Drugs are subject to licensing procedures to ensure their quality, efficacy, and safety, but many drugs used to treat children in hospital are either not licensed for use in children (“unlicensed”) or are prescribed outside the terms of the product licence (“off label”).1 Little is known about such prescribing in general practice, so we conducted a cohort study in primary care in the Netherlands to investigate the subject.
Methods and results
We retrieved data from the integrated primary care information project, a longitudinal observational database containing information from computer based patient records of 150 general practitioners in the Netherlands. The system complies with European Union guidelines on the use of medical data for medical research and has been proved valid for pharmacoepidemiological research.2
Within the dynamic population of children (0-16 years) registered in 1998, we conducted a one year population based cohort study. From a source population of 53 702 eligible children, we randomly sampled 25% (n=13 426; 6941 (51.7%) boys), which formed our final study population. During the year 8271 (61.6%) children consulted their general practitioner at least once; the median was one consultation a year. We classified all 17 453 drug prescriptions issued to 6141 (45.7%) children according to the licensing status of the drug,1 by reference to the official product licence, as provided by the Dutch Medicines Evaluation Board.
Seventy one per cent (12 405) of prescriptions were for drugs licensed for use in children and prescribed in agreement with the product licence. Of the remaining 5048 (28.9%) prescriptions, 2667 (15.3%, 95% confidence interval 14.8% to 15.8%) were for drugs not licensed for use in children and 2381 (13.6%, 13.1% to 14.2%) were off label prescriptions for licensed drugs (table). The drugs most often prescribed unlicensed or off label were fusidic acid (ophthalmological gel), salbutamol (aerosol), deptropine citrate, amoxicillin, and fluticasone (aerosol). The baseline risk of receiving one or more unlicensed or off label prescription was 45.5% (44.3% to 46.8%) for children who received at least one prescription during the study period. The risk was 18% (10% to 26%) higher for girls than for boys. Compared with children aged 6-12 years, the relative risk of receiving unlicensed or off label prescriptions was 2.6 (2.4 to 2.9) in children aged 6-24 months and 1.7 (1.6 to 1.9) in children aged 2-6 years. The overall risk of receiving an unlicensed or off label prescription was 13.9% (13.5% to 14.3%) per consultation.
Comment
The absolute risk of prescription of unlicensed and off label drugs in children was substantial in this Dutch general practice setting. The risk is lower than in secondary and tertiary care,1 but the potential negative health impact of these findings should be considered. Although unlicensed and off label prescribed drugs do not necessarily carry an actual threat to the health of a child, the risk of adverse drug reactions is high, as adequate dosing schemes have often not been assessed.3 For instance, bone demineralisation and impairment of growth may follow long term use of respiratory corticosteroids in children.4 Similarly, the use of highly dosed deptropine citrate in small children can cause hallucinations, agitation, ataxia, and anxiety.5
A considerable number of drugs prescribed to children in general practice are not licensed for use in children or are prescribed off label. Unlicensed and off label prescription of drugs in general practice is less frequent than in a clinical care setting but is still substantial, especially as the absolute number of children using such drugs is much higher than in secondary and tertiary care. This situation is highly unsatisfactory, and efforts should be made to improve it.
Table.
Classification of drugs prescribed to children in primary care
| Category | No (%) (n=17 453) |
|---|---|
| Licensed for use in children | 12 405 (71.1) |
| Off label* for: | |
| Age | 699 (4.0) |
| Dose | 978 (5.6) |
| Frequency | 279 (1.6) |
| Indication | 565 (3.2) |
| Dosage form | 190 (1.1) |
| Route of administration | 4 (<0.1) |
| Total off label prescriptions | 2 381 (13.6) |
| Unlicensed for use in children: | |
| No information in product licence on use in children† | 1 453 (8.3) |
| Contraindicated in children | 152 (0.9) |
| Modified preparation‡ | 1 062 (6.1) |
| New drugs | 0 |
| Total prescriptions for drugs unlicensed in children | 2 667 (15.3) |
As drugs in off label category can be classified under more than one group, totals add up to more than 2381 prescriptions.
No information on use in children found in any subsection of product licence.
Drugs produced under a special manufacturing licence—have not been subject to licensing regulations and therefore have no product licence.
Footnotes
Funding: Sophia Foundation for Scientific Research grant (SSWO project no 293).
Competing interests: None declared.
References
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