Data-Driven Identification of Factors That Influence the Quality of Adverse Event Reports: 15-Year Interpretable Machine Learning and Time-Series Analyses of VigiBase and QUEST.

BACKGROUND: The completeness of adverse event (AE) reports, crucial for assessing putative causal relationships, is measured using the vigiGrade completeness score in VigiBase, the World Health Organization global database of reported potential AEs. Malaysian reports have surpassed the global average score (approximately 0.44), achieving a 5-year average of 0.79 (SD 0.23) as of 2019 and approaching the benchmark for well-documented reports (0.80). However, the contributing factors to this relatively high report completeness score remain unexplored. OBJECTIVE: This study aims to explore the main drivers influencing the completeness of Malaysian AE reports in VigiBase over a 15-year period using vigiGrade. A secondary objective was to understand the strategic measures taken by the Malaysian authorities leading to enhanced report completeness across different time frames. METHODS: We analyzed 132,738 Malaysian reports (2005-2019) recorded in VigiBase up to February 2021 split into historical International Drug Information System (INTDIS; n=63,943, 48.17% in 2005-2016) and newer E2B (n=68,795, 51.83% in 2015-2019) format subsets. For machine learning analyses, we performed a 2-stage feature selection followed by a random forest classifier to identify the top features predicting well-documented reports. We subsequently applied tree Shapley additive explanations to examine the magnitude, prevalence, and direction of feature effects. In addition, we conducted time-series analyses to evaluate chronological trends and potential influences of key interventions on reporting quality. RESULTS: Among the analyzed reports, 42.84% (56,877/132,738) were well documented, with an increase of 65.37% (53,929/82,497) since 2015. Over two-thirds (46,186/68,795, 67.14%) of the Malaysian E2B reports were well documented compared to INTDIS reports at 16.72% (10,691/63,943). For INTDIS reports, higher pharmacovigilance center staffing was the primary feature positively associated with being well documented. In recent E2B reports, the top positive features included reaction abated upon drug dechallenge, reaction onset or drug use duration of <1 week, dosing interval of <1 day, reports from public specialist hospitals, reports by pharmacists, and reaction duration between 1 and 6 days. In contrast, reports from product registration holders and other health care professionals and reactions involving product substitution issues negatively affected the quality of E2B reports. Multifaceted strategies and interventions comprising policy changes, continuity of education, and human resource development laid the groundwork for AE reporting in Malaysia, whereas advancements in technological infrastructure, pharmacovigilance databases, and reporting tools concurred with increases in both the quantity and quality of AE reports. CONCLUSIONS: Through interpretable machine learning and time-series analyses, this study identified key features that positively or negatively influence the completeness of Malaysian AE reports and unveiled how Malaysia has developed its pharmacovigilance capacity via multifaceted strategies and interventions. These findings will guide future work in enhancing pharmacovigilance and public health.

Carbamazepine-Induced Severe Cutaneous Adverse Drug Reactions: A 21-Year Comparison Between Children and Adults in Malaysia.

Severe cutaneous adverse drug reactions (SCARs) are a life-threatening condition. We aimed to identify all carbamazepine-induced SCARs voluntarily reported to the Malaysian pharmacovigilance database and to compare between children and adults. Adverse drug reaction reports for carbamazepine were extracted from 2000 to 2020, and divided into 2 groups, that is, children (aged 0-17 years) and adults (aged 18 years and above). Age, sex, race, and carbamazepine dose were analyzed using multiple logistic regression. Of 1102 carbamazepine adverse drug reaction reports, 416 reports were SCARs (99 children, 317 adults). Stevens-Johnson syndrome and toxic epidermal necrolysis were the main SCAR types for both age groups. Median time-to-onset for any type of SCAR was 13 days, regardless of age. In children, Malay individuals were 3.6 times more likely to report SCARs (95% confidence interval, 1.356-9.546; P = .010) compared to the Chinese population. In adults, carbamazepine-induced SCARs were reported as 3.6 times higher in those with a daily dose of 200 mg or less as compared to a daily dose of 400 mg or more. (95% confidence interval, 2.257-5.758; P < .001) Carbamazepine-induced SCARs reported in Malaysia were predominantly Stevens-Johnson syndrome or toxic epidermal necrolysis, with the majority in Malay individuals. Initiation therapy needs close monitoring between 2 weeks and 1 month.

