World Health Organization Pharmacovigilance Research Articles

Evaluating the impact of loperamide on irinotecan-induced adverse events: a disproportionality analysis of data from the World Health Organization pharmacovigilance database (VigiBase).

SN-38, the active metabolite of irinotecan, may cause adverse events necessitating treatment discontinuation and management. Diarrhea, which is treated with loperamide, is one such event. However, loperamide may delay SN-38 elimination, causing more adverse events. Therefore, understanding the adverse events caused by symptomatic drugs is crucial for safe drug therapy. This study aimed to assess the association between loperamide and irinotecan-induced adverse events. We analyzed data up to December 2022 from VigiBase, the World Health Organization's adverse event database. The study used reporting odds ratios (RORs) to evaluate the associations between concomitant medications and irinotecan-induced adverse events. Fisher's exact probability test was used to analyze the adverse events. Logistic regression analysis was performed to identify associated adverse event signals. Of the 32,520,983 cases analyzed, 57,454 involved the use of irinotecan. Among these, 1589 (2.8%) patients were co-treated with loperamide. Signals for neutropenia (ROR 1.37, 95% confidence interval (CI) 1.20-1.57, p < 0.001), anemia (ROR 1.81, 95% CI 1.43-2.30, p < 0.001), and alopecia (ROR 1.89, 95% CI 1.30-2.74, p < 0.01) were detected with concomitant loperamide. Multivariate logistic regression analysis confirmed that concomitant loperamide use was associated with signals for neutropenia, anemia, and alopecia. Our results suggest that loperamide increases the risk of irinotecan-induced adverse events and enhances irinotecan toxicity. The study methodology may be useful for predicting adverse event risk when choosing symptomatic therapy drugs during irinotecan use.

Lipschütz ulcer following first dose of COVID-19 tozinameran vaccine: Report of a case and review of a World Health Organization pharmacovigilance database.

Lipschütz ulcer (LU) is a condition known for painful vulvar ulcers, typically affecting young women and often linked to infectious agents. Recent reports have indicated a potential connection between LU and COVID-19 vaccination, particularly after the second or booster doses. This study presents a case of LU following the first dose of tozinameran in a young woman who had a previous SARS-CoV-2 infection and investigates similar cases globally. An 18-year-old woman experienced vulvar pain and ulcers 2-days after her initial COVID-19 vaccine dose. After ruling out infections through serological tests, a diagnosis of LU was made, and her symptoms resolved after 10 days. A literature search and VigiBase® analysis revealed 11 cases of LU following COVID-19 vaccination, and 519 vulvovaginal ulcer cases associated with these vaccines were identified in Vigibase®, with a median onset of 2 days. Most LU cases occurred after the second dose or booster shots. The primary hypothesis for this association is a type 3 hypersensitivity reaction mediated by immune complexes, possibly triggered by prior exposure, as many cases occurred after the second dose. Interestingly, the presented case suggests that prior COVID-19 infection could serve as sensitization. In conclusion, this study highlights the potential occurrence of LU after the initial COVID-19 vaccine dose in young patients with prior COVID-19 infection. While the risk of recurrence after subsequent vaccinations or infections remains uncertain, the benefits of vaccination outweigh the risks. Clinicians and patients should be aware of this potential issue to make informed decisions regarding vaccination.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicidality: A replication study using reports to the World Health Organization pharmacovigilance database (VigiBase®)

IntroductionReports of suicidality associated with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been reported to the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA). We previously reported an increased reporting odds ratio (ROR) of some measures of suicidality with semaglutide and liraglutide using the FDA Adverse Event Reporting System (FAERS). Notwithstanding the increased ROR, causality between GLP-1 RAs exposure and any aspect of suicidality is not established. Research design and methodsThe analysis herein aims to extend a previous analysis of the FAERS by evaluating the ROR for suicidality reported to the World Health Organization (WHO) Pharmacovigilance Database (VigiBase). We aimed to characterize the ROR of suicidality associated with GLP-1 RAs, as extrapolated from spontaneous reports. As per our previous report, the ROR was considered significant when the lower limit of the 95 % confidence (CI) was >1.0. ResultsWe searched VigiBase reports from inception to January 2024. The RORs for suicidal ideation were significantly increased for semaglutide (5.82), liraglutide (4.03) and tirzepatide (2.25). For “depression/suicidal”, the ROR was significantly increased for semaglutide (14.74) and liraglutide (5.86); and for suicidal behaviour, the ROR was significantly increased for semaglutide (6.52) and liraglutide (3.90). However, for suicide attempts, the ROR was significantly decreased for semaglutide (0.11), dulaglutide (0.075), exenatide (0.047) and liraglutide (0.15). For completed suicide, the ROR was also significantly decreased for semaglutide (0.01), dulaglutide (0.003), exenatide (0.002) and liraglutide (0.008). ConclusionUnlike our previous report with FAERS, a mixed pattern of ROR emerged in the WHO VigiBase with respect to suicidality and exposure to select GLP-RAs. Causation between GLP-1 RA exposure and suicidality (either increased or decreased) cannot be ascertained from ROR data.

