Warfarin-associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system

AIMS

To study warfarin associated bleeding events reported to the Norwegian spontaneous reporting system and evaluate the differences in assessment of potentially interacting medicines between reporters and evaluators.

METHODS

Data on bleeding events on warfarin were retrieved from the Norwegian spontaneous reporting system database. Key measurements were time to bleeding, use of concomitant medications and the evaluation done by reporters.

RESULTS

In 289 case reports a total of 1261 medicines (median 4.0 per patient, range 1–17) was used. The evaluators (authors of this article) identified 546 medicines including warfarin (median 2.0 per patient, range 1–7) that could possibly cause bleeding alone or in combination. Reporters assessed 349 medicines (median 1.0 per patient, range 1–4) as suspect. Evaluators identified 156 pharmacokinetic and 101 pharmacodynamic interactions, compared with 19 pharmacokinetic and 56 pharmacodynamic interactions reported as suspected by the reporters. Time to bleeding was stated in 224 reports. Among the early bleeding events, the reports on warfarin without interacting medicines showed the highest INR (international normalized ratio). Heparin was used in 17/21 reported bleeding events during the first week on warfarin. Among the late bleeding events, reports with pharmacokinetic interacting medicines had the highest INR.

CONCLUSIONS

Concomitant use of potentially interacting medicines was involved in the majority of the warfarin-associated bleeding events reported to the Norwegian spontaneous reporting system. Reporters assessed mostly warfarin as the only contributor to bleeding. In particular, pharmacokinetically interacting medicines were not suspected as contributing to bleeding.     

Medication incidents reported to an online incident reporting system

Aims  

Approximately 20% of deaths from adverse events are related to medication incidents, costing the NHS an additional ￡500 million annually. Less than 5% of adverse events are reported. This study aims to assess the reporting rate of medication incidents in NHS facilities in the north east of Scotland, and to describe the types and outcomes of reported incidents among different services. Furthermore, we wished to quantify the proportion of reported incidents according to the reporters’ profession.     

Gender differences in the adverse events associated with cardiovascular drugs in a spontaneous reporting system in South Korea

Background Studies on disease-related gender differences in pharmacodynamics and pharmacokinetics are prevalent; however, gender differences in the drug-related adverse events have not been systemically described. Objective To explore gender differences in the adverse events associated with cardiovascular drugs using a spontaneous reporting system. Setting This study was conducted using the Korea adverse event reporting system and national health insurance databases. Methods The number of reported adverse events was divided by the number of patients diagnosed with cardiovascular diseases (Korean Standard Classification of Disease, 7th Revision, I05–I70) and prescribed cardiovascular drugs. We calculated adverse event reporting rates per 100,000 persons and the reporting ratio for women, compared with men. Main outcome measures Reporting ratios across the groups of adverse events and cardiovascular drugs. Results We identified 27,533 adverse events associated with cardiovascular drugs and 9,413,666 patients with cardiovascular disease. Compared with men, reporting ratios of women were higher in the following categories: Overall (1.09, 95% CI, 1.06–1.11), beta blockers (1.20, 95% CI, 1.05–1.39), and calcium channel blockers (1.14, 95% CI, 1.03–1.27). For the adverse events, the reporting ratio was 1.34 (95% CI, 1.14–1.58) for musculoskeletal disorders and 2.54 (95% CI, 2.10–3.07) for oedema in women. Conclusion Our findings on differential adverse events reporting rates associated with the cardiovascular drugs between women and men provide an evidence on possible gender differences in wide range of pharmacotherapy. A clear understanding of the relationship between drug-induced adverse events and gender will aid in the development of therapeutic interventions being tailored to the individual patients.

     

Retrospective analysis of medication incidents reported using an on-line reporting system

Objective To examine the types of prescribing, administration and dispensing incidents reported to an on-line incident-reporting scheme and determine the types of healthcare professionals responsible for reporting such incidents. Method Retrospective analysis of medication-related incidents reported to an on-line incident-reporting scheme in a large (1000-bed) teaching hospital in the UK. Main outcome measures Frequency and type of incidents, the discipline of the health care professional who reported the incident and the stage in the medication use process (prescribing, dispensing, or administration) at which the incident occurred. Results Over a 26-month study period, there were 495 medication-related incidents reported, of which 38.6% (191) were classified to be a “near miss”. Medication-related incidents were reported most often at the stages of administration (230, 46.5%) and prescribing (192, 38.8%), whilst incidents involving dispensing or supply of medication were reported less often (73, 14.7%). Of all the incidents, pharmacists reported 51.9% (257), nursing staff reported 37.6% (186), and doctors reported 9.1% (45). Cardiovascular (149, 30.1%), central nervous system (106, 21.4%), and antibiotic/anti-infective medication (71, 14.3%) were the most common therapeutic categories associated with reports of medication-related incidents. Conclusion An on-line reporting scheme can be used to monitor medication-related incidents at key stages in the medication-use process in secondary care. The types of incidents reported by health care professionals differ markedly, with fewer medication-related incidents being reported by doctors. Future research should explore the prevailing safety culture amongst the different health care disciplines, and examine the impact that information technology has on the willingness of health care professionals to report adverse incidents.     

