WHO Adverse Reaction Terminology Research Articles

AI-powered Solutions for Casualty Assessment in Drug Safety and Patient Care

Objective: An adverse drug reaction is defined as “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which warrants prevention or specific treatment, alteration of the dosage regimen, or withdrawal of the product, as it predicts hazard from future administration.” Methodology: Currently used to report such responses, the International Classification of Diseases will soon incorporate WHO's Adverse Reaction Terminology. A medication's bad effects can fall into one of six types, each having its own mnemonic: withdrawal, therapeutic failure, dose-and time-related, non-dose-related, weird, increased withdrawal, and withdrawal overall (time-related). Factors such as timing, illness pattern, investigation findings, and retesting the medicine could be useful in pinpointing the reason for a suspected adverse drug reaction. Management includes treating the effects of the medication specifically as well as, if feasible, stopping it altogether. Results: Reporting suspected adverse medication reactions is important. Monitoring techniques are able to identify responses and establish connections. There is many software that is used to report and monitor adverse drug reaction responses. Various Pharmacovigilance companies use AI technology to utilize this method to record signals, communicate, and solve new issues in order to limit or avoid harm because of large data size.

A 10‐Year Nationwide Pharmacovigilance Assessment on Anti‐Obesity Medications and Factors Associated with Serious Adverse Events

Study ObjectiveTo compare the adverse events (AEs) profiles of medications prescribed to treat obesity and identify factors associated with serious adverse events (SAEs) by utilizing nationwide spontaneous AE reporting database in Korea.HypothesisThe AE profiles may differ by anti‐obesity agents and patient‐specific factors may aggravate the risk of SAEs.MethodsRetrospective analysis was performed on ADE records spontaneously reported from January 2010 to December 2019 to the Korean Adverse Event Reporting System (KAERS) constructed by Korea Institute of Drug Safety and Risk Management. This analysis included 10 anti‐obesity agents prescribed for overweight, obesity (ICD‐10 code E66) and abnormal weight gain (ICD10 Code E63.5). All AEs were grouped using preferred terms and System Oran Classes (SOC) per the WHO‐Adverse Reaction Terminology. Logistic regression was performed to identify factors associated with SAEs identified based on International Conference on Harmonization E2D Guidelines, and the odds ratio (OR) was reported with 95% confidence intervals (CIs). Any p‐values <0.05 was considered statistically significant. All statistical analyses were performed with SPSS 25.0 (Version 25.0; IBM SPSS Statistics for Windows, Armonk, NY, USA). The study protocol for utilizing the KAERS database was approved by KIDS (No.2007A0051) and the institutional review board of CHA University (Pocheon, South Korea).ResultsTotal of 4,215 AE records associated with anti‐obesity agents were identified, and the most etiologic anti‐obesity agent was phentermine (n=1,385; 32.8%), followed by liraglutide (n=1,155; 27.4%) and lorcaserin (n=690; 16.3%). AEs were frequently reported in females (n=3,458; 88.7%) and patients in their 30s (n=761; 18.1%) or 40s (n=672; 15.9%) of age. The prevalence of SAE was 2.5% (n=105). The highest number of nonserious AEs was gastro‐intestinal system disorders (n=1,233; 30.0%), followed by central & peripheral nervous system disorders (n=782; 19.0%) and psychiatric disorders (n=682; 16.6%). The most common SAEs were associated with psychiatric disorders (n=27; 25.7%), central & peripheral nervous system disorders (n=20; 19.0%), and gastrointestinal system disorders (n=13; 12.4%). The reporting odds ratio of SAE in liver and biliary system disorders from anti‐obesity agent administration was 3.145 (95% CI 6.689‐ 80.557). Factors associated with significantly elevated risk of SAEs was male sex (odds ratio (OR) 6.318; 95% CI 3.583‐10.839), triple agent therapy (OR 3.49; 95% CI:1.481‐8.170), increasing number of medications (OR 1.381; 95% CI 1.204‐1.583), and concomitant administration of fluoxetine (OR 5.146; 95% CI 2.570‐10.268).ConclusionThis is the first study of the study investigating AEs induced by medications primarily prescribed for weight loss by utilizing nationwide spontaneous adverse event reporting system. AEs induced by anti‐obesity agents are most frequently reported with phentermine and liraglutides, primarily manifested by gastrointestinal system disorders. SAEs are substantially associated with male gender, polypharmacy, and type of concomitant medications.

Treatment with an Anti-CK2 Synthetic Peptide Improves Clinical Response in COVID-19 Patients with Pneumonia. A Randomized and Controlled Clinical Trial.

