Off-label drug treatment and related problems in children : a register-based investigation

Introduction: There is a lack of pediatric documentation concerning efficacy and safety of many drugs, which may contribute to off-label drug treatment and increase the risk for adverse drug reactions (ADRs).

Aims: To; (I) analyse the frequency and characteristics of pediatric off-label prescribing; (II) investigate frequency of off-label drug prescribing in pediatric ADR reports; (III) analyse drug related problems, the extent of off-label drug treatment in pediatric questions to a Drug Information Centre (DIC) and pediatric literature information adding to the labelling of the drug in DIC answers.

Methods: Three retrospective register based investigations on drug treatment of children less than 16 years of age were performed. In study I, outpatient records of purchased prescriptions were retrieved and analysed. The analysis was restricted to the drugs that account for 90% of the total use (DU90%). In study II, a nation-wide survey of ADR reports to the Medical Products Agency in relation to prescriptions among suspected drugs in outpatients was performed. In study III, questions and answers (Q&A) to a DIC in Stockholm (1995-2004) were characterised and analysed.

Results: In Stockholm 1.8 prescribed drugs per pediatric outpatient were purchased in the year 2000. Every fifth drug was classified as an off-label prescription. The proportion of off-label prescription was highest for topical drugs, followed by psychotropic drugs. In the year 2000, 112 pediatric ADR reports corresponding to 158 ADRs in outpatients were reported. The off-label proportion in ADR reports was more than 40%. One third of the reports was 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 ADRs. During a 10-year period DIC in Stockholm handled 249 pediatric questions and each question addressed on average 1.5 drugs. The questions mainly concerned drugs licensed in Sweden. Adverse drug reactions (ADRs), drug choice or dosing were the most common drug related problems. Every third question was off-label and among these the most common therapeutic group was psychotropic drugs. In every other response to offlabel questions, pediatric documentation concerning drug efficacy and safety was found. The most common reason for a drug to be classified as off-label was lack of pediatric labelling in the Swedish catalogue of medical products.

Conclusion: This thesis has demonstrated substantial off-label prescribing in primary health care. Off-label prescribing were common in pediatric ADR reports from primary care. We also found literature information adding to the labelling of the drug. There is a great need for evidence based pediatric drug information, which can be retrieved from a DIC. A future challenge is to further diffuse this knowledge to pediatric prescribers through Internet, expert committees and medical journal databases.

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): 779-83. Epub 2003 Feb 22
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): 147-52.
https://pubmed.ncbi.nlm.nih.gov/15072113

III. Kimland E, Bergman U, Lindemalm S, Bottiger Y (2006). Drug related problems and off-label treatment in children at a regional information centre. [Manuscript]