Risk of serious adverse events after the BNT162b2, CoronaVac, and ChAdOx1 vaccines in Malaysia: A self-controlled case series study.

BACKGROUND: Rapid deployment of COVID-19 vaccines is challenging for safety surveillance, especially on adverse events of special interest (AESIs) that were not identified during the pre-licensure studies. This study evaluated the risk of hospitalisations for predefined diagnoses among the vaccinated population in Malaysia. METHODS: Hospital admissions for selected diagnoses between 1 February 2021 and 30 September 2021 were linked to the national COVID-19 immunisation register. We conducted self-controlled case-series study by identifying individuals who received COVID-19 vaccine and diagnosis of thrombocytopenia, venous thromboembolism, myocardial infarction, myocarditis/pericarditis, arrhythmia, stroke, Bell's Palsy, and convulsion/seizure. The incidence of events was assessed in risk period of 21 days postvaccination relative to the control period. We used conditional Poisson regression to calculate the incidence rate ratio (IRR) and 95% confidence interval (CI) with adjustment for calendar period. RESULTS: There was no increase in the risk for myocarditis/pericarditis, Bell's Palsy, stroke, and myocardial infarction in the 21 days following either dose of BNT162b2, CoronaVac, and ChAdOx1 vaccines. A small increased risk of venous thromboembolism (IRR 1.24; 95% CI 1.02, 1.49), arrhythmia (IRR 1.16, 95% CI 1.07, 1.26), and convulsion/seizure (IRR 1.26; 95% CI 1.07, 1.48) was observed among BNT162b2 recipients. No association between CoronaVac vaccine was found with all events except arrhythmia (IRR 1.15; 95% CI 1.01, 1.30). ChAdOx1 vaccine was associated with an increased risk of thrombocytopenia (IRR 2.67; 95% CI 1.21, 5.89) and venous thromboembolism (IRR 2.22; 95% CI 1.17, 4.21). CONCLUSION: This study shows acceptable safety profiles of COVID-19 vaccines among recipients of BNT162b2, CoronaVac, and ChAdOx1 vaccines. This information can be used together with effectiveness data for risk-benefit analysis of the vaccination program. Further surveillance with more data is required to assess AESIs following COVID-19 vaccination in short- and long-term.

Incidence of Antiseizure Medication-Induced Severe Cutaneous Adverse Reactions in Malaysia.

Antiseizure medication can potentially cause severe cutaneous adverse reactions, and certain antiseizure medication-induced severe cutaneous adverse reactions are associated with specific human leukocyte antigen alleles. This caused a change in antiseizure medication prescribing patterns, which may influence the incidence of antiseizure medication-induced severe cutaneous adverse reactions. Thus, we aimed to determine the incidence of antiseizure medication-induced severe cutaneous adverse reactions and its change over 15 years (2006-2019) in Malaysia. This retrospective analysis combined antiseizure medication-induced SCAR cases from the national adverse drug reaction database in the National Pharmaceutical Regulatory Agency, antiseizure medication usage data from the Malaysian Statistics of Medicine, and prescribing data from University Malaya Medical Centre, a national-level tertiary hospital to calculate antiseizure medication-induced SCAR incidence in Malaysia. We observed an upward trend in reported antiseizure medication-induced SCAR cases from 28 cases in 2006 to 92 in 2016. The incidence of carbamazepine (CBZ)-induced severe cutaneous adverse reactions increased from 7.5 per 1000 person-years (2006) to 17.8 per 1000 person-years (2016) but dropped to 7.2 per 1000 person-years subsequently (2019). Concurrently, there was an increase in the incidence of severe cutaneous adverse reactions secondary to phenytoin and lamotrigine. The prevalent users of CBZ had reduced from 22.8% (2006) to 14.1% (2016), whereas the levetiracetam and sodium valproate users increased by 5.5% and 4.8%, respectively. The incidence of CBZ-induced severe cutaneous adverse reactions had reduced since 2016, probably related to the implementation of human leukocyte antigen-B*1502 screening in Malaysia or substitution of CBZ with other antiseizure medications. However, this was accompanied by an increase in SCAR incidence related to phenytoin and lamotrigine.

