Myocarditis After mRNA-1273 Vaccination: A Population-Based Analysis of 151 Million Vaccine Recipients Worldwide

Background: Growing evidence indicates a causal relationship between SARS–CoV–2 infection and myocarditis. Post–authorization safety data have also identified myocarditis as a rare safety event following mRNA COVID–19 vaccination, most notably among younger adult males and after dose 2. To further evaluate the potential risk after vaccination, we queried the Moderna global safety database to assess the occurrence of myocarditis/myopericarditis among mRNA–1273 vaccine recipients worldwide since first international Emergency Use Authorization issuance. Methods: Reports of myocarditis/myopericarditis entered into the Moderna global safety database from December 18, 2020 to September 30, 2021 were reviewed and classified based on the Brighton Collaboration case definition. The cumulative observed occurrence of myocarditis/myopericarditis was assessed by calculating the reported rate after any known dose of mRNA–1273 according to age and sex. This reporting rate was compared to a population–based incidence rate (US military) to calculate observed–to–expected rate ratios (RR). Results: Through September 30, 2021, a total of 1,439 cases of myocarditis/myopericarditis among approximately 151.1 million mRNA–1273 vaccine recipients were reported to the Moderna global safety database. The overall reporting rate among all vaccine recipients was 0.95 cases per 100,000 vaccine recipients, which was lower than the expected rate from the reference population (2.12 cases per 100,000 vaccine recipients; RR [95% CI]: 0.45 [0.42–0.48]). When stratified by sex and age, observed rates were highest for males aged ≤39 years, particularly those aged 18–24 years (7.40 cases per 100,000 vaccine recipients), which was higher than expected (RR [95% CI]: 3.49 [2.88–4.22]). For males and females aged <18 years, the rate ratio for myocarditis was 1.05 (95% CI, 0.52–2.13) and 0.21 (95% CI, 0.04–0.94), respectively. When considering only cases occurring within 7 days after vaccination, the observed rate was highest for males aged 18–24 years after dose 2 (4.9 cases per 100,000 doses administered). Conclusion: Myocarditis/myopericarditis accounted for 0.4% of adverse events reported to the Moderna global safety database after mRNA–1273 vaccination; rates were higher than expected in males aged 18–24 years, with most occurring by 7 days after dose 2, but were not higher than expected for the overall population of vaccine recipients and were lower than that observed in individuals infected with SARS–CoV–2.

14. Postmarketing Safety Experience With MenACWY-TT

Background MenACWY-TT (Nimenrix®), a quadrivalent meningococcal tetanus toxoid conjugate vaccine, was first licensed in 2012 and is available in 82 countries but not in the United States. MenACWY-TT is administered in infants as a 2 + 1 (6 weeks to &lt; 6 months of age) or 1 + 1 (6 to &lt; 12 months of age) schedule with the booster dose at 12 months of age, and from 12 months of age as a single dose. In addition to its widespread use to protect against meningococcal serogroups A, C, W, and Y, MenACWY-TT is a constituent of an investigational pentavalent meningococcal (MenABCWY) vaccine currently undergoing clinical development. Methods Using the MenACWY-TT Periodic Safety Update Report (PSUR) with format and content in accordance with Good Pharmacovigilance Practice Module VII and International Council for Harmonisation Guideline E2C, for data up to April 19, 2020, postmarketing safety experience with MenACWY-TT is considered. The PSUR data included herein are spontaneous adverse events (AEs) from the Pfizer safety database. AEs were coded by system organ class (SOC) and preferred term (PT) using MedDRA v.22.1J. Results The cumulative estimated exposure of MenACWY-TT was nearly 26 million doses, with the majority administered in 0- to 16-year-olds and in the Western European Union (Figure 1). Over the reporting period, 13,301 cumulative AEs occurred. The most common SOCs in the reporting period were general disorders and administration site conditions (n=5169; 39%); nervous system disorders (n=1986; 15%); injury, poisoning and procedural complications (n=1266; 10%); and gastrointestinal disorders (n=1031; 8%) (Figure 2). By PT, the most common AEs were pyrexia (n=1613; 12%), headache (n=738; 6%), and vaccination site pain (n=394; 3%) (Figure 3). Of the 3299 serious AEs reported, the most common were pyrexia (n=317; 10%) and headache (n=209; 6%). Conclusion Based on cumulative safety data in conjunction with existing efficacy and effectiveness data, the benefit-risk profile of MenACWY-TT remains favorable and is consistent with the safety profile of MenACWY-TT established in clinical studies. Disclosures Lidia Serra, MS, Pfizer Inc (Employee, Shareholder) Susan Mather, MD, Pfizer Inc (Employee, Shareholder) Cindy Burman, PharmD, Pfizer Inc (Employee, Shareholder) Chris Webber, MD, Pfizer (Employee, Shareholder)

