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JAMA Network Open Jul 2023Innovative anticancer therapies for children, adolescents, and young adults are regularly prescribed outside their marketing authorization or through compassionate use...
IMPORTANCE
Innovative anticancer therapies for children, adolescents, and young adults are regularly prescribed outside their marketing authorization or through compassionate use programs. However, no clinical data of these prescriptions is systematically collected.
OBJECTIVES
To measure the feasibility of the collection of clinical safety and efficacy data of compassionate and off-label innovative anticancer therapies, with adequate pharmacovigilance declaration to inform further use and development of these medicines.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study included patients treated at French pediatric oncology centers from March 2020 to June 2022. Eligible patients were aged 25 years or younger with pediatric malignant neoplasms (solid tumors, brain tumors, or hematological malignant neoplasms) or related conditions who received compassionate use or off-label innovative anticancer therapies. Follow up was conducted through August 10, 2022.
EXPOSURES
All patients treated in a French Society of Pediatric Oncology (SFCE) center.
MAIN OUTCOMES AND MEASURES
Collection of adverse drug reactions and anticancer activity attributable to the treatment.
RESULTS
A total of 366 patients were included, with a median age of 11.1 years (range, 0.2-24.6 years); 203 of 351 patients (58%) in the final analysis were male. Fifty-five different drugs were prescribed, half of patients (179 of 351 [51%]) were prescribed these drugs within a compassionate use program, mainly as single agents (74%) and based on a molecular alteration (65%). Main therapies were MEK/BRAF inhibitors followed by multi-targeted tyrosine kinase inhibitors. In 34% of patients at least a grade 2 clinical and/or grade 3 laboratory adverse drug reaction was reported, leading to delayed therapy and permanent discontinuation of the innovative therapy in 13% and 5% of patients, respectively. Objective responses were reported in 57 of 230 patients (25%) with solid tumors, brain tumors, and lymphomas. Early identification of exceptional responses supported the development of specific clinical trials for this population.
CONCLUSIONS AND RELEVANCE
This cohort study of the SACHA-France (Secured Access to Innovative Medicines for Children with Cancer) suggested the feasibility of prospective multicenter clinical safety and activity data collection for compassionate and off-label new anticancer medicines. This study allowed adequate pharmacovigilance reporting and early identification of exceptional responses allowing further pediatric drug development within clinical trials; based on this experience, this study will be enlarged to the international level.
Topics: Child; Humans; Male; Adolescent; Young Adult; Infant; Child, Preschool; Adult; Female; Off-Label Use; Prospective Studies; Cohort Studies; Antineoplastic Agents; Brain Neoplasms
PubMed: 37399010
DOI: 10.1001/jamanetworkopen.2023.21568 -
CNS Neuroscience & Therapeutics Sep 2023Sacubitril/valsartan is a new cardiovascular agent characterized by its dual inhibition on the reninangiotensin system (RAS) and the neprilysin. As neprilysin also...
AIM
Sacubitril/valsartan is a new cardiovascular agent characterized by its dual inhibition on the reninangiotensin system (RAS) and the neprilysin. As neprilysin also involved itself in the degradation of amyloid-β, there is an ongoing concern about the effect of sacubitril/valsartan on cognition, especially in case of long-term administration.
METHODS
The FDA Adverse Event Reporting System (FAERS) was mined between 2015Q3 and 2022Q4 to analyze the association between sacubitril/valsartan and adverse events (AEs) involving dementia. Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) with "broad" and "narrow" preferred terms (PTs) relevant to dementia was applied to systematically search demented AE reports. The Empirical Bayes Geometric Mean (EBGM) from Multi-Item Gamma Poisson Shrinker (MGPS) and proportional reporting ratio with Chi-square (PRR, χ ) were used to calculate the disproportionality.
RESULTS
We filtered the query for indication and identified 80,316 reports with heart failure indication in FAERS during the analytical period. Among all the reports, sacubitril/valsartan was listed as primary suspected or secondary suspected drug in 29,269 cases. No significantly elevated reporting rates of narrow dementia were evident with sacubitril/valsartan. The EBGM05 for narrow dementia-related AEs associated with sacubitril/valsartan was 0.88 and the PRR (χ ) was 1.22 (2.40). Similarly, broad demented complications were not over-reported in the heart failure patients administrated with sacubitril/valsartan (EBGM05 1.11; PRR 1.31, χ 109.36).