Retrospective analysis of medication incidents reported using an on-line reporting system

Objective

To examine the types of prescribing, administration and dispensing incidents reported to an on-line incident-reporting scheme and determine the types of healthcare professionals responsible for reporting such incidents.

Method

Retrospective analysis of medication-related incidents reported to an on-line incident-reporting scheme in a large (1000-bed) teaching hospital in the UK.

Main outcome measures

Frequency and type of incidents, the discipline of the health care professional who reported the incident and the stage in the medication use process (prescribing, dispensing, or administration) at which the incident occurred.

Results

Over a 26-month study period, there were 495 medication-related incidents reported, of which 38.6% (191) were classified to be a “near miss”. Medication-related incidents were reported most often at the stages of administration (230, 46.5%) and prescribing (192, 38.8%), whilst incidents involving dispensing or supply of medication were reported less often (73, 14.7%). Of all the incidents, pharmacists reported 51.9% (257), nursing staff reported 37.6% (186), and doctors reported 9.1% (45). Cardiovascular (149, 30.1%), central nervous system (106, 21.4%), and antibiotic/anti-infective medication (71, 14.3%) were the most common therapeutic categories associated with reports of medication-related incidents.

Conclusion

An on-line reporting scheme can be used to monitor medication-related incidents at key stages in the medication-use process in secondary care. The types of incidents reported by health care professionals differ markedly, with fewer medication-related incidents being reported by doctors. Future research should explore the prevailing safety culture amongst the different health care disciplines, and examine the impact that information technology has on the willingness of health care professionals to report adverse incidents.     

上海市药品不良反应自发呈报数据库中神经系统药物不良反应的信号检测

目的对上海市药品不良反应自发呈报数据库进行神经系统药物不良反应（ADR）信号检测,并研究已知ADR报告对ADR信号检测效率的影响。方法建立ADR信息库以自动判别ADR数据库中已知ADR报告,采用PRR信号检测算法对上海市2004--2007年药品不良反应自发呈报数据库进行信号检测,并计算可解释度以评价检出的信号。结果建立了包含1261种药物,4238种药物-事件组合的神经系统ADR信息库;筛除已知ADR报告后神经系统ADR信号检出率提高了24．64％;经信号检测获得神经系统ADR信号98条,包括卡培他滨-咽下困难、吗替麦考酚酯-视觉异常、头孢他啶-精神病等值得关注的信号。结论筛除已知报告能显著提高神经系统ADR信号的检测效率。     

QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system

BACKGROUND: Recent case series have associated the synthetic opioid, methadone, with QT prolongation and torsades de pointes (TdP) ventricular arrhythmia. STUDY OBJECTIVE: To review and analyze adverse events (QT prolongation and TdP) reported to the Food and Drug Administration (FDA) to determine the patient characteristics, dosages of methadone, and outcomes of methadone-treated patients. METHODS: The study design was a retrieval and retrospective analysis of reports of adverse events associated with methadone voluntarily reported to the FDA MedWatch program from 1969 to October 2002. Reports were accessed via QSCAN (DrugLogic, Reston, VA), a commercially available software interface. RESULTS: In a total of 5,503 reports of adverse events associated with methadone, 43 (0.78%) noted the occurrence of TdP and 16 (0.29%) QT prolongation. Doses were reported in 42/59 (71%) of cases; mean dose was 410 +/- 349 mg/day (median 345, range 29-1680). The dosages for 10 of the 42 cases (29%) were within the recommended range for methadone maintenance treatment, 60-100 mg/day. Female gender, interacting medications, hypokalemia, hypomagnesemia, and structural heart disease, risk factors previously identified with other drugs known to cause TdP, were found in 44 (75%) cases. Most adverse events required hospitalization or resulted in prolonged hospitalization (28/59, 47%) and 5/59 (8%) were fatal. CONCLUSIONS: Cases of TdP associated with methadone have been reported to the FDA MedWatch system. Analysis of the cases provides evidence that prolonged QT and TdP can occur over a wide range of dosages including those usually recommended for addiction treatment.     

