Serious Adverse Events Of Interest Research Articles

Retrospective Observational Study of the Long-Term Safety and Efficacy Outcomes of Rituximab Biosimilar: Partial Data of RTXM83-AC-01-11 Subanalysis Study

Introduction Rituximab is a chimeric monoclonal antibody designed against the CD20 receptor displayed on the surface of B cells and used to treat nearly all B-cell non-Hodgkin lymphomas (NHLs). It was the first monoclonal antibody approved in oncology and it has improved outcomes in all B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. In recent years, the approval of several rituximab biosimilar molecules worldwide has further improved the patients' access to this drug, promoting cost-effective treatment. Biosimilar molecules are defined by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a biological molecule product highly similar to the approved reference product with no clinically meaningful differences. The multicentric double-blind international prospective pivotal study RTXM83-AC-01-11 led to the approval of rituximab biosimilar RTXM83. The study evaluated the efficacy, pharmacokinetics (PK)/pharmacodynamics (PD), safety, and immunogenicity profile of RTXM83 (rituximab biosimilar) vs reference rituximab (Mabthera®), both with CHOP, as first-line treatment of Diffuse-Large-B-Cell-Lymphoma (DLBCL). Participants from both arms received 6 cycles of R-CHOP followed by a 9-month follow-up (Candelaria et al., 2019). Data regarding long-term efficacy and safety events are of great relevance to demonstrate the strength of the clinical response and deepen the confidence in the use of biosimilar molecules. Here, we present a partial data analysis regarding the long-term safety of 11 patients included in this retrospective observational study. Aim This national retrospective observational study aimed to collect long-term data regarding safety e efficacy outcomes from Brazilian participants of the pivotal study RTXM83-AC-01-11 which led to the approval of biosimilar rituximab (Vivaxxia®) in Brazil. Methods All 28 Brazilian participants that were randomized and completed the phase III study RTXM83-AC-01-11 were eligible for this observational, retrospective LB2002 study (Clinical trial information: NCT04928573). Participants were invited to sign the consent form and share the disease history collected since their randomization on the RTXM83-AC-01-11 study. This partial analysis shows the participants' demographic and baseline characteristics, baseline disease characteristics, and the long-term safety data collected and monitored until July 1st, 2022. The long-term safety endpoint was the frequency of serious adverse events of interest, and we considered in this analysis the time between the end of the RTXM83-AC-01-11 study and the consent date of the LB2002 study. Results The intention to treat (ITT) and Safety populations comprised the partial analysis of the same 11 participants, 7 of them (63.6%) treated with biosimilar RTXM83 plus CHOP and 4 (36.4%) with Mabthera® plus CHOP. The median study follow-up time was 73.3 months, considered in this analysis as the time between the randomization of RTXM83-AC-01-11 study participants and the consent date of the LB2002 study. Overall, participants' median age was 55 years old, 63.6% were white, 54.5% were female, 18.8% were active smokers and the body mass index (BMI) ranged from 20 to 35.7 Kg/m² (Table 1). Regarding disease characteristics, 9,1% of the overall participants were classified as stage I DLBCL, 45.5% stage II and IV at the time of diagnosis. Of all 11 participants, 72.7% displayed extranodal lesions, and 18.2% had bulky lesions with a median body surface area (BSA) of 1.8 m2 (Table 1). As for prognostic factor and performance status, participants were classified with IPI 1 (45.5%) and 2 (54.5%), ECOG 1 (72.7%) and 2 (18.3%). The long-term safety analysis from the 11 participants revealed that 2 participants (18.2%) suffered from serious adverse events (SAE) among those of interest listed in Table 2. One participant of the RTXM83-CHOP arm had a SAE classified as severe infection related to rituximab (hypogammaglobulinemia). From the R-CHOP/MabThera® 1 participant displayed 1 SAE (secondary neoplasm) with a possible relationship to rituximab. Conclusion The partial analysis of the LB2002 has demonstrated thus far the safety profile of the biosimilar RTXM83 (Vivaxxia®) in the Brazilian population is consistent with the known safety profile of rituximab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Associations of High-Sensitivity Troponin and Natriuretic Peptide Levels With Serious Adverse Events in SPRINT.