CONCLUSION
The number of dementia-related cases reported to FAERS generate no safety signal attributable to sacubitril/valsartan in patients with heart failure for now. Further follow-ups are still warranted to address this question.
Topics: Humans; Tetrazoles; Neprilysin; Pharmacovigilance; Bayes Theorem; Angiotensin Receptor Antagonists; Valsartan; Heart Failure; Biphenyl Compounds; Drug Combinations; Dementia
PubMed: 36971193
DOI: 10.1111/cns.14195 -
Journal of Global Health Sep 2023Despite rising concerns regarding the safety of anti-obesity medications, there is a lack of comprehensive pharmacovigilance investigations utilising real-world data. We...
INTRODUCTION
Despite rising concerns regarding the safety of anti-obesity medications, there is a lack of comprehensive pharmacovigilance investigations utilising real-world data. We aimed to characterise the prevalence and seriousness of adverse drug events (ADEs) related to anti-obesity medications and to identify predictors associated with increased risk of serious adverse events (SAE), thereby conveying evidence on drug safety.
METHODS
We conducted a cross-sectional analysis on ADE cases spontaneously reported to the Korea Adverse Event Reporting System Database (KIDS-KD). ADE reports pertaining to anti-obesity medications prescribed for overweight, obesity (International Classification of Disease, 10th revision (ICD-10) code E66) and abnormal weight gain (ICD-10 code E63.5) were included in the analysis. We performed a disproportionality to detect the association of the system organ class-based ADEs with their seriousness an individual's sex by estimating reporting odds ratios (RORs) and their 95% confidence intervals (CIs). We performed logistic regression to investigate factors that are substantially associated with increased SAE risks by estimating odds ratio (OR) and their 95% CIs.
RESULTS
The most common causative anti-obesity medication was phentermine, followed by liraglutide. ADEs associated with psychiatric disorders (ROR = 1.734; 95% CI = 1.111-2.707), liver and biliary system disorders (ROR = 22.948; 95% CI = 6.613-70.635), cardiovascular disorders (ROR = 5.707; 95% CI = 1.965-16.574), and respiratory disorders (ROR = 4.567; 95% CI = 1.774-11.762) were more likely to be serious events. Additionally, men are more likely to experience ADEs related gastrointestinal disorders (ROR = 1.411) and less likely to have heart and rhythm disorders (ROR = 0.507). The risk of SAE incidences was positively correlated with being male (OR = 2.196; 95% CI = 1.296-3.721), dual or triple combination of anti-obesity medications (OR = 3.258; 95% CI = 1.633-6.501 and OR = 8.226; 95% CI = 3.046-22.218, respectively), and concomitant administration of fluoxetine (OR = 5.236; 95% CI = 2.218-12.365).
CONCLUSIONS
Seriousness of anti-obesity medication-related ADEs differs among system-organ class, while sex-related differences in ADE profiles are also present. The predictors substantially increasing risk of SAE incidences include being male, having a higher number of concomitant medications (including multiple combination of anti-obesity medications), and concurrent use of fluoxetine. Nonetheless, further pharmacovigilance investigation and monitoring are needed to enhance awareness on ADEs induced by anti-obesity medications.
Topics: Humans; Male; Female; Cross-Sectional Studies; Fluoxetine; Pharmacovigilance; Obesity; Cardiovascular Diseases
PubMed: 37651636
DOI: 10.7189/jogh.13.04095 -
Frontiers in Immunology 2024Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, the application of ICIs can also cause... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, the application of ICIs can also cause treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). This study was to evaluate both the irAEs and trAEs of different ICI strategies for NSCLC based on randomized clinical trials (RCTs). The study also examined real-world pharmacovigilance data from the Food and Drug Administration Adverse Event Reporting System (FAERS) regarding claimed ICI-associated AEs in clinical practice.
METHODS
Based on Pubmed, Embase, Medline, and the Cochrane CENTRAL, we retrieved RCTs comparing ICIs with chemotherapy drugs or with different ICI regimens for the treatment of NSCLC up to October 20, 2023. Bayesian network meta-analysis (NMA) was performed using odds ratios (ORs) with 95% credible intervals (95%CrI). Separately, a retrospective pharmacovigilance study was performed based on FAERS database, extracting ICI-associated AEs in NSCLC patients between the first quarter (Q1) of 2004 and Q4 of 2023. The proportional reports reporting odds ratio was calculated to analyze the disproportionality.
