Inconsistencies of absolute drug-drug contraindication reports: Analysis of Summaries of Product Characteristics of commonly prescribed drugs.

AIMS: Prescribing information should follow a defined structure to help prescribers easily find required information. Often information appears in different sections of Summaries of Product Characteristics (SmPCs) in an inconsistent way. Still unknown is how this inconsistency affects absolute contraindications and how it can be improved. Thisstudy aimed to evaluate the structure of absolute contraindications in SmPCs based on absolute drug-drug contraindications (DDCI) in the section 'contraindications' and references to sections 'special warnings and precautions for use' (here as 'warnings') and 'interaction with other medicinal products and other forms of interaction' (here as 'interactions'). METHODS: SmPCs of 693 commonly prescribed drugs were analysed regarding absolute DDCI in 'contraindications' sections. References to sections on 'warnings' and 'interactions' were evaluated to characterize information provided about DDCI. RESULTS: Of 693 analysed SmPCs, 138 (19.9%) contained ≥1 absolute DDCI. Of 178 SmPCs that referred to sections on 'warnings' or 'interactions', 131 (73.6%) did not contain further information on absolute DDCI, whereas 47 (26.4%) did. Such additional information was found in sections on 'interactions' and 'warnings' in 41 (87.2%) and 9 (19.1%) SmPCs, respectively. CONCLUSIONS: Information regarding absolute DDCI was found not only in sections on 'contraindications' but also in sections on 'warnings' and 'interactions'. Information was not given with consistently straightforward phrasing and structure and so can leave uncertainty for prescribers. To improve drug safety, clear definitions and wording for absolute and relative contraindications should be provided, ideally in tables.

[Tendency to fall and injuries related to the Covid-19 pandemic at a department of emergency medicine]. / Sturzneigung und Verletzungen im Zusammenhang mit der COVID-19-Pandemie in einer Klinik für Notfallmedizin.

INTRODUCTION: This study investigates whether restrictions associated with the Covid-19 pandemic, in particular the temporary restrictions on social contacts in 2020, affected the number of inpatients admitted by the Department of Emergency Medicine of Jena University Hospital with a documented susceptibility to falls, injury or a susceptibility to falls resulting in at least one injury. METHODS: Using the ICD-10-GM code for susceptibility to falls (R29.6) and the codes for injuries (S00 to T14) from medicare claims data, the incidence rates of inpatient admissions between the years 2019 and 2020 were compared. In addition to all inpatient admissions recorded by the Department of Emergency Medicine, the cases of inpatients aged 65 years or older were considered separately, as they have an increased risk of having a fall. RESULTS: In 2020, the number of inpatient admissions in all age groups with one or more codes for injuries (S00 to T14) was significantly lower than in 2019 (2019: 19.2%, 2020: 17.3%, p<0.001). Regarding the codes for a documented susceptibility to falls (R29.6) or a documented susceptibility to falls (R29.6) with at least one injury (S00-T14), no differences were observed between the two years. In the group of inpatients 65 years or older, there were also no differences between 2019 and 2020 for any of the diagnoses considered. CONCLUSION: In this monocentric study of Jena University Hospital, it could be demonstrated for the first time that the Covid-19 pandemic had little impact on the number of inpatients admitted to the Department of Emergency Medicine with a documented diagnosis of susceptibility to falls (R29.6) and of susceptibility to falls in combination with at least one documented injury (S00-T14). As observed in previous publications, the number of inpatient admissions with documented injury diagnoses (S00 to T14) decreased.

Inconsistencies and Ambiguities in Liver-Disease-Related Contraindications-A Systematic Analysis of SmPCs/PI of Major Drug Markets.

Liver disease is a common condition worldwide that can cause alterations in drug disposition and susceptibility to drug toxicities, with increased risk of adverse drug reactions. European Summaries of Product Characteristics (SmPCs) and United States Prescribing Information (US PI) should therefore be comprehensible to prescribers regarding their liver-associated contraindications to ensure safe prescribing. This study aimed to evaluate the ambiguity of terminology used in communicating liver-associated absolute contraindications in SmPCs/PI of commonly prescribed drugs in four major drug markets (Germany, Switzerland, the United Kingdom, and the United States) by assigning wordings to different categories and analyzing their clinical comprehensibility. For US PI, 79% did not contain liver-related contraindications, compared to 2, 13, and 6% of German, Swiss, and British SmPCs, respectively. Study findings indicate that out of 228 examined SmPCs/PI containing liver-related contraindications, 77, 79, 76, and 52% contained unclear wording in the German, Swiss, British, and American drug market, respectively. Only 40% (German), 52% (Swiss), 39% (British), and 29% (American) of SmPCs/PI included terms with explicit wording. Including more precise statements in SmPCs/PI based on laboratory parameters (such as albumin) or scores (e.g., the Child-Pugh score) to objectify the severity of liver disease may improve the clarity of SmPCs/PI and the safety of drug prescription.

