World Health Organization Adverse Reaction Research Articles

Incidence of urticaria, angioedema, and type I hypersensitivity reactions associated with fibrinolytic agents in Thailand using the database of the health product vigilance center.

Besides hemorrhage, allergic reactions have also been observed in several clinical trials of fibrinolytic agents. These reactions might negatively affect patient outcomes, especially life-threatening type I hypersensitivity reactions such as anaphylaxis. However, there are limited data on the incidence of these reactions. The aim of study was to analyze the incidence of urticaria, angioedema, and type I hypersensitivity reactions from fibrinolytic agents for various indications. A retrospective analysis of data from the Thai Vigibase database was conducted. All reports of adverse drug reactions from fibrinolytic agents from 1984 to 2017 were identified using the World Health Organization adverse reaction terminology. The proportion of each suspected adverse drug reaction and the cumulative incidence were calculated. A total of 284 reports were identified in the Thai Vigibase database. The overall incidence of urticaria, angioedema, and type I hypersensitivity reactions for the streptokinase group was 52.64/10,000 persons, with individual incidence rates of 9.64/10,000 persons for urticaria, 8.90/10,000 persons for angioedema, and 34.11/10,000 persons for type I hypersensitivity reactions. In the alteplase group, the overall incidence for all suspected reactions was 18.90/10,000 persons, with individual incidence rates of 3.29/10,000 persons for urticaria, 5.75/10,000 persons for angioedema, and 9.86/10,000 persons for type I hypersensitivity reactions. Type I hypersensitivity reactions were the most common allergic reactions from fibrinolytic agents. It is necessary to take these reactions into consideration when using fibrinolytic therapy.

Study on mining of signals of adverse drug reactions of entecavir and tenofovir disoproxil based on the US FAERS database

Objective: To mine the signals of adverse drug reaction (ADR) of entecavir and tenofovir by using the US FDA Adverse Event Reporting System (FAERS) database, so as to provide reference for the safe clinical use of these two drugs. Methods: Reporting odds ratio (ROR) and proportion of report ratio (PRR) method were used to conduct data mining on the 26 quarterly reports of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database between the fourth quarter of 2012 to the first quarter of 2019. The ADR descriptive terminology in the report were standardized by using the World Health Organization Adverse Reaction Terminology (System-Organ Class). ROR and PRR methods common signals were screened. Results: 104 and 187 signals of ADR of entecavir and tenofovir dipivoxil were obtained by ROR and PRR methods. The main screened system-organ classes affected by signals of ADR of entecavir were systemic damage, hepatobiliary system damage, and urinary system damage. The main screened system-organ classes affected by signals of ADR of tenofovir were urinary system damage, skeletal and musculoskeletal system damage, and metabolic and nutritional disorders. Conclusion: The mining signals of adverse drug reaction of entecavir and tenofovir dipivoxil indicate that these two drugs can cause female reproductive system damage, fetal abnormalities, neonatal and infant abnormalities, and male reproductive system damage. However, in addition to the above-mentioned ADR, the ADR instruction manual excludes entecavir and tenofovir dipivoxil primarily for respiratory and visual system damage, and the tenofovir disoproxil primarily for skin and appendage damage, and hearing and vestibular function damage. Therefore, in clinical medication management, it is suggested to pay close attention to the choice of drugs for special population infected with HBV, monitor possible ADR during medication course, and provide pharmacological monitoring to achieve personalized medication.

Comparative Safety Profiles of Sedatives Commonly Used in Clinical Practice: A 10-Year Nationwide Pharmacovigilance Study in Korea.