RESULTS
The NMA included 51 RCTs that involved a total of 26,958 patients with NSCLC. Based on the lowest risk of any trAEs, cemiplimab, tislelizumab, and durvalumab were ranked as the best. Among the agents associated with the lowest risk of grades 3-5 trAEs, tislelizumab, avelumab, and nivolumab were most likely to rank highest. As far as any or grades 3-5 irAEs are concerned, atezolizumab plus bevacizumab plus chemotherapy is considered the most safety option. However, it is associated with a high risk of grades 3-5 trAEs. As a result of FAERS pharmacovigilance data analysis, 9,420 AEs cases have been identified in 7,339 NSCLC patients treated with ICIs, and ICIs were related to statistically significant positive signal with 311 preferred terms (PTs), and comprehensively investigated and identified those AEs highly associated with ICIs. In total, 152 significant signals were associated with Nivolumab, with malignant neoplasm progression, death, and hypothyroidism being the most frequent PTs.
CONCLUSION
These findings revealed that ICIs differed in their safety profile. ICI treatment strategies can be improved and preventive methods can be developed for NSCLC patients based on our results.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Immune Checkpoint Inhibitors; Pharmacovigilance; United States; United States Food and Drug Administration; Randomized Controlled Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Adverse Drug Reaction Reporting Systems; Bayes Theorem; Retrospective Studies
PubMed: 38745663
DOI: 10.3389/fimmu.2024.1396752 -
The Science of the Total Environment Jul 2023Environmental contamination with antibiotic residues has caused significant concern. Antibiotics are continually emitted into the environment which potentially threatens... (Review)
Review
Environmental contamination with antibiotic residues has caused significant concern. Antibiotics are continually emitted into the environment which potentially threatens environmental and human health, particularly, the risk in the development of antibiotic resistance. A list of priority antibiotics in the environment is essential for eco-pharmacovigilance and policy decisions. This study developed a prioritisation system of antibiotics based on their integrated environmental (resistance and ecotoxicity) and human health (resistance and toxicity) risks, considering various aquatic environmental compartments. Data obtained by conducting a systematic review of the literature of antibiotic residues in various aquatic environmental compartments in China was used as an example. The list of priority antibiotics was created by ranking the antibiotics in descending order, based on the risk scores of their a) overall risk, (b) antibiotic resistance risk to environment, (c) ecotoxicity risk, (d) overall environmental risk, (e) antibiotic resistance risk to human health, (f) toxicity risk to human health and (g) overall human health risk. Ciprofloxacin posed the greatest risk and chloramphenicol posed the least risk. The output from this research can be used to implement eco-pharmacovigilance and to develop targeted policies which would prevent / minimise the environmental and human health risks from antibiotic residues. The use of this list of priority antibiotics will allow for a country / region / setting to (a) optimise the use of antibiotics and their prescribing practices, (b) create effective monitoring and mitigation strategies, (c) minimise the discharge of antibiotic residues and (d) focus research efforts.
Topics: Humans; Anti-Bacterial Agents; Environmental Monitoring; Water Pollutants, Chemical; China; Environmental Pollution
PubMed: 37031932
DOI: 10.1016/j.scitotenv.2023.163301 -
Therapie 2023Two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines, tozinameran/BNT162b2 (Comirnaty®, Pfizer-BioNTech) and...
INTRODUCTION
Two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines, tozinameran/BNT162b2 (Comirnaty®, Pfizer-BioNTech) and elasomeran/mRNA-1273 (Spikevax®, Moderna), were approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) at the end of 2020, less than a year after the start of the coronavirus disease 2019 (COVID-19) pandemic. In France, the health authorities have requested an intensive vaccination campaign, accompanied by a reinforced and active pharmacovigilance surveillance. This surveillance and analysis of real-life data, based on spontaneous reports received by the French Network of Regional PharmacoVigilance Centers (RFCRPV), has enabled to identify numerous pharmacovigilance signals. Some of them, such as myocarditis and heavy menstrual bleeding, have been confirmed as adverse effects of these vaccines.
METHOD
We propose a descriptive review of the main pharmacovigilance signals identified by the RFCRPV concerning vaccines from the mRNA platform.