Safety Profile of Ibrutinib: An Analysis of the WHO Pharmacovigilance Database

As ibrutinib has become a standard of care in B-cell malignancies in monotherapy or in combination with other agents, definition of its safety profile appears essential. The aim of this study was to further characterize the safety profile of ibrutinib through the identification of potential safety signals in a large-scale pharmacovigilance database. All serious individual case safety reports (ICSRs) in patients aged ≥18 years involving ibrutinib suspected in the occurrence of serious adverse drug reactions or drug interacting from November 13th, 2013 to December 31st, 2020 were extracted from VigiBase, the World Health Organization global safety database. Disproportionality reporting was assessed using the information component (IC) and the proportional reporting ratio (PRR), with all other anticancer drugs used as the reference group. To mitigate the confounding of age, two subgroups were considered: patients aged&lt;75 years and ≥75 years. A signal of disproportionate reporting (SDR) was defined if both IC and PRR were significant. A total of 16,196 ICSRs were included. The median age of patients was 72.9 years, 42.6% of ICSRs concerned patients aged ≥75 years, and 64.2% male patients. More than half (56.2%) of ICSRs resulted in hospitalization or prolonged hospitalization. Among 713 SDRs, 36 potential safety signals emerged in ibrutinib-treated patients, mainly ischemic heart diseases, pericarditis, uveitis, retinal disorders and fractures. All potential safety signals having arisen in this analysis may support patient care and monitoring of ongoing clinical trials. However, owing to the mandatory limitations of this study, our results need further confirmation using population-based studies.

Zanamivir aqueous solution in severe influenza: A global Compassionate Use Program, 2009–2019

Background Zanamivir is a neuraminidase inhibitor effective against influenza A and B viruses. In 2009, GlaxoSmithKline (GSK) began clinical development of intravenous (IV) zanamivir, and initiated a global Compassionate Use Program (CUP) in response to the evolving H1N1 global pandemic. The goal of the CUP was to provide zanamivir to critically ill patients with limited treatment options. Methods Zanamivir was administered to patients with suspected or confirmed influenza infection, who were not suitable for other approved antiviral treatments. Reporting of serious adverse events (SAEs) was mandatory and recorded in the GSK safety database. A master summary tracking sheet captured requests and patient characteristics. A case report form was available for detailing medical conditions, dosing, treatment duration, and clinical outcomes. Results In total, 4033 requests were made for zanamivir treatment of hospitalized patients from 38 countries between 2009 and 2019. Europe had the highest number of requests (n=3051) followed by North America (n=713). At least 20 patients were aged ≤6 months, of whom 12 were born prematurely. The GSK safety database included 466 patients with ≥1 SAE, of whom 374 (80%) had a fatal outcome. Drug-related SAEs were reported in 41 (11%) patients, including hepatic failure (n=6 [2%]) and acute kidney injury (n=5 [1%)]. Conclusions The CUP fulfilled the need to provide global access to zanamivir prior to product approval. No new safety concerns were identified in the CUP compared with IV zanamivir clinical studies.

