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Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 25 April 2026 | Viewed by 12498

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Dr. Cristina Sofia De Jesus Monteiro

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Guest Editor

Pharmacovigilance Unit, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
Interests: pharmacovigilance; drug safety; adverse drug reactions

Prof. Dr. Samuel Martins Silvestre

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Guest Editor

RISE-Health, Faculty of Sciences, University of Beira Interior, Rua Marquês d'Ávila e Bolama, 6201-001 Covilhã, Portugal
Interests: design of bioactive compounds; chemical synthesis; biological evaluation; compounds with medicinal and pharmaceutical interests
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Special Issue Information

Dear Colleagues,

The evolution of pharmacovigilance is increasingly challenged by phenomena such as drug misuse, off-label use and medication errors, all of which can be linked to underlying pharmacological mechanisms. These issues not only pose a significant risk to patient safety but also emphasise the importance of understanding how pharmacodynamic and pharmacokinetic factors contribute to adverse drug reactions (ADRs) and treatment failures. This Special Issue, entitled “Insights into Pharmacovigilance: Addressing Drug Misuse and Enhancing Drug Safety”, seeks contributions that explore the pharmacological basis of drug safety issues and propose mechanism-based approaches to improve pharmacovigilance systems. We invite original research articles and systematic reviews that go beyond observational data to investigate molecular targets, receptor interactions, metabolic pathways, drug–drug interactions or genetic polymorphisms that may affect drug safety.By linking pharmacological insights with regulatory and clinical perspectives, this Special Issue aims to provide a science-based framework for the optimisation of post-market surveillance and the advancement of drug safety science.

Dr. Cristina Sofia De Jesus Monteiro
Dr. Samuel Martins Silvestre
Guest Editors

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Keywords

adverse drug reaction
pharmacovigilance
drug safety
signal detection
risk management

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Published Papers (8 papers)

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Research

16 pages, 1084 KB

Open AccessArticle

Signal Detection of Adverse Events Associated with Four Dihydropyridine Calcium Channel Blockers Based on the FAERS Database

by Zicong Guo, Yi Guo, Xiaoxiao Quan, Rui Xiao, Jia Li and Wei Liu

Pharmaceuticals 2026, 19(4), 544; https://doi.org/10.3390/ph19040544 - 28 Mar 2026

Viewed by 353

Abstract

Objectives: As widely used first-line antihypertensive drugs, dihydropyridine calcium channel blockers (DHP-CCBs) have relatively few studies comparing their adverse reactions based on real-world data. This study aims to identify and compare the potential adverse drug reaction (ADR) signals of four DHP-CCBs (amlodipine, felodipine, nicardipine, and nifedipine) through the US Food and Drug Administration Adverse Event Reporting System (FAERS), providing a reference for further drug safety assessment and clinical medication risk awareness. Methods: Adverse event reports from medical professionals (Q3 2014–Q4 2024) were analyzed using signal detection methods, including reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and the Medicines and Healthcare Products Regulatory Agency (MHRA) methods. Risk signals for the four DHP-CCBs were compared with both the full database and the DHP-CCBs background. For high-risk signals in amlodipine, multivariate logistic regression was used for validation. The analysis reveals distinct ADR profiles for the four DHP-CCBs. Results: Amlodipine is strongly linked to suicide-related risks, confirmed by logistic regression. Nicardipine and nifedipine show significant risks for pregnancy-related events, such as premature delivery and exposure during pregnancy. Nicardipine is also associated with hyponatremia, hyperkalemia, and lactic acidosis. These adverse events are not yet included in the FDA labeling for any of the DHP-CCBs. Although palpitations and angioedema are listed for felodipine, their signal strength is much higher compared to the other DHP-CCBs. Conclusions: The ADR risk profiles of the four DHP-CCBs differ significantly. This study identified several high-risk adverse events not included in current labels. Clinical use should consider each drug’s risk profile and patient-specific factors, with particular attention to serious risk signals. For pregnant and postpartum women, the benefits and risks of using nicardipine and nifedipine should be carefully evaluated. Full article