BackgroundAssessing the risk of serious adverse events (SAEs) during hypertension treatment is important for understanding the benefit‐harm trade‐offs of lower blood pressure goals. It is unknown whether high‐sensitivity cardiac troponin T (hs‐cTnT) and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) provide information about SAEs.Methods and ResultsIn SPRINT (Systolic Blood Pressure Intervention Trial), hs‐cTnT and NT‐proBNP were measured at baseline in 8828 (94.3%) and 8836 (94.4%) participants, respectively. Multivariable Cox proportional hazards models were used to evaluate hs‐cTnT and NT‐proBNP associations with a composite of SPRINT’s SAEs of interest: hypotension, syncope, bradycardia, acute kidney injury, electrolyte abnormalities, and injurious falls. Elevations in hs‐cTnT and NT‐proBNP were associated with increased composite SAE risk (hazard ratio [HR] per 2‐fold higher hs‐cTnT: 1.15; 95% CI, 1.06‒1.25; HR per 2‐fold higher NT‐proBNP: 1.09; 95% CI, 1.05‒1.14). Compared with both hs‐cTnT and NT‐proBNP in the lower tertiles, both biomarkers in the highest tertile was associated with increased composite SAE risk (HR, 1.56; 95% CI, 1.32‒1.84). Composite SAE risk was higher in the intensive‐treatment group than in the standard‐treatment group for participants with both biomarkers in the lower tertiles, but similar between treatment groups for participants with both biomarkers in the highest tertile (P for interaction=0.008).ConclusionsElevations in hs‐cTnT and NT‐proBNP individually and in combination are associated with higher composite SAE risk in SPRINT. The differential impact of blood pressure treatment on SAE risk across combined biomarker categories may have implications for identifying individuals with more favorable benefit‐harm profiles for intensive blood pressure lowering.

P607 Efficacy and safety of tofacitinib in Ulcerative Colitis patients with extraintestinal manifestations in OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Data from OCTAVE Induction 1&2 and OCTAVE Sustain demonstrated that a history of extraintestinal manifestations (EIMs) was shown not to influence the efficacy of tofacitinib 10 mg twice daily (BID).1 We explored the efficacy and safety of tofacitinib in patients (pts) with and without a history of EIMs in the open-label, long-term extension study, OCTAVE Open. Methods Efficacy and safety (treatment-emergent serious adverse events of interest) data from OCTAVE Open (NCT01470612) were analysed by history of EIMs. Tofacitinib dose in OCTAVE Open was based on baseline remission status; pts in remission received tofacitinib 5 mg BID; all others received 10 mg BID. The frequency of pre-defined prior and active EIMs at OCTAVE Open baseline (peripheral arthritis [PA]; sacroiliitis; ankylosing spondylitis [AS]; myopathy; pyoderma gangrenosum; erythema nodosum; scleritis, episcleritis; uveitis, iritis; oral ulcer/stomatitis; and thromboembolic disorder) and new occurrences of EIMs at Month (M)36, or at early termination, were evaluated in pts with non-missing data. Results In OCTAVE Open, 113/935 (12.1%) had EIMs at baseline (7/174 [4.0%] tofacitinib 5 mg BID; 106/761 [13.9%] tofacitinib 10 mg BID). Pts with EIMs were more likely to be female (61.1%), have a total Mayo score of ≥3 (93.8%) at OCTAVE Open baseline and have disease duration ≥6 years (60.2%), prior tumour necrosis factor inhibitor failure (61.9%), prior immunosuppressant treatment (86.7%) or corticosteroid use (54.0%) at induction study baseline, compared to those without EIMs (38.8%, 78.7%, 49.6%, 50.9%, 74.5% and 43.9%, respectively). There was no consistent trend in the proportions of pts with and without EIMs at baseline who met the OCTAVE Open efficacy endpoints (Table 1). Tofacitinib 5 and 10 mg BID had comparable safety in pts with or without EIMs at baseline (Table 2). In pts with EIMs at baseline, the most frequent active EIMs were PA (51/113 [45.1%]), sacroiliitis (6/113 [5.3%]), oral ulcer/stomatitis (5/113 [4.4%]), myopathy (4/113 [3.5%]) and AS (4/113 [3.5%]). At M36, 4/428 [0.9%] had new occurrences of PA and there were no new occurrences of sacroiliitis (0/468 [0%]), oral ulcer/stomatitis (0/460 [0%]), myopathy (0/469 [0%]) or AS (0/469 [0%]). Conclusion The presence or absence of a history of EIMs at baseline did not impact the long-term efficacy and safety of tofacitinib in pts with UC. New occurrences of EIMs were infrequent. Reference 1. Rubin DT et al. Therap Adv Gastroenterol 2021; 14: 1–12.