Global and Regional Burden of Vaccine-Associated Erythema Multiforme and Their Related Vaccines, 1967–2023: An In-Depth Analysis of the World Health Organization Pharmacovigilance Database

Objective: Vaccine-associated erythema multiforme (EM) remains under-researched, impacting global vaccine safety evaluations. This study examines the global and regional burden of EM and its association with specific vaccines to optimize vaccination strategies. Subject and Methods: We analyzed data from the WHO pharmacovigilance database on vaccine-associated EM from 1967 to 2023 (n = 131,255,418 reports). Reporting frequencies, reported odds ratios (RORs), and information components (IC) were calculated for 16 vaccines across 170 countries. Results: We identified 6,355 cases (males, n = 3,182 [50.07%]) of vaccine-associated EM from a total of 46,378 reports of all-cause EM. While vaccine-associated EM has been consistently reported, there has been a notable increase in reported incidence particularly in 2010 and 2020. Measles, mumps, and rubella vaccines had the highest association with vaccine-associated EM reports (ROR: 8.75 [95% confidence interval, 8.11–9.44]; IC, 3.10 [IC0.25, 2.97]), followed by hepatitis B (8.54 [7.66–9.51]; 3.06 [2.88]), hepatitis A (8.11 [7.01–9.39]; 2.98 [2.74]), typhoid (6.50 [4.75–8.90]; 2.60 [2.07]), encephalitis (5.86 [4.35–7.91]; 2.47 [1.96]), diphtheria, tetanus toxoids, pertussis, polio, and Hemophilus influenza type b (5.70 [5.42–5.99]; 2.46 [2.38]), pneumococcal (5.56 [5.11–6.06]; 2.45 [2.31]), rotavirus (4.96 [4.21–5.84]; 2.29 [2.01]), varicella-zoster (4.44 [3.99–4.95]; 2.13 [1.95]). Vaccine-associated EM reports were more strongly correlated with younger age groups and males. The overall fatality rate of vaccine-associated EM was 0.04%. Conclusions: The rise in vaccine-associated EM across multiple vaccines, especially in younger populations, highlights the need for closer monitoring and more informed vaccination practices to mitigate adverse reactions.

Ischemic cardiopathy induced by capecitabine in gastric cancer: The role of dihydropyrimidine dehydrogenase metabolites

Fluoropyrimidine-based therapies, 5-fluorouracil (5-FU) and its oral prodrugs, capecitabine and tegafur/oteracil/gimeracil (S-1), are pivotal drugs to treat gastric cancer. Fluoropyrimidines are associated with cardiotoxicity including ischemic cardiopathy. The mechanisms of ischemic cardiopathy are considered to be multifactorial, potentially involving metabolites of 5-FU generated by the dihydropyrimidine dehydrogenase (DPD). By using Vigibase®, the World Health Organization pharmacovigilance database, we aimed to investigate the implication of the 5-FU metabolites induced by DPD in the occurrence of ischemic cardiopathy in patients with gastric cancer using capecitabine. In Vigibase®, we included serious reports of ischemic cardiopathy with capecitabine and S-1 from January 1st, 2013, to September 16th, 2023. Among patients with gastric cancer, we calculated the reporting odds ratio (ROR) of ischemic cardiopathy to compare capecitabine (a prodrug without DPD antagonist) with S-1 (a prodrug associated with a DPD antagonist). The ROR was also calculated regardless of the drug indication. An ancillary analysis based on the French pharmacovigilance database was also performed. We evaluated the ROR of serious cardiac disorders induced by 5-FU intravenous infusion according to the DPD status (no deficiency versus complete or partial deficiency). In gastric cancer, 1843reports (including 23 ischemic cardiopathy) for capecitabine and 2225reports (including 17 ischemic cardiopathy) for S-1 were included. Median time-to-onset was 7 (3-26) days for capecitabine and 22 (13.25-30) days for S-1. Capecitabine was associated with an increased ROR of ischemic cardiopathy compared with S-1 in gastric cancer (ROR=1.6; [95% CI=1.5-1.8]) and regardless of the indication (7.3; [95% CI=6.6-8.0]). In the ancillary analysis, among 5-FU users, the lack of DPD deficiency increased the ROR for cardiac disorders (2.1; [95% CI=1.9-2.3]) compared to the DPD deficiency. This work supports the role of toxic 5-FU metabolites generated by dihydropyrimidine dehydrogenase in the occurrence of ischemic cardiopathy among patients with gastric cancer using capecitabine.