Signalling possible drug–drug interactions in a spontaneous reporting system: delay of withdrawal bleeding during concomitant use of oral contraceptives and itraconazole

AIMS: In spontaneous adverse drug reaction reporting systems, there is a growing need for methods facilitating the automated detection of signals concerning possible adverse drug reactions. In addition, special attention is needed for the detection of adverse drug reactions resulting from possible drug-drug interactions. We describe a method for detecting possible drug-drug interactions using logistic regression analysis to calculate ADR reporting odds ratios. METHODS: To illustrate this method, we analysed the adverse drug reaction 'delayed withdrawal bleeding' resulting from a possible interaction between itraconazole and oral contraceptives in reports received by the Netherlands Pharmacovigilance Foundation LAREB between 1991 and 1998. RESULTS: In total 5,503 reports were included in the study. The odds ratio, adjusted for year of reporting, age and source of the reports, for a delayed withdrawal bleeding in women who used both drugs concomitantly compared with women who used neither oral contraceptives, nor itraconazole, was 85 (95% CI: 32-230). CONCLUSIONS: Since spontaneous reporting systems can only generate signals concerning possible relationships, this association needs to be analysed by other methods in more detail in order to determine the real strength of the relationship. This approach might be a promising tool for the development of procedures for automated detection of possible drug-drug interactions in spontaneous reporting systems.     

A computerized system for detecting signals due to drug–drug interactions in spontaneous reporting systems

AIMS

In spontaneous reporting systems (SRS), there is a growing need for the automated detection of adverse drug reactions (ADRs) resulting from drug–drug interactions. In addition, special attention is also needed for systems facilitating automated data preprocessing. In our study, we set up a computerized system to signal possible drug–drug interactions by which data acquisition and signal detection could be carried out automatically and the process of data preprocessing could also be facilitated.

METHODS

This system was developed with Microsoft Visual Basic 6.0 and Microsoft Access was used as the database. Crude ADR reports submitted to Shanghai SRS from January 2007 to December 2008 were included in this study. The logistic regression method, the Ω shrinkage measure method, an additive model and a multiplicative model were used for automatic detection of drug–drug interactions where two drugs were used concomitantly.

RESULTS

A total of 33 897 crude ADR reports were acquired from the SRS automatically. The 10 drug combinations most frequently reported were found and the 10 most suspicious drug–drug ADR combinations for each method were detected automatically after the performance of the system.

CONCLUSIONS

Since the detection of drug–drug interaction depends upon the skills and memory of the professionals involved, is time consuming and the number of reports is increasing, this system might be a promising tool for the automated detection of possible drug–drug interactions in SRS.     

一种ADR信号检测的改进算法及其在上海市ADR自发呈报数据库上的应用

目的 建立改进的信号检测算法并评估其实际检测效果.方法 建立基于新ADR报告(NAR)的信号检测算法;通过理论分析和实际演算比较基于报告数(REP)和基于药物-不良事件组合(DEC)两种算法的ADR检测效果,评估数据库中已知ADR报告对信号检测的影响;并将NAR算法应用于上海市ADR自发呈报数据库.结果 ①对上海市ADR自发呈报数据库部分数据(2006～2007年)进行了信号检测计算,结果发现基于DEC的算法会产生不合逻辑的虚假信号,而基于REP的算法能避免产生这类信号并能发现被DEC算法忽略的有价值信号;筛除已知ADR报告能提高信号检出率57%.②建立了包含2 650种药物,27 230种DEC的已知ADR数据库,可自动筛选NAR.③采用基于NAR的信号检测算法对上海市2004～2007年ADR自发呈报数据库进行检测,产生信号380条,包括加替沙星-低血糖反应、头孢他啶-过敏性休克,菌栀黄-荨麻疹等值得关注的信号.结论 基于NAR的算法能显著提高ADR信号的检测效率.     