This study aims to compare the prevalence and seriousness of adverse events (AEs) among sedatives used in critically ill patients or patients undergoing invasive procedures and to identify factors associated with serious AEs. Retrospective cross-sectional analysis of sedative-related AEs voluntarily reported to the Korea Adverse Event Reporting System from 2008 to 2017 was performed. All AEs were grouped using preferred terms and System Organ Classes per the World Health Organization—Adverse Reaction Terminology. Logistic regression was performed to identify factors associated with serious events. Among 95,188 AEs, including 3132 (3.3%) serious events, the most common etiologic sedative was fentanyl (58.8%), followed by pethidine (25.9%). Gastrointestinal disorders (54.2%) were the most frequent AEs. The most common serious AE was heart rate/rhythm disorders (33.1%). Serious AEs were significantly associated with male sex; pediatrics; etiologic sedative with etomidate at the highest risk, followed by dexmedetomidine, ketamine, and propofol; polypharmacy; combined sedative use; and concurrent use of corticosteroids, aspirin, neuromuscular blockers, and antihistamines (reporting odds ratio > 1, p < 0.001 for all). Sedative-induced AEs are most frequently reported with fentanyl, primarily manifesting as gastrointestinal disorders. Etomidate is associated with the highest risk of serious AEs, with the most common serious events being heart rate/rhythm disorders.

Pharmacovigilance in India and its Impact in Patient Management

ABSTRACT Pharmacovigilance is the pharmacological science relating to the detection, assessment, understanding, and prevention of adverse effects, particularly the long-term and short-term adverse effects of drugs or treatment. The World Health Organization (WHO) established pharmacovigilance Programme for International Drug Monitoring in response to the thalidomide disaster detected in 1961. India joined the WHO adverse drug reaction (ADR) monitoring program based in Uppsala, Sweden, in 1998. The Central Drugs Standard Control Organization (CDSCO), Directorate General of Health Services, under the aegis of the Ministry of Health and Family Welfare, Government of India, in collaboration with Indian Pharmacopoeia Commission, Ghaziabad, is a National Coordinating Centre (NCC). Adverse drug reaction monitoring centers (AMCs) under the Pharmacovigilance Programme of India (PvPI) play a vital role in the collection and follow-up of ADR reports from the patients, as drug trials in animals and humans (Phase I–III) do not predict accurately the adverse drug events. Patients with chronic kidney disease (CKD)/liver disease are at risk of enhanced drug-related events. These patients should be closely monitored for any adverse events and it should be reported. Thus, inculcating the habit of ADR reporting will help in generating data specific to Indian population and will contribute toward patient safety. This will also help in modifying the treatment given to the patients, as early identification of ADRs will help in reducing morbidity and mortality in patients. How to cite this article Sharma G, Kumar R, Singh J, Bhandari V, Singh N. Pharmacovigilance in India and its Impact in Patient Management. Curr Trends Diagn Treat 2017;1(1):27-33.

Ontology-Based Vaccine Adverse Event Representation and Analysis.

