scholarly journals Analysis of Pharmacovigilance Databases for Dolutegravir Safety in Pregnancy

2019 ◽  
Vol 70 (12) ◽  
pp. 2599-2606 ◽  
Author(s):  
Nikolien S van De Ven ◽  
Anton L Pozniak ◽  
Jacob A Levi ◽  
Polly Clayden ◽  
Anna Garratt ◽  
...  
Keyword(s):  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Antiretroviral Drugs ◽  
Data Availability ◽  
New Drugs ◽  
World Health ◽  
European Medicines Agency ◽  
System Organ Class ◽  
Online Data ◽  
Wide Range

Abstract Background The Botswana Tsepamo study reported neural tube defects (NTDs) in 4 of 426 (0.94%) infants of women receiving preconception dolutegravir (DTG) antiretroviral therapy (ART) vs 14 of 11 300 (0.12%) receiving preconception non-DTG ART. Data are needed to investigate this potential safety signal. Clinicians, patients, and pharmaceutical companies can report adverse drug reactions (ADRs) to pharmacovigilance databases. Data from ADRs reported to various pharmacovigilance databases were searched for NTDs. Methods Four pharmacovigilance databases (World Health Organization [WHO] VigiAccess; United Kingdom Medicines Health Regulatory Authority [UK MHRA]; European Medicines Agency [EMA] EudraVigilance; US Food and Drug Administration Adverse Event Reporting System [FAERS]) with online data availability were analyzed for NTD reports for 4 integrase inhibitors (DTG, raltegravir, elvitegravir, bictegravir), 2 protease inhibitors (darunavir, atazanavir), and 2 nonnucleoside reverse transcriptase inhibitors (nevirapine, efavirenz). Reports in the system organ class “congenital or familial disorders” were searched for NTDs. Results NTDs have been reported among infants born from women taking a wide range of antiretrovirals in 4 pharmacovigilance databases (WHO VigiAccess, 116 reactions; UK MHRA, 8 cases; EMA EudraVigilance, 20 cases; FAERS, 44 cases). Six NTDs were identified for DTG across the pharmacovigilance databases. Cases were very hard to interpret, given the lack of clear denominators. Conclusions Pharmacovigilance databases have many limitations, most importantly lack of a clear denominator for patients exposed to the drug of interest and duplicate cases that are difficult to identify. Given widespread use of new antiretroviral drugs worldwide and anticipated use of new drugs, prospective follow-up of pregnant women and birth surveillance studies such as Tsepamo are critically needed.

scholarly journals Real-world data-based adverse drug reactions detection from the Korea Adverse Event Reporting System databases with electronic health records-based detection algorithm

2021 ◽  
Vol 27 (3) ◽  
pp. 146045822110330
Author(s):  
Hyunah Shin ◽  
Jaehun Cha ◽  
Youngho Lee ◽  
Jong-Yeup Kim ◽  
Suehyun Lee
Keyword(s):  
Adverse Event ◽  
Adverse Drug Reactions ◽  
Reporting System ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
World Health ◽  
Drug Reactions ◽  
Event Reporting ◽  
Medical Databases ◽  
Electronic Health

Pharmacovigilance involves monitoring of drugs and their adverse drug reactions (ADRs) and is essential for their safety post-marketing. Because of the different types and structures of medical databases, several previous surveillance studies have analyzed only one database. In the present study, we extracted potential drug–ADR pairs from electronic health record (EHR) data using the MetaNurse algorithm and analyzed them using the Korean Adverse Event Reporting System (KAERS) database for systematic validation. The Medical Dictionary for Regulatory Activities (MedDRA) and World Health Organization (WHO) Adverse Reactions Terminology (WHO-ART) were mapped for signal detection. We used the Side Effect Resource (SIDER) database to select 2663 drug-ADR pairs to investigate unknown drug-induced ADRs. The reporting odds ratio (ROR) value was calculated for the drug-exposed and non-exposed groups of drug–ADR pairs, and 19 potential pairs showed significant signals. Appropriate terminology systems and criteria are needed to handle diverse medical databases.

scholarly journals Cardiac adverse events associated with chloroquine and hydroxychloroquine exposure in 20 years of drug safety surveillance reports