Is ibrutinib-related atrial fibrillation dose dependent? Insights from an individual case level analysis of the World Health Organization pharmacovigilance database

Is ibrutinib-related atrial fibrillation dose dependent? Insights from an individual case level analysis of the World Health Organization pharmacovigilance database

Association between glucagon-like peptide-1 receptor agonists and risk of suicidality: A comprehensive analysis of the global pharmacovigilance database.

To evaluate the potential association between suicidality and glucagon-like peptide-1 receptor agonists (GLP-1RAs), as well as other medications used for obesity and diabetes, using comprehensive global data. This study utilized the World Health Organization's pharmacovigilance database, encompassing adverse drug reaction reports from 1967 to 2023, from 170 countries (total reports, N = 131 255 418). We present the reported odds ratios (RORs) with 95% confidence intervals (CIs) and information component (IC) with IC025 regarding the association between GLP-1RA use and suicidality. Although reports of GLP-1RA-associated suicidality increased gradually from 2005 to 2023 (n = 332), no evidence of an association was observed (ROR 0.15 [95% CI 0.13 to 0.16]; IC -2.77 [IC025 -2.95]). The lack of evidence of an association persisted regardless of whether GLP-1RAs were used for diabetes treatment (ROR 0.13 [95% CI 0.11 to 0.14]; IC -2.95 [IC025 -3.14]) or obesity treatment (ROR 0.44 [95% CI 0.34 to 0.58]; IC -1.16 [IC025 -1.62]). However, an association was found between suicidality and other diabetes medications excluding GLP-1RAs (ROR 1.13 [95% CI 1.10 to 1.15]; IC 0.17 [IC025 0.13]). Similarly, the potential association with suicidality was observed in medications used to treat obesity excluding GLP-1RAs (ROR 1.08 [95% CI 1.01 to 1.14]; IC 0.10 [IC025 0.01]). The suspected association between GLP-1RA use and suicidality, as raised by the European Medicines Agency, was not found in our global analysis. This indicates that the sporadic reports of GLP-1RA-associated suicidality are likely influenced by factors such as comorbidities present in the GLP-1RA user population.

A replication study using the World Health Organization pharmacovigilance database (VigiBase®) to evaluate whether an association between ketamine and esketamine and alcohol and substance misuse exists

Background and objectivesKetamine and esketamine are increasingly prescribed in the treatment of resistant mood disorders and persons at risk of suicide. Ketamine is a drug of misuse with increasing non-therapeutic use in the general population. Herein, our aim was to determine whether ketamine and/or esketamine are disproportionately associated with reports of substance and/or alcohol misuse. MethodsReplicating a similar analysis recently conducted using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, we identified cases of “alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder (SUD), substance abuse, drug dependence, drug use disorder and drug abuse” in association with ketamine and esketamine reported to the World Health Organization Pharmacovigilance Database (WHO VigiBase). We searched the database from inception to January 2024. The reporting odds ratio (ROR) of each of the aforementioned parameters was calculated; acetaminophen was used as the control. The numerator of the equation represents the number of cases (n) and the denominator represents the total cases of psychiatric disorders (N). Significance was obtained when the lower limit of the 95 % confidence (CI) > 1.0. ResultsThe RORs for ketamine was increased for most parameters (i.e., alcohol abuse (3.24), substance dependence (12.48), substance use disorder (170.44), substance abuse (2.94), drug dependence (2.88), drug use disorder (11.54) and drug abuse (2.85), respectively). With respect to esketamine, the RORs were observed to be different from ketamine insofar as we observed a reduction in the RORs for three parameters (i.e., substance abuse (0.41), drug dependence (0.083) and drug abuse (0.052), respectively). The IC025 values were significant for ketamine in cases of alcohol abuse (0.35), substance dependence (0.50), substance use disorder (2.77), substance abuse (0.83), drug dependence (0.97), drug use disorder (1.95) and drug abuse (0.94). Additionally, oxycontin showed significant IC025 values for substance use disorder (0.0014), substance abuse (0.042), and drug dependence (0.17). ConclusionEsketamine was not associated with an increased ROR for any parameter of alcohol and/or substance use disorder. Mixed results were observed with ketamine with some RORs increased and others decreased. Estimating RORs using a pharmacovigilance database does not establish causation in the case of elevated RORs and cannot be assumed to be a therapeutic effect when lower RORs were observed.

