Adverse events reported to the U.S. Food and Drug Administration Adverse Event Reporting System for tisagenlecleucel.

The U.S. Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell therapy, tisagenlecleucel, in August 2017. We sought to describe adverse events (AEs) reported to the FDA Adverse Event Reporting System (FAERS) for tisagenlecleucel in the post-marketing period. We searched FAERS reports to identify U.S. patients treated with tisagenlecleucel between August 30, 2017-August 31, 2019. We reviewed individual reports, calculated AE frequencies and reporting rates (RRs), and used Empirical Bayesian Geometric Mean methods to identify disproportionate reporting. We identified 646 de-duplicated reports with a median age at AE of 18 (interquartile range: 11-56) years. The overall RR was 81.0%, and more than 95% of reports described a serious outcome. Cytokine release syndrome (CRS) was the most frequently reported AE (51.1%) with a RR of 41.4%; neurotoxicity was reported less frequently (21.2%), with a RR of 17.2%. Most disproportionately reported AEs were listed on the package insert or confounded by indication. We identified 13 subsequent neoplasms (SPN), the majority occurring within 6 months of tisagenlecleucel administration, and none reporting evidence of insertional mutagenesis. A total of 165 reports (26%) described a death outcome; most deaths occurred >30 days after treatment. The majority of deaths (64%) were due to progression of the underlying lymphoid neoplasm, and few (<5%) were attributed to CRS or neurotoxicity. We did not identify new safety concerns reported for tisagenlecleucel in the post-marketing period. Reporting rates for CRS and neurotoxicity were lower than identified in the prelicensure clinical trials.

Adverse Events Associated with Use of Digoxin Immune Fab Reported to the US Food and Drug Administration Adverse Event Reporting System, 1986-2019.

BACKGROUND: Digoxin immune fab products, DigiBind and DigiFab, are antidotes for the treatment of patients with life-threatening or potentially life-threatening digoxin toxicity or overdose. Although approved by the US Food and Drug Administration (FDA) in 1986 (DigiBind) and 2001 (DigiFab), there remains a paucity of literature describing the safety of these products in the postmarketing setting. OBJECTIVE: We sought to assess US adverse event (AE) reports submitted to the FDA Adverse Event Reporting System (FAERS) for DigiBind and DigiFab in the postmarketing period. PATIENTS AND METHODS: We searched reports for DigiBind and DigiFab submitted from the time of each product approval through December 31, 2019. Descriptive statistics were used to assess AE reports for DigiBind and DigiFab. Empirical Bayes geometric means (EBGMs) and their 90% confidence intervals were computed to identify disproportionate (i.e., at least twice the expected) reporting of DigiBind and DigiFab. Reports describing selected AEs and death outcomes were individually reviewed. RESULTS: A total of 78 DigiBind and 43 DigiFab reports were identified, of which 68 DigiBind (87.2%) and 27 DigiFab (62.8%) reports were serious. Among the most frequently reported AEs for both products [DigiBind, DigiFab, respectively] were cardiac (bradycardia [3.8%, 3.9%], cardiac arrest [3.3%, 3.9%], and hypotension [2.4%, 2.6%]) and non-cardiac (nausea [1.9%, 2.6%] and hyperkalemia [1.4%, 1.9%]) events. These AEs were labeled events or confounded by indication for use (digoxin toxicity). Nineteen (24.4%) DigiBind and 13 (30.2%) DigiFab reports described an outcome of death, of which seven (53.8%) DigiFab reports were attributed to poisoning with non-digoxin cardiac glycosides. No deaths could be attributed to DigiBind or DigiFab administration. CONCLUSIONS: Our analysis did not identify new safety concerns for DigiBind or DigiFab. Most AEs reported were labeled events or confounded by indication for use.

Case series of reports of pruritus and sipuleucel-T submitted to the Food and Drug Administration Adverse Event Reporting System.

Sipuleucel-T, an autologous active cellular immunotherapy, is indicated for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer. The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) received a report of pruritus without rash following the second dose of sipuleucel-T in a patient who had otherwise not started any new medications concurrent with the first and second doses of sipuleucel-T. No further sipuleucel-T was administered, but symptoms persisted for at least 6 weeks despite treatment with several medications aimed at symptomatic relief of pruritus. Rash is the only dermatologic adverse event included in the sipuleucel-T U.S. package insert. A search of the FAERS database yielded seven additional U.S. reports of pruritus and sipuleucel-T identified as the primary suspect medication; two of these occurred prior to the administration of sipuleucel-T (following leukapheresis). In data mining analyses, pruritus following sipuleucel-T was not reported more frequently than expected when compared to all other adverse event-drug/biologic combinations in FAERS. Thus, pruritus following sipuleucel-T administration was rarely, but not disproportionately, reported to FAERS. Although we cannot exclude the possibility that diabetes, malignancy, or other conditions may have contributed to pruritus in our index patient, in view of the timing of sipuleucel-T therapy and onset of symptoms, a drug/biologic-related reaction is plausible. In the appropriate clinical scenario, sipuleucel-T (or its components) should not be overlooked as a potential etiological agent in pruritus.

Adverse events after anthrax vaccination reported to the Vaccine Adverse Event Reporting System (VAERS), 1990-2007.

During the period March 1, 1998 to January 14, 2007, approximately 6 million doses of Anthrax vaccine adsorbed (AVA) vaccine were administered. As of January 16, 2007, 4753 reports of adverse events following receipt of AVA vaccination had been submitted to the Vaccine Adverse Event Reporting System (VAERS). Taken together, reports to VAERS did not definitively link any serious unexpected risk to this vaccine, and review of death and serious reports did not show a distinctive pattern indicative of a causal relationship to AVA vaccination. Continued monitoring of VAERS and analysis of potential associations between AVA vaccination and rare, serious events is warranted.

Transfusion-transmitted Klebsiella pneumoniae fatalities, 1995 to 2004.

Transfusion-transmitted bacterial sepsis is the third most common cause of transfusion-related fatalities reported to the Food and Drug Administration. Between October 1, 1995, and September 30, 2004, there were 665 reported transfusion fatalities. Eighty-five (13%) deaths were due to transfusion-transmitted bacterial infections, of which 58 (68%) were due to gram-negative organisms. The most common gram-negative organism associated with transfusion-transmitted deaths after receipt of platelets was Klebsiella pneumoniae. This article summarizes retrospectively the case series of deaths due to transfusion-transmitted K pneumoniae infection, reported to the Food and Drug Administration, 1995 to 2004. There were 12 deaths due to transfusion-transmitted K pneumoniae infection with 7 (58%) of the 12 cases occurring in 2002. Eleven deaths were caused by the transfusion of contaminated platelets and 1 death attributed to contaminated red blood cells. Extensive review of the seven 2002 fatality reports did not identify a common (shared) lot for items used during collection or processing of the blood product. In conclusion, in cases of suspected transfusion-transmitted septicemia, broad spectrum antibiotic coverage including coverage of gram-negative organisms should be considered. Strict adherence to infection control measures while collecting, processing, and handling all blood and blood components in both the clinical settings and in the laboratory should be followed. Further development of simple and effective test procedures for detecting bacteria in the blood is needed.