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Isaac V. Cohen ◽  
Tigran Makunts ◽  
Talar Moumedjian ◽  
Masara A. Issa ◽  
Ruben Abagyan
Keyword(s):  
Adverse Event ◽  
Side Effects ◽  
Lupus Erythematosus ◽  
Adverse Event Reporting System ◽  
The United States ◽  
Adverse Event Reporting ◽  
World Health ◽  
Cardiac Complications ◽  
Cardiac Side Effects ◽  
Therapeutic Decision Making

Abstract Chloroquine (CQ) and hydroxychloroquine (HCQ) are on the World Health Organization’s List of Essential Medications for treating non-resistant malaria, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, both drugs are currently used off-label in hospitals worldwide and in numerous clinical trials for the treatment of SARS-CoV-2 infection. However, CQ and HCQ use has been associated with cardiac side effects, which is of concern due to the higher risk of COVID-19 complications in patients with heart related disorders, and increased mortality associated with COVID-19 cardiac complications. In this study we analyzed over thirteen million adverse event reports form the United States Food and Drug Administration Adverse Event Reporting System to confirm and quantify the association of cardiac side effects of CQ and HCQ. Additionally, we identified several confounding factors, including male sex, NSAID coadministration, advanced age, and prior diagnoses contributing to drug related cardiotoxicity. These findings may help guide therapeutic decision making and ethical trial design for COVID-19 treatment.

scholarly journals BIOSIMILARS: OPPORTUNITIES, CHALLENGES, AND THE GENERAL PRINCIPLES GOVERNING THEIR DEVELOPMENT AROUND THE GLOBE

2021 ◽  
pp. 1-9
Author(s):  
ISHITA KATHURIA ◽  
VIKAS KUMAR SRIVASTAVA
Keyword(s):  
Treatment Options ◽  
Genetic Material ◽  
World Health ◽  
European Medicines Agency ◽  
The European Union ◽  
Biologic Drugs ◽  
Wide Range ◽  
The One ◽  
Health Organization ◽  
Rare Illnesses

Biologic drugs have revolutionized the treatment of many life-threatening and rare illnesses such as cancer and autoimmune diseases. Biologics are broadly referred as substances that are produced by living cells and are used in the treatment, prevention, or diagnosis of diseases. They include a wide range of substances, such as genetic material, antibodies, vaccines, or processes which act by influencing cellular processes that block disease or affect diseased cells. Biologics have become striking treatment options and the size of the market has grown hastily. It is expected that by 2023, most of the patents will expire in the European Union opening a large potential market. Keeping this in mind, the ability to launch substitutes to original biologics, also known as biosimilars, presents many opportunities to generic companies. The field of biosimilars seems to be “breaking” the traditional division between the creations of innovative NCE-based medicines by research-based companies, on the one hand, and, on the other hand, mapping of these medicines by the generic companies. The field of biosimilars so far presents some considerable challenges, namely, regulatory, safety, economic, and legal which are still being debated and discussed in different forums. In this article, we have tried to summarize the general principles and regulations governing the development of biosimilars by regulatory authorities such as the World Health Organization, European Medicines Agency, US Food and Drug Administration, and Health Canada. Furthermore, we have tried to throw some light on the opportunities, challenges, and current scenarios pertaining to biosimilars.

scholarly journals Importance of Prospective Studies in Pregnant and Breastfeeding Women Living With Human Immunodeficiency Virus

2019 ◽  
Vol 69 (7) ◽  
pp. 1254-1258 ◽  
Author(s):  
Angela Colbers ◽  
Mark Mirochnick ◽  
Stein Schalkwijk ◽  
Martina Penazzato ◽  
Claire Townsend ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Pregnant Women ◽  
Clinical Care ◽  
Antiretroviral Drugs ◽  
New Drugs ◽  
European Medicines Agency ◽  
Controlled Clinical Trial ◽  
Women Living With Hiv ◽  
Immunodeficiency Virus ◽  
Living With Hiv

Abstract Recently, the US Food and Drug Administration and European Medicines Agency issued warnings on the use of dolutegravir and darunavir/cobicistat for treatment of pregnant women living with human immunodeficiency virus (HIV). It took 3–5 years to identify the risks associated with the use of these antiretroviral drugs, during which time pregnant women were exposed to these drugs in clinical care, outside of controlled clinical trial settings. Across all antiretroviral drugs, the interval between registration of new drugs and first data on pharmacokinetics and safety in pregnancy becoming available is around 6 years. In this viewpoint, we provide considerations for clinical pharmacology research to provide safe and effective treatment of pregnant and breastfeeding women living with HIV and their children. These recommendations will lead to timelier availability of safety and pharmacokinetic information needed to develop safe treatment strategies for pregnant and breastfeeding women living with HIV, and are applicable to other chronic disease areas requiring medication during pregnancy.

