Adverse drug reactions and off-label and unlicensed medicines in children: a nested case?control study of inpatients in a pediatric hospital
© Bellis et al.; licensee BioMed Central Ltd. 2013
Received: 2 April 2013
Accepted: 19 July 2013
Published: 7 November 2013
Off-label and unlicensed (OLUL) prescribing has been prevalent in pediatric practice. Using data from a prospective cohort study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that OLUL status is a risk factor for ADRs.
A nested case?control study was conducted within a prospective cohort study. Details of all medicines administered were recorded, including information about OLUL status. The odds ratio for OLUL medicines being implicated in a probable or definite ADR was calculated. A multivariate Cox proportional hazards regression model was fitted to the data to assess the influence that OLUL medicine use had on the hazard of an ADR occurring.
A total of 10,699 medicine courses were administered to 1,388 patients. The odds ratio (OR) of an OLUL medicine being implicated in an ADR compared with an authorized medicine was 2.25 (95% confidence interval (CI) 1.95 to 2.59). Medicines licensed in children but given to a child below the minimum age or weight had the greatest odds of being implicated in an ADR (19% of courses in this category were implicated, OR 3.54 (95% CI 2.82 to 4.44). Each additional OLUL medicine given significantly increased the hazard of an ADR (hazard ratio (HR) 1.3 95% CI 1.2 to 1.3, P <0.001). Each additional authorized medicine given also significantly increased the hazard (HR 1.2 95% CI 1.2 to 1.3, P <0.001).
OLUL medicines are more likely to be implicated in an ADR than authorized medicines. The number of medicines administered is a risk factor for ADRs highlighting the need to use the lowest number of medicines, at the lowest dose for the shortest period, with continual vigilance by prescribers, in order to reduce the risk of ADRs.
KeywordsAdverse drug reactions Pediatrics Prescribing Off-label Unlicensed
The use of OLUL medicines in children is a potential risk factor for adverse drug reactions (ADRs). For instance, in a study of 936 patients, Turner et al. found that the proportion of OLUL medicines administered to pediatric inpatients was significantly associated with ADR risk . However, this has not been demonstrated by all studies, many of which were small, employed different methodologies and used inexact and varying definitions. Thus, there is a need for further research in this area .
Using the dataset generated by our study evaluating the incidence of ADRs in pediatric inpatients (see accompanying paper), we have employed a nested case?control design to assess the impact of OLUL prescribing on ADR risk in pediatric inpatients. We hypothesized that OLUL prescribing was a risk factor for ADRs in pediatric inpatients.
Selection of cases and controls
We have utilized a prospective cohort study design, undertaken between 1 October 2009 and 30 September 2010, to determine the burden of ADRs in pediatric inpatients (see accompanying paper). The prospective cohort included all inpatients 0 to 16 years old, with the exception of patients in the operating theater, recovery or in the department of radiology, or in the pediatric intensive care unit (PICU) for the entire duration of their admission. Since some patients had multiple admissions over the study period, the cases for the nested case?control study were children on their first admission who had experienced at least one probable or definite ADR (n = 694). These cases were matched 1:1 to controls who were children on their first admission who had not experienced any probable or definite ADRs. Matching was based on the closest date and time of admission, which were chosen in order to ensure that we could assess the relevance of factors such as age and gender as predictors for the occurrence of ADRs. A nested case-control design was chosen because it was not possible to follow up all patients across all their admissions (n = 6,601) in the prospective cohort study and the design allowed us to assess carefully the drugs prescribed and whether those drugs were prescribed within the MA, in both cases and controls.
Off-label and unlicensed categories
Medicines licensed for use in children
Authorized - medicine used within the terms of its marketing authorization
Dose greater than recommended
Dose greater than recommended and contraindication exists
Not licensed in child of this age (or child below minimum weight stated)
Not licensed in child of this age and contraindication exists
Not licensed by this route
Not licensed by this route and contraindication exists
Not licensed by this route or in a child of this age
Not licensed by this route or in a child of this age and contraindication exists
Not licensed for this indication
Not licensed for this indication and contraindication exists
Not licensed for this indication or at this dose
Not licensed for this indication or at this dose and contraindication exists
Not licensed for this indication or at this age
Not licensed for this indication or at this age and a contraindication exists
Not licensed for this indication or by this route
Not licensed for this indication or by this route and a contraindication exists
Not licensed for this indication or by this route or at this age
Not licensed for this indication or by this route or at this age and a contraindication exists
Medicines not licensed for use in children
Not licensed for use in children
Not licensed for use in children and a contraindication exists
Not licensed for use in children or in adults by this route
Not licensed for use in children or in adults by this route and a contraindication exists
Not licensed for use in children or in adults for this indication
Not licensed for use in children or in adults for this indication and a contraindication exists
Not licensed for use in children or in adults for this indication or in adults by this route
Not licensed for use in children or in adults for this indication or in adults by this route and a contraindication exists.