The instrumental role of CK2 in the SARS-CoV-2 infection has pointed out this protein kinase as promising therapeutic target in COVID-19. Anti-SARS-CoV-2 activity has been reported by CK2 inhibitors in vitro; however, no anti-CK2 clinical approach has been investigated in COVID-19. This trial aimed to explore the safety and putative clinical benefit of CIGB-325, an anti-CK2 peptide previously assessed in cancer patients. A monocentric, controlled, and therapeutic exploratory trial of intravenous CIGB-325 in adults hospitalized with COVID-19 was performed. Twenty patients were randomly assigned to receive CIGB-325 (2.5 mg/kg/day during 5-consecutive days) plus standard-of-care (10 patients) or standard-of-care alone (10 patients). Adverse events were classified by the WHO Adverse Reaction Terminology. Parametric and nonparametric statistical analyses were performed according to the type of variable. Considering the small sample size, differences between groups were estimated by Bayesian analysis. CIGB-325 induced transient mild and/or moderate adverse events such as pruritus, flushing, and rash in some patients. Both therapeutic regimens were similar with respect to SARS-CoV-2 clearance in nasopharynx swabs over time. However, CIGB-325 significantly reduced the median number of pulmonary lesions (9.5 to 5.5, p = 0.042) at day 7 and the proportion of patients with such an effect was also higher according to Bayesian analysis (pDif > 0; 0.951). Also, CIGB-325 significantly reduced the CPK (p = 0.007) and LDH (p = 0.028) plasma levels at day 7. Our preliminary findings suggest that this anti-CK2 clinical approach could be combined with standard-of-care in COVID-19 in larger studies.

A case report of eyelid Merkel cell carcinoma occurring under treatment with nivolumab for a lung adenocarcinoma

BackgroundMerkel cell carcinoma (MCC) is a rare neuroendocrine malignancy of the skin characterized by high aggressiveness. Four main factors are implicated in its development: immunosuppression, ultraviolet radiation, age and the Merkel cell polyomavirus (MCPyV). In recent years, immune checkpoint inhibitors have shown clinical activity in MCC treatment.Case presentationWe report the case of an 82-year-old man with a lung adenocarcinoma diagnosis, who underwent immunotherapy with nivolumab as second-line treatment. Seven months after the diagnosis of lung cancer during the nivolumab treatment, the patient developed an eyelid MCC, initially misdiagnosed as a chalazion. A palliative radiotherapy was performed with clinical benefit. After a total of seven cycles of nivolumab, computed tomography showed a lung and cerebral disease progression. In addition, clinical conditions worsened leading to the patient’s death 13 months after the initial lung cancer diagnosis.ConclusionsCases of co-occurrence of MCC and non-small cell lung cancer (NSCLC) have rarely been reported. Interestingly, common risk factors may be postulated for both cancers. Considering the rarity of this adverse event, its short-term temporal relation with the administration of the drug, which makes a relation improbable, and the coexistence of other risk factors, which may provide plausible explanations, it is possible to conclude according to the WHO Adverse Reaction Terminology that a causal relation between the occurrence of this serious adverse event and the exposure to the drug is unlikely. However, the case deserves to be reported in the literature.

VigiRank for statistical signal detection in pharmacovigilance: First results from prospective real-world use.

PurposevigiRank is a data‐driven predictive model for emerging safety signals. In addition to disproportionate reporting patterns, it also accounts for the completeness, recency, and geographic spread of individual case reporting, as well as the availability of case narratives. Previous retrospective analysis suggested that vigiRank performed better than disproportionality analysis alone. The purpose of the present analysis was to evaluate its prospective performance.MethodsThe evaluation of vigiRank was based on real‐world signal detection in VigiBase. In May 2014, vigiRank scores were computed for pairs of new drugs and WHO Adverse Reaction Terminology critical terms with at most 30 reports from at least 2 countries. Initial manual assessments were performed in order of descending score, selecting a subset of drug‐adverse drug reaction pairs for in‐depth expert assessment. The primary performance metric was the proportion of initial assessments that were decided signals during in‐depth assessment. As comparator, the historical performance for disproportionality‐ guided signal detection in VigiBase was computed from a corresponding cohort of drug‐adverse drug reaction pairs assessed between 2009 and 2013. During this period, the requirement for initial manual assessment was a positive lower endpoint of the 95% credibility interval of the Information Component measure of disproportionality, observed for the first time.Results194 initial assessments suggested by vigiRank's ordering eventually resulted in 6 (3.1%) signals. Disproportionality analysis yielded 19 signals from 1592 initial assessments (1.2%; P < .05).ConclusionsCombining multiple strength‐of‐evidence aspects as in vigiRank significantly outperformed disproportionality analysis alone in real‐world pharmacovigilance signal detection, for VigiBase.

Reported Adverse Drug Reactions in Infants: A Nationwide Analysis in Malaysia.