Adverse drug reactions in Germany: direct costs of internal medicine hospitalizations.

PURPOSE: German hospital reimbursement modalities changed as a result of the introduction of Diagnosis Related Groups (DRG) in 2004. Therefore, no data on the direct costs of adverse drug reactions (ADRs) resulting in admissions to departments of internal medicine are available. The objective was to quantify the ADR-related economic burden (direct costs) of hospitalizations in internal medicine wards in Germany. METHODS: Record-based study analyzing the patient records of about 57,000 hospitalizations between 2006 and 2007 of the Net of Regional Pharmacovigilance Centers (Germany). All ADRs were evaluated by a team of experts in pharmacovigilance for severity, causality, and preventability. The calculation of accurate person-related costs for ADRs relied on the German DRG system (G-DRG 2009). Descriptive and bootstrap statistical methods were applied for data analysis. RESULTS: The incidence of hospitalization due to at least 'possible' serious outpatient ADRs was estimated to be approximately 3.25%. Mean age of the 1834 patients was 71.0 years (SD 14.7). Most frequent ADRs were gastrointestinal hemorrhage (n = 336) and drug-induced hypoglycemia (n = 270). Average inpatient length-of-stay was 9.3 days (SD 7.1). Average treatment costs of a single ADR were estimated to be approximately €2250. The total costs sum to €434 million per year for Germany. Considering the proportion of preventable cases (20.1%), this equals a saving potential of €87 million per year. CONCLUSIONS: Preventing ADRs is advisable in order to realize significant nationwide savings potential. Our cost estimates provide a reliable benchmark as they were calculated based on an intensified ADR surveillance and an accurate person-related cost application.

Impact of N-acetyltransferase polymorphism (NAT2) in hepatocellular carcinoma (HCC)--an investigation in a department of surgical medicine.

In the multifactorial aetiology of hepatocellular carcinoma (HCC), an association and interaction between genetic polymorphisms of xenobiotic metabolizing enzymes, lifestyle factors, and cancer risk has been postulated. N-acetyltransferase (NAT2) is involved in the metabolic activation and detoxification of aromatic amines. Aromatic amines are potential hepatocarcinogens in humans. In the present study, we investigated if genetic NAT2 polymorphism is related to HCC. Genotyping of NAT2 was performed in 70 HCC patients and 87 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The results of this investigation show that 46 out 70 HCC patients (65.7%) and 50 out of 87 controls (57.5%) were of the slow acetylator genotypes. The frequency of distribution of slow and rapid acetylators (genotypes) was not significantly different between cases and controls (p > 0.05). Slow acetylator genotypes were not associated with a significantly increased HCC risk (odds ratio, 1.4; 95% confidence interval, 0.74-2.72). A significant association between NAT2 genetic polymorphism and HCC was observed among smokers. Slow acetylator genotypes significantly increased the HCC risk in cigarette smokers (odds ratio, 3.5; 95% confidence interval, 1.38-9.05). Our results suggest that genetic NAT2 polymorphism may play a role in lifestyle factors-related hepatocarcinogenesis. NAT2 activity may be particulary critical in smoking related hepatocarcinogenesis.

Adverse drug reaction monitoring in Jena. Relevance of polymorphic drug metabolizing enzymes for inducing adverse drug reactions.

Inter-subject variability in therapeutic drug response and drug toxicity is a major problem in clinical practice. In this field genetic polymorphisms of drug metabolizing enzymes play an important role. In a multicenter study supported by the German Federal Institute for Drugs and Medical Devices (BfArM, Z 12.01-68502-201) adverse drug reactions (ADRs) leading to hospital admission to departments of internal medicine have been registered and evaluated. The aim of the presented part of the study was to look for evident differences in genotypes for polymorphic drug metabolizing enzymes between adverse drug reaction cases and controls. All cases found in the local area--Jena and Weimar--were genotyped for N-acetyl-transferase 2 (NAT2), cytochrom P450 (CYP) 2D6 and 2C19 in comparison to a control population of the same region. The investigation on genotype was carried out for about 2 years (2000-2002). 254 blood samples from patients of the ADR study were analyzed. The genotype of drug metabolizing enzymes was determined by means of polymerase chain reaction using allel specific primers or restriction enzyme analysis. Within all ADRs cases genotyped, no exceptional frequencies for slow acetylators or poor metabolizers (PM) of CYP2D6 or CYP2C19 were found. About 65% of the individuals with ADR genotypically displayed a slow acetylator state. 6.3% PM for CYP2D6, including CYP2D6*3, *4 and *6 alleles, and 2.0% PM frequency for CYP2C19 (*2) have been found in ADR cases. A direct connection between PM genotype and the ADR observed may be assumed only in few of them. Further investigations on genotype and ADR-associated drugs require a much larger sample of patients to obtain more data allowing to focus an association on specific drugs, ADR and polymorphisms genotype of drug metabolizing enzymes might be useful.

