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Aims To estimate the 3 month prevalence of adverse drug events (ADEs), categories of ADEs and preventable ADEs, and the preventability of ADEs among adults in Sweden. Further, to identify drug classes and organ systems associated with ADEs and estimate their seriousness. Methods A random sample of 5025 adults in a Swedish county council in 2008 was drawn from the Total Population Register. All their medical records in 29 inpatient care departments in three hospitals, 110 specialized outpatient clinics and 51 primary care units were reviewed retrospectively in a stepwise manner, and complemented with register data on dispensed drugs. ADEs, including adverse drug reactions (ADRs), sub-therapeutic effects of drug therapy (STEs), drug dependence and abuse, drug intoxications from overdose, and morbidities due to drug-related untreated indication, were detected during a 3 month study period, and assessed for preventability. Results Among 4970 included individuals, the prevalence of ADEs was 12.0% (95% confidence interval (CI) 11.1, 12.9%), and preventable ADEs 5.6% (95% CI 5.0, 6.2%). ADRs (6.9%; 95% CI 6.2, 7.6%) and STEs (6.4%; 95% CI 5.8, 7.1%) were more prevalent than the other ADEs. Of the ADEs, 38.8% (95% CI 35.8–41.9%) was preventable, varying by ADE category and seriousness. ADEs were frequently associated with nervous system and cardiovascular drugs, but the associated drugs and affected organs varied by ADE category. Conclusions The considerable burden of ADEs and preventable ADEs from commonly used drugs across care settings warrants large-scale efforts to redesign safer, higher quality healthcare systems. The heterogeneous nature of the ADE categories should be considered in research and clinical practice for preventing, detecting and mitigating ADEs.

Purpose To assess refill adherence to dispensed oral long-term medications among the adult population and to investigate whether the percentages of self-reported adverse drug reactions (ADRs) and sub-therapeutic effects (STEs) differed for medications with adequate refill adherence, oversupply, and undersupply. Method Survey responses on self-reported ADRs and STEs were linked to the Swedish Prescribed Drug Register in a cross-sectional population-based study. Refill adherence to antihypertensive, lipid-lowering, and oral anti-diabetic medications was measured using the continuous measure of medication acquisition (CMA). The percentages of self-reported ADRs and STEs were compared between medications with adequate refill adherence (CMA 0.8–1.2), oversupply (CMA > 1.2), and undersupply (CMA 0.5) for ADRs and 1.1%, 1.6%, and 1.5% (p > 0.5) for STEs. Conclusions Adequate refill adherence was found in two thirds of the medication therapies. ADRs and STEs were unexpectedly equally commonly reported for medications with adequate refill adherence, oversupply, and undersupply. These results suggest that a better understanding of patients' refill behaviors and their perceived medication adverse outcomes is needed and should be considered in improving medication management. The impact of individual and healthcare factors that may influence the association between refill adherence and reported medication adverse outcomes should be investigated in future studies. Copyright © 2013 John Wiley & Sons, Ltd.

PURPOSE: Several studies indicate that the medical burden of fatal adverse drug reactions (FADRs) is significant, but the preventability of FADRs in the general population is largely unknown. The a ...

BACKGROUND: Tramadol is a weak opioid analgesic, which is generally considered to be safe. However, conflicting data exist on the dependence potential of tramadol. OBJECTIVE: The aim of this study ...

In a systematic screening of the World Health Organization Adverse Drug Reaction database, VigiBase, in July 2008, a measure of association used to detect interactions (Omega) highlighted azithromycin with the individual statins atorvastatin, lovastatin and simvastatin and rhabdomyolysis. The aim was to examine all reports including rhabdomyolysis-azithromycin and statins in VigiBase to assess if the data were suggestive of an interaction.The individual case reports in VigiBase and the original files were reviewed. In order to investigate the reporting over time for rhabdomyolysis with azithromycin and statins to VigiBase, Omega values were generated retrospectively.The reporting over time showed that rhabdomyolysis under concomitant use of azithromycin and statins was reported more often than expected from 2000 and onwards in Vigibase. After exclusion of possible duplicates and follow-up reports, 53 cases from five countries remained. Rhabdomyolysis occurred shortly after initiation of azithromycin in 23% of cases. In 11 patients an interaction had been suggested by the reporter. With the exception of one patient, the statin doses reported were within the recommended daily doses.Case reports in VigiBase are suggestive that interactions between azithromycin and statins resulting in rhabdomyolysis may occur. This analysis showed the potential of the newly developed disproportionality measure, Omega, which can help to identify drug interactions in VigiBase in the future. The results also showed that reviewing spontaneous reports can add information to drug interactions not established previously.