Worldwide post-marketing safety surveillance experience with tofacitinib in ulcerative colitis.

SummaryBackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Post‐marketing surveillance (PMS) is an important part of monitoring adverse events (AEs).AimsTo report an analysis of PMS case safety reports for tofacitinib in patients with UCMethodsWorldwide tofacitinib PMS reports received in the Pfizer safety database from 30 May 2018 (first regulatory approval) to 25 August 2020 were analysed. The type and estimated reporting rate (RR) of serious AEs of interest, including infection, gastrointestinal, vascular, respiratory, neoplasm and cardiac events, were reviewed. Patient‐years of exposure (PY) was estimated based on worldwide sales data and the calculated daily regimens of tofacitinib 5 or 10 mg twice daily, immediate‐ or extended‐release formulations.ResultsDuring the 27‐month reporting period, worldwide post‐marketing exposure to tofacitinib was 8916 PY. Overall, 4226 case reports were received and included 12 103 AEs, of which 1839 were serious AEs (SAEs). Among the cases reported, 1141 (27.0%) included an SAE and 18 (0.4%) were fatal. The RR (per 100 PY) for SAEs of interest by Medical Dictionary for Regulatory Activities System Organ Class were 3.28 for infections, 1.26 for vascular disorders, 0.74 for respiratory disorders, 0.55 for neoplasms and 0.50 for cardiac disorders.ConclusionsThe types of AEs were consistent with those reported in tofacitinib clinical trials. Most reported AEs were non‐serious. Limitations of PMS reports and reliance on estimated RRs due to lack of precise values for exposure, required for incidence rate calculation, should be considered when interpreting these results.

Which Is Safer, Chinese Medicine or Western Medicine? Comparative Analysis Based on Chinese Spontaneous Reporting Database

To compare the safety differences between Chinese medicine (CM) and Western medicine (WM) based on Chinese Spontaneous Reporting Database (CSRD). Reports of adverse events (AEs) caused by CM and WM in the CSRD between 2010 and 2011 were selected. The following assessment indicators were constructed: the proportion of serious AEs (PSE), the average number of AEs (ANA), and the coverage rate of AEs (CRA). Further comparisons were also conducted, including the drugs with the most reported serious AEs, the AEs with the biggest report number, and the 5 serious AEs of interest (including death, anaphylactic shock, coma, dyspnea and abnormal liver function). The PSE, ANA and CRA of WM were 1.09, 8.23 and 2.35 times higher than those of CM, respectively. The top 10 drugs with the most serious AEs were mainly injections for CM and antibiotics for WM. The AEs with the most reports were rash, pruritus, nausea, dizziness and vomiting for both CM and WM. The proportions of CM and WM in anaphylactic shock and coma were similar. For abnormal liver function and death, the proportions of WM were 5.47 and 3.00 times higher than those of CM, respectively. Based on CSRD, CM was safer than WM at the average level from the perspective of adverse drug reactions.

