Antje Neubert

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.

Drug use in children: Cohort study in three European countries

Objective To provide an overview of drug use in children in three European countries. Design Retrospective cohort study, 2000-5. Setting Primary care research databases in the Netherlands (IPCI), United Kingdom (IMS-DA), and Italy (Pedianet). Participants 675 868 children aged up to 14 (Italy) or 18 (UK and Netherlands). Main outcome measure Prevalence of use per year calculated by drug class (anatomical and therapeutic). Prevalence of “recurrent/chronic” use (three or more prescriptions a year) and “non-recurrent” or “acute” use (less than three prescriptions a year) within each therapeutic class. Descriptions of the top five most commonly used drugs evaluated for off label status within each anatomical class. Results Three levels of drug use could be distinguished in the study population: high (>10/100 children per year), moderate (1-10/100 children per year), and low (<1/100 children per year). For all age categories, anti-infective, dermatological, and respiratory drugs were in the high use group, whereas cardiovascular and antineoplastic drugs were always in the low use group. Emollients, topical steroids, and asthma drugs had the highest prevalence of recurrent use, but relative use of low prevalence drugs was more often recurrent than acute. In the top five highest prevalence drugs topical inhaled and systemic steroids, oral contraceptives, and topical or systemic antifungal drugs were most commonly used off label. Conclusion This overview of outpatient paediatric prescription patterns in a large European population could provide information to prioritise paediatric therapeutic research needs.

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

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.

Women encounter ADRs more often than do men

BackgroundSeveral publications indicate that the female gender experiences a higher incidence of adverse drug reactions (ADRs) than does the male gender. The reasons, however, remain unclear. Gender-specific differences in the pharmacokinetic and pharmacodynamic behaviour of drugs could not be identified as an explanation. The aim of this study was to analyse ADR risk with respect to gender, age and number of prescribed drugs.MethodsA prospective multicenter study based on intensive pharmacovigilance was conducted. Information on patient characteristics and evaluated ADRs was stored in a pharmacovigilance database—KLASSE.ResultsIn 2,371 patients (1,012 female subjects), 25,532 drugs were prescribed. In 782 patients, at least one ADR was found. A multivariate regression analysis adjusting for age, body mass index (BMI) and number of prescribed drugs showed a significant influence of female gender on the risk of encountering ADRs [odds ratio (OR) 1.596, confidence interval (CI) 1.31–1.94; p < 0.0001). Dose-related ADRs (51.8%) were the dominant type in female subjects. Comparing system organ classes of the World Health Organisation (SOC-WHO), cardiovascular (CV) ADRs were particularly frequent in female subjects (OR 1.92, CI 1.15–3.19; p = 0.012).ConclusionOur data confirm the higher risk of ADRs among female subjects compared with a male cohort. Several explanations were investigated. No single risk factor could be identified.

Defining off-label and unlicensed use of medicines for children: Results of a Delphi survey

The aim of this Delphi survey is to develop common definitions for unlicensed and off-label drug use in children to be used for research and regulatory purposes. After a literature review on the current status of unlicensed/off-label definitions, a two-stage, web-based Delphi survey was conducted among experts in Europe. Their opinion on concerns, rules and scenarios regarding the unlicensed and off-label use of medicines were obtained. Results were then consulted with the European Medicines Agency (EMEA) before the final proposal was circulated to participants. Eighty-four experts were invited to participate (scientists, health professionals, pharmaceutical companies, regulatory agencies), 34 responded to the first round questionnaire and participated in subsequent rounds. Consensus was reached for the majority of questions. The lowest level of consensus reached was for questions related to a different formulation or if a drug was given although contraindicated. At the final step, 85% of the responding experts agreed on the proposed definition for off-label (use of a drug already covered by a Marketing Authorisation, in an unapproved way) and 80% on the definition for unlicensed (use of a drug not covered by a Marketing Authorisation as medicinal for human use), respectively. Results will facilitate the conduct of pharmacoepidemiological studies and allow comparison between different countries. The Delphi panel agreed that the definitions should be circulated within the scientific community and recommended to be adopted by relevant regulatory authorities.

Role of P-Glycoprotein Inhibition for Drug Interactions : Evidence from In Vitro and Pharmacoepidemiological Studies

ObjectivesWe determined in vitro the potency of macrolides as P-glycoprotein inhibitors and tested in hospitalised patients whether coadministration of P-glycoprotein inhibitors leads to increased serum concentrations of the P-glycoprotein substrates digoxin and digitoxin.MethodsIn vitro, the effect of macrolides on polarised P-glycoprotein-mediated digoxin transport was investigated in Caco-2 cells. In a pharmacoepidemiological study, we analysed the serum digoxin and digitoxin concentrations with and without coadministration of P-glycoprotein inhibitors in hospitalised patients.ResultsAll macrolides inhibited P-glycoprotein-mediated digoxin transport, with concentrations producing 50% inhibition (IC50) values of 1.8, 4.1, 15.4, 21.8 and 22.7 μmol/L for telithromycin, clarithromycin, roxithromycin, azithromycin and erythromycin, respectively. Coadministration of P-glycoprotein inhibitors was associated with increased serum concentrations of digoxin (1.3 ± 0.6 vs 0.9 ± 0.5 ng/mL, p < 0.01). Moreover, patients receiving macrolides had higher serum concentrations of cardiac glycosides (p < 0.05).ConclusionMacrolides are potent inhibitors of P-glycoprotein. Drug interactions between P-glycoprotein inhibitors and substrates are likely to occur during hospitalisation.