Spontaneously Reported Suspected Adverse Drug Reactions in Association with Complementary and Alternative Medicine Products

* Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal. * The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%. * In previous studies the incidence of fatal adverse drug reactions in hospitalized patients has been reported, but the incidence of fatal adverse drug reactions in the general population is largely unknown.* Fatal adverse drug reactions account for approximately 3% of all deaths in the general population. * Haemorrhages amount to almost two-thirds of the fatal adverse drug reactions and antithrombotic agents are implicated in more than half of the suspected fatal adverse drug reactions. * Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden.To determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population.Every seventh randomly selected deceased in three counties in South-east Sweden during 1 January 2001-31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centres and medicolegal files) were reviewed to identify suspected drug-related fatalities.Of 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal haemorrhages (n = 18; 37%), central nervous system haemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other haemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs.The medical burden of FADRs is significant. Haemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs.

To describe spontaneously reported cases of torsades de pointes (TdP) in Sweden and to investigate if this adverse drug reaction (ADR) was labelled in the summary of product characteristics (SPC) for the drugs implicated.Reported cases of TdP 1991-2006 were identified and evaluated with regard to drug use and other possible risk factor.Among a total of 61 788 ADRs, 88 cases of TdP were identified. In these cases, 27 different suspected drugs were implicated. Cardiac drugs were involved in most reports (74%; 65/88), with sotalol being the most frequently suspected drug (57%, 58/88). In addition to drug treatment two or more established risk factors were present in 85% of the cases (75/88). Heart disease (90%; 79/88) was the most common risk factor followed by age over 65 years (72%; 63/88) and female gender (70%; 62/88). TdP or QT prolongation were labelled in the SPC for 33% (9/27) of the drugs implicated in the 88 cases. However, supporting evidence for an association was found elsewhere in 56% (15/27) for the different drugs implicated in the reports. Although citalopram was the third most common suspected drug in the reports (10%; 9/88), TdP was not listed in the SPC.TdP is a rarely reported ADR. Several risk factors are often present. In two thirds of the drugs implicated in the reports neither TdP nor QT prolongation was labelled in the SPC. Further investigations are needed regarding the association between citalopram and TdP.

1. Several studies suggest an association between venous thromboembolism and the use of antipsychotic drugs, especially clozapine, but the biological mechanisms are unknown. It has been suggested that antipsychotic drugs enhance aggregation of platelets and thereby increase the risk of venous thrombosis. The purpose of the present study was to examine the effects of clozapine and its main metabolite, N-desmethyl clozapine, as well as olanzapine, risperidone and haloperidol, on platelet adhesion and aggregation and on plasma coagulation in vitro. 2. Blood was collected from healthy subjects free of medication. Platelet adhesion to different protein surfaces and aggregation were measured in microplates. The coagulation methods of activated partial thromboplastin time (APTT) and prothrombin time were performed in platelet-poor plasma. 3. Clozapine was the only compound that increased platelet adhesion and aggregation and shortened APTT. The effect appeared at therapeutic concentrations and was significant but weak. 4. This weak effect of clozapine on haemostasis may explain, in part, the association of this compound and venous thromboembolism.

To evaluate the frequency, severity and preventability of warfarin-induced cerebral haemorrhages due to warfarin and warfarin-drug interactions in patients living in the county of Ostergötland, Sweden.All patients with a diagnosed cerebral haemorrhage at three hospitals during the period 2000-2002 were identified. Medical records were studied retrospectively to evaluate whether warfarin and warfarin-drug interactions could have caused the cerebral haemorrhage. The proportion of possibly avoidable cases due to drug interactions was estimated.Among 593 patients with cerebral haemorrhage, 59 (10%) were assessed as related to warfarin treatment. This imply an incidence of 1.7/100,000 treatment years. Of the 59 cases, 26 (44%) had a fatal outcome, compared to 136 (25%) among the non-warfarin patients (p0.01). A warfarin-drug interaction could have contributed to the haemorrhage in 24 (41%) of the warfarin patients and in 7 of these (12%) the bleeding complication was considered being possible to avoid.Warfarin-induced cerebral haemorrhages are a major clinical problem with a high fatality rate. Almost half of the cases was related to a warfarin-drug interaction. A significant proportion of warfarin-related cerebral haemorrhages might have been prevented if greater caution had been taken when prescribing drugs known to interact with warfarin.