Global burden of anticancer drug-induced acute kidney injury and tubulointerstitial nephritis from 1967 to 2023

This study aims to figure out the worldwide prevalence of anticancer therapy-associated acute kidney injury (AKI) and tubulointerstitial nephritis (TIN) and the relative risk of each cancer drug. We conducted an analysis of VigiBase, the World Health Organization pharmacovigilance database, 1967–2023 via disproportionate Bayesian reporting method. We further categorized the anticancer drugs into four groups: cytotoxic therapy, hormone therapy, immunotherapy, and targeted therapy. Reporting odds ratio (ROR) and information component (IC) compares observed and expected values to investigate the associations of each category of anticancer drugs with AKI and TIN. We identified 32,722 and 2056 reports (male, n = 17,829 and 1,293) of anticancer therapy-associated AKI and TIN, respectively, among 4,592,036 reports of all-drug caused AKI and TIN. There has been a significant increase in reports since 2010, primarily due to increased reports of targeted therapy and immunotherapy. Immunotherapy exhibited a significant association with both AKI (ROR: 8.92; IC0.25: 3.06) and TIN (21.74; 4.24), followed by cytotoxic therapy (7.14; 2.68), targeted therapy (5.83; 2.40), and hormone therapy (2.59; 1.24) for AKI, and by cytotoxic therapy (2.60; 1.21) and targeted therapy (1.54; 0.61) for TIN. AKI and TIN were more prevalent among individuals under 45 years of age, with a female preponderance for AKI and males for TIN. These events were reported in close temporal relationship after initiation of the respective drug (16.53 days for AKI and 27.97 days for TIN), and exhibited a high fatality rate, with 23.6% for AKI and 16.3% for TIN. These findings underscore that kidney-related adverse drug reactions are of prognostic significance and strategies to mitigate such side effects are required to optimize anticancer therapy.

Cardiovascular and Cerebrovascular Adverse Events Associated with Intravitreal Anti-VEGF Monoclonal Antibodies: A World Health Organization Pharmacovigilance Study

PurposeTo analyze cardiovascular and cerebrovascular adverse events (ADRs) after intravitreal anti-vascular endothelial growth factor (VEGF; aflibercept, bevacizumab, brolucizumab, and ranibizumab) treatment. SubjectsVigiBase, a World Health Organization (WHO) global safety report database DesignPharmacovigilance study MethodsThe individual-case-safety reports (ICSR) of cardiovascular and cerebrovascular ADRs after intravitreal anti-VEGF treatment were compared with those reported in the full database. From 2004 to 2023, 23,129 ADRs after intravitreal anti-VEGF therapy and 25,015,132 ADRs associated with any drug (full database). Main Outcome MeasuresThe reporting odds ratio (ROR) and information components (IC) were calculated, and the 95% lower credibility interval endpoint of the information component (IC025) was used for disproportionate Bayesian reporting. Inter-drug comparisons were performed using the ratio of odd ratio (rOR). ResultsCompared with the full database, anti-VEGFs were associated with an increased reporting of myocardial infarction (IC025 0.75; ROR: 1.78 [95% CI 1.70–1.86]), angina pectoris (IC025 0.53; ROR: 1.61 [95% CI 1.47–1.77]), arrythemias including atrial fibrillation, atrial flutter, ventricular fibrillation, supraventricular tachycardia (all IC025 >0, ROR>1), hypertension (IC025 2.22; ROR: 4.91 [95% CI 4.82–5.01]), and hypertensive crisis (IC025 1.97; ROR: 4.49 [95% CI 4.07–4.97]). Moreover, anti-VEGFs were associated with a higher reporting of cerebrovascular ADRs such as cerebral infarction (IC025 4.34; ROR: 23.19 [95% CI 22.10–24.34]), carotid artery stenosis (IC025 1.85; ROR: 5.24 [95% CI 3.98–6.89]), cerebral hemorrhage (IC025 2.29; ROR: 5.38 [95% CI 5.03–5.76]), and subarachnoid hemorrhage (IC025 1.98; ROR: 4.81 [95% CI 4.14–5.6]). Inter-drug comparison indicated that compared to ranibizumab, patients with aflibercept showed overall under-reporting of cardiovascular and cerebrovascular ADRs such as myocardial infarction (rOR 0.55 [95% CI 0.49–0.52]), atrial fibrillation (rOR 0.28 [95% CI 0.23–0.35]), cerebrovascular accident (rOR, 0.15 [95% CI 0.14–0.17]), and cerebral hemorrhage (rOR, 0.51 [95% CI 0.40–0.65]). ConclusionsIn this pharmacovigilance case-noncase study, significantly increased reporting of cardiovascular and cerebrovascular ADRs were identified after intravitreal anti-VEGF treatment. While ranibizumab may exhibit superior systemic safety regarding its biological characteristics, it is crucial not to overlook the occurrence of cardiovascular and cerebrovascular ADRs considering its higher reporting rate than bevacizumab or aflibercept.