Spontaneous adverse drug reactions (ADRs) reporting is a useful source of drug safety information in infants as only adult patients are routinely tested in clinical trials. This study was aimed to evaluate the spontaneously reported ADRs using WHO Adverse Reaction Terminology and to identify the common drugs associated with ADRs in children under 2 years of age. A retrospective analysis of ADR data for children below 2 years old from 2000 to 2013 was conducted using the data extracted from Malaysia’s national pharmacovigilance database, QUEST2 System. From 2000 to 2013, Malaysia’s National Pharmaceutical Control Bureau received a total of 11,932 reports for children from various healthcare facilities in Malaysia. 14.0% (n = 1667) of the ADRs reported for those children were related to children under 2 years old. The data retrieved was analyzed in terms of age, gender, source of reporting, type of reporters, suspected medicines and characteristics of ADRs (category, onset, severity, and outcomes). A total of 1312 ADRs reported in 907 ADR reports were analyzed. The most common ADRs reported were skin appendage disorders (60.1%), and the most frequently reported symptoms were rash (n = 215), maculopapular rash (n = 206), urticaria (n = 169), erythematous rash (n = 76), and pruritus (n = 58). In general, drugs from antibacterials for systemic use (58.8%) appeared to be the most common contributors to ADRs in children below 2 years old. Penicillins and other β-Lactam Antibacterials accounted for more than 40% of all drugs implicated in ADRs. The majority of ADRs were subacute reactions that occurred within 24 h of exposure to the drug. A high proportion of ADRs was classified as mild, and most victims had no sequela. Only one fatality was seen. There were 10 cases for each symptom, namely erythema multiforme and Stevens–Johnson Syndrome, observed in this study. A large proportion of ADRs in children under 2 years old were mainly caused by drugs from antibacterial for systemic use, with most of the ADRs manifesting in skin reactions. This study also reveals rare cutaneous ADRs experienced by Malaysian children under the age of 2, which constitutes a crucial cause of harm among children.

Adverse events following immunization with oral poliovirus in Kinshasa, Democratic Republic of Congo: preliminary results

Aim: We investigated the nature and frequency of adverse events following immunization (AEFI) associated with oral polio vaccines (OPV) in the general population in Kinshasa, Democratic Republic of Congo (DR Congo).Methods: The DR Congo National Pharmacovigilance Centre organized active AEFI surveillance during mass immunization campaigns for the general population from March to June 2011. A patient individual case safety report was used as a questionnaire and addressed to pupils and students from high schools and universities who had any adverse events after OPV administration. We used the preferred term from the WHO Adverse Reaction Terminology for AEFI designation. Here is presented the results of the second step of the mass immunization campaign.Results: A total of 767 patients reported AEFI during the second step. Sex distribution shows that 512 (66·8%) students were females, while 255 (33·2%) were males, giving a female/male ratio 2∶1. The average age was 16·8±5·19 years (ranged: 6–35·5 years). Each person reported a mean of 1·33±0·6 AEFI. The average AEFI onset duration was 1·74±1·16 days post-vaccination, ranging from 1 to 9 days. Headache (22·4%), abdominal pain (17·2%), fever (11·7%), diarrhea (9·9%), and asthenia (7·5%) were the common symptoms. Paralysis and asthma-like reactions were rare and serious adverse events in this study. The most affected systems were gastro-intestinal (33·5%) and nervous system (29·3%). Rechallenge was positive for 173 persons (22·6%).Conclusion: OPV-related AEFIs are not uncommon, although it is under-reported. Active AEFI surveillance during mass immunization campaigns is very important and may help to detect rare and serious adverse events. Further investigation will be important to identify risk of AEFI with OPV in adults and is warranted to elucidate the cause of this association in the Congolese environment.

Possible occurrence of paraesthesia in patients taking norethisterone: an analysis on the WHO Global Individual Case Reports database (VigiBase)

Objective: Progestogens are widely used to treat a large number of common conditions. We aimed to investigate a potential signal concerning progestogens and paraesthesia.Methods: Data were obtained from the VigiBase, the WHO Global Individual Case Safety Reports (ICSR) database, which is maintained by the Uppsala Monitoring Centre. We collected all suspected reports of paraesthesia associated with oral progestogens, reported between January 1972 and June 2012 and classified in VigiBase according to WHO-Adverse Reaction Terminology critical term ‘paraesthesia’. A disproportionality analysis was conducted using the Information Component (IC) and the standard deviation (IC025) as a measure.Results: Out of the total number of reports collected in the VigiBase (7,332,991), paraesthesia was associated with progestogen therapy in 920 reports, coming from 22 countries. Progestogens had the highest number of suspected reports (n = 864) than the other Anatomical Therapeutic Chemical (ATC) considered. Only norethisterone was associated with paraesthesia with positive IC (0.47) and IC025 (0.02).Conclusions: Norethisterone-associated paraesthesia appears to be a rare outcome. However, the widespread use of progestogens in medical practice suggests that it is a complaint that can affect a large number of women. Since paraesthesia can be caused by several drugs, clinicians should consider that it may be also caused by norethisterone.

