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Pharmaceuticals
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Drug Safety and Risk Management in Clinical Practice
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Drug Safety and Risk Management in Clinical Practice

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

Deadline for manuscript submissions: closed (25 September 2025) | Viewed by 7296

Special Issue Editor

Dr. Andreea Maria Farcas

E-Mail Website
Guest Editor
Pharmacovigilance Research Center, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
Interests: drug safety; drug utilization studies; adherence studies; patient-centered research; risk minimization measure effectiveness

Special Issue Information

Dear Colleagues,

Safety monitoring of drugs throughout their whole life cycle is of paramount importance in order to protect public health and fulfill the whole scope of pharmacovigilance, which is to detect, assess, understand, and prevent adverse effects or any other medicine-/vaccine-related problems. Upon authorization on the market, all medications and vaccines have gone through an extensive clinical trial program to ensure their efficacy and safety. Nevertheless, some adverse effects might not become apparent until after these products have been used for an extended period of time and by a large and diverse population, including those with concurrent illnesses and medications. Therefore, drug safety surveillance through spontaneous reporting systems (SRS) and post-authorization safety studies (PASS) using real-world data will provide information and new insights into the safety profiles of the drugs. Such information must be continuously analyzed, and results should be made available for healthcare professionals and regulatory bodies in case new safety concerns are discovered. If the benefit-risk profile of the drugs is impacted, regulatory authorities can propose risk minimization interventions in order to prevent or reduce adverse effects. This Special Issue welcomes reviews and original papers related to drug safety, such as, but not limited to, studies using active or passive methods for drug/vaccine monitoring (PASS, analysis of data from SRS, including signal detection/disproportionality analysis), studies on risks in special populations, and studies on risk minimization measures, including evaluations of the effectiveness of risk minimization measures.

Dr. Andreea Maria Farcas
Guest Editor

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Keywords

  • drug safety
  • adverse drug reactions
  • risk minimization measures
  • effectiveness of risk minimization measures
  • drug utilization studies

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Published Papers (6 papers)