Cardiotoxic profiles of CAR-T therapy and bispecific T-cell engagers in hematological cancers

BackgroundChimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers, which redirect T-cells to tumor antigens, have immensely benefitted patients with relapsed/refractory B-cell cancers. How these therapies differ in cardiotoxicity is underexplored. We used the World Health Organization pharmacovigilance database, VigiBase, to compare cardiotoxicity profiles between CD19-targeted CAR-T therapy and blinatumomab (a CD19/CD3-targeted bispecific T-cell engager).MethodsSafety reports in VigiBase were filtered for diffuse large B-cell lymphoma (DLBCL, n = 17,479) and acute lymphocytic leukemia (ALL, n = 28,803) for all adverse reactions. Data were further filtered for patients taking CAR-T therapy or blinatumomab. Reporting odds ratios (ROR) and fatality rates were compared between CAR-T cell products (e.g. tisagenlecleucel and axicabtagene ciloleucel), and between CAR-T therapy and blinatumomab.ResultsTisagenlecleucel is associated with cardiac failure (IC025 = 0.366) with fatality rates of 85.7% and 80.0% in DLBCL and pediatric ALL patients respectively. For DLBCL patients, axicabtagene ciloleucel has greater reporting for hypotension than tisagenlecleucel (ROR: 2.54; 95% CI: 1.28–5.03; p = 0.012), but tisagenlecleucel has higher fatality rates for hypotension than axicabtagene ciloleucel [50.0% (tisagenlecleucel) vs 5.6% (axicabtagene ciloleucel); p < 0.001]. Blinatumomab and tisagenlecleucel have similar fatality rates for hypotension in pediatric ALL patients [34.7% (tisagenlecleucel) vs 20.0% (blinatumomab); p = 0.66].ConclusionsTisagenlecleucel is associated with severe and fatal adverse cardiac events, with higher fatality rates for hypotension compared to axicabtagene ciloleucel in DLBCL patients, but similar hypotension fatality rates compared to blinatumomab in pediatric ALL patients. Effective management necessitates experienced physicians, including cardio-oncologists, skilled in interdisciplinary approaches to manage these toxicities.

Thirst and drugs: A study in the World Health Organization's pharmacovigilance database.

Thirst is a complex physiological compensatory mechanism but could also be associated with drugs. This association was poorly investigated previously. Using the WHO global pharmacovigilance database, Vigibase®, disproportionality analyses potential associations between exposure to drugs and thirst reports were performed. All reports of thirst in adults between 01/01/2000 and 31/12/2023 were included. Results are expressed as reporting odds ratio (ROR). Analysis of the 3186 reports of thirst (978 'serious') allowed, first, to confirm the association between thirst and exposure to vasopressin antagonists (tolvaptan), lithium, gliflozins (dapagliflozin, empagliflozin), pregabalin and antimuscarinic drugs (glycopyronium, oxybutynin, tiotropium). Second, new safety signals were described with monoamine reuptake inhibitors (antidepressants: duloxetine, venlafaxine; anti-obesity agent: sibutramine), antipsychotic (olanzapine), glucocorticoid (prednisolone), diuretic (furosemide) drugs as well with ribavirin or sodium oxybate. This study is the first to offer a list of drugs associated with thirst in humans.