(This article belongs to the Special Issue Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety)

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18 pages, 1920 KB

Open AccessArticle

Pharmacogenetic Associations with Statin Regimen Modification, Intolerance, and Adverse Outcomes in Coronary Artery Disease Patients

by Rania Abdel-latif, Shaban Mohammed, Mohamad Saad, Khalid Kunji, Wadha Al-Muftah, Ayman El-Menyar and Jassim Al Suwaidi

Pharmaceuticals 2026, 19(3), 514; https://doi.org/10.3390/ph19030514 - 21 Mar 2026

Viewed by 364

Abstract

Background: Statins are central to primary and secondary prevention of atherosclerotic cardiovascular disease but are often underutilized due to myopathy and intolerance. While individual pharmacogenetic (PGx) variants, particularly in SLCO1B1, are linked to statin-associated muscle symptoms, the real-world impact of both clinical and cumulative PGx burden on regimen modification and adverse outcomes remains unclear. We aimed to evaluate the existing uncertainty regarding whether combined PGx scores can effectively guide statin dose titration and regimen modification, thereby filling a key clinical gap. Methods: A retrospective cohort study of 911 statin-treated patients with coronary artery disease was conducted from the Qatar Cardiovascular Biorepository with available whole-genome sequencing data. Variants in SLCO1B1, ABCG2, and CYP2C9 were combined into a functional PGx burden score, and their associations with statin regimen modification, intolerance, myopathy, liver injury, adherence, and composite adverse events were evaluated. The composite adverse events were defined as the occurrence of any statin-related adverse event, including statin-associated myopathy, liver injury, or poor medication adherence, during the follow-up period. Patients were classified as having experienced the composite outcome if at least one of these events occurred. Results: Over 12 months following statin initiation, 10.2% of patients underwent dose escalation, 11.4% de-escalation, and 78.4% remained on the same regimen. PGx burden is not statistically significantly associated with statin intolerance (OR 1.14; 95% CI: 0.73–1.76), composite adverse outcome (OR 1.08; 95% CI 0.82–1.42), or time to regimen change (HR 1.02; 95% CI 0.77–1.35). However, higher PGx burden showed a directional tendency toward dose de-escalation (RRR 1.18, 95% CI 0.76–1.84) and lower likelihood of escalation (RRR 0.93, 95% CI 0.56–1.54). Conclusions: Clinical factors, particularly statin intensity and myopathy, were the primary determinants of regimen modification. The PGx burden contributes to vulnerability to statin-related adverse effects in a context-dependent manner but does not independently drive statin regimen modification in routine clinical practice. Prospective studies are warranted to assess the clinical utility of PGx-guided workflows in statin therapy. Full article

(This article belongs to the Special Issue Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety)

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19 pages, 2580 KB

Open AccessArticle

Quantitative Analysis of the Vitamin D₃ Content in Dietary Supplements Marketed in Hungary Using High-Performance Liquid Chromatography

by András Nagy, Róbert György Vida, Eszter Fliszár-Nyúl, Gábor Lovász, Katalin Fábián and Gábor Pozsgai

Pharmaceuticals 2026, 19(3), 493; https://doi.org/10.3390/ph19030493 - 17 Mar 2026