Vaccine is the one of the greatest inventions of modern medicine that has contributed most to the relief of human misery and the exciting increase in life expectancy. In 1796, an English country physician, Edward Jenner, discovered that inoculating mankind with cowpox can protect them from smallpox (Riedel S, Edward Jenner and the history of smallpox and vaccination. Proceedings (Baylor University. Medical Center) 18(1):21, 2005). Based on the vaccination worldwide, we finally succeeded in the eradication of smallpox in 1977 (Henderson, Vaccine 29:D7-D9, 2011). Other disabling and lethal diseases, like poliomyelitis and measles, are targeted for eradication (Bonanni, Vaccine 17:S120-S125, 1999).Although vaccine development and administration are tremendously successful and cost-effective practices to human health, no vaccine is 100% safe for everyone because each person reacts to vaccinations differently given different genetic background and health conditions. Although all licensed vaccines are generally safe for the majority of people, vaccinees may still suffer adverse events (AEs) in reaction to various vaccines, some of which can be serious or even fatal (Haber et al., Drug Saf 32(4):309-323, 2009). Hence, the double-edged sword of vaccination remains a concern.To support integrative AE data collection and analysis, it is critical to adopt an AE normalization strategy. In the past decades, different controlled terminologies, including the Medical Dictionary for Regulatory Activities (MedDRA) (Brown EG, Wood L, Wood S, et al., Drug Saf 20(2):109-117, 1999), the Common Terminology Criteria for Adverse Events (CTCAE) (NCI, The Common Terminology Criteria for Adverse Events (CTCAE). Available from: http://evs.nci.nih.gov/ftp1/CTCAE/About.html . Access on 7 Oct 2015), and the World Health Organization (WHO) Adverse Reactions Terminology (WHO-ART) (WHO, The WHO Adverse Reaction Terminology - WHO-ART. Available from: https://www.umc-products.com/graphics/28010.pdf ), have been developed with a specific aim to standardize AE categorization. However, these controlled terminologies have many drawbacks, such as lack of textual definitions, poorly defined hierarchies, and lack of semantic axioms that provide logical relations among terms. A biomedical ontology is a set of consensus-based and computer and human interpretable terms and relations that represent entities in a specific biomedical domain and how they relate each other. To represent and analyze vaccine adverse events (VAEs), our research group has initiated and led the development of a community-based ontology: the Ontology of Adverse Events (OAE) (He et al., J Biomed Semant 5:29, 2014). The OAE has been found to have advantages to overcome the drawbacks of those controlled terminologies (He et al., Curr Pharmacol Rep :1-16. doi:10.1007/s40495-016-0055-0, 2014). By expanding the OAE and the community-based Vaccine Ontology (VO) (He et al., VO: vaccine ontology. In The 1st International Conference on Biomedical Ontology (ICBO-2009). Nature Precedings, Buffalo. http://precedings.nature.com/documents/3552/version/1 ; J Biomed Semant 2(Suppl 2):S8; J Biomed Semant 3(1):17, 2009; Ozgur et al., J Biomed Semant 2(2):S8, 2011; Lin Y, He Y, J Biomed Semant 3(1):17, 2012), we have also developed the Ontology of Vaccine Adverse Events (OVAE) to represent known VAEs associated with licensed vaccines (Marcos E, Zhao B, He Y, J Biomed Semant 4:40, 2013).In this book chapter, we will first introduce the basic information of VAEs, VAE safety surveillance systems, and how to specifically query and analyze VAEs using the US VAE database VAERS (Chen et al., Vaccine 12(10):960-960, 1994). In the second half of the chapter, we will introduce the development and applications of the OAE and OVAE. Throughout this chapter, we will use the influenza vaccine Flublok as the vaccine example to launch the corresponding elaboration (Huber VC, McCullers JA, Curr Opin Mol Ther 10(1):75-85, 2008). Flublok is a recombinant hemagglutinin influenza vaccine indicated for active immunization against disease caused by influenza virus subtypes A and type B. On January 16, 2013, Flublok was approved by the FDA for the prevention of seasonal influenza in people 18years and older in the USA. Now, more than 3years later, an exploration of the reported AEs associated with this vaccine is urgently needed.

Adverse drug reactions in Colombian patients, 2007-2013: Analysis of population databases.

Recognizing adverse drug reactions (ADRs) is becoming more important in clinical practice. To determine the frequency of adverse drug reactions and ADR suspicions among the population affiliated to the Colombian health system and to describe the drugs, reactions and associated variables. We revised ADRs and ADRs suspicion databases from drugs dispensed by Audifarma, S.A., both for inpatient and outpatient care from 2007 to 2013. Variables included ADR report date, city, drug, drug's Anatomical Therapeutic Classification (ATC), ADR severity, ADR type, ADR classification and ADR probability according to the World Health Organization's definitions. We obtained 5,342 reports for 468 different drugs. The ATC groups with the most reports were anti-infectives for systemic use (25.5%), nervous system agents (17.1%) and cardiovascular system drugs (15.0%). The drugs with the highest number of reports were metamizole (4.2%), enalapril (3.8%), clarithromycin (2.8%), warfarin (2.5%) and ciprofloxacin (2.4%). The most common ADR, classified following the World Health Organization adverse reaction terminology, were: skin and appendages disorders (35.3%), general disorders (14.2%) and gastrointestinal system disorders (11.8%). Overall, 49.4% of the ADRs were classified as "moderate" and 45.1% as "mild". An increasing number of ADR reports were found coinciding with a worldwide tendency. Differences between inpatient and outpatient ADR reports were found when compared to scientific publications. The information on ADR reports, mainly gathered by the Instituto Nacional de Vigilancia de Medicamentos y Alimentos - Invima, should be made public for academic and institutional use.