#1187 Acute kidney injury and tubulointerstitial nephritis following prescription of anticancer drugs: VigiBase analysis

Abstract Background and Aims Anticancer drugs can have varying effects on the kidneys, depending on their characteristics. Various anticancer drugs may be nephrotoxic and can potentially cause renal impairment. We aimed to analyze the risk of renal adverse reactions according to different types of anticancer drugs using a global reporting system. Method We conducted an analysis on VigiBase, the World Health Organization pharmacovigilance database from Dec 1967 to Jul 2023 via disproportionate Bayesian reporting method. We further categorized the anticancer drugs into four groups: cytotoxic therapy, hormone therapy, immunotherapy, and targeted therapy. Reporting odds ratio (ROR) compares observed and expected values to find the associations of each category of anticancer drugs with acute kidney injury (AKI) and tubulointerstitial nephritis (TIN). Results We observed 32,722 AKI and 2,056 TIN reports which were reported as anticancer drug-related renal adverse reactions. Noteworthy trends emerged in AKI reports following anticancer drugs: cytotoxic therapies consistently dominated with 13,925 cases, while AKI cases related to targeted therapies and immunotherapies surged to 14,236 and 3,816 cases over three decades, respectively. Notably, TIN exhibited a significant increase, particularly after the popular usage of immunotherapy between 2015 and 2020, surpassing other categories of anticancer drugs. The highest disproportionality signal for AKI was associated with immunotherapies (ROR, 8.92; confidence interval [CI], 8.63–9.21, followed by cytotoxic therapies (ROR, 7.14; 95% CI, 7.01–7.26), targeted therapies (ROR, 5.83; 95% CI, 5.73–5.93), and hormone therapies (ROR, 2.59; 95% CI, 2.41–2.79). In the case of TIN, a significantly higher disproportionality signal was found for immunotherapies (ROR, 21.74; 95% CI, 20.39–23.18), followed by cytotoxic therapies (ROR, 2.60; 95% CI, 2.40–2.82), and targeted therapies (ROR, 1.54; 95% CI, 1.40–1.69). Hormone therapies did not exhibit a significant disproportionality signal. Separate analyses were also conducted for the ROR of AKI and TIN for each individual anticancer drug. Conclusion AKI and TIN were substantially observed following the administration of anticancer drugs. Noticeably, renal adverse reactions following immunotherapy, which have been experiencing an increase in utilization, were more prominent than other types of anticancer drugs. Clinicians should consider the increased risk of renal adverse reactions after specific anticancer drugs.

Characteristics and outcomes of gemcitabine-associated pulmonary hypertension.

Despite its known cardiac and lung toxicities, the chemotherapy drug gemcitabine has only rarely been associated with pulmonary hypertension (PH), and the underlying mechanism remains unclear. The objective of the present study was to assess the association between gemcitabine and PH. We identified incident cases of precapillary PH confirmed by right heart catheterisation in patients treated with gemcitabine from the French PH Registry between January 2007 and December 2022. The aetiology, clinical, functional, radiological and haemodynamic characteristics of PH were reviewed at baseline and during follow-up. A pharmacovigilance disproportionality analysis was conducted using the World Health Organization (WHO) pharmacovigilance database. We identified nine cases of pulmonary arterial hypertension, either induced (in eight patients) or exacerbated (in one patient) by gemcitabine. Patients exhibited severe precapillary PH, with a median mean pulmonary arterial pressure of 40 (range 26-47) mmHg, a cardiac index of 2.4 (1.6-3.9) L·min-1·m-2 and a pulmonary vascular resistance of 6.3 (3.1-12.6) Wood units. The median time from the initiation of gemcitabine to the onset of PH was 7 (4-50) months, with patients receiving a median of 16 (6-24) gemcitabine injections. Six patients showed clinical improvement upon discontinuation of gemcitabine. In the WHO pharmacovigilance database, we identified a significant signal with 109 cases reporting at least one adverse event related to PH with gemcitabine. Both clinical cases and pharmacovigilance data substantiate a significant association between gemcitabine use and the onset or worsening of precapillary PH. The observed improvement following the discontinuation of treatment underscores the importance of PH screening in gemcitabine-exposed patients experiencing unexplained dyspnoea.

