Drug Safety最新文献

Introduction: Available data regarding the safety and efficacy of sotrovimab in pregnant patients remain limited due to their exclusion from clinical trials.

Methods: The COVID-19 International Drug Pregnancy Registry (COVID-PR) was established to gather comprehensive safety data from pregnant women who have received monoclonal antibody (mAb) or antiviral treatments for mild, moderate, or severe coronavirus disease 2019 (COVID-19) during pregnancy. Participants actively contributed self-reported data concerning their COVID-19 symptoms, in addition to sociodemographic and health-related characteristics. Obstetric, neonatal, and infant outcomes were also documented, with follow-up extending up to 12 months after childbirth.

Results: As of 30 November 2023, sotrovimab was administered to 39 participants enrolled in the COVID-PR. At the time of this report, 26 participants had given birth, with nine deliveries performed via cesarean section. The infants' birthweight ranged from 2381 g to 4762 g, with a mean of 3439.91 g. Twenty-five infants were born at ≥37 weeks. A total of 31 adverse events (AEs) were reported by 12 participants. The most frequently reported AE was gestational hypertension, observed in three participants. COVID-19 re-infection, fatigue, gestational diabetes, headache, and morning sickness were each reported by two participants. Of the reported AEs, eight (in five participants) were classified as serious, including four AEs (prolonged labor, pre-eclampsia, polyhydramnios, premature labor) that affected pregnancy. Seven of these eight serious AEs (SAEs) were found to be unrelated to sotrovimab, with one event (urinary retention) not assessable. A total of 44 AEs were reported in 19 delivered infants or in utero fetuses. The most common were COVID-19 (n = 6 events), ear infection (n = 5 events), neonatal dyspnea (n = 3 events), and respiratory syncytial virus infection (n = 3 events). Sixteen AEs (in 11 infants/fetuses) were classified as serious, including one report each of fetal cardiac disorder, congenital ankyloglossia, persistent right umbilical vein, and congenital hydronephrosis; the latter was considered a major congenital malformation. For all assessable SAEs, causality of sotrovimab treatment was ruled out based on lack of a temporal relationship alone or in combination with absence of a plausible mechanism.

Conclusion: A sizable proportion of sotrovimab-treated participants in the COVID-PR had underlying medical conditions associated with an increased risk of severe COVID-19. None of the assessable SAEs were considered to be related to sotrovimab treatment.

Background: Clomiphene citrate is an ovulation inductor for which inadvertent post-conceptional exposures may occur in early pregnancy. In preclinical studies, post-conceptional exposures showed a teratogenic effect in different species. In humans, to date, little is known about the outcomes of inadvertently post-conceptionally exposed pregnancies.

Objectives: The objectives of our study were to assess the association between post-conceptional exposures to clomiphene citrate and major and minor congenital malformations in the offspring.

Methods: A retrospective cohort study of prospectively ascertained cases was undertaken, based on clinical data from the Centre de Référence sur les Agents Tératogènes (CRAT), Paris, France. Women with post-conceptional exposure to clomiphene citrate (n = 309), and unexposed pregnant women (n = 1236, 1:4 ratio) with prospectively collected data, known pregnancy outcome and delivery date prior to 01/02/2022, were matched by calendar year. An adjudication committee classified major and minor congenital malformations according to the EUROCAT (European Registration of Congenital Anomalies and Twins) classification.

Results: Among post-conceptional exposed women, no increased risk of major malformation was found (crude relative risk = 0.64, 95% confidence interval 0.19-2.15) as compared to unexposed women. Three major and ten minor congenital malformations were reported in the exposed group. An increased risk of minor malformations was found (crude relative risk = 4.05, 95% confidence interval 1.70-9.64) although there was no specific clinical pattern.

Conclusions: Post-conceptional exposure to clomiphene citrate was not associated with an increased risk of major congenital malformations. Given potential confounding and information biases, the results about minor malformations should be interpreted with caution as no specific clinical pattern was identified.

Introduction: Lenalidomide, pomalidomide, and thalidomide are effective treatments for multiple myeloma but are teratogenic. To mitigate this risk, the US Food and Drug Administration (FDA) required risk evaluation and mitigation strategy (REMS) programs for these drugs, which include pregnancy testing among women of childbearing potential-twice before initiation, weekly in the first month on treatment, and every 2-4 weeks thereafter.

Objective: We evaluated dispensing trends of lenalidomide, pomalidomide, and thalidomide and assessed adherence to REMS pregnancy testing requirements among at-risk patients taking these drugs.