Adverse reactions to contrast media: an analysis of spontaneous reports in the database of the pharmacovigilance programme of India.

Contrast media are used widely to improve medical imaging. Like all other pharmaceuticals, these agents are not completely devoid of risk, and continuous monitoring of adverse reactions with these agents is important. Spontaneous reporting is the simplest method for understanding the safety profile of pharmaceutical products after their approval. Our objective was to identify the pattern and characteristics of adverse reactions attributed to contrast media in the Indian population reported to the National Coordination Centre for the Pharmacovigilance Programme of India (NCC-PvPI). Individual case safety reports (ICSRs) attributed to contrast media submitted spontaneously to the NCC-PvPI were extracted from the database for July 2010 to September 2013. We analysed these reports for information related to reporter's professional category, patient's age and sex, reporter's diagnosis of the reaction, seriousness of the reaction, type of contrast media exposure, system organ class (SOC) affected (as described in World Health Organization Adverse Reaction Terminology [WHO-ART]) and outcome. Of the total 59,915 ICSRs in the database, 415 (0.7%) were suspected adverse reactions to contrast media; 44 reports were serious, including three fatal cases. The most affected SOCs were skin and appendage disorders, body as a whole-general disorders, gastrointestinal system disorders and respiratory system disorders. Hypersensitivity reactions were reported in the majority of ICSRs. The contrast media with the highest number of reports were iohexol (40.7%), iomeprol (17.8%), iopamidol (12%) and diatrizoate (12%). Most of the reactions to contrast media were allergic-like, and no previously unrecognised adverse reactions were observed in the Indian population. Further data and increased awareness among healthcare professionals is required to signal and prevent the consequences of adverse reactions attributed to contrast media.

Pattern Of Use Of Highly Active Antiretroviral Therapy Regimens And Pattern Of Occurrence Of Adverse Drug Reactions In An Indian Human Immunodeficiency Virus Positive Patients.

ABSTRACT Background: In India, Human immunodeficiency (HIV) infected patients with highly active antiretroviral therapy (HAART) are at higher risk of developing adverse drug reactions (ADRs). Objectives: The aim of this study was to characterize the pattern of use of HAART, occurrence, incidence, severity and causality of ADRs to HAART in Indian HIV positive patients. Methods: This was a prospective observational study conducted between August 2009 and May 2012. Enrolled HIV positive patients were intensively monitored for ADRs with fixed dose antiretroviral therapy as per National AIDS Control organization (NACO).World Health Organization (WHO) definition of ADR was adopted to detect ADRs to HAART and classified based on WHO adverse reaction terminologies. Naranjo’s scale was used for causality assessment of ADRs. Preventability was assessed using Thornton and Schuman criteria and severity was assessed using the modified Hart wig and Siegel scale. Pattern of ADRs was assessed with patient demographics, ADRs characteristics, and pattern of drug and reaction characteristics. P-value <0.05 was considered as statistically significant. Results: A total of 426 ADRs to HAART were evaluated from 1982 HIV positive patients during the study period. The overall incidence of ADRs to HAART was 21.4%. Significant difference was seen in the incidence of ADRs in the age group of 41-60 years (p <0.001), CD4+T-cell counts of 350-500 cells/μl (p <0.001), females (p <0.001). Three fatal ADRs of with cutaneous drug eruptions of Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) was 1.1%. Anemia (31.7%) accounted for majority of the reports followed by vomiting (15.5%), skin rash (12.9%) and peripheral neuropathy (10.7%). The suspected drug was withdrawn for the management of the ADRs in majority (27.9%) of the reports. Higher incidence rate of ADRs was noted with lamivudine (3TC) + nevirapine (NVP) + stavudine (D4T) (22.9%). In, naranjo's causality assessment, majority of the ADR reports were rated as possible (69%). Symptomatic treatment for ADRs was given in 91.8% of the reports and 86.4% of the reports the patient recovered from the suspected adverse reaction at the time of evaluation. Conclusion: In India, occurrence of ADRs to HAART in HIV infected patients was found to be higher with zidovudine induced anemia (31.7%). The higher percentage of ADRs to HAART was seen with female patients, age 41-60 years; CD4+ T-cell counts 350-500 cells/μl. Physician must focus for monitoring all lab investigations for early detection and prevention of adverse effects associated with HAART.

