Expert Opinion on Drug Safety最新文献

Introduction: Several sarcomeric gene abnormalities associated with left ventricular thickening, hypercontractility, and high left ventricular ejection fraction define hypertrophic cardiomyopathy (HCM). Standard treatment options such as beta-adrenergic blockers, calcium channel blockers, and/or disopyramide improve symptoms in many patients, but have limited ability to modify disease progression. Two new cardiac myosin inhibitors (CMIs), mavacamten and aficamten, reduce the intensity of myosin - actin cross-bridge formation and could treat causes of HCM.

Areas covered: Drug clearance concepts, relevant information pertaining to cytochrome P450 (CYP450) isoenzymes involved in the disposition of mavacamten and aficamten, genetic polymorphisms associated with CYP450 isoenzymes, and relevance of multi-drug interactions leading to changes in the systemic exposure of CMIs.

Expert opinion: Both mavacamten and aficamten exhibit complex disposition and are extensively metabolized by CYP450 isoenzymes including CYP2C9, CYP2C19, and CYP2D6, which exhibit genetic polymorphisms. CYP3A4 contributes less to the metabolism of mavacamten and aficamten. However, CYP3A4 can influence the disposition of these CMIs and other drugs, as CYP3A4 is subjected to induction and inhibition, and modulation by inflammatory factors. Therefore, multi-drug interactions due to changes in the metabolic clearances of CMIs are expected in HCM patients with other chronic conditions and polypharmacy.

Background: Rufinamide (RUF) is an antiepileptic drug recently introduced for managing seizures in Lennox-Gastaut syndrome (LGS), but its adverse reactions are not well understood. This study aims to evaluate RUF's safety profile using data from the FDA Adverse Event Reporting System (FAERS).

Methods: Disproportionality analysis was conducted to assess RUF-associated adverse drug events (ADEs), using reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma-Poisson shrinker (MGPS).

Results: We collected 338 ADE reports related to RUF. Nervous system disorders were the most frequently reported signals, and several new ADEs were detected, including atonic seizures, sudden unexplained death in epilepsy, seizure clusters, multi-drug resistance, and Stevens-Johnson syndrome. Nearly half of the ADEs in pediatric patients were psychological or neurological. Disproportionality analysis within 4 weeks of treatment showed high RORs for QT shortening, sudden death, and atonic seizures.

Conclusions: Our study revealed prospective signals of new ADEs linked to RUF as well as revealed that both prescribers and patients were more conscious of the risks involved in its clinical use.

Background: Azithromycin and clarithromycin are commonly used to treat community-acquired pneumonia in adults aged ≥ 65, such as mycoplasma pneumonia. This study aims to evaluate adverse events (AEs) associated with azithromycin and clarithromycin in this age group by analyzing the FDA Adverse Event Reporting System (FAERS), providing insights for clinical use and management of AEs in this population.

Research design and methods: We retrieved reports of AEs related to azithromycin and clarithromycin from the FAERS database. Disproportionality analysis was conducted using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Gamma Poisson Shrinkage (MGPS) to identify AEs associated with azithromycin and clarithromycin in adults aged ≥ 65.

Results: A total of 2,019 adverse event reports were retrieved for azithromycin, and 2,392 for clarithromycin. Off-label use (n = 349) and drug interactions (n = 487) were the most reported AEs in adults aged ≥ 65 for azithromycin and clarithromycin, respectively. Prolonged QT interval showed the strongest signal among AEs for azithromycin in this age group. Drug interaction-related medication errors had the strongest signal for clarithromycin. Seven signals not explicitly included in the azithromycin package insert were identified in adults aged ≥ 65. Fourteen signals not explicitly included in the clarithromycin package insert were identified.

Conclusions: Among adults aged ≥ 65, cardiac-related adverse events are more closely associated with azithromycin than with clarithromycin. Conversely, AEs related to drug interactions and psychiatric symptoms are more associated with clarithromycin. Additionally, clinicians should be vigilant regarding AEs not specified in the package inserts. The findings of this study may help optimize the selection of azithromycin and clarithromycin based on patient circumstances and assist clinicians in focusing on relevant AEs for early intervention.

Background: Lapatinib, an FDA-approved tyrosine kinase inhibitor, treats HER2+ advanced/metastatic breast cancer. This study comprehensively analyzed its adverse reaction profile using FDA Adverse Event Reporting System (FAERS) to guide clinical use.