Long-Term Safety Experience with Arsenic Trioxide in Patients with Acute Promyelocytic Leukemia

Introduction: Therapeutic agents approved by the FDA are required to undergo postmarketing safety surveillance to meet regulatory and contractual requirements. Arsenic trioxide (Trisenox®) is approved for the treatment of patients with acute promyelocytic leukemia (APL) in the second-line setting, but is also commonly used in first-line regimens in combination with all-trans retinoic acid. Here, we summarize the accumulated safety data from global postmarketing surveillance of arsenic trioxide since its initial approval in 2000 to better understand its long-term safety in patients with APL.Methods: Cumulative data were collected from patients with APL since initial approval in 2000 from spontaneous reports submitted by healthcare professionals and consumers. The data collected were housed in the Teva Pharmaceuticals safety database. Adverse events (AEs) were coded according to MedDRA terms and classified by seriousness and expectedness (unexpected AEs are those not included in the product label at the time of the report or those that occurred at a higher incidence than previously reported).Results: As of July 7, 2016, a total of 2197 AE reports were received in association with arsenic trioxide use in patients with APL. There were 1735 reports classified as serious and 462 classified as nonserious. The most frequently reported (≥ 30 reports) serious AEs and serious AEs of interest are summarized in the table. Serious QT prolongation was the most commonly reported event, but the majority of events were expected, including four cases of torsades de pointes that may be associated with prolonged QT. Serious hematologic toxicities, including neutropenia and leukocytosis, were also common and expected, as was liver toxicity. The most common serious and unexpected events reported included white blood cell decrease, pancytopenia, increased gamma-glutamyltransferase level, and cardiac disorders (primarily ventricular tachycardia, ventricular extrasystoles) that may be associated with prolonged QT in some patients.Conclusions: The overall safety profile of arsenic trioxide is consistent with known toxicities; the majority of serious AEs are associated with QT prolongation. The clinical significance of the reported QT events is unclear, and reporting rates may change in the future because of evolving criteria for QT assessments (Roboz GJ, et al. J Clin Oncol 2014;32(33):3723). This overview was limited by voluntary reporting. However, the long-term, real-world experience with arsenic trioxide administration as a single agent or in combination provides a broader understanding of its safety profile.Sponsor: Teva Branded Pharmaceutical Products R&D [Display omitted] DisclosuresLo-Coco:Teva, Novartis, Baxalta, Pfizer: Consultancy; Teva, Lundbeck: Honoraria, Speakers Bureau. Pathak:Teva Pharmaceuticals: Employment, Equity Ownership.

Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: what size of data platforms and which study designs do we need to assess safety issues?

BackgroundData on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project.MethodsWe used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0–18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children.ResultsThe source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest).ConclusionsPatterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children.

A Phase Ib Trial of Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphoma (PTCL): The Ro-CHOP Study