Drugs associated with epidermal necrolysis in children: A World Health Organization pharmacovigilance database analysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare life-threatening mucocutaneous reactions most often induced by drugs. To date, no large pharmacovigilance study has been conducted in the paediatric population. To describe the spectrum of drugs associated with SJS-TEN in children through the analysis of cases reported in the WHO pharmacovigilance database (VigiBase). Disproportionality study using data from VigiBase. All paediatric (age under 18 years) cases reported between January 1, 1967, and July 6, 2022, were included. For each molecule, a case-non-case study was performed to assess a potential pharmacovigilance signal by computing the lower end of the 95% credibility interval for the information component (IC025). We performed sensitivity analyses, (i) taking into account only cases reported by physicians and (ii) taking into account only cases reported in the last 10 years. Among 31,376,783 adverse drug reactions reported in VigiBase, 2,248,727 were paediatric cases and 7342 were encoded as paediatric SJS-TEN. Significant statistical pharmacovigilance signals were observed for 165 drugs. The two most represented drug classes were antiepileptics and anti-infectious drugs. The five drugs with the highest IC025 were lamotrigine (IC025 4.99), carbamazepine (IC025 4.88), phenobarbital (IC025 4.67), phenytoin (IC025 4.52) and nimesulide (IC025 4.23). Acetaminophen was significantly associated with paediatric SJS-TEN (IC025 2.85) and we also described various new suspected drugs. Vaccines had no significant pharmacovigilance signal. These results were confirmed with the sensitivity analyses. This study updates the spectrum of drugs potentially associated with paediatric SJS-TEN.

Arterial hypertension associated with PARPi: A meta-analysis of 41 placebo randomized controlled trials combined with a World Health Organization's pharmacovigilance study.

Arterial hypertension has been recently reported from randomized controlled trials (RCTs) assessing poly (ADP-ribose) polymerase inhibitor (PARPi). In a context of increasing use of PARPi, it is crucial to properly assess risk and incidence of this adverse event for clinical practice. We performed a systematic review and meta-analysis in MEDLINE, Cochrane CENTRAL and ClinicalTrials.gov up to January 4, 2023 with an ongoing surveillance up to June 7, 2023. RCTs comparing PARPi to placebo in adult patients with solid tumors were included if hypertension was reported. The primary outcome was the summary risk ratio (RR, with 95% CIs) of any hypertension of PARPi class in placebo RCTs. Secondary outcomes were the summary risk and incidence of hypertension of each individual PARPi. To provide clinical features of PARPi-associated hypertension, we independently queried the WHO's pharmacovigilance database, up to September 1, 2022. In total, 41 placebo RCTs (n = 15 264 adult patients) were included. PARPi class was not associated with an increased risk of hypertension compared with placebo. In individual analyses, the risk of hypertension was lower with olaparib than placebo (RR 0.77 [95% CI: 0.68-0.86], P < 0.01; I2= 19%, χ2 P = 0.26). Niraparib monotherapy increased the risk of any (RR 2.84 [95% CI: 1.76-4.57], P < 0.01; I2= 66%, χ2 P = 0.01) hypertension with a summary incidence of 19.87% (95% CI: 15.23-25.50). In real-life setting, niraparib-associated hypertension occurs within 20 days and was serious in 66%. Co-prescription of at least one antihypertensive or therapy-induced hypertension was reported in 20.5% or 14.4% of cases, respectively. In a context of extensive assessment of niraparib in combination, these data reinforce the need of a close monitoring of this adverse event to preserve its clinical benefit on patients' survival.

Revealing the reporting disparity: VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK

BackgroundPharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs). ObjectiveIn a 2021 article, the United Kingdom (UK) had >90 % of European clozapine-related fatal outcomes in VigiBase, the World Health Organization's pharmacovigilance database. Two possibly opposing hypotheses could explain this disparity: 1) fewer reported fatal outcomes in other Western European countries mainly reflect underreporting to VigiBase, and 2) the higher number of UK reports reflects higher real relative mortality. MethodsVigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions. ResultsThe UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label “death” was the top cause in the world (46 %) and in the UK (33 %). “Pneumonia” was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1–10 % of the UK clozapine fatal outcome number. ConclusionsDifferent Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases.