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

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.

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

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.

Risk Factors Associated with Adverse Drug Reactions Following Hospital Admission : A Prospective Analysis of 907 Patients in Two German University Hospitals

AbstractBackground: Since the 1970s, studies have examined potential risk factors associated with adverse drug reactions (ADRs) in a variety of settings. However, no pharmacoepidemiological study exists that incorporates clinical and laboratory parameters in a multiple regression model in order to consider predictors for ADRs. Objectives: To characterize risk factors associated with ADRs in patients admitted to university hospital departments of internal medicine. Design and Setting: Intensive pharmacovigilance was carried out in departments of internal medicine of two university hospitals. All admissions were followed prospectively for the occurrence of ADRs by members of a pharmacoepidemiological team consisting of physicians, pharmacologists and pharmacists. To identify patients at high risk for experiencing ADRs, patient histories and several clinical and laboratory data, determined at the time of admission, were taken into consideration. In addition to the drug prescribed, 40 parameters defined vital status at admission. These included temperature, heart rate, blood pressure (systolic-diastolic), body mass index, nicotine and alcohol use, and first laboratory test results after admission on nutrition status, inflammation, liver, kidney, pancreas or thyroid status, electrolytes, blood count and coagulation. Results: 907 patients were observed during the study period. The mean age of the study population was 60 + 16 years. The median number of different drugs administered per patient during hospitalization was 9.6 + 7.7. In 345 patients, 592 ADRs were evaluated: 33.4% possible, 61.5% probable and 4.7% highly probable. Two ADR-related deaths were observed during the study period. Analysing ADR predictors, 17 of 40 parameters reached significance in univariate analysis, but only five in a multivariate binary regression model: raised temperature (odds ratio [OR] 1.609; 95% CI 1.133, 2.285), low erythrocyte levels (OR 0.386; 95% CI 0.194, 0.768), low thrombocyte levels (OR 0.788, 95% CI 0.627, 0.989), high number of drugs (OR 1.117; 95% CI 1.076, 1.159) and female sex (OR 1.562; 95% CI 0.785, 2.013) were independent predictors for ADRs. Conclusion: For the patients investigated, of the large number of clinical data available only five independent factors predict ADR occurrence. Taking these results into account, physicians will be able to focus early on patients at risk for ADRs. To minimize ADR occurrence, ADR predictors should be integrated into the clinical pathway.

An increase in the prevalence of type 1 and 2 diabetes in children and adolescents: results from prescription data from a UK general practice database

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Increasing antidiabetic drugs use in youths has been reported in the USA, however there is a lack of epidemiological evidence in the UK. There is an increase in the prevalence of both type 1 and 2 diabetes, but precise estimates are difficult to obtain and as such are uninformative for future health services planning. WHAT THIS STUDY ADDS The prevalence of children receiving insulin and oral antidiabetic drugs has increased twofold and eightfold, respectively, between 1998 and 2005. The data reflect the prevalence of both type 1 and type 2 diabetes rapidly increase in recent years. The prevalence of antidiabetic drug use increases with increasing age, especially among those aged 12-18 years. Consideration needs to be given to the funding and design of future services for children and particularly adolescents with diabetes to take account of these epidemiological findings. AIMS Despite evidence of an increase in the incidence of both type 1 and type 2 diabetes in youths, there are few data on the prevalence of either type in children and adolescents. The aim of this study was to investigate the prevalence of childhood diabetes over an 8-year period in the UK. METHODS This was a retrospective cohort study that covered 8 years (January 1998 to December 2005) of UK IMS Disease Analyzer (IMS DA) data. The cohort comprised all children and adolescents aged 0-18 years who received at least one antidiabetic drug prescription during the study period. The prevalence of antidiabetic drug prescribing was used as a proxy for diabetes itself. RESULTS Data were available on 505 754 children aged 0-18 years and a total of 37 225 antidiabetic prescriptions were issued. Insulin use increased significantly from 1.08 per 1000 children [95% confidence interval (CI) 0.96, 1.20] in 1998 to 1.98 (95% CI 1.80, 2.10) in 2005 (P < 0.001), more markedly in those aged 12 and 18 years. The use of oral antidiabetic drugs for diabetes treatment rose significantly from 0.006 per 1000 children in 1998 (95% CI 0.0043, 0.017) to 0.05 (95% CI 0.025, 0.080) (P < 0.001) in 2005. CONCLUSIONS This study indicates a significant increase in prevalence on both type 1 and type 2 diabetes treatment in children and adolescents in the UK. Thus, this supporting evidence from other sources that the prevalence of childhood diabetes is rising rapidly. Further epidemiological studies are required to investigate the aetiology and risk factors.