Photodynamic Therapy of Bladder Cancer – A Phase I Study Using Hexaminolevulinate (HAL)

ObjectivesTo assess the safety and feasibility of hexaminolevulinate (HAL) based photodynamic therapy (PDT) as adjuvant treatment after transurethral resection of the bladder (TURB) in patients with intermediate or high-risk urothelial cell carcinoma (UCC) of the bladder. Materials and methodsSeventeen patients received 50 ml of either a 16 mM (4 patients) or 8 mM HAL (13 patients) solution instilled intravesically. Bladder wall irradiation was performed using an incoherent white light source coupled via a quartz fiber assembled into a flexible transurethral irrigation catheter. Each patient received 3 treatments with HAL-PDT 6 weeks apart. After PDT, patients were followed by regular cystoscopy for up to 21 months to assess time to recurrence. Reported adverse events (AEs) were coded according the World Health Organization Adverse Reaction Terminology (WHO-ART). Efficacy was assessed by cystoscopy, cytology, and histology, and was defined as the number of patients who were tumor-free at 6 or 21 months after initial PDT treatment. Transient bladder irritability was reported by 15 of the 17 patients and resolved completely in all patients. No evidence of a cumulative effect of treatment on the incidence of AEs could be detected. PDT treatment was performed without any technical complications. Furthermore preliminary assessment of efficacy showed that of the 17 patients included, 9 (52.9%; 95% CI: 27.8–77.0) were tumor-free at 6 months, 4 (23.5%; 95% CI: 6.8–49.9) were tumor-free at 9 months, and 2 (11.8%, 95% CI: 1.5–36.4) were tumor-free after 21 months. ConclusionsPDT using hexaminolevulinate and an incoherent white light system with the special flexible irradiation catheter system is technically feasible and safe and may offer an alternative in the treatment of non-muscle-invasive intermediate and high-risk bladder cancer.

Anakinra, a recombinant human IL-1 receptor antagonist, in clinical practice. Outcome in 60 patients with severe rheumatoid arthritis

We evaluated both the efficacy and safety of anakinra in daily routine rheumatoid arthritis clinical practice. We studied 60 cases, including patients with previous anti-TNFalpha exposure, treated with anakinra (100 mg/daily s.c.) in combination with methotrexate (7.5-10 mg/week i.m.) or leflunomide (20 mg/die) in a two year observational study. Efficacy measures were assessed using the American College of Rheumatology (ACR) response criteria. Safety was evaluated according to a modified World Health Organization adverse reaction term dictionary. At week 14, ACR 20% response criteria have been fulfilled by 53 (91.3%) out of 58 patients, 51 (87.9%) of them achieving also an ACR 50%and 15 (25.8%) an ACR 70%response. Thirteen patients touched 102 weeks of treatment: ACR 20% response was achieved in 92.3%, while ACR 50% and ACR 70% were respectively found in 84.6% and 38.4% of the cases. The mean decrease in HAQ score was 0.38, p<0.001. Of the 16 patients who were previously treated with anti-TNFalpha blockers, 81.2% responded to anakinra. There was no significant difference in the ACR response between groups with and without previous anti-TNFalpha exposure. Seventeen patients (28.3%) stopped anakinra because of side-effects (5%) or failure to respond (23.3%). Only 4 cases of pulmonitis, of which 2 have been hospitalised, and 1 case with tuberculosis (previously treated with infliximab) were observed. Our clinical experience confirms that anakinra is effective and safe in the treatment of rheumatoid arthritis. Anakinra seems also useful in patients with previous anti-TNFalpha blockers failures. Even though major adverse events were rare, clinicians should be aware of such a possibility.