Ticlopidine Safety Profile: A Case/Non-Case Study on the Basis of the Spontaneous ADRs Reporting in Italy

INTRODUCTON: Ticlopidine is an antiplatelet agent available from several decades. Its most important adverse drug reactions (ADRs) involve haematological system. Our aim was to evaluate the safety profile of ticlopidine in the real life, on the basis of spontaneous ADR reporting. Spontaneous reports from 8 Italian Regions collected from 1990 to March 2007 were analysed. According to WHO Adverse Reaction Terminology for causality assessment only "certain", "probable" or "possible" ADRs were included. Association between drugs and any ADR was assessed by using the case/non-case methodoloy. Reporting odds ratio (ROR) was computed as a measure of disproportionality. Overall, 478 reports concerning ticlopidine were analysed. The system organ classes with significant disproportionality for ticlopidine included White Cell Disorders (ROR=22.43, 95% CI 18.54-27.12), Red Cell Disorders (8.22; 6.03-11.18), Liver And Biliary System (6.67; 5.35-8.32), Platelet, Bleeding & Clotting (6.59; 5.16-8.40). Fifteen percent of the ADRs occurred beyond the first three months of ticlopidine therapy. In 386 reports (80.7%), ticlopidine was the only suspected drug. Safety profile of ticlopidine can be considered well-established in terms of ADRs type but their frequency and severity continue to be higher in its current use. Since this drug is still widely used in Italy, both healthcare providers and patients should be aware of its ADRs. More specifically, patients should be regularly monitored during the whole period of use and not only in the first months of treatment.

Identifying Adverse Events of Vaccines Using a Bayesian Method of Medically Guided Information Sharing

The detection of adverse events following immunization (AEFI) fundamentally depends on how these events are classified. Standard methods impose a choice between either grouping similar events together to gain power or splitting them into more specific definitions. We demonstrate a method of medically guided Bayesian information sharing that avoids grouping or splitting the data, and we further combine this with the standard epidemiological tools of stratification and multivariate regression. The aim of this study was to assess the ability of a Bayesian hierarchical model to identify gastrointestinal AEFI in children, and then combine this with testing for effect modification and adjustments for confounding. Reporting odds ratios were calculated for each gastrointestinal AEFI and vaccine combination. After testing for effect modification, these were then re-estimated using multivariable logistic regression adjusting for age, sex, year and country of report. A medically guided hierarchy of AEFI terms was then derived to allow information sharing in a Bayesian model. All spontaneous reports of AEFI in children under 18 years of age in the WHO VigiBase™ (Uppsala Monitoring Centre, Uppsala, Sweden) before June 2010. Reports with missing age were included in the main analysis in a separate category and excluded in a subsequent sensitivity analysis. The 15 most commonly prescribed childhood vaccinations, excluding influenza vaccines. All gastrointestinal AEFI coded by WHO Adverse Reaction Terminology. A crude analysis identified 132 signals from 655 reported combinations of gastrointestinal AEFI. Adjusting for confounding by age, sex, year of report and country of report, where appropriate, reduced the number of signals identified to 88. The addition of a Bayesian hierarchical model identified four further signals and removed three. Effect modification by age and sex was identified for six vaccines for the outcomes of vomiting, nausea, diarrhoea and salivary gland enlargement. This study demonstrated a sequence of methods for routinely analysing spontaneous report databases that was easily understandable and reproducible. The combination of classical and Bayesian methods in this study help to focus the limited resources for hypothesis testing studies towards adverse events with the strongest support from the data.

Safety Reporting and Adverse-Event Profile of Mirtazapine Described in Randomized Controlled Trials in Comparison with Other Classes of Antidepressants in the Acute-Phase Treatment of Adults with Depression

