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.

Magnetic Active Agent Release System (MAARS): evaluation of a new way for a reproducible, externally controlled drug release into the small intestine.

Human absorption studies are used to test new drug candidates for their bioavailability in different regions of the gastrointestinal tract. In order to replace invasive techniques (e.g. oral or rectal intubation) a variety of externally controlled capsule-based drug release systems has been developed. Most of these use ionizing radiation, internal batteries, heating elements or even chemicals for the localization and disintegration process of the capsule. This embodies potential harms for volunteers and patients. We report about a novel technique called "Magnetic Active Agent Release System" (MAARS), which uses purely magnetic effects for this purpose. In our trial thirteen healthy volunteers underwent a complete monitoring and release procedure of 250 mg acetylsalicylic acid (ASA) targeting the flexura duodenojejunalis and the mid-part of the jejunum. During all experiments MAARS initiated a sufficient drug release and was well tolerated. Beside this we also could show that the absorption of ASA is about two times faster in the more proximal region of the flexura duodenojejunalis with a tmax of 47±13 min compared to the more distal jejunum with tmax values of 100±10 min (p=0.031).

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.

[Adverse drug reactions and interactions - cause of admission to hospital and after discharge]. / Unerwünschte Arzneimittelwirkungen und Interaktionen bei Krankenhausaufnahme und Entlassung.

Adverse drug reactions (ADRs) and interactions not only cause hospitalisation but also occur during the hospital stay itself. There, they contribute significantly to patient morbidity and mortality and furthermore create considerable additional costs for the healthcare systems. The majority of ADRs are dose-dependent and commonly found also for long-established and well known drugs. This is inherently related to the drug's mode of action. Accordingly, even rare side effects like rhabdomyolysis or arrhythmia turn out to be the limiting factor in the use of certain drugs which may even result in their withdrawal from the market. Detection and analysis of ADRs directly in the hospitals is therefore highly important. This provides a unique opportunity to investigate serious cases leading to hospitalisation, and, also prevent further occurrence of ADRs after discharge from hospital and thus enhance the protection of the patients. Clinically most relevant interactions have been found for drug metabolizing enzymes (e.g. CYP3A4, 1A2, 2D6), and drug efflux transporters (e.g. P-glycoprotein). Data based drug-interaction software is an important tool for physicians to either reduce ADRs or to select alternatives with lower interaction potential.

[Analysis of hospital admissions associated with digitalis glycosides]. / Fingerhut--ein alter Hut?: Eine Analyse stationärer Aufnahmen durch digitalisassoziierte unerwünschte Arzneimittelwirkungen.

BACKGROUND: Although the value of digitalis glycosides in the treatment of heart failure is limited, approximately 255 million DDDs of digitalis glycosides (DGs) were prescribed in Germany in 2004. METHOD: The authors analyzed data from adverse drug reactions (ADRs) resulting in hospitalization in the four German Pharmacovigilance Centers (PVCs) associated with DGs between 2000 and 2004. All patients with an at least "probable" ADR were included. RESULTS: Out of 3,092 ADR patients, in 314 patients (10.2%, 244 women) admission was caused by a DG-related ADR. Patients with DG-related ADR had a significantly lower body weight and were significantly older than patients with other ADRs. Per 1,000 patients exposed to DGs the incidence [95% CI] was calculated to 1.9 [1.0; 3.3] ADRs per 3 months exposition. Oral digitoxin was involved in 296 patients (228 women). 70.6% of women but only 29.3% of men were overdosed (> 1 mug/kg body weight per day). Women received significantly higher body weight-related digitoxin doses and had significantly higher digitoxin plasma levels than men. ADRs in patients with nonelevated digitoxin serum level were mainly caused by pharmacodynamic drug-drug interactions (e.g., beta-blockers). Overall, 42.4% of the ADRs were supposed to be preventable. CONCLUSION: Body weight-adapted dosing of digitoxin is essential for preventing DG-ADRs, particularly in elderly women with low body weight. Beyond giving attention to pharmacodynamic and pharmakokinetic drug-drug interactions, regular measurements of digitoxin plasma concentrations are crucial accounting for the increased half-life of digitoxin in the very old.

Inappropriate dosage instructions in package inserts.

OBJECTIVE: Regardless of all efforts by the supervisory authority and the manufacturers to ensure that package inserts are patient-oriented, they are still under discussion. The survey package insert test (PAINT) aimed to examine the availability and comprehensibility of the information contained on five package inserts and five model versions for the same drugs. METHODS: A questionnaire containing 15 questions referring to the package insert contents was developed for a written survey. In a cross-over test design, each participant received an original package insert and a newly developed model version within an interval of 4 weeks. RESULTS: One thousand one hundred and five participants gave significantly more correct answers (92.6-94.4%) to all 15 questions relating to the model package inserts, in comparison to the originals (74.7-85.8%). Most of the problems regarding the original versions were associated with the fact that the dosage instructions were given in active substance quantities rather than "tablet" or "volume", non-quantifiable phrases in the dosage instructions (e.g. take 1-3 times 2-4 tablets) and in the frequency of side effects (e.g. rare). Information regarding suitable counter measures to possible side effects, was also difficult to understand. CONCLUSION: Optimizing package inserts, particularly dosage instructions and information regarding possible side effects, is essential and achievable. PRACTICE IMPLICATIONS: Our recommendations are as follows: (1) every dose should be quantified in number of tablets or in volume; (2) use a dosage instruction table; (3) provide short and precise information only; (4) do not use non-quantifiable statements.

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.

[Severe electrolyte imbalance and edema in therapy with rosiglitazone]. / Schwere Elektrolytstörung und Odeme unter Therapie mit Rosiglitazon.

CASE REPORT: A case of a 49-year-old male with preexisting liver damage is reported. The patient was admitted to hospital with severe electrolyte disorder and face edema after therapy first with 4 mg for 2 months and later for 5 months with 8 mg rosiglitazone. The initial electrolyte values were: sodium 110 mmol/l, potassium 3.3 mmol/l, calcium 2.0 mmol/l, chloride 81 mmol/l. An already known hypercholesterolemia worsened substantially to values up to 28.5 mmol/l. Under substitution therapy with sodium chloride infusion and potassium, the electrolyte level normalized rapidly. The hypercholesterolemia improved over several weeks after stopping the drug, and the general condition of the patient improved clearly. CONCLUSION: Rosiglitazone has been certified in Germany since July 2000. Although a liver toxicity with rosiglitazone has been denied, the administration of this drug in patients with liver damage is contraindicated. Especially when prescribing new drugs one has to pay special attention to contraindications and comedication since often not all therapeutic mechanisms and side effects are fully known/understood. Interaction between different drugs and their influences on existing diseases are only noticed after a widespread application of the drug.