RESULTS
Most pharmacovigilance signals were common to both mRNA vaccines: myocarditis, menstrual disorders, acquired haemophilia, Parsonage-Turner syndrome, rhizomelic pseudo-polyarthritis and hearing disorders. Other signals were more specific, such as arterial hypertension with tozinameran or delayed reaction site injection with elasomeran.
CONCLUSION
This non-exhaustive review illustrates the experience of RFCRPV in identifying and monitoring pharmacovigilance signals related to mRNA vaccines in France during the COVID-19 pandemics, and the crucial role of pharmacological and clinical expertise in this area. It also highlights the predominant contribution of spontaneous reporting in the generation of pharmacovigilance signals, particularly for serious and rare adverse events not detected before marketing.
PubMed: 37012149
DOI: 10.1016/j.therap.2023.03.005 -
Human Vaccines & Immunotherapeutics Dec 2023COVID-19 vaccine-related adverse events are mostly minor to moderate, and serious events are rare. Single cases of Raynaud's phenomenon (RP) in temporal proximity to...
COVID-19 vaccine-related adverse events are mostly minor to moderate, and serious events are rare. Single cases of Raynaud's phenomenon (RP) in temporal proximity to COVID-19 vaccination have been reported. Demographic data, medical history, and detailed information regarding vaccination status and RP characteristics were obtained from patients with confirmed RP after COVID-19 vaccination. Fifteen participants reported the initial manifestation of RP, which occurred in 40% after the first, in 33% after the second, and in 27% after the third vaccination. RP development and occurrence of episodes were not linked to any specific vaccine type. New onset of disease was observed in 40% of the vaccinees after BNT162b2, in 33% after mRNA-1273, and in 27% after ChAdOx1 vaccination. Three out of four participants with preexisting RP prior to COVID-19 vaccination reported aggravation in frequency and intensity after immunization. Although COVID-19 vaccination is pivotal in controlling the pandemic, the observed temporal association between vaccine administration and RP occurrence warrants global activities to support pharmacovigilance for the detection of adverse reactions, one of which may include RP.
Topics: Humans; BNT162 Vaccine; COVID-19; COVID-19 Vaccines; Raynaud Disease; Vaccination
PubMed: 37067070
DOI: 10.1080/21645515.2023.2199653 -
Frontiers in Pharmacology 2023Testosterone is an essential sex hormone in maintaining masculine characteristics, which is prescribed for male hypogonadism as testosterone replacement treatment...
Testosterone is an essential sex hormone in maintaining masculine characteristics, which is prescribed for male hypogonadism as testosterone replacement treatment (TRT). Herein, we investigated long-standing controversies about the association between TRT and major adverse cardiovascular events (MACEs), based on real world adverse event (AE) reports, registered in the Food and Drug Administration Adverse Event Reporting System (FAERS). Publicly available FAERS data from 1 January 2004 to 31 December 2022 were retrieved from the Food and Drug Administration (FDA) website. The data mining protocol including the reporting odds ratio (ROR) and the Bayesian confidence propagation neural network (BCPNN) was applied to analyze overreporting caused by risk factors and MACEs, including TRT, morbidities, and ages. The ROR and the BCPNN were also applied to investigate the annually developing trend of pharmacovigilance (PV) signals in the real world, retrospectively. A total of 3,057 cases referring to MACEs, with a median age of 57 years old (yo), were identified from 28,921 cases of testosterone users. MACEs related to PV signals have emerged since 2014, including cardiac death, non-fatal myocardial infarction, and non-fatal stroke. Myocardial infarction (MI) (ROR: 9.46; IC: 3.08), acute myocardial infarction (AMI) (ROR: 16.20; IC: 3.72), ischemic cardiomyopathy (ROR: 11.63; IC: 2.20), and cardiomyopathy (ROR: 5.98; IC: 1.96) were the most significant signals generated, and weaker signals included cardiac failure acute (ROR: 4.01; IC: 0.71), cardiac arrest (ROR: 1.88; IC: 0.56), and ventricular fibrillation (VF) (ROR: 2.38; IC: 0.38). The time-to-onset (TTO) of MACEs was calculated with a median of 246 days for AMI. For myocardial infarction and cardiomyopathy, TRT statistically tended to increase the risk of MACEs, while for cardiac arrhythmia, cardiac failure, and stroke, TRT demonstrated beneficial effects among the population with morbidities, such as testosterone deficiency (TD), diabetes mellitus (DM), and hypertension. MACEs were rare but led to serious outcomes including significant increase in death and disability. Since 2018, and before 2014, reports referring to TRT associated with MACEs were relatively scarce, which indicated that there might be a considerable number of cases that went unrecorded, due to neglection. Health workers and testosterone users might pay more attention to testosterone-induced MACEs.