Viewed by 736

Abstract

Background/Objectives: The use of over-the-counter vitamin D₃ supplements has increased substantially in recent years. Compared with pharmaceuticals, dietary supplements are subject to less stringent regulatory oversight, raising concerns regarding labeling accuracy, consumer knowledge, and patient safety. This study aimed to assess public knowledge and preferences related to vitamin D₃ supplementation and to evaluate the content accuracy and short-term stability of commonly used products. Methods: A cross-sectional online survey containing 39 questions was conducted in Hungary between 1 May and 30 June 2024. Based on survey responses, the most frequently used vitamin D₃ supplements (five soft gel capsules and four tablets) were selected for laboratory analysis. Vitamin D₃ content was quantified using a validated high-performance liquid chromatography (HPLC) method with UV detection. Soft gel capsules were additionally exposed to natural daylight for one month to assess short-term photostability. Results: In total, 367 participants (mean age 31.0 ± 12.5 years) completed the survey, and only 3.5% answered correctly all knowledge-based questions. Six commonly reported supplement brands accounted for approximately 90% of responses. Measured vitamin D₃ content remained within the tolerance limit (−20% to +50%). Following sunlight exposure, three of four capsule products showed no substantial vitamin D₃ loss, while one exhibited a 14.7% decrease. Conclusions: Most analyzed vitamin D₃ supplements complied with labeled content claims, but substantial knowledge gaps were identified that may affect patient safety. The validated HPLC method supports pharmacovigilance-oriented quality monitoring of vitamin D₃ supplements and underscores the need for improved professional counseling. Full article

(This article belongs to the Special Issue Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety)

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23 pages, 1835 KB

Open AccessArticle

Divergent System Organ Class Safety Profiles of Isotretinoin Versus Topical Retinoids: An EudraVigilance Disproportionality Analysis

by Denisa Viola Szilagyi, Delia Mirela Tit, Ruxandra Cristina Marin, Gabriela S. Bungau, Mirela Marioara Toma, Manuela Bianca Pasca, Daniela Gitea and Laura Maria Endres

Pharmaceuticals 2026, 19(1), 127; https://doi.org/10.3390/ph19010127 - 11 Jan 2026

Cited by 1 | Viewed by 793

Abstract

Background/Objectives: Isotretinoin remains an essential therapy for severe acne, yet its safety profile continues to raise concerns. This study analyzed adverse event reporting patterns for isotretinoin versus topical retinoids using EudraVigilance data. Methods: Aggregated ADR data for isotretinoin and four topical retinoids (tretinoin, adapalene, tazarotene, trifarotene) were retrieved from the EMA ADRreports portal (April 2025). Disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals at the MedDRA system organ class (SOC) level. Significant demographic differences (age and sex; both p < 0.001) justified stratified ROR analyses for SOCs showing positive signals. Results: Among 35,030 isotretinoin and 3795 topical retinoid reports, isotretinoin showed strong over-reporting in six SOCs: psychiatric disorders (ROR 11.96; 95% CI 10.11–14.14), gastrointestinal disorders (3.88; 3.50–4.31), musculoskeletal and connective tissue disorders (2.89; 2.50–3.35), surgical and medical procedures, social circumstances, and ear and labyrinth disorders. Fourteen SOCs demonstrated significant under-reporting, including neoplasms, immune system disorders, cardiac disorders, and blood/lymphatic disorders. Stratified analyses confirmed the robustness of the positive signals. Psychiatric disorders exhibited the highest disproportionality in males (22.10; 16.11–30.31) and adolescents aged 12–17 (25.85; 13.32–50.19). Gastrointestinal and musculoskeletal signals remained significant across all age and sex strata. Conclusions: Isotretinoin presents a distinct safety profile characterized by consistently elevated reporting of psychiatric, gastrointestinal, and musculoskeletal adverse events, independent of age and sex. These results refine the comparative safety landscape of systemic versus topical retinoids and support focused pharmacovigilance monitoring. Full article

(This article belongs to the Special Issue Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety)

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17 pages, 406 KB

Open AccessArticle

Balancing Pain Relief and Safety: Gastrointestinal and Cardiovascular Risk Assessment in Nonsteroidal Anti-Inflammatory Drug Users and the Role of Gastroprotective Co-Therapy

by Javedh Shareef, Sathvik Belagodu Sridhar, Zainab Mohamed Saeed and Amal Mohamed Rashed Alsereidi

Pharmaceuticals 2026, 19(1), 67; https://doi.org/10.3390/ph19010067 - 29 Dec 2025