Incidence of allopurinol-induced severe cutaneous adverse drug reaction in Malaysia.

AIMS: Allopurinol is known to cause severe cutaneous adverse drug reactions (SCAR) in Malaysia. However, the incidence of allopurinol-induced SCAR is unknown. Therefore, we aimed to determine the incidence of allopurinol-induced SCAR in Malaysia over 5 years from 2015 to 2019. METHODS: This retrospective analysis was done in collaboration with the National Pharmaceutical Regulatory Agency (NPRA). All allopurinol-induced adverse drug reaction cases reported to NPRA from 2015 to 2019 were extracted. Allopurinol-induced SCAR cases were identified and the incidence over the 5 years was calculated. RESULTS: Incidence of allopurinol-induced SCAR averaged at 2.5 cases per 1000 new users over the 5-year period, with a reducing trend from 3.2 per 1000 new users in 2015 to 2.25 per 1000 in 2019; despite the increasing number of adverse drug reaction cases being reported over the years. Stevens-Johnson syndrome was the commonest form of allopurinol-induced SCAR reported, at 143 cases (46.8% of total SCAR reported). Among Malaysia's 3 main ethnicities, the Chinese had the highest percentages of allopurinol-induced SCAR when compared to the Bumiputera and Indians (3.18 × 10-4 %). CONCLUSION: The estimated incidence of allopurinol-induced SCAR in Malaysia from 2015 to 2019 was 2.5 cases per 1000 new users. This figure is consistent with the incidence reported in other Asian countries, namely Taiwan and Thailand.

Allopurinol-Induced Severe Cutaneous Adverse Drug Reactions: An Analysis of Spontaneous Reports in Malaysia (2000-2018).

INTRODUCTION: Allopurinol-induced severe cutaneous adverse drug reactions (SCARs) are potentially debilitating and life-threatening reactions, which can cause a financial burden to the healthcare system. OBJECTIVES: We aimed to identify risk factors for allopurinol-induced SCARs and to assess their impact on fatality. METHODS: Adverse drug reaction (ADR) reports with allopurinol as suspected drug were extracted from the Malaysian pharmacovigilance database from year 2000 to 2018. Multiple logistic regression analysis was used to identify significant predictors of allopurinol-induced SCARs. We further analysed the association between covariates and SCARs-related fatality in a separate model. Level of significance was set at p value < 0.05. RESULTS: Out of 1747 allopurinol ADR reports, 612 involved SCARs (35%). The strongest predictors significantly associated with SCARs were underlying renal disease (odds ratio [OR] 2.02; 95% confidence interval [CI] 1.36, 3.00; p = 0.001), allopurinol-prescribed dose of 300 mg/day or higher (OR 1.72; 95% CI 1.38, 2.15; p < 0.001), females (OR 1.54; 95% CI 1.24, 1.93; p < 0.001), age 65 years and above (OR 1.31; 95% CI 1.04, 1.64; p = 0.020), and allopurinol-prescribed indication. SCARs cases were higher in patients who received allopurinol for unspecified hyperuricaemia (OR 1.87; 95% CI 1.29, 2.70; p = 0.001) and off-label indications (OR 3.45; 95% CI 2.20, 5.42; p < 0.001) compared to registered indications. Fatality was associated with older age and a diagnosis of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap or TEN. CONCLUSIONS: Malaysian pharmacovigilance data show that predictors of allopurinol-induced SCARs were elderly females, patients with underlying renal disease and high allopurinol doses. These patients need close monitoring and must be educated to stop allopurinol at the first signs of rash.