PubMed: 37502210
DOI: 10.3389/fphar.2023.1182113 -
European Annals of Allergy and Clinical... Nov 2023Kikuchi-Fujimoto Disease (KFD) or histiocytic necrotizing lymphadenitys is a rare disorder characterized by subacute necrotizing regional lymphadenopathy. It is usually...
Kikuchi-Fujimoto Disease (KFD) or histiocytic necrotizing lymphadenitys is a rare disorder characterized by subacute necrotizing regional lymphadenopathy. It is usually presented as painful cervical nodes and associated with fever, headache, night sweats, nausea, vomiting and sore throat. Etiology of KFD is still unclear, two theories have been proposed: infections and autoimmune origin. Due to recent reports of KFD related to COVID-19 vaccination, the novelty of the mechanism of these vaccines and the immunomodulated role of both matters, a literature and adverse event databases review was carried out in order to shed light on the relationship between these two matters. A search in the Spanish and the European adverse events databases (FEDRA and Eudravigilance) was performed. Search criteria were any drug and the diagnosis "Histiocytic necrotizing lymphadenitis" according to the Medical Dictionary for Medical Activities version 25.0. All adverse events registered as June 2, 2022, were included. FEDRA encompassed two KFD reports, one related to a mRNA COVID-19 vaccine. Eudravigilance included a total of 62 KFD cases, 14 of them associated to COVID-19 vaccines and eight to other vaccines. Pharmacovigilance is of utter importance in detecting adverse events caused by new vaccines. More research is needed to establish a final connection between KFD and COVD-19 vaccines, but due to the physiopathology of the condition, how vaccines stimulate the immune system and the high number of reported KFD cases with vaccines given its rare incidence, it is plausible to think that both entities are related.
Topics: Humans; COVID-19; COVID-19 Vaccines; Histiocytic Necrotizing Lymphadenitis; Pharmacovigilance; Vaccination
PubMed: 36458479
DOI: 10.23822/EurAnnACI.1764-1489.273 -
Frontiers in Pharmacology 2023Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are commonly used anticoagulants for the management of arterial and venous thromboses. However, it...
Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are commonly used anticoagulants for the management of arterial and venous thromboses. However, it is crucial to be aware that LMWH can, in rare cases, lead to a dangerous complication known as heparin-induced thrombocytopenia (HIT). The objective of this study was to evaluate the pharmacovigilance and clinical features of HIT associated with LMWH, as well as identify treatment strategies and risk factors to facilitate prompt management. We extracted adverse event report data from the FDA Adverse Event Reporting System (FAERS) database for pharmacovigilance assessment. Case reports on LMWH-induced thrombocytopenia dated up to 20 March 2023 were collected for retrospective analysis. Significantly elevated reporting rates of HIT were shown in adverse event (AE) data of LMWHs in the FAERS database, while tinzaparin had a higher proportional reporting ratio (PRR) and reporting odds ratio (ROR) than other LMWHs, indicating a greater likelihood of HIT. Case report analysis indicated that a total of 43 patients showed evidence of LMWH-induced thrombocytopenia with a median onset time of 8 days. Almost half of the events were caused by enoxaparin. LMWHs were mainly prescribed for the treatment of embolism and thromboprophylaxis of joint operation. Patients with a history of diabetes or surgery appeared to be more susceptible to HIT. Clinical symptoms were mostly presented as thrombus, skin lesion, and dyspnea. Almost 90% of the patients experienced a platelet reduction of more than 50% and had a Warkentin 4T score of more than 6, indicating a high likelihood of HIT. In all patients, LMWHs that were determined to be the cause were promptly withdrawn. Following the discontinuation of LMWHs, almost all patients were given alternative anticoagulants and eventually achieved recovery. LMWH-induced thrombocytopenia is rare but serious, with increased risk in patients with diabetes or a surgical history. Prompt recognition and management are crucial for the safe use of LMWHs.
PubMed: 37808193
DOI: 10.3389/fphar.2023.1247253