scholarly journals Cardiac Events Potentially Associated to Remdesivir: An Analysis from the European Spontaneous Adverse Event Reporting System

2021 ◽  
Vol 14 (7) ◽  
pp. 611
Author(s):  
Concetta Rafaniello ◽  
Carmen Ferrajolo ◽  
Maria Giuseppa Sullo ◽  
Mario Gaio ◽  
Alessia Zinzi ◽  
...  
Keyword(s):  
Adverse Event ◽  
Adverse Event Reporting System ◽  
Fatal Outcome ◽  
Individual Case ◽  
Adverse Event Reporting ◽  
European Medicines Agency ◽  
Cardiac Events ◽  
Potential Safety ◽  
Increased Risk ◽  
Pharmacovigilance Risk Assessment Committee

Remdesivir was recommended for hospitalized patients with COVID-19. As already reported in the Summary of Product Characteristics, most of remdesivir’s safety concerns are hepatoxicity and nephrotoxicity related. However, some cases have raised concerns regarding the potential cardiac events associated with remdesivir; therefore, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency requested to investigate all available data. Therefore, we analyzed all Individual Case Safety Reports (ICSRs) collected in the EudraVigilance database focusing on cardiac adverse events. From April to December 2020, 1375 ICSRs related to remdesivir were retrieved from EudraVigilance, of which 863 (62.8%) were related to male and (43.3%) adult patients. A total of 82.2% of all AEs (N = 2604) was serious and one third of the total ICSRs (N = 416, 30.3%) had a fatal outcome. The most frequently reported events referred to hepatic/hepatobiliary disorders (19.4%,), renal and urinary disorders (11.1%) and cardiac events (8.4%). Among 221 cardiac ICSRs, 69 reported fatal outcomes. Other drugs for cardiovascular disorders were reported as suspected/concomitant together with remdesivir in 166 ICSRs (75.1%), 62 of which were fatal. Moreover, the mean time to overall cardiac event was 3.3 days (±2.2). Finally, disproportionality analysis showed a two-fold increased risk of reporting a cardiac adverse event associated with remdesivir compared to both hydroxychloroquine and azithromycin. This study showed that remdesivir could be associated to risk of cardiac events, suggesting a potential safety signal which has not been completely evaluated yet. Further studies are needed to confirm these findings.

scholarly journals Cardiac Inflammation after COVID-19 mRNA Vaccines: A Global Pharmacovigilance Analysis

2021 ◽  
Author(s):  
Laurent Chouchana ◽  
Alice Blet ◽  
Mohammad Al-Khalaf ◽  
Tahir S Kafil ◽  
Girish Nair ◽  
...  
Keyword(s):  
Adverse Event Reporting System ◽  
Individual Case ◽  
Global Scale ◽  
Adverse Event Reporting ◽  
World Health ◽  
Medical Attention ◽  
Safety Signal ◽  
Individual Case Safety Report ◽  
Disproportionate Reporting ◽  
The U.S