Research design and methods: Adverse event (AE) reports for lapatinib from the second quarter of 2007 to the second quarter of 2024 in FAERS were analyzed using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinkage (MGPS) and Bayesian Confidence Propagation Neural Network (BCPNN) to identify AE signals.

Results: Among 8300 AE reports, females (91.47%) and ages 40-59.9 (33.71%) were predominant. 20 system organ classifications (SOCs) were affected, with gastrointestinal disorders (ROR = 3.46) and skin disorders (ROR = 2.47) most significant. Based on the PT level, a total of 111 PTs were analyzed that met the four algorithms, including typical AEs such as diarrhea (n = 3410), vomiting (n = 856), and rash (n = 856), as well as some rare AEs that were not prompted by the drug inserts, such as neutropenia (n = 252), pericardial effusion (n = 43), lymphedema (n = 20). The majority of lapatinib-associated AEs had onset within 30 days (51%).

Conclusions: Lapatinib has a generally favorable safety profile, but gastrointestinal toxicity and dermatotoxicity require close monitoring to prevent serious AEs.

Introduction: Futibatinib is a small, potent, covalent, irreversible fibroblast growth factor receptor (FGFR) 1-4 inhibitor that has been added as a new standard of care for previously treated unresectable and/or advanced FGFR2 fusion/rearrangement-positive BTC. FGFR2 fusions/rearrangements play a key role in BTC survival, proliferation, invasion, and development of distant metastasis. The inhibition of this pathway is an important target in the treatment of BTC.

Areas covered: The article covers the development of futibatinib for the treatment of refractory unresectable/advanced BTC, its mechanism of action, and key pharmacodynamic/pharmacokinetic data with a focus on the safety profile. Data are based on published clinical trials, pooled analysis, and retrospective studies indexed in PubMed (2010-2024).

Expert opinion: Futibatinib is an FDA and EMA approved FGFR2 inhibitor for the treatment of patients with refractory BTC with FGFR2 fusions/rearrangements. Ongoing drug development strategies are centered on designing new FGFR2 fusion inhibitors able to overcome on-target and off-target resistances coupled with a high target selectivity to spare the most common treatment-related adverse events (hyperphosphatemia, stomatitis, alopecia, nail toxicity, skin reactions, eye toxicity).

Background: Olaparib, niraparib, and rucaparib are the three primary poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors that are currently available in the market. Previous studies indicate different incidences of adverse events based on the PARP inhibitor or country.

Research design and methods: This study used data from the United States Food and Drug Administration Adverse Event Reporting System collected between January 2018 and December 2023. The data analyzed in this study involved patients receiving PARP inhibitors for treating ovarian cancer. A comparative analysis of the three PARP inhibitors was conducted using the reporting odds ratio (ROR) and the adjusted ROR (aROR) controlling for patient background differences.

Results: The aROR for niraparib was significant at > 1.000, including platelet count decreased (p < 0.001) and thrombocytopenia (p < 0.001) when olaparib was set as the reference. Conversely, the aROR for niraparib was significant at < 1.000, including anemia (p < 0.001). Additionally, significant differences were observed in various adverse events for rucaparib. Moreover, significant differences were observed when comparing between countries.

Conclusions: This study indicates that the types of adverse events may vary by PARP inhibitor and by country. These results will be beneficial in clinical practice.

Objective: The study aims to thoroughly assess the adverse events related to infections and infestations associated with biological agents used for psoriasis using the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) database.

Methods: We analyzed FAERS data from the first quarter of 2004 to the fourth quarter of 2023. The study included TNF-α inhibitors (etanercept, infliximab, adalimumab), IL-12/23 inhibitors (ustekinumab), IL-23p19 inhibitors (guselkumab), and IL-17 inhibitors (secukinumab, ixekizumab). We used disproportionality analysis and Bayesian methods to quantify the related adverse event (AE) signals.

Results: Most AEs related to infections and infestations are already listed on the drug packaging labels. Notably, TNF-α inhibitors are associated with a significantly higher incidence of tuberculosis-related diseases compared to other biological agents. In contrast, IL-17 inhibitors show a greater variety and number of fungal infection-related AEs than their counterparts. Furthermore, our study has identified new potential AEs that require the attention of clinicians.