Automatic Rail Surface Defects Inspection Based on Mask R-CNN

Rail surface defects have negative impacts on riding comfort and track safety, and could even lead to accidents. Based on the safety database (2020) of the Federal Railroad Administration (FRA), rail surface defects have been among the main factors causing derailments. During the past decades, there have been many efforts to detect such rail surface defects. However, the applications of earlier methods are limited by the high requirements of specialized equipment and personnel training. To date, rail surface defect inspection is still a very labor-intensive and time-consuming process, which hardly satisfies the field maintenance expectations. Therefore, a cost-effective and user-friendly automatic system that can inspect the rail surface defects with high accuracy is urgently needed. To address this issue, this study proposes a computer vision-based instance segmentation framework for rail surface defect inspection. A rail surface database including 1,040 images (260 source images and 780 augmented images) has been built. The classic instance segmentation model, Mask R-CNN, has been re-trained and fine-tuned for inspecting rail surface defects with the customized dataset. The influences of different backbones and learning rates are investigated and discussed. Experimental results indicate the ResNet101 backbone reaches better inspection capability. With a learning rate of 0.005, the re-trained Mask R-CNN model can achieve the best performance on the bounding box and mask predictions. Sixteen images are used to test the inspection performance of the fine-tuned model. The results are promising and indicate potential field applications in the future.

Study of Safety of Medicinal Products in Pregnant Women in Crimea

According to international epidemiological studies, about 80% of women have to use medicinal products during pregnancy, mainly during the first weeks of organogenesis in the case of an unplanned pregnancy, and for the treatment of chronic diseases or acute conditions developing during pregnancy. Specificity of pharmacokinetics and pharmacodynamics in pregnant women contributes to the development of adverse drug reactions (ADRs), many of which are serious and pose a threat to the life of the patient. The aim of the study was to retrospectively assess the frequency and development of ADRs in pregnant women living in the Republic of Crimea, based on the data in the regional safety database ARCADe (Adverse Reactions in Crimea, Autonomic Database). Materials and methods: the authors analysed spontaneous ADR reports registered in the ARCADe database from 1 January 2009 until 31 December 2018 for the category of patients described as “Pregnant women/childbirth”. Results: during the specified period, 268 ADR cases in pregnant women were added to the database. The most common reasons of ADRs in this category of patients were antibacterials for systemic use (130 cases, 48.5%), agents that have an effect on haematopoiesis and blood (54 cases, 20.15%), and agents that have an effect on the functions of the gastrointestinal tract (29 cases, 10.82%). The study of ADR clinical manifestations revealed a high incidence of local allergic reactions (140 cases, 52.2%), inhibition of haematopoiesis (60 cases, 22.4%), and dyspepsia (36 cases, 13.4%). The analysis of the severity of the registered ADRs demonstrated that in 15 cases (5.6%) the use of the prescribed medicinal product posed a threat to the patient’s life and required urgent pharmacotherapy and discontinuation of the suspected medicine, in 8 cases (3%) it resulted in hospitalisation or prolongation of hospital treatment, and in 3 cases (1.12%) it resulted in the temporary inability to work. Conclusions: the results of the study indicate the need for further retrospective and prospective studies aimed at analysing the safety of medicine use in pregnant women and assessing the risks of toxic effects on the foetus.

POS0022 PHARMACOVIGILANCE PREGNANCY DATA IN A LARGE POPULATION OF PATIENTS WITH CHRONIC INFLAMMATORY DISEASE EXPOSED TO CERTOLIZUMAB PEGOL: PREGNANCY OUTCOMES AND CONFOUNDERS

