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Title: Adverse drug reactions in children : the contribution of off-label and unlicensed prescribing
Author: Bellis, Jennifer
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2013
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Adverse drug reactions (ADRs) in children are common but their predictors are not fully characterised. It is known that both increasing age and number of concomitant medicines increase ADR risk in children, and there is also some evidence that off-label and unlicensed medicine use may contribute. The purpose of the thesis was to characterise ADRs in children, focusing on known risk factors, which have not been adequately evaluated in the literature. The contribution of off-label and unlicensed prescribing to ADR risk in children was assessed in two large prospective studies. In the first study, which evaluated ADR-related hospital admissions, off-label or unlicensed medicines were more likely to be implicated in an ADR than authorised medicines (relative risk 1.67, 95% CI 1.38, 2.02, p < 0.001). In a multivariate analysis, patients admitted under the care of oncology were more likely to have experienced an ADR (odds ratio (OR) 25.70, 95% CI 14.56, 45.38, p < 0.001). The following risk factors were also associated with increased ADR risk: increasing age (OR 1.04, 95% CI 1.00, 1.08, p = 0.045), number of authorised medicines (OR 1.25, 95% CI 1.16, 1.35, p < 0.001) and number of off-label or unlicensed medicines (OR 1.23, 95% CI 1.10, 1.36, p < 0.001). In a sub-group analysis which excluded oncology patients, age and number of authorised medicines predicted ADR risk (OR 1.05, 95% CI 1.01, 1.09, p = 0.023 and OR 1.33, 95% CI 1.23, 1.44, p < 0.001 respectively) but the number of off-label and unlicensed medicines did not (OR 1.04, 95% CI 0.89, 1.12, p = 0.627). The second prospective study examined ADRs occurring in paediatric inpatients. Again, off-label or unlicensed medicines were more likely to be implicated in an ADR than authorised medicines (OR 2.25, 95% CI 1.95, 2.59, p < 0.001). Medicines licensed in children but given to a child below the minimum age or weight recommended had the greatest risk of being implicated in an ADR. Multivariate analysis showed that increasing age (HR 1.04, 95% CI 1.02, 1.05, p < 0.001) and receipt of a general anaesthetic (HR 5.30, 95% CI 4.42, 6.35, p < 0.001) were positive predictors of ADR risk. Both the number of authorised (HR 1.22, 95% CI 1.17, 1.26, p < 0.001) and the number of off-label or unlicensed (HR 1.27, 95% CI 1.20, 1.34, p < 0.001) medicines were predictors of ADR risk. ADR detection in the above studies was based on intensive surveillance. One possible method of detecting ADRs may be through the ICD-10 clinical coding system but this has not been investigated for paediatrics. Only 31.5% of the 241 ADRs evaluated from the prospective admissions study were coded correctly using at least one ICD-10 code. The clinical coding system could contribute to pharmacovigilance if deficiencies in how ADRs are recorded in the case notes and the clinical coding system can be addressed. An important ADR detected in the admissions study was the occurrence of haemorrhage post-tonsillectomy which has been attributed to the use of dexamethasone. In order to analyse this further, a systematic review and meta-analysis of dexamethasone and non-steroidal anti-inflammatory drug (NSAID) use in paediatric tonsillectomy was undertaken. Although there were a large number of randomised controlled trials and observational studies in this area, analysis of all of these led to the conclusion that there was insufficient evidence to rule out an increased risk of haemorrhage with dexamethasone use whether in combination with NSAID or not (Peto odds ratio for dexamethasone versus another intervention 1.41, 95% CI 0.89, 2.25, p = 0.15). Further, well powered, well designed studies are needed in this area. An important ADR detected in the in-patient study was post-operative nausea and vomiting. More detailed analysis was therefore undertaken to identify the risk factors for post-operative vomiting (POV), with a view to developing a risk score. The following were all identified as predictors of POV risk: age (OR 1.06, 95% CI 1.03, 1.10, p<0.001), duration of anaesthesia (OR 1.00, 95% CI 1.00, 1.01, p <0.001) and the use of intra-operative analgesics (OR 2.22, 95% CI 1.58, 3.12, p < 0.001). However, it was not possible to develop a robust model to predict the risk of POV because of the heterogeneity of the patient groups, the types of surgery, and the different clinical practices between different anaesthetists in terms of anti-emetic (choice, timing and doses). The use of off-label and unlicensed medicines in children is common but necessary and these medicines are frequently associated with ADRs. The rational prescribing of medicines is an important measure in the reduction of ADR risk and a solid evidence-base is a pre-requisite. The aim should be that the minimum number of medicines is used safely and effectively, at the lowest dose possible, for the minimum duration necessary.
Supervisor: Pirmohamed, Munir; Nunn, Anthony; Kirkham, Jamie Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RJ Pediatrics