This study is, to our knowledge, the first national population survey of paediatric drug utilization at hospital level. The strength of this study is the large population-based sample covering information on a national level. One weakness is the lack of exact information on the amount of missing data and that the study approach was descriptive and therefore did not analyse associations between off-label drug use and underlying conditions. Psychiatric drugs are almost lacking in this data set, probably because few paediatric psychiatric patients were actually treated as hospital in-patients. As the study did not collect information on the number of children that did not receive any drug treatment, it is not possible to calculate prevalence.
To investigate the external validity of the data regarding the number of patients, information concerning all paediatric hospital admissions during the two study periods was retrieved from the National Board of Health and Welfare (16
). The study appears to have captured information from at least 70% of all admitted children during the study periods, which supports that our data adequately reflect paediatric drug use at Swedish hospitals in general (16
). Therefore, we believe that the study provides a good estimate of the current drug use by children at Swedish hospitals.
In accordance with other studies, this study could confirm that children are exposed to a large proportion of drug treatment that is not authorized by regulatory authorities (4
), meaning that the safety and efficacy of the treatment is neither well studied, nor sufficiently documented. Neonates, in particular, and infants have the highest use of EPDs, which generally are poorly documented, and unlicensed drugs, as well as a substantial off-label
drug use, which is in agreement with other studies (1
). It should be noted that the definition of off-label
drug use is sometimes regarded differently by different investigators resulting in difficulties when comparing studies.
Another finding was that these young children generally received drug treatment for a longer duration. As neonates and infants are particularly vulnerable because of their small body size and immature renal and hepatic function, further evidence of both safety and efficacy of drugs is urgently needed in these age groups.
The high rate of off-label
prescriptions indicates a lack of appropriate dosage form in relation to age and/or weight and strongly supports the need for suitable paediatric drug forms and strengths (20
). Thus, safer use of many drugs could be achieved by providing the actual dose sizes needed for neonates, infants and children.
Medicinal products from the ATC-group ‘blood or blood-forming organs’ (B) were given to many paediatric patients with a high proportion of off-label
classification. The major part of this off-label
classification was fluid therapy with carbohydrates and electrolytes. Those drugs often lack paediatric information, or there is a stated lack of clinical data in the SmPC, which has also been reported by others (19
). It could be argued that fluid therapy could be used according to clinical guidelines rather than requesting all individual products to have specific dosing information. An important reason for a considerable use of electrolyte substitution and carbohydrate products being classified as off-label
was the fact that those products, intended for intravenous use, were used orally, presumably because of lack of authorized oral drug forms, as has also been reported elsewhere (17
). This is a safety concern because there is an apparent risk of confusing the routes of administration.
Medicinal products for the nervous system (N), with paracetamol as the most commonly prescribed substance both on-label and off-label
, were frequently prescribed, a finding that has also been reported by others (19
). In our data, use of paracetamol was mainly classified as off-label
for age or weight, which can be explained by unclear information in several of the SmPCs for generic products.
A substantial off-label
drug use was also found for other analgesics, such as opioids, diclofenac and midazolam, which has been highlighted by other authors (17
) as an area where clinical trials appear to be needed to provide well-documented doses for all age groups. As a consequence, analgesics are listed on the European Medicines Agency (27
) priority list of paediatric drugs.
The finding in our study that the most common reason for off-label
drug prescribing is a total absence of paediatric information in the SmPC, in contrast to the situation in adults, in whom off-label
use often concerns the indication, is in agreement with other studies (28
). In recent years, the Paediatric Regulation has resulted in an increase in clinical trials in children, which will provide data on efficacy and safety of many new drugs for children. As a consequence of the Paediatric Regulation, age appropriate formulations will also be available to a higher extent for new products. The use of several drugs that explicitly lack paediatric data also underlines the need for SmPC update for many old products, for which data may be available (29
). The Paediatric Regulation requests that paediatric studies on old products be submitted to competent authorities for assessment, which may result in an update of the SmPC. This is, however, going to be a time-consuming activity as there are around 1000 such old products on the market in Europe. Several important areas of high off-label
drug use of old medicines will probably remain as there is no legal pressure and limited financial incentive to perform clinical studies in children.
A few studies have shown that off-label
drug use is more often associated with paediatric adverse drug reactions (ADR) than on-label use (8
). For EPD and unlicensed drugs, there is currently no clear process for collecting information on ADRs as there is for the monitoring of pharmacovigilance of authorized drugs. Therefore, spontaneous reporting of ADRs remains an important tool to discover hazardous effects, even though it is well known that the spontaneous reporting system is subject to substantial under-reporting (33