Mirtazapine has a unique mechanism of antidepressant action, and thus is thought to have a different profile of adverse events from that of other antidepressants. To present a methodologically rigorous systematic review of the adverse event profile of mirtazapine and point to possible problems with safety reporting in randomized controlled trials (RCTs) of the acute-phase treatment of major depression in adults with mirtazapine in comparison with other types of antidepressant. The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register was electronically searched using the following search terms: 'depress*', 'dysthymi*', 'adjustment disorder*', 'mood disorder*', 'affective disorder', 'affective symptoms' and 'mirtazapine'. Pharmaceutical companies and experts in this field were contacted, and the reference lists of the relevant RCTs were checked, for additional data. No language restriction was imposed. Two authors independently assessed the quality of trials for inclusion in the review. Disagreements were resolved by consensus. Two authors independently extracted data on adverse events. Disagreements were resolved by consensus. The adequacy of safety reporting was assessed by one author. Regarding the adequacy of safety reporting, the qualitative and quantitative parameters of safety reporting were determined. Regression analyses were conducted to assess characteristics of trials influencing safety reporting. The primary and secondary outcomes in the systematic review of the adverse events associated with mirtazapine were defined as the proportion of patients having each of 43 adverse events listed in the modified version of the WHO Adverse Reaction Terminology, and the proportion of patients experiencing at least one adverse event, respectively. Meta-analyses were conducted for these outcomes. Twenty-five RCTs involving 4842 patients were identified as meeting our inclusion criteria. With regard to safety reporting, only two trials and no trials were rated as 'adequate' in terms of the reporting of clinical adverse events and laboratory-determined toxicity, respectively. The proportion of text in the results sections of the study reports devoted to safety reporting was a mean of 22%. No associations were observed between the adequacy of safety reporting and any characteristics of the trials; however, sample size over 100 participants in total and over 50 subjects in a study arm, double blindness and sponsorship by the company marketing mirtazapine were significantly associated with a greater number of reported adverse events in mirtazapine recipients. In terms of individual adverse events, mirtazapine was significantly less likely to cause hypertension or tachycardia (risk ratio [RR] 0.51) and tremor (RR 0.43) than tricyclic antidepressants (TCAs). In comparison with selective serotonin uptake inhibitors (SSRIs), mirtazapine was significantly more likely to cause weight gain or increased appetite (RR 3.68), increased salivation (RR 3.66), somnolence (RR 1.62) and fatigue (RR 1.45), but less likely to cause flatulence (RR 0.26), sweating (RR 0.28), sexual dysfunction (RR 0.34), tremor (RR 0.37), nausea or vomiting (RR 0.40), sleep disturbance (RR 0.55) and diarrhoea (RR 0.61). In comparison with the serotonin-noradrenaline (norepinephrine) reuptake inhibitor (SNRI) venlafaxine, mirtazapine was significantly more likely to cause fatigue (RR 2.02), but less likely to cause sleep disturbance (RR 0.03), sweating (RR 0.03) and constipation (RR 0.25). Relative to trazodone, mirtazapine was significantly more likely to cause weight gain or increased appetite (RR 4.00). Approximately 70% of patients treated with mirtazapine experienced at least one adverse event, with no significant difference in comparison with other antidepressants. The study confirmed the paucity of adequate safety reporting in trials comparing mirtazapine with other types of antidepressant in the acute-phase treatment of depression in adults. Based on the available evidence, mirtazapine appears to have a unique adverse-event profile. Using these findings, clinicians can inform their patients, not only of the simple frequency of adverse events with mirtazapine, but also of the relative difference in the frequency of adverse events in comparison with that of other antidepressants, to aid pragmatic clinical decisions.

SNOMED CT - advances in concept mapping, retrieval, and ontological foundations. Selected contributions to the Semantic Mining Conference on SNOMED CT (SMCS 2006).

SNOMED CT - advances in concept mapping, retrieval, and ontological foundations. Selected contributions to the Semantic Mining Conference on SNOMED CT (SMCS 2006).

VigiBase, the WHO Global ICSR Database System: Basic Facts

The main aim of the WHO International Drug Monitoring Programme, started in 1968, is to identify the earliest possible pharmacovigilance signals. The program now has more than 80 member countries from all parts of the world contributing individual case safety reports (ICSRs) to the WHO Global ICSR Database System, VigiBase. VigiBase is maintained and developed on behalf of WHO by the Uppsala Monitoring Centre (UMC), situated in Uppsala, Sweden. The database system includes the ICH E2B compatible ICSR database, the WHO Drug Dictionaries (WHO-DD and -DDE), and the medical terminologies WHO Adverse Reaction Terminology (WHO-ART), International Classification of Diseases (ICD), and the Medical Dictionary for Regulatory Activities (MedDRA). Apart from data management and quality assurance tools, the VigiBase system includes a web-based reporting tool, an automated signal detection process using advanced data mining, and search facilities, available to the member countries and, on request, to other stakeholders.