Clozapine-associated pericarditis and pancreatitis in children and adolescents: A systematic literature review and pharmacovigilance study using the VigiBase database

BackgroundThe literature has paid very little attention to pericarditis, pericardial effusion and pancreatitis during clozapine treatment in children and adolescents. MethodsCases of clozapine-associated pericarditis and pancreatitis in children were studied using searches in: 1) PubMed (June 16, 2023), and 2) the World Health Organization's pharmacovigilance database (June 1, 2022), VigiBase. VigiBase uses a logarithmic measure of disproportionality called the information component (IC). ResultsThe PubMed search yielded 3 clozapine-associated pericarditis cases, 1 pancreatitis case and 1 with both. VigiBase provided a significant clozapine-associated pericarditis IC = 3.6 with an IC025 = 2.9 (only 3 cases were expected while 22 were observed). VigiBase provided a significant clozapine-associated pancreatitis IC = 2.2 with an IC025 = 1.4 (only 3 cases were expected while 16 were observed). In VigiBase clozapine-associated pericarditis and pericardial effusion in youth looked similar and on a continuum with myocarditis, as myocarditis, pericarditis and pancreatitis appeared to occur mainly during clozapine titration. Combining PubMed and VigiBase we identified: 1) 29 cases of at least possible clozapine-associated pericarditis/pericardial effusion (6 probable and 23 possible) including 7 cases with and 22 without myocarditis, and 2) 17 cases of clozapine-associated pancreatitis (1 definite and 16 possible). Two of the pancreatitis cases occurred during overdoses. No fatal outcomes were found in any clozapine-associated pericarditis and pancreatitis cases. ConclusionsDespite the lack of attention in the literature to clozapine-associated pericarditis and pancreatitis, results demonstrate that they can happen in youth, particularly during titration. Pericarditis and pancreatitis appear to be forms of clozapine-associated inflammation during dose titration.

The Christmas adverse event syndrome: An analysis of the WHO pharmacovigilance database

We hypothesized that during the Christmas season the safety profile and the toxicity of some drugs may be exacerbated. We therefore assessed and characterized changes in drug safety profiles over the Christmas period. We performed a retrospective longitudinal analysis of adverse events reported in the World Health Organization (WHO) pharmacovigilance database between April 1st 2017 to March 31th 2023. We extracted cases reported by the 5 main contributors' countries of the WHO pharmacovigilance database with a Christmas tradition: USA, France, Germany, Italy and UK. We analyzed 4,999,459 individual case safety reports from USA (n=3,498,961), France (n=419,018), Germany (n=398,763), Italy (n=251,641) and UK (n=431,076), reported between April 1st 2017 to March 31th 2023. Monthly reports of adverse events were analyzed. Time trend, seasonal effect a Christmas effect (December-January) were explored. We found 91 adverse events significantly more frequently reported during the Christmas period, independently after controlling for winter effect and general tendency. The main type of adverse events were psychiatric disorders, infections and skin and subcutaneous disorders. The highest numbers of attributable cases to Christmas were found for drug dependence, emotional distress, and drug withdrawal syndrome. The most involved drugs were oxycodone in psychiatric disorders (n=47,527), docetaxel in skin disorders (n=9440) and social circumstances (n=1940), olmesartan in gastrointestinal disorders (n=1263), fentanyl in cardiac disorders (n=929), adalimumab in infections (n=11,316) and immune system disorders (n=3781), and collagenase clostridium histolyticum in reproductive system disorders (n=318). Our study shows that a range of drugs adverse events are more frequently reported at Christmas compared to other periods of the year, notably psychiatric disorders, infections, and skin disorders.

Pulmonary hypertension associated with diazoxide: the SUR1 paradox.

The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in the ABCC8 gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Conversely, activation of SUR1 and SUR2 leads to the relaxation of pulmonary arteries and reduces cell proliferation and migration. Diazoxide, a SUR1 activator, has been shown to alleviate experimental PH, suggesting its potential as a therapeutic option. However, there are paradoxical reports of diazoxide-induced PH in infants. This review explores the role of SUR1/2 in the pathophysiology of PH and the contradictory effects of diazoxide on the pulmonary vascular bed. Additionally, we conducted a comprehensive literature review of cases of diazoxide-associated PH and analysed data from the World Health Organization pharmacovigilance database (VigiBase). Significant disproportionality signals link diazoxide to PH, while no other SUR activators have been connected with pulmonary vascular disease. Diazoxide-associated PH seems to be dose-dependent and potentially related to acute effects on the pulmonary vascular bed. Further research is required to decipher the differing pulmonary vascular consequences of diazoxide in different age populations and experimental models.