Self-medication with over-the-counter and prescribed drugs causing adverse-drug-reaction-related hospital admissions: results of a prospective, long-term multi-centre study.

BACKGROUND: Self-medication, including both the use of over-the-counter (OTC) drugs and the use of formerly prescribed drugs taken without a current physician's recommendation, is a public health concern; however, little data exist regarding the actual risk. OBJECTIVE: We aimed to analyse self-medication-related adverse drug reactions (ADRs) leading to hospitalisation. METHODS: In a multi-centre, observational study covering a hospital catchment area of approximately 500,000 inhabitants, we analysed self-medication-related ADRs leading to hospital admissions in internal medicine departments. Data of patients with ADRs were comprehensively documented, and ADR causality was assessed using Bégaud's algorithm. The included ADRs occurred between January 2000 and December 2008 and were assessed to be at least 'possibly' drug related. RESULTS: Of 6,887 patients with ADRs, self-medication was involved in 266 (3.9 %) patients. In 143 (53.8 %) of these patients, ADRs were due to OTC drugs. Formerly prescribed drugs and potential OTC drugs accounted for the remaining ADRs. Most self-medication-related ADRs occurred in women aged 70-79 years and in men aged 60-69 years. Self-medication-related ADRs were predominantly gastrointestinal complaints caused by non-steroidal anti-inflammatory drugs (most frequently OTC acetylsalicylic acid [ASA, aspirin]). In 102 (38.3 %) of the patients with self-medication-related ADRs, a relevant drug-drug interaction (DDI), occurring between a self-medication and a prescribed medication, was present (most frequently ASA taken as an OTC drug and prescribed diclofenac). CONCLUSION: In the general population, self-medication plays a limited role in ADRs leading to hospitalisation. However, prevention strategies focused on elderly patients and patients receiving interacting prescribed drugs would improve patient safety.

Bleeding complications and liver injuries during phenprocoumon treatment: a multicentre prospective observational study in internal medicine departments.

BACKGROUND: Even after the recent approval of newer oral anticoagulants for clinical use, the vitamin K antagonist phenprocoumon remains an important treatment option for many patients. In order to quantify the hitherto "accepted" risks of phenprocoumon treatment, we analyzed adverse drug reactions (ADRs) that led to hospitalization on the internal medicine wards of four German pharmacovigilance centers. METHODS: We prospectively analyzed ADRs leading to hospitalization on the internal medicine wards of the hospitals belonging to the German Network of Regional Pharmacovigilance Centers (Rostock, Greifswald, Jena, and the Sophien- und Hufeland-Klinikum in Weimar) in the years 2000 to 2008. RESULTS: The 851 patients hospitalized for a phenprocoumon-associated ADR accounted for 12.4% of the 6887 ADR-related hospitalizations in the period of the study. 723 (85%) were admitted for a hemorrhage, usually in the gastrointestinal tract (482 patients); 8 patients died as a consequence of hemorrhage associated with phenprocoumon exposure. Using drug utilization data for the catchment areas of the participating hospitals, we calculate a rate of 5 to 7 hemorrhages leading to hospitalization in an internal medicine ward per 1000 patient-years under phenprocoumon treatment. One-third of the patients who had a hemorrhage were taking other interacting drugs, mainly inhibitors of platelet aggregation and non-steroidal anti-inflammatory drugs. Among the patients who were taking phenprocoumon because of a history of thromboembolic events or for atrial fibrillation, 60% to 70% of those who had hemorrhages had an international normalized ratio (INR) that was above the upper limit of the therapeutic range. Phenprocoumon-associated impairment of liver function arose in 23 patients (2.7%). CONCLUSION: In this study, about one-eighth of all ADR-related admissions to hospital internal medicine wards were associated with phenprocoumon. There is a need for a comparative risk-benefit assessment of phenprocoumon and the newer oral anticoagulants under real-life conditions.

Association of metabolic gene polymorphisms with tobacco consumption in healthy controls.

Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected.