children,12 the formulary published by the Royal College of Paediatrics and Child Health in collaboration with the Neonatal and Paediatric Pharmacists Group. Recently, a smaller abridged version of Medicines for Children, Pocket Medicines for Children, has also become available.13 Although some of these formularies have not been updated recently, their availability and established presence in paediatric training still make their use quite widespread. These formularies were reviewed for available dosing information on the most common off-label and unlicensed medications prescribed in our paediatric gastroenterology unit.


  1. Top of page
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

A total of 308 children (aged 20 days to 17 years; median, 8.1 years) received 869 prescriptions dispensed over a 6-month period. After exclusion of 92 for reasons described above, 777 prescriptions were further analysed.

Patients received 69 different medications. The 20 most common medications are listed in Table 1. The five most common diagnostic categories accounting for these prescriptions are shown in Table 2.

Table 1.  Twenty most commonly prescribed medications (n = 777)
 Medication% of total (n = 777)
  • Omeprazole suspension is unlicensed. Omeprazole tablets/MUPS (multiple unit pellet system, dispersable tablets) are licensed but off-label when used in children of < 2 years of age.

  • *

     Off-label medications.

  • † 

    Unlicensed medications.

 2Paraffin oil*7.3
11Polyethylene glycol (Movicol)*1.4
12Mesalazine (Pentasa)*1.2
15Mesalazine (Asacol)*0.6
Table 2.  Five most common diagnoses for which medications were prescribed
1 Gastro-oesophageal reflux disease282
2 Constipation209
3 Inflammatory bowel disease171
4 Triple therapy for Helicobacter pylori51
5 Malabsorption/nutritional deficiencies34

Of the 777 prescriptions, 384 (49%) were either unlicensed or off-label. Of these, 291 (76%) were for off-label medications: 208 were off-label because of the indication and 83 because of paediatric age. Of the 777 prescriptions, 93 were for unlicensed drugs, of which 37 were due to the manipulation of the formulation. Table 3 lists the most common medications prescribed in each category.

Table 3.  Commonly prescribed unlicensed and off-label medications in children
MedicationNo. of prescriptions
Unlicensed medications
 Omeprazole suspension28
 Mercaptopurine liquid9
 Glyceryl-trinitrate ointment6
 Tacrolimus ointment24
 Mesalazine (Pentasa)15
 Polyethylene glycol (Movicol)11
 Paraffin oil9
 Tripotassium dicitratobismuthate4

Only Medicines for Children contained information about more than half (9/13) of the paediatric doses of the most commonly prescribed off-label/unlicensed medications in paediatric gastroenterology.12 Paediatric doses for these 13 medications were poorly reported in the remaining formularies: Pocket Medicines for Children (6/13), Guy's Hospital Paediatric Formulary (6/13), Alder Hey Book of Children's Doses (5/13) and the British National Formulary (4/13).


  1. Top of page
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

We have shown for the first time that about one-half of the medications prescribed by a paediatric gastroenterological unit to children being discharged home are off-label or unlicensed. We have also shown that three of the four most commonly used paediatric formularies contain very limited information about dosage of these medications. Even the Royal College of Paediatrics and Child Health Formulary, Medicines for Children, did not contain details on the doses of four of our most commonly prescribed medications.12

Other paediatric sub-specialities show a similar experience. Up to 70% of medications used in neonatology are off-label or unlicensed.14 Whilst in-patient prescription can be closely monitored within the hospital setting, it is sub-specialities such as paediatric gastroenterology, caring for chronically ill children on an out-patient basis, that are most likely to require the use of unlicensed medication in the community. It is clear that specific information about medications used in many paediatric sub-specialities, and often re-prescribed by general practitioners, is scarce and difficult to access.

The use of off-label/unlicensed medications is essential in the practice of paediatrics because so often there is no alternative. Prescription of off-label/unlicensed medications remains the responsibility of the prescribing clinician and dispensing pharmacist to ensure that these medications are used in the best interests of the child. If a drug is well known and its exact dose, likely effects and side-effects have been clearly stated by a specialist, a general practitioner may be happy to re-prescribe an off-label/unlicensed medication, even without satisfactory information from a formulary. However, if the drug is relatively uncommon or there is only limited information about the drug in communications from a specialist unit, many general practitioners will seek reassurance from a formulary before writing a prescription for an off-label/unlicensed medication.

Our study has shown that information about the doses of the off-label/unlicensed medications used in paediatric specialities is often missing from even the most commonly used paediatric formularies. This may be due to the fact that the Guy's Hospital Paediatric Formulary and Alder Hey Book of Children's Doses are written for these hospitals, but sold nationally to try and compensate for the lack of paediatric prescribing information. The British National Formulary contains information about licensed drugs only and therefore is inadequate. Our study has also shown that, whilst not containing details of all the medications used in paediatric gastroenterology, Medicines for Children is the most informative of the available formularies.12

The information about off-label/unlicensed medications in Medicines for Children12 is more useful and child-focused than that in the encyclopaedic British National Formulary.9 As an example, the information in Medicines for Children about azathioprine contains a prominent warning about the concurrent use of live vaccines. This information is present in the ‘Interactions’ section of the British National Formulary, but could easily be missed because the specific warning is in a different section from azathioprine.

Medicines for Children was a joint venture between the Royal College of Paediatrics and Child Health and the Neonatal and Paediatric Pharmacist's Group. It is the first attempt at a national, peer-reviewed, paediatric formulary, written by paediatric pharmacists, paediatricians and anaesthetists. It has been extensively peer-reviewed and reflects current knowledge and practice in paediatric therapeutics. As it was produced to fill the gap in the available evidence on the use of unlicensed and off-label medications in children, it clearly cannot be wholly evidence based.

In the late 1990s, the USA took the initiative of specifically trying to stimulate clinical trials in children. In 1997, as part of the Food and Drug Administration Modernization Act (Pub.L. 105–115), Congress enacted a new law that provided marketing incentives to manufacturers who conducted studies of drugs in children. This law, which provides 6 months exclusivity in return for conducting paediatric studies, is commonly known as the paediatric exclusivity provision. It has been highly successful in stimulating paediatric research studies into both new and more established medications.

The European Commission has also proposed regulatory actions to promote the licensing of medications in children.15 This has been welcomed by the Royal Pharmaceutical Society of Great Britain.16 Adequate resources for paediatric clinical trials are essential if children are to be given medications that are safe and effective for use in their age group. Until better information becomes available, paediatric formularies will remain the only easily accessible source of information for medical practitioners and pharmacists.

Medicines for Children appears to be the best available source of information on the drugs frequently used in paediatric gastroenterology, and should be made available to all general practitioners and pharmacists.12 Paediatricians and their sub-specialist colleagues must become aware of the licensing status of the medications that they prescribe and seek to optimize the information available to all involved in the care of children receiving these medications. With local prescribing policies often restricting general practitioners to prescribing only licensed medications, children and their families may find repeat prescriptions increasingly difficult to obtain. Paediatric gastroenterologists would do well to provide information to families on drugs that are likely to cause particular problems. This can then be disseminated to local practitioners, nurses and pharmacists.


  1. Top of page
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
  • 1
    Turner S, Nunn AJ, Fielding K, Choonara I. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study. Acta Paediatr 1999; 88(9): 9658.
  • 2
    Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. Br Med J 2000; 320(7227): 7982.
  • 3
    Craig JS, Henderson CR, Magee FA. The extent of unlicensed and off-label drug use in the paediatric ward of a district general hospital in Northern Ireland. Ir Med J 2001; 94(8): 23740.
  • 4
    ‘t Jong GW , Vulto AG, De Hoog M, Schimmel KJ, Tibboel D, Van Den Anker JN. A survey of the use of off-label and unlicensed drugs in a Dutch children's hospital. Pediatrics 2001; 108(5): 108993.
  • 5
    Turner S, Nunn AJ, Choonara I. Unlicensed drug use in children in the UK. Paediatr Perinat Drug Ther 1997; 1: 525.
  • 6
    McIntyre J, Conroy S, Avery A, Corns H, Choonara I. Unlicensed and off label prescribing of drugs in general practice. Arch Dis Child 2000; 83(6): 498501.
  • 7
    Royal College of Paediatrics and Child Health. The Use of Unlicensed Medicines or Licensed Medicines for Unlicensed Applications in Paediatric Practice 2002;
  • 8
    Association of British Pharmaceutical Industry. Compendium of Data Sheets and Summaries of Product Characteristics 2001. London: Datapharm Publications Ltd, 2001.
  • 9
    British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary, 43rd edn. London: British Medical Association, 2002.
  • 10
    Guy's, St Thomas's and Lewisham Hospitals. Guy's, St Thomas's and Lewisham Hospitals Paediatric Formulary, 6th edn. London: Guy's and St Thomas’ Hospital Trust, 2001.
  • 11
    Alder Hey Children's Hospital. Alder Hey Book of Children's Doses. Liverpool: Alder Hey Children's Hospital, 1994.
  • 12
    Royal College of Paediatrics and Child Health. Medicines for Children. London: British Medical Association, 1999.
  • 13
    Royal College of Paediatrics and Child Health/Neonatal and Paediatric Pharmacists Group. Pocket Medicines for Children. London: Royal College of Paediatrics and Child Health Publications Ltd, 2001.
  • 14
    Conroy S, McIntyre J, Choonara I. Unlicensed and off label drug use in neonates. Arch Dis Child Fetal Neonatal Ed 1999; 80(2): F1424.
  • 15
    European Commission Enterprise Directorate-General. Pharmaceuticals, Better Medicines for Children: Proposed Regulatory Actions on Paediatric Medicinal Products 2002;
  • 16
    Moffat AC. Better Medicines for Children: European Commission's Consultation Document. Letter to the European Commission Enterprise Directorate-General from the Royal Pharmaceutical Society of Great Britain, 2002;