Prevalence, Clinical Features and Avoidability of Adverse Drug Reactions as Cause of Admission to??a??Geriatric Unit

Drug use increases with advancing age, and in older patients it is associated with an increase in adverse drug reactions (ADRs). ADRs are a primary cause of morbidity and mortality worldwide. To evaluate the prevalence, clinical characteristics and avoidability of ADR-related hospital admissions in elderly patients. From November 2004 to December 2005, all patients aged >or=65 years consecutively admitted to the Geriatric Unit of the Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo in Italy, were evaluated for enrolment in the study. ADRs were defined according to the WHO Adverse Reaction Terminology system. Drugs were classified according to Anatomical Therapeutic Chemical classification system. The Naranjo algorithm was used to evaluate the relationship between drug use and the ADR (definite, probable, possible or doubtful) and Hallas criteria were used to evaluate the avoidability of the ADR (definitely avoidable, possibly avoidable or unavoidable). All cases of a suspected ADR were discussed by a team trained in drug safety, including three geriatricians, one clinical pharmacologist and one pharmacist. Only cases of an ADR with an agreement >or=80% were included. Of the 1756 patients observed, 102 (5.8%, 42 males, 60 females, mean age 76.5 +/- 7.4 years, range 65-93 years) showed certain (6.8%) or probable (91.2%) ADR-related hospitalization. Gastrointestinal disorders (48 patients, 47.1%); platelet, bleeding and clotting disorders (20 patients, 19.6%); and cardiovascular disorders (13 patients, 12.7%) were the most frequent ADRs. NSAIDs (23.5%), oral anticoagulants (20.6%), low-dose aspirin (acetylsalicylic acid) [13.7%] and digoxin (12.7%) were the drugs most frequently involved in ADRs. Of the ADRs, 45.1% were defined as definitely avoidable, 31.4% as possibly avoidable, 18.6% as unavoidable and 4.9% as unclassifiable. Of 78 patients with definitely or possibly avoidable ADRs, 17 patients (21.8%) had received an inappropriate prescription, 29 patients (37.2%) had not received a prescription for an effective gastroprotective drug concomitantly with NSAID or low-dose aspirin treatment and 32 patients (41%) were not monitored during drug treatment. In the elderly, almost 6% of hospitalizations are ADR related. Most of these ADRs are potentially avoidable. Strategies that reduce inappropriate prescriptions and monitoring errors, as well as improving active prevention of ADRs, are needed in elderly subjects.

Hepatic adverse drug reactions: a case/non-case study in Italy

Adverse drug reactions (ADRs) can involve all tissues and organs. Liver injuries are considered among the most serious and are a cause for concern among physicians and patients. To assess the extent of drug-induced liver injuries in Italy we compared the number of cases of hepatic ADRs with reports of all other drug-related reactions present in the same database. Spontaneous reports from six Italian Regions collected from January 1990 to May 2005 were analysed. Adverse reactions were classified according to WHO Adverse Reaction Terminology for causality assessment, and only those with "certain", "probable" or "possible" causality assessment were included. Association between drugs and hepatic ADRs was assessed using the case/non case method, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. On May 2005, the database contained 35,767 ADR reports, of which 11,829 were excluded because they were unclassifiable or unlikely in terms of causality assessment. Therefore, the analysis was carried out on 23,938 reports, of which 1,069 concerned hepatic ADRs (cases) and 22,869 concerned non-cases. The proportion of serious ADRs was about 40% in the overall database, and about 74% among cases. The drug classes with the highest number of cases were statins (ROR = 2.9, 95% CI 2.4-3.5), antiplatelet agents (ROR = 3.5; 95% CI 2.6-4.6), NSAIDs (ROR = 2.9; 95% CI 2.1-3.9) and macrolides (ROR = 1.7; 95% CI 1.2-2.3). Hepatic adverse drug reactions remain a serious concern for several drugs widely used in clinical practice. Monitoring hepatic enzymes on a monthly basis for the first 6 months of treatment has been suggested for patients taking medications known to be hepatotoxic. A better knowledge of the epidemiology and mechanisms of hepatic ADRs may contribute to minimising their occurrence.

Hepatic disorders in patients treated with COX-2 selective inhibitors or nonselective NSAIDs: A case/noncase analysis of spontaneous reports

