Manfred Criegee-Rieck

The Impact of Unlicensed and Off-Label Drug Use on Adverse Drug Reactions in Paediatric Patients

AbstractBackground 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-Nüremberg, 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.

Incidence and costs of adverse drug reactions during hospitalisation: computerised monitoring versus stimulated spontaneous reporting.

AbstractObjective: To implement a computer-based adverse drug reaction monitoring system and compare its results with those of stimulated spontaneous reporting, and to assess the excess lengths of stay and costs of patients with verified adverse drug reactions. Design: A prospective cohort study was used to assess the efficacy of computer-based monitoring, and case-matching was used to assess excess length of stay and costs. Setting: This was a study of all patients admitted to a medical ward of a university hospital in Germany between June and December 1997. Patients and participants: 379 patients were included, most of whom had infectious, gastrointestinal or liver diseases, or sleep apnoea syndrome. Patients admitted because of adverse drug reactions were excluded. Methods: All automatically generated laboratory signals and reports were evaluated by a team consisting of a clinical pharmacologist, a clinician and a pharmacist for their likelihood of being an adverse drug reaction. They were classified by severity and causality. For verified adverse drug reactions, control patients with similar primary diagnosis, age, gender and time of admission but without adverse drug reactions were matched to the cases in order to assess the excess length of hospitalisation caused by an adverse drug reaction. Results: Adverse drug reactions were detected in 12% of patients by the computer-based monitoring system and stimulated spontaneous reporting together (46 adverse reactions in 45 patients) during 1718 treatment days. Computer-based monitoring identified adverse drug reactions in 34 cases, and stimulated spontaneous reporting in 17 cases. Only 5 adverse drug reactions were detected by both methods. The relative sensitivity of computer-based monitoring was 74% (relative specificity 75%), and that of stimulated spontaneous reporting was 37% (relative specificity 98%). All 3 serious adverse drug reactions were detected by computer-based monitoring, but only 2 out of the 3 were detected by stimulated spontaneous reporting. The percentage of automatically generated laboratory signals associated with an adverse drug reaction (positive predictive value) was 13%. The mean excess length of stay was 3.5 days per adverse drug reaction. 48% of adverse reactions were predictable and detected solely by computer-based monitoring. Therefore, the potential for savings on this ward from the introduction of computer-based monitoring can be calculated as EUR56 200/year (

Readmissions and adverse drug reactions in internal medicine: the economic impact

US59 600/year) [1999 values]. Conclusion: Computer monitoring is an effective method for improving the detection of adverse drug reactions in inpatients. The excess length of stay and costs caused by adverse drug reactions are substantial and might be considerably reduced by earlier detection.

Identification of Adverse Drug Reactions in Geriatric Inpatients Using a Computerised Drug Database

Background.  Recent studies show that nearly half of the hospitalized patients are readmitted within 6 months from discharge. No data exist about the relationship between adverse drug reactions (ADRs) and readmittance to a department of internal medicine.

Lack of awareness of community-acquired adverse drug reactions upon hospital admission : dimensions and consequences of a dilemma.

Introduction and objectiveGeriatric patients with multiple comorbidities are at high risk of experiencing an adverse drug reaction (ADR) during hospitalisation. The aim of the study was to compare the rate of ADRs as predicted by a computerised pharmacological database to the actual rate determined by direct observation in a sample of geriatric patients.Study designDuring a 4-month period, geriatric patients were monitored using prospective observation. Patients were intensively screened for ADRs by a pharmacoepidemiological team (PET), consisting of two pharmacists and a physician. Actual ADRs detected by the PET were compared with those predicted by a computerised drug database. Furthermore, the set of actual ADRs, which resulted from drug-drug interactions (DDIs), were contrasted with potential DDIs signalled by the database. The main outcome measures were the incidence of actual ADRs. For the detection rate of the database we focused on frequent ADRs (>1% according to product information and database) and all DDIs indicated automatically by the database.Results163 patients (121 female), mean age 79.8 ± 7.1 years (range 60–98), were included in the study which was conducted on a geriatric rehabilitation hospital ward. The mean duration of hospitalisation was 24.3 ± 8.4 days. Elderly patients received an average of 14.0 drugs (range 2–35) during their hospital stay.Of all patients, 60.7% experienced at least one ADR. The PET detected a total of 153 ADRs, with a mean of 0.9 ADRs per patient (range 0–5). The computerised drug database predicted an average of 309 potential ADRs for each patient; however, only 21 ADRs per patient were of high frequency. In 48% of ADR-positive patients (defined by PET) at least one of these frequent ADRs occurred.DDIs were detected by the PET in 14.7% of patients. Our database indicated a mean of 12 potential DDIs per patient. In 14 out of 24 DDI-positive patients, at least one signal indicated a real DDI. The database sensitivity was consequently 58.3%.ConclusionIn geriatric patients the incidence of ADRs is high. Computerised drug databases are a useful tool for detecting and avoiding ADRs. Our software, however, also produced a large number of signals that did not relate to actual ADRs found by the PET. The sheer number of these ‘false’ signals shows the need for refinement and optimisation of databases for daily clinical use.