Purpose One of the main methods for monitoring the safety of marketed drugs is spontaneously reporting of suspected adverse drug reactions (ADRs). The objective of this study was to describe the pattern of spontaneously reported fatal adverse drug reactions (FADRs) by analysing data from the national spontaneous reporting system in Sweden. Methods In Sweden it is compulsory to report all new or serious suspected ADRs to the Medical Products Agency. The information in these reports is stored in the national database SWEDIS (Swedish Drug Information System). All suspected FADRs reported to SWEDIS between 1 January 1995 and 31 December 2004 were reviewed and analysed. Results During the study period 990 reports of FADRs were found. The main distribution of suspected FADRs was: haemorrhages (n = 603; 60.9%), blood and bone marrow dysfunction (n = 71; 7.2%), sudden death (n = 38; 3.8%) and pulmonary embolism (n = 30; 3.0%). Antithrombotic agents were the drugs most frequently implicated in the FADRs (n = 605; 61.1%). Vitamin K antagonists were reported in 453 cases (45.8%) and acetylsalicylic acid in 82 cases (8.3%). Among the fatalities with blood and bone marrow dysfunction methotrexate was the most frequently reported drug. For sudden death and pulmonary embolism, antipsychotics and oestrogen containing drugs, respectively, were most commonly reported. Conclusions Bleeding complications amounted more than half of all reports of FADRs and vitamin K antagonists were implicated in most of these reports. However, as spontaneous reporting systems are primarily set up for signalling purposes, the data must be interpreted with utmost care. Copyright © 2006 John Wiley & Sons, Ltd.

Background. We wanted to study the incidence of venous thromboembolism (VTE), acquired risk factors of VTE and preventable cases among users of combined oral contraceptives (COCs). Methods. Al ...

OBJECTIVE: This study was carried out in order to investigate the utilization pattern of metamizole to better estimate the quantitative risk of agranulocytosis since a cluster of such cases have be ...

PURPOSE: To assess the occurrence and pattern of adverse drug reactions as a cause for acute hospital admission.METHODS: In 681 randomly selected patients, acutely admitted to a clinic of internal ...

Aims The study was carried out in order to assess the effects of gender and the use of oral contraceptives (OCs) on CYP2D6 and CYP2C19 activities in healthy volunteers. Methods Six hundred and eleven Caucasian volunteers (330 males and 281 females; age range 18–49 years) were phenotyped with respect to CYP2D6 and CYP2C19 by means of the probe drugs dextromethorphan and mephenytoin, respectively. Extensive metabolisers were selected for this study. Results The median dextromethorphan/dextrorphan metabolic ratio in non-OC using females was significantly lower than in males (0.067 vs 0.080; P = 0.033) (mean difference in ln dextromethorphan/dextrorphan metabolic ratio 0.023, 95% CI 0.03–0.43). For the mephenytoin S/R ratio, no such difference was observed. However, OC using females had a significantly higher median mephenytoin S/R ratio than non-OC using females (0.230 vs 0.090; P

Aims To assess the effects of caffeine on the pharmacokinetics of clozapine in healthy volunteers. Methods This was an open label randomized crossover study in 12 nonsmoking healthy male volunteers. The subjects received a single oral dose of 12.5 mg clozapine in each phase with or without concomitant intake of caffeine (mean dose: 550 mg day−1, range: 400–1000 mg day−1 ). Serum concentrations of clozapine and its metabolites desmethyl-clozapine and clozapine-N-oxide were measured during a 48 h period in each phase. In addition, serum concentrations of caffeine and the metabolite paraxanthine were monitored. Results A 19% increase in mean clozapine AUC(0,∞) (P=0.05) and a 14% decrease of mean oral clearance of clozapine were observed during concomitant intake of caffeine (P=0.05) compared with intake of only clozapine. Statistically significant decreases of mean ratios between AUC(0,12h) for desmethyl-clozapine and AUC(0,12h) for clozapine (−18%), and between AUC(0,12h) for clozapine-N-oxide and AUC(0,12h) for clozapine (−23%) were observed during the caffeine phase (P=0.03 and 0.02, respectively). Oral clearance of clozapine and the ratio AUC(0,12h) for desmethyl-clozapine/AUC(0,12h) for clozapine were correlated with the paraxanthine/caffeine ratio in serum after intake of caffeine (rs=0.62; P=0.03 and rs=0.77; P=0.003, respectively). Conclusions These results suggest that caffeine in daily doses of 400–1000 mg inhibits the metabolism of clozapine to an extent that might be clinically significant in certain individuals.