Association Between Statin Use and Lupus-Like Syndrome Using Spontaneous Reports

Several case reports of lupus-like syndrome suggest that statins could have triggered the development of this rare autoimmune disease. However, data on the association between statin use and lupus-like syndrome are scarce. We assessed whether there was an association between statin use and the occurrence of lupus-like syndrome. A case/noncase study based on individual case safety reports listed in the World Health Organization global individual case safety reports database (VigiBase) was conducted. According to World Health Organization adverse reaction terminology, cases were defined as reports of lupus-like syndrome. Each case was matched with 5 noncases by age, gender, and time of reporting. Use of statins was classified according to the Anatomical Therapeutic Chemical classification code system. Covariates, ie, use of corticosteroids, immunosuppressive drugs, nonsteroidal anti-inflammatory drugs, antidepressants, antiepileptics, proton pump inhibitors, and cardiovascular drugs, were determined. Multivariate logistic regression was used to calculate the reporting odds ratios with 95% confidence intervals. We identified 3362 reports of lupus-like syndrome as cases and 27,092 reports of other adverse drug reactions as noncases. Statins were more frequently reported as suspected drug in cases (3.2%) than in noncases (1.5%). After adjustment for several covariates, statins were associated with the reporting of lupus-like syndrome (reporting odds ratios 2.01; 95% confidence intervals 1.61-2.51). We found an association between reporting of statins and lupus-like syndrome. Further studies are needed to confirm this finding in more detail and establish causality.

Was the thrombotic risk of rofecoxib predictible from the French Pharmacovigilance Database before 30 September 2004?

Rofecoxib was withdrawn from the market on 30 September 2004 following the results of a randomized controlled trial. Following this sudden decision, several controversies occurred in the literature to determine whether this adverse drug reaction (ADR) could have been detected earlier. The aim of this study was to investigate whether this kind of signal could have been seen using the French Pharmacovigilance Database before this date of rofecoxib withdrawal. Using cases registered in the French Pharmacovigilance Database from May 2000 to December 2006, we applied the case-noncase method to "serious" thrombotic ADRs reported with oral formulations of rofecoxib or celecoxib in patients older than 15 years. Cases were all notifications of thrombotic ADRs [World Health Organization Adverse Reaction Terminology (WHO-ART) codes 1300] occurred under coxib (rofecoxib, celecoxib) and noncases all other reports registered in the database (whatever the drug). We calculated a cumulative odds ratio (OR) from 20 May 2000 to 31 December 2006, with a special interest for the period before the 30 September 2004. Among the 50,087 "serious" ADRs registered in the database during this period, 1,127 were thrombotic ones. Rofecoxib exposure was significantly associated with high values of odds ratio (OR) [4.2 (95% CI 1.97-8.61)] for thrombotic ADRs as early as the end of 2001. The values of ADR reporting ORs remained high (3.0-3.5) until 2006. For celecoxib, a significant trend occurred only from September 2004. Despite the compulsory limits of the case/noncase methodology, this study found an association between rofecoxib exposure and the occurrence of "serious" thrombotic ADRs as early as the end of the first year of rofecoxib marketing in France. The association between celecoxib and the occurrence of such ADRs appears less clear. Our work also shows the potential use of careful analysis of pharmacovigilance databases (investigating, for example, cumulative values of risk) in the early identification of new ADRs.

Improving global monitoring of vaccine safety: A quantitative analysis of adverse event reports in the WHO Adverse Reactions Database

The World Health Organization (WHO) Programme for International Drug Monitoring (PIDM) was initially developed for chemical rather than biological products. The PIDM made considerable achievements in analysing drug-related adverse event reports, progress was more limited for vaccine-related reports. In 2005, the Global Advisory Committee on Vaccine Safety, called for a global consultation to address the need for improved monitoring and analysis of vaccine-related adverse event reports on an international level. In preparation for this consultation, the WHO Adverse Reactions Database was quantitatively assessed and results of this analysis are presented in this paper. Three countries contributed 82% of vaccine-related reports in the database. The mean difference between onset date and report date was 2.4 years. Several issues of concern were identified, such as the fact that many member countries do not forward any or all reports of adverse events following immunization to the PIDM, and the poor timeliness and regularity of reporting, which could prevent timely generation of safety signals.