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Research

17 pages, 3759 KB  
Article
Disproportionality Analysis of Oral Toxicities Associated with PI3K/AKT/mTOR Pathway Inhibitors Using the FAERS Database
by Monica Marni, Djamilla Simoens, Nicholas Romero, Walter Keith Jones and Simon Kaja
Pharmaceuticals 2025, 18(10), 1580; https://doi.org/10.3390/ph18101580 - 19 Oct 2025
Abstract
Background: Stomatitis is a common adverse event associated with targeted therapies for hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer, particularly those inhibiting the PI3K/AKT/mTOR pathway. While mTOR-inhibitor-associated stomatitis is well established, less is known about its occurrence with other kinase inhibitors in real-world [...] Read more.
Background: Stomatitis is a common adverse event associated with targeted therapies for hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer, particularly those inhibiting the PI3K/AKT/mTOR pathway. While mTOR-inhibitor-associated stomatitis is well established, less is known about its occurrence with other kinase inhibitors in real-world settings. We performed a pharmacovigilance disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) to evaluate stomatitis reports for alpelisib, capivasertib, everolimus, and palbociclib. Methods: Events were identified using four term sets—Stomatitis, Original Trial Terms (OTT), Comprehensive Trial Terms (CTT), and Stomatitis-Associated Main Terms (SAMT)—which reflect varying definitions and medical terminologies. Disproportionality analyses using reporting odds ratio (ROR), proportional reporting ratio (PRR), and Information Component (IC) were calculated with 95% confidence intervals. Results: All agents showed ROR and PRR >1, indicating higher odds and reporting proportions of stomatitis compared with other drugs. These findings were confirmed by IC analysis. Everolimus demonstrated the strongest association (ROR: 30.72 [29.61–31.88]), followed by alpelisib (ROR: 13.11 [11.79–14.58]) and palbociclib (ROR: 11.73 [11.35–12.11]). Capivasertib had the lowest reporting odds (ROR: 3.14 [1.81–5.43]), though limited by fewer reports. Differences between CTT and SAMT were minimal (~2%). Conclusions: These results support the use of the SAMT as an efficient screening tool. Furthermore, these findings underscore the need for optimized stomatitis detection and continued monitoring, particularly for PI3K and mTOR inhibitors, in both clinical trials and postmarketing surveillance. Full article
(This article belongs to the Special Issue Drug Safety and Risk Management in Clinical Practice)
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20 pages, 1679 KB  
Article
Steroid-Induced Thrombosis: A Comprehensive Analysis Using the FAERS Database
by Ayame Watanabe and Yoshihiro Uesawa
Pharmaceuticals 2025, 18(10), 1463; https://doi.org/10.3390/ph18101463 - 28 Sep 2025
Viewed by 557
Abstract
Background/Objectives: Thrombosis, a critical condition that can have severe consequences, such as myocardial infarction and cerebral infarction, can be induced by steroid drugs. Although the mechanisms for inducing thrombosis are known for some types of steroid drugs, much remains unknown about the differences [...] Read more.
Background/Objectives: Thrombosis, a critical condition that can have severe consequences, such as myocardial infarction and cerebral infarction, can be induced by steroid drugs. Although the mechanisms for inducing thrombosis are known for some types of steroid drugs, much remains unknown about the differences in the tendency and mechanisms for thrombosis. Methods: To address this knowledge gap, we analyzed the relationship between thrombosis and steroid use by utilizing the U.S. Food and Drug Administration Adverse Event Reporting System database. From the database, we extracted demographic and drug information and information on reported adverse events from 2004 to 2024. We characterized drugs according to physiological function, receptor specificity, and Anatomic Therapeutic Chemical classification and calculated the proportion of steroid drugs that were likely to induce thrombosis. Results: Among steroid drugs, sex hormones such as androgens, progestogens, and estrogens appeared to have particularly high potential for causing thrombotic events. Results of principal component analysis and cluster analysis indicated that sex hormone preparations were associated with an increased risk of venous thrombosis. In addition, cardiovascular medications and mineralocorticoids, which are used to treat diseases of major organs, showed a tendency to induce large-vessel occlusions. Conclusions: These findings may be useful for selecting steroid drugs for patients who are at risk for similar adverse effects. Full article
(This article belongs to the Special Issue Drug Safety and Risk Management in Clinical Practice)
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16 pages, 606 KB  
Article
Pre-Emptive Drug Safety Evaluation of Iclepertin (BI-425809) Using Real-World Data and Virtual Addition of This Medication to the Actual Drug Regimen of Individuals from Large Populations
by Sebastian Härtter, Veronique Michaud, Matt K. Smith, Pamela Dow, Gerald Condon, Michael Desch and Jacques Turgeon
Pharmaceuticals 2025, 18(10), 1453; https://doi.org/10.3390/ph18101453 - 28 Sep 2025
Viewed by 381
Abstract
Introduction. Adverse drug events (ADEs) are between the third and sixth most common cause of death worldwide. Biosimulation studies performed using real-world data could generate relevant drug safety information without exposing patients to ADEs. Methods. Iclepertin (BI-425809) was virtually added to [...] Read more.