Background To counter the COVID-19 pandemic, mRNA vaccines, namely tozinameran and elasomeran, have been authorized in several countries. These next generation vaccines have shown high efficacy against COVID-19 and demonstrated a favorable safety profile. As widespread vaccinations efforts are taking place, incidents of myocarditis and pericarditis cases following vaccination have been reported. This safety signal has been recently confirmed by the European Medicine Agency and the U.S. Food and Drug Administration. This study aimed to investigate and analyze this safety signal using a dual pharmacovigilance database analysis. Methods This is as an observational study of reports of inflammatory heart reactions associated with mRNA COVID-19 vaccines reported in the World Health Organization's global individual case safety report database (up to June 30th 2021), and in the U.S. Vaccine Adverse Event Reporting System (VAERS, up to May 21st 2021). Cases were described, and disproportionality analyses using reporting odds-ratios (ROR) and their 95% confidence interval (95%CI) were performed to assess relative risk of reporting according to patient sex and age. Results At a global scale, the inflammatory heart reactions most frequently reported were myocarditis (1241, 55%) and pericarditis (851, 37%), the majority requiring hospitalization (n=796 (64%)). Overall, patients were young (median age 33 [21-54] years). The main age group was 18-29 years old (704, 31%), and mostly males (1555, 68%). Pericarditis onset was delayed compared to myocarditis with a median time to onset of 8 [3-21] vs. 3 [2-6] days, respectively (p=0.001). Regarding myocarditis, an important disproportionate reporting in males (ROR, 9.4 [8.3-10.6]) as well as in adolescents (ROR, 22.3 [19.2-25.9]) and 18-29 years old (ROR, 6.6 [5.9-7.5]) compared to older patients were observed. Conclusions The inflammatory heart reactions, namely myocarditis and pericarditis, have been reported world-wide shortly following COVID-19 mRNA vaccination. An important disproportionate reporting among adolescents and young adults, particularly in males, was observed especially for myocarditis. Guidelines must take this specific risk into account and to optimize vaccination protocols according to sex and age. While the substantial benefits of COVID-19 vaccination still prevail over risks, clinicians and the public should be aware of these reactions and seek appropriate medical attention.

scholarly journals InferBERT: A Transformer-Based Causal Inference Framework for Enhancing Pharmacovigilance

2021 ◽  
Vol 4 ◽  
Author(s):  
Xingqiao Wang ◽  
Xiaowei Xu ◽  
Weida Tong ◽  
Ruth Roberts ◽  
Zhichao Liu
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Causal Inference ◽  
Language Processing ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Language Models ◽  
Data Sets ◽  
Clinical Events ◽  
Wide Range

Background: T ransformer-based language models have delivered clear improvements in a wide range of natural language processing (NLP) tasks. However, those models have a significant limitation; specifically, they cannot infer causality, a prerequisite for deployment in pharmacovigilance, and health care. Therefore, these transformer-based language models should be developed to infer causality to address the key question of the cause of a clinical outcome.Results: In this study, we propose an innovative causal inference model–InferBERT, by integrating the A Lite Bidirectional Encoder Representations from Transformers (ALBERT) and Judea Pearl’s Do-calculus to establish potential causality in pharmacovigilance. Two FDA Adverse Event Reporting System case studies, including Analgesics-related acute liver failure and Tramadol-related mortalities, were employed to evaluate the proposed InferBERT model. The InferBERT model yielded accuracies of 0.78 and 0.95 for identifying Analgesics-related acute liver failure and Tramadol-related death cases, respectively. Meanwhile, the inferred causes of the two clinical outcomes, (i.e. acute liver failure and death) were highly consistent with clinical knowledge. Furthermore, inferred causes were organized into a causal tree using the proposed recursive do-calculus algorithm to improve the model’s understanding of causality. Moreover, the high reproducibility of the proposed InferBERT model was demonstrated by a robustness assessment.Conclusion: The empirical results demonstrated that the proposed InferBERT approach is able to both predict clinical events and to infer their causes. Overall, the proposed InferBERT model is a promising approach to establish causal effects behind text-based observational data to enhance our understanding of intrinsic causality.Availability and implementation: The InferBERT model and preprocessed FAERS data sets are available on GitHub at https://github.com/XingqiaoWang/DeepCausalPV-master.

Acute Generalized Exanthematous Pustulosis in Association with Hydroxyzine and Cetirizine

2017 ◽  
Vol 1 (3) ◽  
pp. 112-116
Author(s):  
Ofir Noah Nevo ◽  
Lois La Grenade ◽  
Ida-Lina Diak ◽  
Robert Levin
Keyword(s):  
Drug Product ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Cross Reactivity ◽  
World Health ◽  
Uppsala Monitoring Centre ◽  
Active Metabolites ◽  
Monitoring Centre ◽  
Acute Generalized Exanthematous Pustulosis ◽  
Exanthematous Pustulosis