Medicines excluded from analysis
Category cannot be assigned
Manufactured under a specials manufacturing license
Awaiting a MA (for example, previous trial medicine)
Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated for all OLUL medicines implicated in a probable or definite ADR. Additionally, ORs with accompanying 95% CI were calculated for each OLUL category implicated in a probable or definite ADR in comparison to authorized medicines.
A Cox proportional hazards regression model for an ADR was fit to the data. Results are given in terms of the hazards ratio (HR) and associated 95% CI. In addition to the number of OLUL medicines, the following risk factors were included in the model: age, gender, having received a general anesthetic (GA), oncology patient status and the number of authorized medicines. Due to clinical importance, all risk factors remained in the final model.
All statistical analysis was carried out using the statistical software package R (version 2.13.2) using a two-sided significance level of 0.05 (5%) throughout.
This study was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines .
This study used routinely collected clinical data in an anonymized format. The Chair of Liverpool Paediatric LREC informed us that this study did not require individual patient consent or review by an Ethics Committee.
Clinical data for 1,388 patients were analyzed throughout their first admission. A total of 694 (50%) were cases; 634 (45.6%) were female; 294 (21.2%) were <1 year old, 341 (24.6%) were 1 to 4 years old, 384 (27.7%) were 5 to 11 years old and 369 (26.6%) were teenagers (>12 years old). The median age was 5.9 years (interquartile range (IQR) 1.4 to 12.4 years). A total of 10,699 drug courses were administered in this study.
A total of 10,699 medicine courses were administered to the 1,388 patients included in this study. Within this nested cohort, there were 785 suspected ADRs deemed definite or probable in 694 patients during their first admission. Of the suspected ADRs, 62 (7.9%) were deemed definite and 723 (95.1%) probable. Of these ADRs, 505 (64.3%) involved one medicine course, 172 (21.9%) involved two medicine courses, 77 (9.8%) involved three and 31 (3.9%) involved four or more. Of the 10,699 total medicine courses, 10,145 (94.8%) could be categorized using one of the definitions listed in Table?1. The remaining 554 (5.2%) courses could not be categorized because the prescription record did not provide the required information (for example, missing dose information or insufficient detail about the exact preparation used).
A total of 6,980 (68.8%) of all medicine courses were authorized, 2,407 (23.7%) were off-label and 758 (7.5%) were unlicensed. A total of 435 (6.2%) of all authorized medicine courses were implicated in at least one probable or definite ADR compared with 298 (12.4%) of off-label medicine courses and 113 (14.9%) of unlicensed medicine courses. Comparing the rate of OLUL prescribing among age groups, the neonatal category had the fewest patients (n = 75) but the greatest proportion of OLUL prescriptions (58.9%). The proportion of OLUL prescriptions implicated in at least one ADR was greatest in the 'school-aged? category (17.0% of prescriptions; see Additional file 1). The OR ratio of an OLUL medicine being implicated in an ADR when compared with an authorized medicine course was 2.25 (95% CI 1.95 to 2.59).
Total number of medicine courses in each authorized, off-label or unlicensed category and number implicated in at least one PD ADR (n = 10,145)
Number of medicine courses
% of courses implicated in at least one PD ADR
Odds ratio of ADR versus authorized
Medicines licensed for use in children
0.26 to 0.67
2.82 to 4.44
0.70 to 3.83
2.00 to 3.13
2.43 to 11.18
Medicines not licensed for use in children
2.41 to 4.91
0.72 to 15.52
1.61 to 4.16
2.05 to 3.38
1.21 to 7.02
Table?2 shows the proportion of medicine courses from each category implicated in at least one probable or definite ADR in comparison to the proportion of authorized medicine courses implicated (n = 6,980; 6.2%). Further analysis was completed on categories that contained >100 medicine courses. Results showed that category 3: medicines licensed for use in children but given at a dose greater than recommended had a lower risk of being implicated in an ADR than category 1: authorized medicines (OR 0.42, 95% CI 0.26 to 0.67). Category 5: medicines licensed in children but given to a child below the minimum age or weight had the greatest risk of being implicated in an ADR (OR 3.54, 95% CI 2.82 to 4.44).