Background:Hepatic adverse events associated with the use of nonaspirin drugs and NSAIDs are uncommon, but the widespread use of these drugs may impact public health. Objective:We conducted a case/noncase analysis of spontaneous reports to compare the hepatic safety profile of cyclooxygenase (COX)-2 selective inhibitors with that of nonselective NSAIDs. Methods:This case/noncase analysis was conducted using the US Food and Drug Administration Freedom of Information (FDA/FOI) database (through quarter 1, 2003) and the World Health Organization Uppsala Monitoring Centre (WHO/UMC) database (through quarter 3, 2003). Council for International Organizations of Medical Sciences and WHO Adverse Reaction Terminology preferred terms were used to classify hepatic disorders with broad and specific case definitions. After reports involving established hepatotoxic drugs (bromfenac, nimesulide, sulindac) were excluded, the proportion of reports (PRs) of each case definition was calculated for each NSAID. Crude and adjusted reporting odds ratios (RORs) were used to compare the overall proportions of hepatic disorders and hepatic failure of celecoxib and rofecoxib versus nonselective NSAIDs. Results:A total of 158,539 and 185,253 reports of NSAIDs were identified in the FDA/FOI and WHO/UMC databases and 25% and 16%, respectively, involved other hepatotoxic drugs. The PRs of hepatic disorders for all COX-2 selective inhibitors and non-selective NSAIDs were 3.0% in the FDA/FOI database and 2.7% in the WHO/UMC database. In the FDA/FOI and WHO/UMC databases, respectively, mmesulide (16.7% and 14.4%), bromfenac (12.0% and 20.7%), diclofenac (8.1% and 4.7%), and sulindac (6.1 % and 9.9%) were reported to be associated with higher proportions of overall hepatic disorders compared with those of other NSAIDs. Crude and adjusted RORs for the prevalences of overall hepatic disorders and hepatic failure with celecoxib and rofecoxib versus the other NSAIDs were <1 (indicating that the proportion was not higher than that of the comparator) in both databases. The interpretation of the results was unchanged when bromfenac, nimesulide, and sulindac were excluded from the analysis. Conclusions:In this case/noncase analysis, bromfenac, nimesulide, sulindac, and diclofenac had higher proportions of reports of hepatic disorders compared with those of other NSAIDs in the FDA/FOI and WHO/UMC databases. The analysis did not raise a safety concern for celecoxib or rofecoxib versus NSAIDs for overall hepatic disorders and hepatic failure.

Fluvastatin and Hepatic Reactions

Signal detection is a crucial element in recognising new adverse drug reactions (ADRs) as soon as possible. HMG-CoA reductase inhibitors ('statins'), the most potent cholesterol-lowering drugs, are generally well tolerated but can occasionally lead to liver toxicity. Pre- and postmarketing studies on statins revealed an incidence of 0.1-3% elevation in hepatic transaminase levels. However, these elevations are asymptomatic, reversible, dose related or probably due to other causes. Postmarketing studies clearly showed the lack of evidence of hepatotoxicity from statins, apart from some isolated case reports of serious hepatic damage described in the literature. It is still unclear whether serious hepatic reactions are dose related and more frequent than the expected rate in the general population. In this study, the hypothesis that fluvastatin could cause serious liver injuries more than the other statins is investigated, in the light of a quantitative and qualitative signal analysis, drug consumption data and evidence from the literature. The Italian Interregional Group of Pharmacovigilance (Gruppo Interregionale di Farmacovigilanza; GIF) is an example of signal detection within the Italian spontaneous ADR reporting system. The GIF database holds reports of suspected ADRs submitted by five Italian pharmacovigilance regional centres. In the GIF database, all reports of suspected ADRs are classified according to the WHO criteria for causality assessment. The reactions are coded according to the WHO Adverse Reaction Terminology and classified as serious or non-serious events on the basis of the WHO Critical Term List. Every 6 months the GIF database is analysed to extract potential signals through a qualitative case-by-case analysis and using a quantitative methodology called proportional reporting ratio (PRR). This methodology permitted us to identify the potential signal 'fluvastatin and hepatic reactions'. At 31 December 2004, the GIF database contained 35 757 reports with an annual reporting rate of 170 reports per million inhabitants. We found a total of 1260 reports of ADRs related to statins, including 178 of hepatic reactions. Sixty-nine reports were attributed to fluvastatin, which showed the highest PRR in comparison with the other statins. Fluvastatin was associated with 33 serious reactions, mainly hepatitis and cholestatic hepatitis. The number of reports of severe hepatotoxicity associated with fluvastatin started to increase from 2002. About half of them did not report other suspected or concomitant drugs and in one third the hepatotoxicity occurred after <1 month of therapy. Twenty-seven out of 33 patients were female, and fluvastatin was administered at 80 mg/day in 81% of cases reporting complete data on drug dosage. In the literature, serious hepatic reactions are rarely described in patients taking statins; however, data gathered by GIF suggest that cases of hepatotoxicity are reported more often than expected. In addition, GIF data seem to reveal that fluvastatin is more likely to cause hepatic reactions than the other statins. However, this is a preliminary signal and future evaluations are certainly needed to confirm it and to quantify this possible risk.

