Drug treatment in children with focus on off-label drug use

There is a lack of paediatric documentation concerning efficacy and safety of many drugs, which contribute to drug use outside the terms of the product license (off-label). In the present thesis, four studies (I-IV), using different settings and design to evaluate pharmacological treatment in children, with focus on off-label drug use, is presented.

Outpatient records of purchased prescriptions were retrieved to investigate the frequency and characteristics of paediatric off-label prescribing (I). In Stockholm, 1.8 prescribed drugs per child were purchased in the year 2000. Every fifth drug was classified as an off-label prescription. The proportion of off-label prescriptions was highest for topical drugs, due to lack of paediatric information.

A survey of all adverse drug reaction reports to the Medical Products Agency concerning paediatric outpatients in the year 2000 was performed, to investigate the frequency of off-label drug prescribing (II). One hundred and twelve paediatric cases, corresponding to 158 adverse reactions were reported. One third of the reports were regarded as serious, and these were more often associated with off-label drug prescribing. Antiasthmatic drugs were most commonly reported. Psychiatric symptoms were the most commonly reported adverse drug reactions.

Paediatric questions and answers to a Drug Information Centre in Stockholm were retrieved and analysed regarding off-label drug use and paediatric literature information adding to the labelling of the drug (III). During a 10-year period, 249 paediatric questions were handled. Every third question concerned off-label treatment, often concerning psychotropic drugs. In every other response to off-label questions, additional paediatric documentation concerning the drug was found in the literature.

In a prospective, nation-wide, cross-sectional study, paediatric prescriptions and offlabel drug use to children at hospitals in Sweden were analysed (IV). Enrolment of more than 200 hospital departments resulted in data from 2947 paediatric patients, that received altogether11294 prescriptions within two two-day-periods in 2008. Half of all administered prescriptions concerned either off-label drug use or unlicensed or extemporaneously prepared drugs. Paracetamol was the most common drug used both on- and off-label. Absence of paediatric information was the main reason for the large proportion of off-label prescribing of carbohydrates and electrolytes in hospitals.

This thesis has demonstrated substantial off-label prescribing to children in both primary and hospital health care. A common reason for this is the lack of paediatric documentation. Children have the same right as adults to well documented and safe drug therapy. Therefore, it is necessary to improve paediatric documentation through harmonization of existing scientific knowledge and clinical experience, improved structure of SPC information, and more appropriate administration forms. Furthermore, the documentation of drug treatment and its outcomes, including the reporting of adverse drug reactions, need to be improved.

List of scientific papers

I. Ufer M, Rane A, Karlsson A, Kimland E, Bergman U. (2003). "Widespread off-label prescribing of topical but not systemic drugs for 350,000 paediatric outpatients in Stockholm." Eur J Clin Pharmacol. 58(11): 779-783
https://pubmed.ncbi.nlm.nih.gov/12634986

II. Ufer M, Kimland E, Bergman U. (2004). "Adverse drug reactions and off-label prescribing for paediatric outpatients: a one-year survey of spontaneous reports in Sweden." Pharmacoepidemiol Drug Saf 13(3): 147-152
https://pubmed.ncbi.nlm.nih.gov/

15072113

III. Kimland E, Bergman U, Lindemalm S, Böttiger Y (2007). "Drug related problems and off-label drug treatment in children as seen at a drug information centre." Eur J Pediatr 166(6): 527-532
https://pubmed.ncbi.nlm.nih.gov/17195069