AbstractAbstract 1617 Background:Romidepsin is a selective class 1 histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma and PTCL who have received at least 1 prior therapy. In recurrent/refractory PTCL, it has been evaluated as a single agent in 2 phase II studies with overall response rates of 25–38% (Piekarz, Blood 2011;117:5827; Coiffier, J Clin Oncol 2012;30:631). Toxicity was mainly hematologic and digestive. The aim of the present study was to evaluate the safety, tolerability and efficacy of different doses of romidepsin in association with CHOP in patients with previously untreated PTCL. Methods:Patients with biopsy-proven PTCL were planned to receive 8 cycles of CHOP (cyclophosphamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1,4 mg/m2 day 1, prednisone 40 mg/m2 days 1 – 5) in association with varying doses of romidepsin. Based on pharmacokinetic data and results of previous phase II studies, the starting dose of 10 mg/m2 on days 1 & 8 was chosen. The dose-variation scheme follows a traditional “3+3” design. Dose-limiting toxicity (DLT) were considered during the first 2 cycles. Results:Eighteen patients (11 male, 7 female, aged 31 to 78) have been included and are analyzable for toxicity during the first two cycles. Diagnoses were: PTCL, not otherwise specified (n=10), angioimmunoblastic TCL (n=4), other PTCL (n=4). ECOG performance status was good (0–1) in all but one patient; 17/18 had stage III-IV disease; LDH levels were elevated in 11/18. The age-adjusted IPI score was 0 (n=1), 1 (n=14), 2 (n=3). Significant, albeit tolerable haematological toxicity having been observed in the first two cohorts, the definition of DLT was modified during the course of the study. The study diagram is shown in the figure. Accrual of the phase Ib part of the study is now completed and the phase II part is ongoing with a dose of 12 mg/m2 D1&8. Serious adverse events of interest included: One episode of acute pulmonary edema after course 1 in 1 patient, acute coronary syndrome (n=1), deep venous thrombosis (n=1) and cardiac arrhythmia (n=1). Among 14 evaluable patients, 3 progressed during treatment or shortly after end of treatment; and 11 responded (partial response 3/14, complete response 8/14) for an overall response rate of 78%. The 4 other patients have not yet reached the 8 cycles. Conclusion:Romidepsin can be combined with CHOP at the price of foreseeable hematological toxicity. Some cardiovascular events have been observed but the relationship with romidepsin is questionable. The dose of 12 mg/m2 on days 1& 8 is currently evaluated in the phase 2 part of the study. Response rates seem promising, but longer follow-up is needed. Updated results will be presented at the meeting. [Display omitted] Disclosures:Ribrag:Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; astrazeneca: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; bayer: Research Funding; sanofi: Research Funding. Coiffier:Celgene: Consultancy.

Postmarketing surveillance of serious adverse events associated with the use of rofecoxib from 1999–2002

ABSTRACTObjective: The authors performed a postmarketing database analysis to evaluate the incidence of cardiovascular and other serious adverse events (SAEs) reported to the US Food and Drug Administration's Adverse Event Reporting System (AERS) involving the use of rofecoxib.Research design and methods: The authors studied all adverse events involving rofecoxib reported to the AERS from inception of the drug until 2002. An emphasis was placed on cardiovascular and other SAEs of interest categorized using the high level group terms hemorrhage, edema, thrombosis, embolism, and death.Results: There were 31,024 reports of SAEs associated with the use of rofecoxib, which was considered primary suspect in 97.8% of these reports. There were 3915, 3677, 1653, 1917, and 233 reports of hemorrhage, edema, death, thrombosis, and embolism, respectively. Relative to the overall population in this dataset, reports of hemorrhage, death, thrombosis, and embolism consisted of a greater proportion of males. The mean age for patients that reported hemorrhage, death, and thrombosis was older, whereas the mean age for embolism and edema was younger than the overall population in this dataset. Aspirin was the most commonly reported concomitant medication (7.4% of reports) followed by acetaminophen (5.4%). Reports containing concomitant use of anti-coagulants, Cox-1, and nonselective inhibitors (each p < 0.001) but not Cox-2 inhibitors were associated with increased age while only anti-coagulants and Cox-1 inhibitors (each p < 0.001) were associated with more males. Reports containing concomitant use of an anti-coagulant or an NSAID accounted for a disproportionate incidence of hemorrhage, edema, embolism, and death. Most notably, the odds of a hemorrhagic event for those reporting concomitant use of an anti-coagulant, Cox-1, non-selective, or Cox-2 inhibitor was 3.05 (p < 0.001), 3.07 (p < 0.001), 2.07 (p < 0.001), and 1.18 (p < 0.001), respectively. Some weaknesses of this type of analysis are the retrospective nature of such a study, the inability to find causality, and that the data can contains multiple reports from any one individual.Conclusions: It can be postulated that in addition to the risk of heart attack and stroke, rofecoxib users were at increased risk of hemorrhage, in addition to other thrombotic and embolic adverse events, which was exacerbated in those taking blood thinners or NSAIDs.