Medicines course frequency administered, implicated and off-label, unlicensed or unknown (only medicines with > 100 courses shown, n = 7,007)
Medicine (number of courses)
Number of courses off-label or unlicensed (%)a
Number of authorized courses implicated in at least one PD ADR (%)
Number of off-label or unlicensed courses implicated in at least one PD ADR (%)
Number of courses unknown
Medicines with only authorized courses
Medicines with off-label courses
Medicines with unlicensed courses
Fentanyl and Levobupivicaine epidural (106)
Medicines with off-label and unlicensed courses
Codeine Phosphate (752)
Off-label and unlicensed category proportions for medicines with >10% of courses implicated in at least one PD ADR
Fentanyl + Levobupivicaine Epidural (implicated)
ADR risk factors
ADR risk factors assessed by multivariate analysis
HR (95% CI)
0.896 (0.770 to 1.042)
Age on admission (years)
1.036 (1.021 to 1.052)
Received a GA
5.295 (4.417 to 6.349)
0.926 (0.661 to 1.298)
Number of authorized medicines
1.217 (1.171 to 1.263)
Number of off-label and/or unlicensed medicines
1.267 ( 1.201 to 1.336)
Number of uncategorized medicines
1.138 (0.969 to 1.338)
In the largest study undertaken so far, we have investigated the role of OLUL medicines in predisposing pediatric inpatients to ADRs. The prevalence of OLUL prescriptions in pediatric inpatients ranges from 18% to 60% and 3.4% to 36%, respectively . The corresponding figures in our dataset were 23.7% and 7.5%, respectively. These are collectively similar to previous UK studies, where combined OLUL prescribing rates of 35%  and 30%  have been reported. This is perhaps not surprising since many of the medicines used in children are the older generic medicines, which pre-date the introduction of pediatric regulation in 2007 . Our findings, however, contrast with OLUL prescribing rates in other European countries, where rates of up to 66% have been reported . This reflects differences in study settings, definitions of OLUL prescribing and pharmacy practice between countries. With respect to the latter, for example, there is extensive modification and manufacture of medicines by hospital pharmacies in the Netherlands . Our data show that OLUL medicines were significantly more likely to be implicated in an ADR than medicines used within the terms of their MA (OR 2.25, 95% CI 1.95 to 2.59). The risk estimate is higher than that found previously [5, 13] which may be a reflection of the fact that the previous studies were smaller (OR 1.5, 95% CI 1.11 to 1.93 and OR 1.08, 95% CI 0.50 to 2.35) [5, 13], looked at different ward types (for example, included pediatric intensive care)  and used different definitions of OLUL medicines . We also categorized ADR risk according to the type of OLUL medicine use. By focusing on six categories which all had more than 100 medicine courses, we found that (1) medicines licensed for use in children but given at a dose greater than recommended had a lower risk of being implicated in an ADR than authorized medicines; and (2) medicines licensed in children but given to a child below the minimum age or weight had the greatest risk of being implicated in an ADR. These two findings seem counter-intuitive but can be explained by the fact that 69% of the medicine courses given at a higher dose than recommended were paracetamol. This reflects the widespread use of 15 to 20 mg/kg doses for 'severe symptoms? as recommended in the BNFC . Paracetamol at these doses is relatively safe, particularly in in-patient settings and, indeed, paracetamol was rarely implicated in ADRs throughout the entire study (Table?4).