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

AbstractObjective: Adverse drug reactions (ADRs) are a well-known cause of hospital admission. Nevertheless a quantitative estimate of the preventability of and physicians’ awareness of these reactions is lacking. Study Design and Methods: Using intensive bedside and computer-assisted drug surveillance methods a 13-month prospective pharmacoepidemiological survey was carried out on patients admitted to two medical wards of the Erlangen-Nuremberg University Hospital in Erlangen, Germany. This study aimed to define the incidence of preventable and unavoidable ADRs. In addition we investigated the awareness of the physicians to ADRs at the time of admission and the rate of contraindicated pre-admission prescriptions. Results: In 78 (8.5%) of 915 (10.9%) admissions a total of 102 (42 preventable) community-acquired ADRs were detected on admission. In 45 (3.8%) of the admissions ADRs led directly to hospitalisation. 56.9% of the ADRs were not recognised by the attending physician on admission. Marked correlation was found between the awareness of ADRs and their probability and severity scores (r = 0.85 and r = 0.94, respectively; p < 0.05). The most frequently detected ADRs were due to direct toxicity and secondary pharmacological effects. Idiosyncratic reactions were often missed and 18.6% of all drugs prescribed prior to admission were contraindicated. Leading the list were diuretics, analgesics/NSAIDs and antipsychotics/sedatives. Conclusions: Awareness of existing ADRs on hospital admission and appropriate prescribing prior to hospital admission require attention. Early detection of ADRs on hospital admission can be achieved by the use of computer support systems. Many ADRs could be prevented by adhering to indications and contraindications.

Implementation of a computer-assisted monitoring system for the detection of adverse drug reactions in gastroenterology

ObjectiveThe 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.MethodsA 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.ResultsA 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%.ConclusionThis 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.

Comparative evaluation of different medication safety measures for the emergency department: physicians’ usage and acceptance of training, poster, checklist and computerized decision support

Aim : To investigate the effectiveness of a computer monitoring system that detects adverse drug reactions (ADRs) by laboratory signals in gastroenterology.

Cytochrome p450 polymorphisms in geriatric patients: impact on adverse drug reactions--a pilot study.

BackgroundAlthough usage and acceptance are important factors for a successful implementation of clinical decision support systems for medication, most studies only concentrate on their design and outcome. Our objective was to comparatively investigate a set of traditional medication safety measures such as medication safety training for physicians, paper-based posters and checklists concerning potential medication problems versus the additional benefit of a computer-assisted medication check. We concentrated on usage, acceptance and suitability of such interventions in a busy emergency department (ED) of a 749 bed acute tertiary care hospital.MethodsA retrospective, qualitative evaluation study was conducted using a field observation and a questionnaire-based survey. Six physicians were observed while treating 20 patient cases; the questionnaire, based on the Technology Acceptance Model 2 (TAM2), has been answered by nine ED physicians.ResultsDuring field observations, we did not observe direct use of any of the implemented interventions for medication safety (paper-based and electronic). Questionnaire results indicated that the electronic medication safety check was the most frequently used intervention, followed by checklist and posters. However, despite their positive attitude, physicians most often stated that they use the interventions in only up to ten percent for subjectively “critical” orders. Main reasons behind the low usage were deficits in ease-of-use and fit to the workflow. The intention to use the interventions was rather high after overcoming these barriers.ConclusionsMethodologically, the study contributes to Technology Acceptance Model (TAM) research in an ED setting and confirms TAM2 as a helpful diagnostic tool in identifying barriers for a successful implementation of medication safety interventions. In our case, identified barriers explaining the low utilization of the implemented medication safety interventions - despite their positive reception - include deficits in accessibility, briefing for the physicians about the interventions, ease-of-use and compatibility to the working environment.

Memorandum on the Use of Information Technology to Improve Medication Safety

Background and objectiveUp to 23% of the population, depending on their ethnic background, has genetically determined differences in the metabolism of drugs by the cytochrome P450 (CYP) enzymes CYP2C9, CYP2C19 and CYP2D6. The aim of this survey was to determine the relationship between genetical polymorphisms in these CYP enzymes and adverse drug reactions (ADRs) in geriatric patients.Study designIn a prospective 6-month cohort study of 243 patients in a geriatric rehabilitation ward, mean age 80.2 ± 7.7 years, ADRs were identified by intensive monitoring by a pharmacoepidemiological team, consisting of pharmacists and physicians. 125 out of these 243 patients were genotyped cross-sectionally for polymorphisms of CYP2C9, CYP2C19 and CYP2D6 by the TaqMan-polymerase chain reaction. The main outcome measures were the prevalence of genetical polymorphisms and the patients’ risk for developing an ADR as related to the genotype.ResultsPatients received an average of 14.2 drugs during hospitalisation which led to 251 ADRs in the whole cohort and 149 ADRs in the cross-sectional genotyping study. Genotype frequencies of CYP2C9 enzyme were 25.9% (n = 29) intermediate metabolisers (IMs) and 2.7% (n = 3) poor metabolisers (PMs). For the enzyme CYP2C19, 26.8% (n = 33) IMs and 0.8% (n = 1) PMs were detected. For the enzyme CYP2D6, 24.1% (n = 26) IMs and 3.7% (n = 4) PMs were found in the analysed patient population. In total, 61.6% (n = 77) of genotyped patients experienced mutations in at least one of the three cytochrome enzymes. The ADR rate did not differ significantly between patients with genetic mutations and wild-type genotype patients. Moreover, only eight out of 40 ADRs which were associated with drugs metabolised by CYP2C9, CYP2C19 or CYP2D6 were detected in patients with IM genotype and none in patients with PM genotype.ConclusionIn this investigation geriatric patients showed a high rate of ADRs. However, no association between the ADR rate and the patients’ genotype could be detected, which most likely was a result of the small number of patient samples analysed.Although prophylactic genotyping would have not prevented ADRs in this pilot study, physicians nevertheless have to be aware of potential genetic mutations in patients with polypharmacy.