The impact of unlicensed and off-label drug use on adverse drug reactions in paediatric patients.

BACKGROUND AND OBJECTIVE: Many drugs that are used to treat children are either not licensed for use in paediatric patients (unlicensed) or prescribed outside the terms of the product licence (off label). The incidence of adverse drug reactions (ADRs) associated with the use of such drugs is yet to be established. This study investigates, for the first time in a German patient population, the impact of unlicensed and off-label drug use on ADRs in paediatric patients. PATIENTS AND METHODS: An 8-month prospective pharmacoepidemiological cohort-based survey was conducted on a ten-bed paediatric isolation ward at the University Hospital Erlangen-Nuremberg, Germany. All patients were intensively monitored for ADRs by a pharmacoepidemiological team. ADRs were characterised according to international classification methods. All drug prescriptions were evaluated retrospectively as to unlicensed or off-label use on the basis of the product information. RESULTS: A total of 178 patients were included in the study and 740 drug prescriptions were given to 156 patients (median three prescriptions per patient). In 198 cases (27.7% of all prescriptions) drugs were used in either an unlicensed (n = 3) or off-label (n = 195) manner. A total of 46 ADRs were observed in 31 patients (17.4%). Patients receiving at least one unlicensed or off-label drug prescription during hospitalisation (n = 92) experienced an ADR significantly more frequently (n = 26 patients) than patients receiving only licensed drugs (n = 64 vs 5 patients). ADRs were associated with 29 (5.6%) of the 517 licensed drug prescriptions and with 12 (6.1%) of the 198 unlicensed or off-label drug prescriptions. The majority of ADRs caused by unlicensed and off-label drug use were recognised by the attending physician. However, statistical analysis revealed no significant difference in the number of licensed and unlicensed/off-label drug prescriptions causing ADRs. CONCLUSION: This study demonstrated that at a paediatric isolation ward the incidence of ADRs caused by unlicensed or off-label drug use was not significantly more than that caused by the licensed drug use. However, patients treated with unlicensed or off-label drugs were shown to possess a significantly increased risk for developing ADRs.

Are computerised monitoring systems of value to improve pharmacovigilance in paediatric patients?

OBJECTIVE: The aim of the present study was to evaluate a computerised monitoring system (CMS) based on laboratory test results for the detection of adverse drug reactions (ADRs) on a paediatric ward. METHODS: A prospective, 6-month pharmacoepidemiological survey was performed on a 22-bed paediatric isolation ward. ADRs were identified by intensive chart review. In addition to spontaneous reporting by the treating physician, automatic laboratory signals generated by a CMS were evaluated for their association with ADRs. ADRs were classified by the affected target organs according to the WHO-ART system organ classes. RESULTS: A total of 73 ADRs were identified in 439 admissions (396 patients) by chart review. The CMS alerted 31 (42.4%) ADRs while 23 (31.5%) ADRs were found solely by treating physicians. Eight ADRs were detected by both approaches resulting in a total detection rate of 74% (compared with intensive pharmacovigilance). Out of a total of 27,434 laboratory tests performed routinely, 1,563 were classified as abnormal by the predefined CMS and used as the basis of alerts. The sensitivity of the system with respect to patients alerted was 90.3% and the specificity only 19.6%. CONCLUSION: This study demonstrates that, using CMS, a different kind of mild adverse events were detected compared to the observation by the treating physician. The system presented appears to be sufficiently sensitive, but the specificity is too low to make it acceptable for physicians in daily practice. In children, clinically important ADRs can be detected best by intensified surveillance.

Survey of adverse drug reactions on a pediatric ward: a strategy for early and detailed detection.

OBJECTIVE: Adverse drug reactions (ADRs) occur frequently in children. However, the exact incidence of ADRs is unknown. Therefore, we studied ADRs in 1 ward and assessed whether a general approach, eg, by a computerized monitoring system, to detect ADRs in children is feasible and likely to yield a higher rate of early detected ADRs. The aim was to assess the usefulness of a computerized monitoring system before implementing costly adaptations. METHODS: An 8-month prospective study was conducted at a 10-bed pediatric isolation ward of the University Hospital. Charts were reviewed once weekly by a pharmacoepidemiological team. Clinical signs as well as laboratory changes were documented and assessed. Algorithms were used to assess the probability and severity of each detected event. RESULTS: All 214 patients admitted were enrolled in the study. A total of 68 ADRs were detected in 46 of 214 patients by the pharmacoepidemiological team. Thirty-four ADRs (50%) were detected by the staff physician, and 27 (40%) were detected primarily by analyzing laboratory parameters. Antibiotics-associated ADRs (50%) predominated, followed by glucocorticoids (16%), tuberculostatic (4%), and immunosuppressive agents (4%). In 5 cases, an ADR was responsible for the prolongation of hospital stay, and in 4 children, the ADR was responsible for hospitalization. CONCLUSIONS: The detection rate of ADRs would almost be doubled by a computerized monitoring system analyzing laboratory data. Implementation of a computer monitor system that automatically generates laboratory signals may help to identify ADRs in children, and to reduce morbidity and hospital stay, as well as costs.