Introduction. Adverse drug events (ADEs) are between the third and sixth most common cause of death worldwide. Biosimulation studies performed using real-world data could generate relevant drug safety information without exposing patients to ADEs. Methods. Iclepertin (BI-425809) was virtually added to the actual drug regimens of n = 4,405,063 individuals. Changes in risk level were estimated for drug-induced long QT syndrome and CYP450 drug interactions. The properties used for iclepertin included: dose of 10 mg (oral) once daily; bioavailability (F) = 71%; Cmax of 222 nM; CYP3A4 weak affinity substrate (partial metabolic clearance of ~80%); IC50 for hERG block of 30 μM. Results. A change in total medication risk score (MRS) was observed (6.3 ± 6.6 to 7.2 ± 6.6) following the addition of iclepertin in ~50% (n = 2,138,247) of the studied population. Among individuals with a change in MRS, ~65% had a 2-unit increase (max 11 units). The number of individuals classified in the High/Severe MRS category increased by 0.33%. The addition of iclepertin to individuals receiving CYP3A4 perpetrator drugs produced a greater change in MRS (+1.5) when compared to individuals not exposed to CYP3A4 perpetrators (+0.8). An additional 0.0032% of the population (n = 139) would be at risk of QT prolongation following the intake of iclepertin. Subset analyses performed in individuals with schizophrenia (targeted indication) demonstrated that these individuals had higher MRS values (13.0 ± 10.3) compared to those without schizophrenia (6.2 ± 6.9). However, the addition of iclepertin did not produce a greater increase in MRS in the schizophrenia population vs. the control population. Our pharmacoeconomic model did not account for any beneficial effects of the drug but the model based on MRS changes predicted a USD 91 yearly increase in medical expenditures (emergency department visits and hospitalizations) per individual (USD 3172 to USD 3263) following the addition of iclepertin. A similar increase was observed in the schizophrenia population following iclepertin addition. Conclusions. The increase in MRS associated with the addition of iclepertin to the drug regimen of a large population was minimal and mostly driven by CYP3A4 interactions. Using this model, interactions can be identified a priori, making risk mitigable and preventable without exposing patients to toxicity. Full article
(This article belongs to the Special Issue Drug Safety and Risk Management in Clinical Practice)
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13 pages, 424 KB  
Article
Impact of Co-Occurring Psychiatric Comorbidities and Substance Use Disorders on Outcomes in Adolescents and Young Adults with Opioid Use Disorder: A Retrospective Cohort Study
by Ligang Liu, Erin R. McKnight, Andrea E. Bonny, Heqing Tao, Pujing Zhao and Milap C. Nahata
Pharmaceuticals 2025, 18(5), 609; https://doi.org/10.3390/ph18050609 - 23 Apr 2025
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Abstract
Background/Objectives: Adolescents and young adults (AYAs) with opioid use disorder (OUD) frequently have co-occurring psychiatric conditions and substance use disorders (SUDs). This study evaluated the association of psychiatric comorbidities and other SUDs with treatment retention and urine drug test (UDT) results in AYAs [...] Read more.
Background/Objectives: Adolescents and young adults (AYAs) with opioid use disorder (OUD) frequently have co-occurring psychiatric conditions and substance use disorders (SUDs). This study evaluated the association of psychiatric comorbidities and other SUDs with treatment retention and urine drug test (UDT) results in AYAs with OUD. Methods: This retrospective cohort study included AYAs enrolled in the Substance Use Treatment and Recovery clinic from 2009 to 2022. Participants were categorized into four groups: no comorbidities, only mental health disorders, only other SUDs, and both disorders. Treatment outcomes included retention time and UDT results for medication for OUD (MOUD) and illicit substances, including tetrahydrocannabinol (THC). Kruskal–Wallis tests were used to evaluate differences across groups, and regression models identified variables associated with outcomes. Statistical significance was set at p < 0.05. Results: Among 157 patients, the median retention time was 300 days. Depression (p = 0.04), post-traumatic stress disorder (p = 0.002), and alcohol use disorder (p = 0.04) were associated with prolonged retention, whereas cannabis use disorder predicted shorter retention (p = 0.02). The median proportion of positive UDTs was 0.9 for MOUD, 0.1 for illicit substances, and 0.0 for THC. Older age (p = 0.02) and the use of antidepressants and anxiolytics were associated with greater adherence to MOUD. Cannabis use disorder (p = 0.02) and male sex (p = 0.04) predicted positive UDTs for THC, while MOUD use was linked to lower THC positivity (p = 0.02). The main limitations of this study were related to its retrospective study design and single-center setting. Conclusions: Psychiatric and substance use comorbidities significantly influence retention and treatment adherence in AYAs with OUD. Integrated treatment may improve engagement and outcomes. Further research is needed to tailor interventions for AYAs with co-occurring disorders. Full article
(This article belongs to the Special Issue Drug Safety and Risk Management in Clinical Practice)
