Primary care

Unlicensed and off label prescription of drugs to children: population based cohort study

Geert W `t Jong, researcher ^a, Ingo A Eland, researcher ^b, Miriam C J M Sturkenboom, assistant professor of pharmaco-epidemiology ^c, John N van den Anker, professor of pediatrics ^d, Bruno H Ch Stricker, professor of pharmaco-epidemiology ^b. 

^a Department of Paediatrics, Sophia Children's Hospital, Erasmus Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands, ^b Pharmaco-epidemiology Unit, Departments of Epidemiology & Biostatistics and Internal Medicine, Erasmus Medical Center Rotterdam, ^c Departments of Epidemiology & Biostatistics and Medical Informatics, Erasmus Medical Center Rotterdam, ^d Department of Pediatrics, Ohio State University, Columbus, OH 43210, USA

Correspondence to: B H Ch Stricker stricker{at}epib.fgg.eur.nl

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

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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

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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.

	Acknowledgments

   Contributors: GW`tJ contributed to the design, assessed the prescriptions for unlicensed and off label use, and conducted the statistical analyses. IAE contributed to the design and prepared the data for assessment. BHChS and JNvdA had the original idea for the study. MCJMS coordinated access to the IPCI database and contributed to the statistical analysis. GW`tJ wrote the paper, and all other authors were involved in editing the manuscript. BHChS is the guarantor.

	Footnotes

Funding: Sophia Foundation for Scientific Research grant (SSWO project no 293).

Competing interests: None declared.

	References

Top Methods and results Comment References

1.	t Jong GW, Vulto AG, de Hoog M, Schimmel KJ, Tibboel D, van den Anker JN. Survey of the use of off-label and unlicensed drugs in a Dutch children's hospital. Pediatrics 2001; 108: 1089-1093[Abstract/Free Full Text].
2.	Vlug AE, van der Lei J, Mosseveld BM, van Wijk MA, van der Linden PD, Sturkenboom MC, et al. Postmarketing surveillance based on electronic patient records: the IPCI project. Methods Inf Med 1999; 38: 339-344[Web of Science][Medline].
3.	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: 965-968[CrossRef][Web of Science][Medline].
4.	Allen DB. Effect of inhaled beclomethasone dipropionate and budesonide on growth in children with asthma. Respir Med 1998; 92(suppl B): 37-45.
5.	Stricker BHCh, Prins AMA, Schilte PPM. Ernstige psychische bijwerkingen bij kinderen door gebruik van hoge doseringen deptropine. Ned Tijdschr Geneeskd 1992; 136: 1362-1365[Medline].

(Accepted 2 January 2002)