Risk of Cardiovascular Events in Patients Receiving Celecoxib: A Meta-Analysis of Randomized Clinical Trials

Some nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 selective inhibitors, have been associated with increased cardiovascular (CV) events in recent clinical trials or observational studies. To determine whether the cyclooxygenase-2 selective inhibitor celecoxib affects CV risk, the incidence of CV events was analyzed in patients treated with celecoxib, placebo, or nonselective NSAIDs in the clinical trial database for celecoxib using defined Antiplatelet Trialists' Collaboration end points of nonfatal myocardial infarction, nonfatal stroke, and CV death. Patient data were derived from studies in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, low back pain, and Alzheimer's disease. This meta-analysis included (1) 7,462 patients exposed to celecoxib 200 to 800 mg/day for 1,268 patient-years compared with 4,057 patients treated with placebo for 585 patient-years, and (2) 19,773 patients treated with celecoxib 200 to 800 mg/day for 5,651 patient-years compared with 13,990 patients treated with nonselective NSAIDs (diclofenac, ibuprofen, naproxen, ketoprofen, and loxoprofen) for 4,386 patient-years. CV events were adjudicated by a 3-member expert end point committee (WBW, JSB, PBG) blinded to treatment group and study. The incidence rates of the combined CV events were not significantly different between patients treated with celecoxib and placebo or between those treated with celecoxib and nonselective NSAIDs. Event rates were similar for adjudicated and nonadjudicated data. Dose of celecoxib, the use of aspirin, or the presence of CV risk factors did not alter these results. In conclusion, these analyses failed to demonstrate an increased CV risk with celecoxib relative to placebo and demonstrated a comparable rate of CV events with celecoxib treatment compared with nonselective NSAIDs.

An independent assessment of MEDWatch reporting for abuse/dependence and withdrawal from Ultram (tramadol hydrochloride)

Objective: Assess the validity of medical products reporting program (MEDWatch) reports of abuse/dependence and withdrawal associated with Ultram (tramadol). Methods: Reports of possible abuse/dependence or withdrawal associated with Ultram during 13 quarters following launch were spontaneously reported to the manufacturer Ortho-McNeil Pharmaceutical (OMP) and also solicited from 255 NIDA grantees and addiction treatment professionals by an Independent Steering Committee (ISC). Reports were classified by the ISC using DSM-IV criteria, by the Drug Safety and Surveillance (DSS) units of Robert Wood Johnson Pharmaceutical Research Institute (PRI) using World Health Organization Adverse Reaction Terms (WHOART) terms, and reported to the food and drug administration (FDA) via MEDWatch. Rates of abuse/dependence and withdrawal per 100 000 persons exposed were calculated separately for classifications made by the PRI and the ISC, and confidence intervals calculated to determine the degree to which they agreed. Results: For 681 reports submitted to PRI, confidence intervals of ISC ratings contained PRI ratings 12 of 13 times for abuse/dependence, and 12 of 13 times for withdrawal. For 242 reports submitted to the ISC, confidence intervals of ISC ratings contained PRI ratings 10 of 13 times for abuse/dependence, and 12 of 13 times for withdrawal. Proactive surveillance increased the total number of cases of abuse/dependence but not withdrawal. Many cases of withdrawal without signs or symptoms of abuse/dependence were identified. Conclusions: There was good/excellent concordance between MEDWatch and ISC classifications. Proactive surveillance increased cases of abuse/dependence but not withdrawal. Withdrawal with no signs or symptoms of dependence was common. More use of proactive surveillance is likely to improve assessments of public health risks associated with adverse events.