Determinants of signal selection in a spontaneous reporting system for adverse drug reactions

AIMS: Detection of new adverse drug reactions (ADR) after marketing is often based on a manual review of reports sent to a Spontaneous Reporting System (SRS). Among the many potential signals that are identified, only a limited number are important enough to require further attention. The goal of this study is to gain insight into factors contributing to the selection and dissemination of possible signals originating from the SRS maintained by the Netherlands Pharmacovigilance Foundation. METHODS: In a case control design, all signals (n = 42) disseminated to the Medicines Evaluation Board from the second quarter of 1997 until the third quarter of 2000, which could be expressed as a combination of a single ATC code and a single WHO preferred term, were included. For each case, four controls were matched in time. Logistic regression analysis was used to investigate the influence of various factors, such as the fact whether the ADR or drug is new, the strength of the association, the seriousness of the reaction and the documentation of the reports. RESULTS: Multivariate analysis showed that the presence of a 'serious report' (Odds Ratio 3.8, 95% CI 1.3, 11.0), a WHO 'critical term' (OR 4.7, 95% CI 1.8, 13), the ADR being unlabelled (OR 6.1, 95% CI 2.3, 16) and the presence of a disproportionate association (OR 3.5, 95% CI 1.4, 8) were all independently associated with signal selection. The number of reports and the time after marketing of the drug had no influence. CONCLUSIONS: This study showed that selection of signals is based on both qualitative and quantitative aspects. Knowledge of these factors may improve the efficiency of the underlying signal selection process.     

Dietary supplement-related adverse events reported to the California Poison Control System.

PURPOSE: Dietary supplement (DS)-related adverse events (AEs) reported to the California Poison Control System (CPCS) were studied. METHODS: The CPCS database was used to search for all telephone calls from consumers concerning DS-related AEs received during the six-month period between April and September 2002. The calls were characterized according to the substance involved, the caller's age (adult or pediatric), and the type of ingestion (accidental or intentional). Each exposure in which symptoms were reported was categorized as involving an AE. Each AE was assessed for severity and causality. RESULTS: Data on a total of 1183 telephone calls were retrieved, of which 828 calls (70%) met the study's inclusion criteria. DS exposure occurred in 389 adults (47%) and 438 children (53%). DS ingestion was accidental in 360 patients (43%) and intentional in 467 patients (56%). Exposure resulted in an AE in 480 patients (58%). AEs were reported in 353 patients (74%) who ingested products containing ephedra; other exposures frequently involved zinc, kava, creatine, and valerian. AEs were classified as moderate in 198 patients (41%) who ingested a DS and as severe in 40 patients (8%). One patient had a fatal reaction. Among the 480 AEs in DS-exposed consumers, the DS was classified as the definite cause of 1 AE (<1%) and a probable cause of 237 (49.4%). The most frequently reported AE symptoms were increased heart rate (45%), agitation (30%), vomiting (30%), and nausea (15%). CONCLUSION: A majority of DS-related AEs reported by consumers to CPCS involved ephedra-containing products.     

Making the most of spontaneous adverse drug reaction reporting

The primary purpose of spontaneous adverse drug reaction reporting is to provide early warnings or "signals" of previously unrecognized drug toxicity. The method was developed in the 1960s in response to the thalidomide tragedy and is now well-established throughout the developed world. Health professionals are the key original source of reports, the value of patient reporting is yet unclear. Electronic transmission of all reports is likely to become the norm within a few years. This is well-advanced between pharmaceutical companies and regulatory authorities but still in its infancy for health professionals in many parts of the world. Considered globally, the process may be inefficient and movement towards centralization of databases with appropriate access controls is logical. Alternative methods for capturing clinical suspicions of adverse drug reactions should be investigated and could provide more systematic data. However much it can be improved, spontaneous adverse drug reaction reporting is unlikely to identify all important unrecognized drug safety hazards. Complementary approaches therefore still need to be identified and developed.     

Application of quantitative signal detection in the Dutch spontaneous reporting system for adverse drug reactions.

The primary aim of spontaneous reporting systems (SRSs) is the timely detection of unknown adverse drug reactions (ADRs), or signal detection. Generally this is carried out by a systematic manual review of every report sent to an SRS. Statistical analysis of the data sets of an SRS, or quantitative signal detection, can provide additional information concerning a possible relationship between a drug and an ADR. We describe the role of quantitative signal detection and the way it is applied at the Netherlands Pharmacovigilance Centre Lareb. Results of the statistical analysis are implemented in the traditional case-by-case analysis. In addition, for data-mining purposes, a list of associations of ADRs and suspected drugs that are disproportionally present in the database is periodically generated. Finally, quantitative signal generation can be used to study more complex relationships, such as drug-drug interactions and syndromes. The results of quantitative signal detection should be considered as an additional source of information, complementary to the traditional analysis. Techniques for the detection of drug interactions and syndromes offer a new challenge for pharmacovigilance in the near future.