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17 pages, 1365 KB  
Article
Oncoral Follow-Up for Outpatients Treated with Oral Anticancer Drugs Assessed by Relative Dose Intensity
by Virginie Larbre, Florence Ranchon, Delphine Maucort-Boulch, Elsa Coz, Chloé Herledan, Anne-Gaëlle Caffin, Amandine Baudouin, Magali Maire, Nicolas Romain-Scelle, Charles-Hervé Vacheron, Lionel Karlin, Gilles Salles, Hervé Ghesquières and Catherine Rioufol
Pharmaceuticals 2025, 18(4), 565; https://doi.org/10.3390/ph18040565 - 13 Apr 2025
Viewed by 862
Abstract
Objectives: The multidisciplinary city-hospital Oncoral follow-up of cancer outpatients has been set up to ensure the safety of oral anticancer drugs (OADs). The aim of this study was to assess Oncoral by Relative Dose Intensity (RDI) in patients with hematological malignancies treated [...] Read more.
Objectives: The multidisciplinary city-hospital Oncoral follow-up of cancer outpatients has been set up to ensure the safety of oral anticancer drugs (OADs). The aim of this study was to assess Oncoral by Relative Dose Intensity (RDI) in patients with hematological malignancies treated with ibrutinib as a model. Methods: The study included all outpatients treated with ibrutinib and followed in Oncoral between January 2016 and June 2020. Patients benefited from interviews leading to pharmacist and nurse interventions (PNI) on drug-related problems as adverse events (AE), drug–drug interactions (DDI), and drug intake. Results: In total, 83 patients were enrolled. At least one PNI was performed for 86.7%, focusing on drug intake and DDIs (54.5%), the management of AEs (27.0%), and community–hospital coordination (18.5%). Major DDIs with ibrutinib were found in 10 patients, with at least one moderate interaction in 28%. Grade 3–4 AEs mainly concerned cytopenia and infection. Adherence tended to decrease after the first 6 months. At 6 months, the mean RDI was 93.7 ± 11.3%; RDI reductions occurred in 43% patients. RDI was lower in patients who discontinued treatment before day 90 and worsened over time in patients still being treated at month 6 (Friedman’s test, p < 0.01). Age and gender were predictors of early treatment termination (OR 1.10 [1.03; 1.19] and 6.44 [1.65; 37.21]). The estimates of 30-month OS and PFS were 73.8% (95% CI [64.7%; 84.2%]) and 61.8% (95% CI [51.8%; 73.7%]). Conclusions: The Oncoral follow-up is a secure, coordinated pathway assessed by RDI. Multidisciplinary follow-up should be the gold-standard for outpatients receiving OADs. Full article
(This article belongs to the Special Issue Drug Safety and Risk Management in Clinical Practice)
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15 pages, 1154 KB  
Article
Safety of Inclisiran: A Disproportionality Analysis from the EudraVigilance Database
by Giuseppe Cicala, Michelangelo Rottura, Viviana Maria Gianguzzo, Federica Cristiano, Selene Francesca Anna Drago, Giovanni Pallio, Natasha Irrera, Egidio Imbalzano, Edoardo Spina and Vincenzo Arcoraci
Pharmaceuticals 2024, 17(10), 1365; https://doi.org/10.3390/ph17101365 - 12 Oct 2024
Cited by 4 | Viewed by 2936
Abstract
Introduction: The discovery of serine protease proprotein convertase subtilisin-kexin type 9 (PCSK9) has revolutionized pharmacological lipid-lowering treatments. The first PCSK9 antagonists (PCSK9-A), evolocumab and alirocumab, were approved in 2015. Targeting PCSK9 synthesis marked a major advancement in this field, leading to the development [...] Read more.
Introduction: The discovery of serine protease proprotein convertase subtilisin-kexin type 9 (PCSK9) has revolutionized pharmacological lipid-lowering treatments. The first PCSK9 antagonists (PCSK9-A), evolocumab and alirocumab, were approved in 2015. Targeting PCSK9 synthesis marked a major advancement in this field, leading to the development of inclisiran, a long-acting siRNA targeting PCSK9 mRNA. However, real-world safety data on this drug are still limited. Therefore, this study aims to provide a real-world safety evaluation of inclisiran, comparing its characteristics to those of PCSK9-As. Methods: A retrospective pharmacovigilance study was conducted using EudraVigilance (EV). Inclisiran-related individual case safety reports (I-ICSRs) from 01/01/2021 to 06/30/2023 were retrieved. ICSRs for evolocumab or alirocumab from 01/01/2015 to 06/30/2023 were collected as a reference group (RG). ADRs were classified using the MedDRA dictionary. Data were evaluated using descriptive and disproportionality analyses. Crude reporting odds ratio (ROR) with 95% confidence intervals (CI) were used as disproportionality measures. Results: Of the 15,236 ICSRs, 3.7% (n = 563) involved inclisiran, with the rest in the RG. Most I-ICSRs involved female patients (51.7%) aged 18 to 64 (52.8%). The most-reported ADRs for inclisiran were “general disorders and administration site conditions” (n = 347) and “investigations” (n = 277). Significant disproportionality was found in I-ICSRs compared to the RG for “Myalgia” (ROR: 2.43; 95% CI: 1.94–3.04), “Low-density lipoprotein increased” (ROR: 11.95; 95% CI: 9.10–15.52), and “Drug ineffective” (ROR: 6.37; 95% CI: 4.64–8.74). Conclusions: The inclisiran safety profile aligns with the existing literature and pre-commercial data. However, further studies are needed to fully understand the observed differences with PCSK9-As. Full article
(This article belongs to the Special Issue Drug Safety and Risk Management in Clinical Practice)
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