Reliability, validity, and responsiveness of Severity of Dyspepsia Assessment (SODA) in a randomized clinical trial of a COX-2-specific inhibitor and traditional NSAID therapy

OBJECTIVES: We aimed to assess the Severity of Dyspepsia Assessment (SODA) scales as measures of change in dyspepsia-related health in a blinded, randomized, controlled trial in arthritis patients treated with nonsteroidal anti-inflammatory drugs. METHODS: Three thousand nine hundred seven arthritis patients completed SODA at baseline and weeks 4, 13, 26, and 52 and/or at early termination. Using baseline and 4-wk data, reliability was evaluated with Cronbach’s α and the intraclass correlation coefficient (ICC). Dyspepsia adverse events were defined based on a combined set of World Health Organization Adverse Reaction Terminology terms. The ability of SODA to measure change in dyspepsia-related health was evaluated by comparing SODA change scores by dyspepsia adverse event severity level and withdrawal status. Responsiveness was further evaluated by the area under the curve (AUC) from receiver operating characteristic curves using withdrawal due to dyspepsia as the criterion. RESULTS: The SODA scales—Pain Intensity (α = 0.93), Non Pain Symptoms (α = 0.82), and Satisfaction (α = 0.89)—demonstrated excellent internal consistency reliability using baseline data. Reproducibility was fair to good: Pain Intensity ICC = 0.49, Non Pain Symptoms ICC = 0.61, and Satisfaction ICC = 0.45. SODA change scores (4-wk score − baseline score) increased, or worsened, with increasing dyspepsia severity and differentiated between adjacent levels of dyspepsia severity for eight of nine adjacent comparisons ( p < 0.05). SODA change scores also differentiated between those who did and did not withdraw ( p < 0.001). Responsiveness was highest with the Pain Intensity scale (AUC = 0.78), followed by the Non Pain Symptoms (AUC = 0.74) and Satisfaction (AUC = 0.75) scales. CONCLUSIONS: SODA is a reliable, valid instrument for use as a measure of dyspepsia tolerability in future clinical trials involving cyclo-oxygenase-2-specific and/or traditional nonsteroidal anti-inflammatory drugs.

Are Angiotensin II Receptor Antagonists Safe in Patients With Previous Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema?

To the Editor: We describe the results of a literature and pharmacovigilance survey on the clinically relevant problem of whether angiotensin II receptor antagonists (ARAs) can be safely used in patients with previous angiotensin-converting enzyme (ACE) inhibitor–induced angioedema. The results suggest that patients with previous ACE inhibitor–induced angioedema are at increased risk for relapse angioedema during the use of an angiotension II receptor antagonist, and therefore angiotensin II antagonist should not be considered a safe substitute in patients with previous ACE inhibitor–induced angioedema. ACE inhibitors (ACEIs) are widely applied as blood pressure–lowering agents. Although ACEIs are generally well tolerated, they are also involved in the activation of bradykinin, enkephalins, and other biologically active peptides, which may result in adverse effects such as cough, increased bronchial reactivity, and angioedema. An attempt to achieve a more specific blockade of the effects of angiotensin II resulted in the introduction in 1995 of angiotensin II receptor antagonists (ARAs), starting with losartan and followed by irbesartan, valsartan, candesartan, and eprosartan. Because the pharmacology of ARAs is substantially different from ACEIs, the adverse …

World Health Organization Adverse Reaction Terminology Dictionary

The World Health Organization Adverse Reaction Terminology (WHO ART) Dictionary was developed in 1968 and is hierarchical in nature. At the top of the hierarchy are 30 system organ classes, followed by high-level terms, preferred terms, and included terms. Some preferred terms are also high-level terms.The WHO ART Dictionary is used at Schering Corporation for standardized coding of adverse drug events occurring in clinical trials, postmarketing, and in published literature. Automatic encoding is primarily used in the data entry process for clinical trials, whereby literal terms are keypunched into the computer and are electronically matched to the corresponding WHO preferred term. Common terms not automatically matched to a WHO term may be added to the dictionary as “lexicon terms” to increase the automatic matching rate to at least 75%. Terms are stored as the literal term, the preferred term, the system organ class, and sometimes the included term. In the postmarketing setting, coding of adverse drug e...