Viewed by 1252

Abstract

Background/Objectives: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management but pose gastrointestinal (GI) and cardiovascular (CV) risks, particularly during long-term use. This study evaluated NSAID-prescribing patterns and the appropriateness of gastroprotective co-therapy among patients with varying GI and CV risk profiles. Methods: An observational, cross-sectional study was conducted in the outpatient pharmacy department over six months (March 2023 to August 2023) at a public secondary care facility. Data pertaining to patient demographics, NSAIDs prescription, and GI/CV risks were collected and reviewed from electronic health records. Descriptive statistics, chi-square tests, and logistic regression were performed. Results: A total of 1005 prescriptions containing 2051 NSAIDs were analyzed. Selective COX-2 inhibitors and non-selective NSAIDs were the most frequently prescribed. Only 42.1% of patients received proton-pump inhibitors despite guideline recommendations. Non-selective NSAIDs were significantly associated with CV history and GI risk (p < 0.0001). Logistic regression showed age, gender, CV history, and GI risk significantly influenced NSAID selection. Notably, non-selective NSAIDs continued to be prescribed among moderate- and high-GI-risk patients. Conclusions: Suboptimal adherence to guideline-recommended gastroprotective strategies was evident, particularly among high-risk patients. Comprehensive GI and CV risk assessment and the rational use of gastroprotective co-therapy are essential. Integrating evidence-based digital tools may enhance safer NSAID prescribing in routine practice. Full article

(This article belongs to the Special Issue Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety)

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18 pages, 480 KB

Open AccessArticle

Safety of Drugs Used in Difficult-to-Treat Epileptic Syndromes: A Disproportionality Analysis Using the Eudravigilance Database

by Arianna Scala, Teresa Angela Trunfio, Chiara Pennisi, Giovanni Enrico Lombardo, Vincenzo Micale, Serena Di Martino, Giorgia Fiorenza, Adriana Carol Eleonora Graziano, Marilena Briglia, Fabio Allia, Giovanni Giurdanella, Roberta Malaguarnera, Rosalia Battaglia, Cecilia Gozzo, Fanny Erika Palumbo, Calogero Vetro, Giovanni Improta, Mario Damiano Toro, Filippo Drago, Giovanni Luca Romano and Lucia Gozzo Show full author list Hide full author list

Pharmaceuticals 2025, 18(12), 1895; https://doi.org/10.3390/ph18121895 - 16 Dec 2025

Viewed by 1030

Abstract

Background/Objectives: Difficult-to-treat epileptic syndromes include conditions typically emerging in the first years of life and are characterized by a high rate of drug refractoriness. This study aimed to better define the safety profile of drugs used as adjunctive therapies for seizures associated with these syndromes using real-world pharmacovigilance data. Methods: We retrospectively analyzed the publicly available data regarding Individual Case Safety Reports (ICSRs), presenting stiripentol, cannabidiol, or fenfluramine as suspected drugs, reported on the Eudravigilance database until the third quarter of 2024. Data were evaluated with descriptive analyses and then with disproportionality measures, including the reporting odds ratio. Results: A total of 5986 ICSRs met the inclusion criteria (71.6% from cannabidiol, 14.5% fenfluramine, and 13.9% stiripentol). Significantly higher probabilities of reporting Cardiac disorders, Vascular disorders, and Respiratory, thoracic, and mediastinal disorders were observed with fenfluramine. Cannabidiol was associated with Product issues, whereas stiripentol was associated with injury, poisoning, procedural complications, Metabolism and nutrition disorders, and Blood and lymphatic system disorders. Conclusions: Our analysis did not highlight new and unexpected serious safety signals but confirmed the need to strictly monitor patients for the risk of adverse events. However, further prospective studies are required to better clarify the safety profile of these drugs in order to optimize their use. Full article

(This article belongs to the Special Issue Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety)