Methods: Using three US health insurance claims databases (Optum Clinformatics® [2004-2020], Merative Marketscan [2003-2019], and Medicaid [2000-2018]), we assessed monthly use of the drugs, patient characteristics and treatment persistence among drug initiators, and claims-based evidence for adherence to pregnancy testing requirements among initiators with child-bearing potential.

Results: Lenalidomide was the most prescribed agent following its approval in 2006 and through the end of the study period. A total of 48,311 lenalidomide (mean age = 59 years [standard deviation (SD) = 16]), 17,550 thalidomide (mean age = 65 years [SD = 12]), and 6560 pomalidomide initiators (mean age = 65 years [SD = 11]) were identified; 45% of initiators of each drug were women. Among initiators under follow-up on day 90, 70% were still on therapy. Initiators of childbearing potential comprised 3% (N = 1,920) of all initiators; among this cohort, 12% had evidence in claims data of two pregnancy tests before initiation, and 9% with at least 33 days of follow-up of four tests during the first month of treatment. By contrast, 52% who received a refill had claims-based evidence of a pregnancy test within 7 days of dispensing.

Conclusion: Although most patients who initiated lenalidomide, pomalidomide, and thalidomide were not of child-bearing potential, further investigation into actual non-adherence to pregnancy testing is needed.

Introduction: Off-label underdosed direct oral anticoagulants (DOACs) are commonly utilised in Asian patients with atrial fibrillation (AF) since they are prone to bleeding with OACs. However, the efficacy and safety of off-label underdosing DOACs are controversial. This study aimed to compare the effectiveness and safety of off-label underdosed DOACs in Asian patients with AF.

Methods: PubMed, Embase, Cochrane library, and ClinicalTrials.gov were searched from 2010 to July 5, 2024, for randomised controlled trials or observational studies that compared off-label DOACs and on-label/warfarin in Asian patients with AF. The primary outcomes included ischaemic stroke or systemic embolism (ISSE) and major bleeding (MB), while secondary outcomes included all-cause death, gastrointestinal bleeding (GIB), intracranial haemorrhage (ICH), and myocardial infarction (MI). Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects models.

Results: Twenty observational studies were included. Seventeen studies compared off-label underdosed DOACs versus on-label DOACs, whereas five studies compared off-label underdosed DOACs versus warfarin. Off-label underdosed DOACs were associated with higher risk of ISSE (pooled HR [pHR] = 1.17; 95% CI: 1.00-1.38, p = 0.048) and ICH (pHR = 1.27; 95% CI: 1.06-1.52, p = 0.010) versus on-label. Subgroup analysis demonstrated increased ISSE risk with off-label underdosed rivaroxaban compared to on-label (pHR = 1.49; 95% CI: 1.07-2.08). Compared to warfarin, off-label underdosed DOACs were associated with decreased risk of MB (pHR = 0.46; 95% CI: 0.32-0.65, p < 0.001), GIB (pHR = 0.52; 95% CI: 0.29-0.93, p = 0.028), ICH (pHR = 0.60; 95% CI: 0.42-0.86, p = 0.005), and all-cause death (pHR = 0.70; 95% CI: 0.56-0.87, p = 0.001), while illustrating similar ISSE risk.

Conclusions: Off-label underdosed DOACs, particularly rivaroxaban, was associated with increased ISSE risk but did not decrease bleeding compared to on-label. Adherence to appropriate DOAC doses should be emphasised to achieve the best clinical outcomes for Asian patients with AF.

Spontaneous reporting systems (SRS) provide valuable data for detecting unidentified adverse events not observed in clinical trials and for conducting safety assessments that accurately reflect real-world clinical practice. With the increasing number of publications using the SRS for disproportionality analysis (DA), there is an increasing demand for a comprehensive understanding of the research limitations associated with the SRS. However, there is a lack of understanding of the caveats associated with adjusting covariates in DA of the SRS. Herein, we summarized the use of covariate adjustment and its caveats in DA. The Council for International Organizations of Medical Sciences VIII suggests considering adjustments such as stratification when they can enhance the sensitivity and/or specificity of statistical analysis. However, several database-specific and statistical caveats have been identified when adjusting for covariates derived from the SRS. Disproportionality analysis may be affected not only by reporting bias at the time of enrollment but also by sparse-data bias due to variations in the number of enrollment reports. Statistical evidence is needed to determine in which cases and to what extent sensitivity and/or specificity are affected. Nevertheless, it is important for researchers to acknowledge that certain limitations discussed in this context may be inherent and cannot be rectified. Based on this understanding, they can then make an informed decision on whether to perform a covariate adjustment.