Multivariate analysis indicated that risk factors for ADRs were the administration of a GA and the number of medicines administered per day, consistent with the findings of the cohort study (see accompanying paper). Furthermore, our finding is consistent with that of Santos et al.  who found that off-label medicine use was significantly associated with ADR risk (RR 2.44, 95% CI 2.12 to 2.89). However, in our study, we have dissected medicine use and show that the number of OLUL medicines administered per day had an influence on ADR risk similar to that of the number of authorized medicines administered per day. Most studies, including those in adults, have shown that ADR risk increases with the number of medicines used by patients, [5, 13, 15–17] which reflects the complex interaction that occurs between drugs targeting different biological systems within the body, the interaction with disease (that is, sicker patients are more likely to require a higher number of medicines) and the occurrence of drug-drug interactions.
Our findings, which relate to both OLUL and authorized medicines, highlight the need for good prescribing practice in reducing ADRs. Thus, the minimum number of drugs should be given for the treatment of a disease process, at the lowest possible dose for the shortest possible time. Nevertheless, our data implicate OLUL medicines as risk factors for ADRs in pediatric inpatients. Off-label use is complicated and in some cases can be justified by the fact that evidence which may not necessarily have led to a change in the SmPC is available in the scientific literature as a result of academic investigations . For instance, a substantial proportion of off-label prescribing in pediatric oncology may reflect evidence-based protocol recommendations for specific oncological diseases. In contrast, the evidence for the use of some analgesic medicines in children is less robust . Some of the most commonly implicated medicines in our study were frequently used off-label (for example, dexamethasone). However, we have no evidence that if these products were used in accordance with a MA, they would be implicated in any fewer ADRs. An area of concern identified in our data is the use of fentanyl, either when used off-label or unlicensed, where about 48% of courses were implicated in ADRs. A key issue with fentanyl may be the dose used in children, suggesting a need for further evaluation of dosing strategies.
With all drugs, irrespective of their licensing status, the dose administered and, thus, the systemic exposure to that medicine is an important determinant of the likelihood of an ADR. The importance of this is highlighted by our finding that medicines licensed in children but given to a child below the minimum age or weight had the greatest risk of being implicated in an ADR, reflecting the lack of pharmacokinetic data in children of different ages and/or weights. Advances in the development, and application, of pediatric pharmacokinetic models will be important in defining, and implementation of, age- and weight (or body surface area)- specific dosing regimens . While such approaches are now being incorporated in pediatric investigation plans for new medicines, the challenge for all stakeholders will be how to improve this knowledge for medicines already on the market, most of which are not only generic off-patent compounds but are also the most widely used.
Our study has several limitations: we required a minimum amount of information to be available about the use of a medicine before it could be categorized as off-label. The absence of this information was a result of how medicines were recorded on prescription charts; in general, they were prescribed by the name of the active ingredient and details such as the exact preparation administered were not recorded. Hence, the prescription chart records were adequate for their primary purpose but not for our study. We did not consider the implications of dosage form manipulation by parents or nursing staff, but this is a significant aspect of drug administration in pediatrics which does warrant investigation . Further limitations are the assumptions outlined in our methodology which pertain to the SmPC definitions of age, gestational age and the classification of cytotoxic medicines.
In one of the largest inpatient pediatric studies, we have shown that OLUL prescribing is a risk factor for ADRs and identified some drugs/classes where further work is needed. The reasons for this are complex and varied, and the finding must be put in context of the fact that the number of medicines per se, irrespective of the licensing status, is also a risk factor for ADRs. Better dosing schedules for medicines, particularly those with a narrow therapeutic index, are likely to be key in reducing the burden of ADRs in children. Clinicians prescribing for children should be vigilant for the occurrence of ADRs and should prescribe the minimum number of drugs at the lowest possible dose and shortest duration of time, with continual monitoring to stop drugs when relevant and to ensure that ADRs are detected as early as possible.
MP, AJN, MAT, MPir and RLS planned the study, were involved in study design and critically revised the manuscript. JRB, AJN, MP and JJK designed the study, developed the methodology and the study protocol. JRB, ST, LEB, HLM, KAB and JCD collected data. JJK, EJC and JRB designed the analysis plan. EJC and JRB conducted the analysis. MPir acts as guarantor and accepts responsibility for the integrity of the work as a whole. All authors read and approved the final manuscript.
Adverse drug reactions
British National Formulary for Children
Off-label and unlicensed
Summary of Product Characteristics.
We wish to thank the National Institute for Health Research (NIHR) for their support. All authors were funded by the NIHR grant number RP-PG-0606-1170. This article presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
We would also like to thank Barbara Richards for her valuable contribution to data collection.
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