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19 pages, 1157 KB

Open AccessArticle

Prescribed Drugs and Interpersonal Violence: A Case–Non-Case Study in the Spanish Pharmacovigilance Database

by Ana Avedillo-Salas, Ana Fanlo-Villacampa, Francisco Javier Lanuza-Giménez and Jorge Vicente-Romero

Pharmaceuticals 2025, 18(12), 1845; https://doi.org/10.3390/ph18121845 - 3 Dec 2025

Viewed by 1007

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Background/Objectives: Interpersonal violence is an increasing public health concern, and its prediction and prevention remain global challenges. This study aimed to identify prescribed medications associated with interpersonal violence in Spain. Methods: A descriptive, longitudinal and retrospective study and case-non case study of spontaneous reports of adverse drug reactions corresponding to interpersonal violence recorded in the Spanish Pharmacovigilance Database (FEDRA^®) from 1984 to 31 March 2021. Results: 533 cases were reported in the study period. The mean age was 46.70 years with ages ranging from 1 to 99 years. There were no sex differences except in child and adolescent age group where most reports were from male. Main therapeutic groups involved were nervous system (62.3%), anti-infectives for systemic use (10%) and respiratory system (8.6%). Mostly drugs reported were montelukast, levetiracetam, bupropion, donepezil, perampanel, quetiapine, fluoxetine, and lorazepam. A statistically significant association/disproportion in the notification has been found in the reporting of interpersonal violence and different drugs according to the literature, notably atomoxetine, perampanel, memantine, donepezil, montelukast and methylphenidate. Conclusions: The results highlight that interpersonal violence, while rare, could occur as a clinically relevant adverse reaction to a small subset of medications. They underscore the importance of careful prescribing, especially in vulnerable populations and in individuals with a history of psychiatric disorders. Full article

(This article belongs to the Special Issue Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety)

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25 pages, 1030 KB

Open AccessArticle

Real-World Evidence of Neuropsychiatric Adverse Reactions to Isotretinoin: Insights from EudraVigilance (2005–2025)

by Denisa Viola Szilagyi, Delia Mirela Tit, Claudia Teodora Judea-Pusta, Andrei-Flavius Radu, Gabriela S. Bungau, Ada Radu, Laura Maria Endres and Ruxandra-Cristina Marin

Pharmaceuticals 2025, 18(9), 1252; https://doi.org/10.3390/ph18091252 - 24 Aug 2025

Cited by 4 | Viewed by 5985

Abstract

Background/Objectives: Isotretinoin is a highly effective therapy for severe acne, but its potential neuropsychiatric adverse reactions (NPsRs) have been controversial. This study evaluated EudraVigilance data from 2005 to 2025 to better understand the frequency, typology, and predictors of such events. Methods: We conducted a retrospective analysis of 33,381 individual case safety reports (ICSRs) related to isotretinoin. Using descriptive statistics, chi-square tests, and logistic regression, we assessed associations between NPsRs and variables such as age, sex, geographic region, and reporter type. Results: A total of 9793 cases (29.3%) involved at least one NPsR. Depression (31%) and suicidal ideation (8.6%) were the most frequently reported symptoms. Adolescents (12–17 years) had the highest proportion of NPsR cases, while male patients and reports submitted by non-healthcare professionals were significantly overrepresented. Reports from non-European Economic Area countries also had slightly increased odds of including NPsRs. All predictors were statistically significant in the logistic regression model, though the explained variance was modest (Nagelkerke R² = 0.065). Conclusions: Neuropsychiatric reactions remain a prominent and persistent signal in isotretinoin pharmacovigilance, particularly among younger patients and non-professional reporters. Although causality cannot be inferred from spontaneous reporting data and confounding factors like acne-related depression cannot be excluded, these findings highlight the clinical value of pre-treatment psychiatric screening, patient-centered education, and proactive mental health monitoring throughout isotretinoin therapy. Full article

(This article belongs to the Special Issue Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety)

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