Conclusion: In clinical practice, it is advisable to monitor the risks of infections and infestations in patients receiving biological agents for psoriasis to enable early detection and intervention. Our findings highlight the need for further epidemiological investigations to establish causality and guide clinical practice in managing these risks effectively.

Background: Tafasitamab is the first anti-CD19 monoclonal antibody approved for relapsed/refractory diffuse large B-cell lymphoma patients ineligible for autologous stem cell transplantation. The study was designed to evaluate tafasitamab-associated adverse events (AEs) by data mining the United States Food and Drug Administration Adverse Event Reporting System (FAERS).

Research design and methods: A disproportionality analysis was performed to assess the safety profile of tafasitamab based on the reports from the FAERS database between 2020Q3 and 2023Q3. Proportional reporting ratio (PRR) and empirical Bayesian geometric mean (EBGM) were used to identify the signals of AEs in patients receiving tafasitamab.

Results: A total of 529 reports with tafasitamab as the primary suspect drug were collected, including 1,262 AEs. Of these, 28 repeated AEs were identified using two algorithms. After excluding events unrelated to drug therapy, the top five repeated AEs by intensity ranking were cytopenia, immunosuppression, neutropenic sepsis, blood lactate dehydrogenase increased, and hematotoxicity. Unexpected significant AEs included polyneuropathy, splenomegaly, hemophagocytic lymphohistiocytosis, hypercalcemia, and ascites.

Conclusions: This study provides additional evidence for risk identification of tafasitamab in the real world, which could help clinicians and pharmacists increase vigilance and improve the safety of tafasitamab in clinical practice.

Background: Ustekinumab is a fully human interleukin-12/23 (p40) inhibitor used to treat immune-mediated diseases. However, the limitations of clinical trials and the expanding target population necessitate an update on the ustekinumab-associated adverse events (AEs). We conducted signal mining for ustekinumab-related AEs using the United States Food and Drug Administration Adverse Event Reporting System (FAERS).

Research design and methods: AE reports were collected from 2009 Q3 to 2024 Q1. Four disproportionality analysis algorithms - reporting odds ratio, medicines and healthcare products regulatory agency, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker - were used to quantify the signals of ustekinumab.

Results: During this period 69,345 AE reports associated with ustekinumab were collected, and ustekinumab was identified as the primary suspect. Overall, 319 signals involving 15 system organ classes were identified, and 111 signals had a medium or strong value for IC₀₂₅. Of them, 67 were classified as important medical events. Squamous cell carcinoma, pertussis, vulval abscess, breast abscess, and fistula exhibited higher signal intensities.

Conclusions: Our study identified the risk signals for ustekinumab using real-world data and provides further evidence to support its rational use. Due to the limitations of FAERS, further studies are warranted to verify these findings.

Background: Anti-herpesvirus drug safety profiles have not been systematically compared. Understanding variations in adverse events (AEs) could provide reference for rational clinical use.

Methods: We collected data on acyclovir, ganciclovir, valaciclovir, and foscarnet from the FDA Adverse Event Reporting System (FAERS) database from Q1 2004 to Q3 2023. Disproportionality analyses were conducted to evaluate the risk of AEs.

Results: All drugs exhibited significant associations with hematotoxicity, with ganciclovir and foscarnet being more myelosuppressive. The correlation with renal impairment ranked as follows: foscarnet, ganciclovir, valaciclovir, and acyclovir (ROR = 16.72, 7.06, 3.51, and 2.02, respectively). Regarding hepatotoxicity, ganciclovir was associated with acute-on-chronic liver failure (ROR = 52.83), and foscarnet was associated with fulminant hepatitis (ROR = 49.91). In the nervous system, acyclovir showed the highest intensity of neurotoxicity (ROR = 14.95). Valaciclovir ranked first in toxic encephalopathy (ROR = 64.70). Foscarnet showed the highest intensity of status epilepticus (ROR = 6.45). Besides, acyclovir showed the strongest association with severe cutaneous adverse reactions (SCARs).

Conclusions: Our study revealed differences in safety profiles of four anti-herpesvirus medications. Ganciclovir exhibited the highest risk of hematotoxicity but appeared relatively safe in seizures and SCARs. Foscarnet was more likely to induce nephrotoxicity, seizures, and electrolyte imbalances than others. Acyclovir and valaciclovir were strongly associated with plasmacytosis, neurotoxicity, and SCARs.