Background:Chronic inflammatory diseases (CID) in women of reproductive age are increasingly being treated with tumour necrosis factor inhibitors (TNFi), in line with recent guidelines.1 However, data on TNFi-exposed pregnancy outcomes are still limited. Certolizumab pegol (CZP), a PEGylated, Fc-free TNFi, has no/minimal placental transfer from mother to infant during the third trimester.2Objectives:To assess pregnancy outcomes from the UCB Pharmacovigilance safety database from over 1,300 prospectively reported pregnancies with maternal CZP exposure.Methods:Details of CZP-exposed pregnancies from the UCB Pharmacovigilance safety database were reviewed up to November 1, 2020. Analysis was limited to prospectively reported cases with known pregnancy outcomes to avoid potential reporting bias. Confounders (specific CID, non-biologic medications and maternal infection) were evaluated using a multivariate stepwise regression model; results from the confounders analysis are reported as odds ratios (OR) with 95% confidence intervals (CI). Patients with missing information about presence or absence of confounders were excluded from the model.Results:1,392 prospective pregnancies (1,425 fetuses) with maternal CZP exposure and known outcomes were reported (Figure 1). Mean (SD) maternal age was 31.9 (5.1) years. Of these, 1,021/1,392 (73.3%) pregnancies had at least first-trimester CZP exposure and 547/1,392 (39.3%) were exposed during all trimesters. Overall, there were 1,259/1,425 (88.4%) live births, 150/1,425 (10.5%) abortions (miscarriages and terminations), 11/1,425 (0.8%) stillbirths, and 5/1,425 (0.4%) ectopic pregnancies. Congenital malformations were reported in 35/1,425 fetuses (2.5%) and in 30/1,259 live-born infants (2.4%); 26 (2.1%) congenital malformations were major according to the Metropolitan Atlanta Congenital Defects Program criteria. There was no pattern of specific congenital malformations. Preterm births occurred in 124/1,259 (9.8%) live births, and 101/1,259 (8.0%) of infants had low birth weight (<2.5 kg). In the confounders analysis, reported corticosteroid use was independently associated with increased odds of preterm birth (OR [95% CI]: 2.1 [1.3–3.4]; p<0.005) and low birth weight (OR [95% CI]: 1.7 [1.0–2.9]; p<0.05), but decreased odds of abortion (OR [95% CI]: 0.5 [0.3–0.9]; p<0.05). Reported NSAID use was associated with increased odds of abortion (OR [95% CI]: 2.2 [1.2–4.0]; p<0.05), as was methotrexate/leflunomide use (OR [95% CI]: 3.2 [1.7–6.2]; p<0.0005). Maternal infections were associated with increased odds of preterm birth (OR [95% CI]: 1.9 (1.1–3.5; p<0.05). Finally, there was an association between a diagnosis of Crohn’s disease and odds of abortion (OR [95% CI]: 2.5 [1.5–4.1]; p=0.0005), and between rheumatoid arthritis and low birth weight (OR [95% CI]: 1.9 [1.1–3.3]; p<0.05).Conclusion:This prospective analysis, including more than 1,000 pregnancies with CZP exposure in at least the first trimester, represents one of the largest cohorts of pregnancies with known outcomes in patients with CID. Our data confirm the impact of specific CID, concomitant drugs or comorbidities on pregnancy outcomes. In particular, additional use of corticosteroids was highlighted as a risk factor for preterm birth and low birth weight in our cohort of CZP-treated patients. No increase in adverse pregnancy outcomes or specific congenital malformations was observed in CZP-exposed pregnancies, compared to the general population,3,4 which offers further reassurance for women of childbearing age considering CZP treatment.References:[1]Sammaritano LR. Arthritis Rheum 2020;72:529–56;[2]Mariette X. Ann Rheum Dis 2018;77:228–33;[3]Ventura SJ. Natl Vital Stat Rep 2012;60:1–21;[4]Lee H. BMC Pregnancy Childbirth 2020;20:33.Acknowledgements:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Megan Clowse Consultant of: UCB Pharma, Grant/research support from: Janssen, Pfizer, Rebecca Fischer-Betz Consultant of: AbbVie, BMS, Celgene, Chugai, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi, UCB Pharma, Catherine Nelson-Piercy Consultant of: Alliance Pharma, UCB Pharma, Angela Scheuerle Consultant of: Antiretroviral Pregnancy Registry, Harmony Biosciences, IQVIA, ICON, NovoNordisk, PPD, Roche, Sanofi-Genzyme, Syneos, UCB Pharma, ViiV, Thomas Kumke Shareholder of: UCB Pharma, Employee of: UCB Pharma, Bernard Lauwerys Employee of: UCB Pharma, Rachna Kasliwal Employee of: UCB Pharma, Frauke Förger Speakers bureau: Mepha, Roche, UCB Pharma, Grant/research support from: UCB Pharma.