Purpose: Describe our review of the occurrence of acute generalized exanthematous pustulosis (AGEP) with hydroxyzine, and its active metabolites, cetirizine, and levocetirizine.Methods: The Division of Pharmacovigilance of the Food and Drug Administration (FDA) searched the FDA Adverse Event Reporting System (FAERS) and the medical literature for cases of AGEP reported in association with use of hydroxyzine, cetirizine, and levocetirizine. Causality was assessed using a modified World Health Organization Uppsala Monitoring Centre (WHO-UMC) causality assessment tool.Results: The FDA identified 26 cases of AGEP reported in association with the use of hydroxyzine (n = 21), cetirizine (n = 5), and levocetirizine (n = 3) (three cases included more than one drug product). Hydroxyzine causality was probable in five of the cases, and cetirizine causality was probable in two of the cases. All levocetirizine cases were assessed as unlikely. Conclusions: Our findings supported an association between hydroxyzine and cetirizine and AGEP. As a result, FDA has required labeling changes for hydroxyzine products to inform clinicians to avoid using hydroxyzine, cetirizine, and levocetirizine in patients who have experienced AGEP or other hypersensitivity reactions to any one of the above agents due to the risk of cross-reactivity.

scholarly journals Fatal Events Associated with Adverse Drug Reactions in the Korean National Pharmacovigilance Database

2021 ◽  
Vol 12 (1) ◽  
pp. 5
Author(s):  
Hyeong-Geun Jo ◽  
Kyeoul Jeong ◽  
Ji-Young Ryu ◽  
Soyun Park ◽  
Yun-Seok Choi ◽  
...  
Keyword(s):  
Contrast Media ◽  
Adverse Drug Reactions ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
World Health ◽  
Reporting Odds Ratio ◽  
Global Public Health ◽  
Drug Reactions ◽  
Cross Sectional ◽  
Relative Paucity

Adverse drug reactions (ADRs) pose a global public health threat, substantially contributing to death. Due to the relative paucity of clinical evidence regarding fatal ADRs, this study was performed to characterize the epidemiology of fatal ADRs in Korea. This was a retrospective, cross-sectional analysis of ADR cases reported to the Korea Adverse Event Reporting System from 2010 to 2019. All ADRs were coded using the World Health Organization-Adverse Reaction Terminology system and classified as either fatal or non-fatal events. Logistic regression was performed to identify factors associated with fatal events. Among 289,756 ADR records, 629 fatal events (0.2%) occurred. The most common causative agent of fatal ADRs was antibacterials (20.3%), followed by antimycobacterials (5.4%), analgesics (4.0%), and contrast media (1.9%). Among antimicrobials, vancomycin was most frequently implicated without significantly increasing the risk of fatal events. The risk for fatal ADRs was significantly increased with male sex; advanced age; polypharmacy; piperacillin/β-lactamase inhibitor; cefotetan; ceftriaxone; combination antimycobacterial therapy consisting of rifampicin, isoniazid, pyrazinamide, and ethambutol; morphine; and iopromide (reporting odds ratio > 1, p < 0.05 for all). Although fatal ADRs are uncommon (<1%) in Korea, they are primarily caused by commonly used medications including antibiotics, analgesics, and contrast media.

scholarly journals Determinants of cardiac adverse events of chloroquine and hydroxychloroquine in 20 years of drug safety surveillance reports

2020 ◽  
Author(s):  
Isaac V. Cohen ◽  
Tigran Makunts ◽  
Talar Moumedjian ◽  
Masara Issa ◽  
Ruben Abagyan
Keyword(s):  
Adverse Event ◽  
Side Effects ◽  
Lupus Erythematosus ◽  
Adverse Event Reporting System ◽  
The United States ◽  
Adverse Event Reporting ◽  
World Health ◽  
Cardiac Complications ◽  
Cardiac Side Effects ◽  
Therapeutic Decision Making

AbstractChloroquine (CQ) and hydroxychloroquine (HCQ) are on the World Health Organization’s List of Essential Medications for treating non-resistant malaria, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, both drugs are currently used off-label in hospitals worldwide and in numerous clinical trials for the treatment of SARS-CoV-2 infection. However, CQ and HCQ use has been associated with cardiac side effects, which is of concern due to the higher risk of COVID-19 complications in patients with heart related disorders, and increased mortality associated with COVID-19 cardiac complications. In this study we analyzed over thirteen million adverse event reports form the United States Food and Drug Administration Adverse Event Reporting System to confirm and quantify the association of cardiac side effects of CQ and HCQ. Additionally, we identified several confounding factors, including male sex, NSAID coadministration, advanced age, and prior diagnoses contributing to the risk of drug related cardiotoxicity. These findings may help guide therapeutic decision making and ethical trial design for COVID-19 treatment.

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