Medical Dictionary for Regulatory Activities (MedDRA)*

Medical Dictionary for Regulatory Activities (MedDRA), as the ICH approved standard terminology for all drug regulatory activities, is in many aspects different from previously used terminologies, mainly in size, specificity, structure, rules and conventions. All these aspects impact on retrieval strategies, analysis and presentation of the coded data. After shortly describing the key features of MedDRA and their theoretically anticipated impact on data analysis and presentation, two examples for display of MedDRA coded data are described, one from a clinical study project and one from spontaneous reporting. The first example compares the adverse drug reaction (ADR) profile of the same data coded in WHO Adverse Reaction Terminology (WHO-ART) and recorded in MedDRA; the second example demonstrates different ways of presenting the ADR profile of an antibacterial, using different elements in MedDRA with the aim of presenting the ADR profile in a way that best transports the medical concepts reported with this drug. Based on some results obtained from these examples and based on analysis of the content of MedDRA version 6.0, the following limitations of MedDRA for data analysis have been identified: (i) the Preferred Term level is generally too granular, bearing the danger of underestimating risks, and the midlevels are currently not a robust, consistent and non-ambiguous level for data aggregation; and (ii) the rules relating to multiaxiality add complexity for data aggregation because related medical concepts may be split into different System Organ Classes, which may mislead frequency analysis. In the absence of guidance from regulatory agencies and with the growing need for analysis of MedDRA-encoded data, there is a risk of diminishing the benefits of MedDRA as a standard terminology through the use of user-specific and non-standardised data analysis and presentation strategies. MedDRA would benefit from a redesign of the group terms (High Level Group Terms/High Level Terms) to become a robust, consistent and non-ambiguous level for data analysis and aggregation. This should be done in an interdisciplinary effort coordinated by the MedDRA Maintenance Supply and Support Organisation (MSSO).

Medical Dictionary for Regulatory Activities (MedDRA)*

Medical Dictionary for Regulatory Activities (MedDRA), as the ICH approved standard terminology for all drug regulatory activities, is in many aspects different from previously used terminologies, mainly in size, specificity, structure, rules and conventions. All these aspects impact on retrieval strategies, analysis and presentation of the coded data. After shortly describing the key features of MedDRA and their theoretically anticipated impact on data analysis and presentation, two examples for display of MedDRA coded data are described, one from a clinical study project and one from spontaneous reporting. The first example compares the adverse drug reaction (ADR) profile of the same data coded in WHO Adverse Reaction Terminology (WHO-ART) and recorded in MedDRA; the second example demonstrates different ways of presenting the ADR profile of an antibacterial, using different elements in MedDRA with the aim of presenting the ADR profile in a way that best transports the medical concepts reported with this drug. Based on some results obtained from these examples and based on analysis of the content of MedDRA version 6.0, the following limitations of MedDRA for data analysis have been identified: (i) the Preferred Term level is generally too granular, bearing the danger of underestimating risks, and the midlevels are currently not a robust, consistent and non-ambiguous level for data aggregation; and (ii) the rules relating to multiaxiality add complexity for data aggregation because related medical concepts may be split into different System Organ Classes, which may mislead frequency analysis. In the absence of guidance from regulatory agencies and with the growing need for analysis of MedDRAencoded data, there is a risk of diminishing the benefits of MedDRA as a standard terminology through the use of user-specific and non-standardised data analysis and presentation strategies. MedDRA would benefit from a redesign of the group terms (High Level Group Terms/High Level Terms) to become a robust, consistent and non-ambiguous level for data analysis and aggregation. This should be done in an interdisciplinary effort coordinated by the MedDRA Maintenance Supply and Support Organisation (MSSO).

Towards linking patients and clinical information: detecting UMLS concepts in e-mail

The purpose of this project is to explore the feasibility of detecting terms within the electronic messages of patients that could be used to effectively search electronic knowledge resources and bring health information resources into the hands of patients. Our team is exploring the application of the natural language processing (NLP) tools built within the Lister Hill Center at the National Library of Medicine (NLM) to the challenge of detecting relevant concepts from the Unified Medical Language System (UMLS) within the free text of lay people’s electronic messages (e-mail). We obtained a sample of electronic messages sent by patients participating in a randomized field evaluation of an internet-based home care support service to the project nurse, and we subjected elements of these messages to a series of analyses using several vocabularies from the UMLS Metathesaurus and the selected NLP tools. The nursing vocabularies provide an excellent starting point for this exercise because their domain encompasses patient’s responses to health challenges. In successive runs we augmented six nursing vocabularies (NANDA Nursing Diagnosis, Nursing Interventions Classification, Nursing Outcomes Classification, Home Health Classification, Omaha System, and the Patient Care Data Set) with selected sets of clinical terminologies (International Classification of Primary Care; International Classification of Primary Care- American English; Micromedex DRUGDEX; National Drug Data File; Thesaurus of Psychological Terms; WHO Adverse Drug Reaction Terminology) and then additionally with either Medical Subject Heading (MeSH) or SNOMED International terms. The best performance was obtained when the nursing vocabularies were complemented with selected clinical terminologies. These findings have implications not only for facilitating lay people’s access to electronic knowledge resources but may also be of assistance in developing new tools to aid in linking free text (e.g., clinical notes) to lexically complex knowledge resources such as those emerging from the Human Genome Project.