Food And Drug Administration Adverse Event Reporting Research Articles

Post-marketing safety evaluation of lurbinectedin: a pharmacovigilance analysis based on the FAERS database.

Background: On 15 June 2020, the United States Food and Drug Administration (FDA) approved lurbinectedin for treating adult patients with metastatic small-cell lung cancer whose disease has progressed despite prior platinum-based chemotherapy. Following its market approval, safety data on lurbinectedin in large populations is currently lacking. Therefore, this study aims to evaluate adverse events (AEs) associated with lurbinectedin using the FDA's Adverse Event Reporting System (FAERS)database. Methods: Data concerning lurbinectedin from the FAERS database were extracted for the period from June 2020 to September 2023. Four disproportionality analysis algorithms were utilized to assess potential AEs linked to lurbinectedin: reporting odds ratio (ROR), proportional reporting ratio, disproportionate multi-item gamma Poisson shrinker, and Bayesian confidence propagation neural network. These algorithms were applied to quantify signals of lurbinectedin-related AEs. Result: A total of 5,801,535 AE reports were retrieved from the FAERS database, with 511 related to lurbinectedin. These lurbinectedin-induced AEs were observed in 23 system organ classes (SOCs). After simultaneously applying the four algorithms, 47 lurbinectedin-induced AE signals were detected in 23 SOCs. At the SOC level, blood and lymphatic system disorders (ROR, 6.70; 95% confidence interval [CI]: 5.47-8.22) were the only SOC that met all four algorithms. Lurbinectedin's most frequent adverse event was death (ROR: 6.11%, 95% CI: 4.86-7.68), while extravasation exhibited the strongest signal intensity in the ROR algorithm (ROR: 326.37%, 95% CI: 191.66-555.75). Notably, we identified a novel signals: tumor lysis syndrome (ROR: 63.22%, 95% CI: 33.87-117.99). The mean time of onset of AEs was 66 days, the median time of onset was 25days (interquartile range: 8-64days), and most AEs occurred within the first month of lurbinectedin treatment. Conclusion: Our study provided a comprehensive evaluation of lurbinectedin's safety profile in the post-marketing setting. In addition to the adverse events consistent with the existing clinical trials and labeling information, we have also identified an unreported signal related to tumor lysis syndrome. This finding will better guide the clinical practice of lurbinectedin and provide valuable evidence for future research.

How routine pharmacovigilance failed to identify finasteride's persistent sexual side effects.

How routine pharmacovigilance failed to identify finasteride's persistent sexual side effects.

Adverse Events Associated With the Use of Sipuleucel-T Reported to the US Food and Drug Administration’s Adverse Event Reporting System, 2010-2017

Sipuleucel-T was the first therapeutic cancer vaccine approved by the US Food and Drug Administration (FDA) in 2010. Although almost a decade has passed since its approval for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC), there remains a paucity of literature describing safety data in the postmarketing period. To describe the postmarketing safety experience for sipuleucel-T. In this case series study, US reports for sipuleucel-T submitted to the FDA's Adverse Event Reporting System were searched and reviewed between April 29, 2010, and December 31, 2017. This system is a spontaneous safety surveillance database for drug and therapeutic biologic products. The analysis of 3216 reports and select case reviews were undertaken between February and November 2018. Descriptive statistics were used to assess adverse event reports for sipuleucel-T. Empirical Bayes Geometric Means (EBGM) and their 90% confidence intervals (CIs) were computed to identify disproportionate (ie, at least twice the expected) reporting of sipuleucel-T-event pairs. Selected adverse events and death reports were individually reviewed. In total, 3216 reports were identified for sipuleucel-T, of which 2014 (62.6%) were serious. For all included reports, the patients' median (interquartile range) age was 73 (67-79) years, and 3149 were specified to be males. Chills (n = 318), malaise (n = 196), pyrexia (n = 189), culture positive (n = 184), fatigue (n = 180), and nausea (n = 173) were among the most commonly reported adverse events. Infusion-related reactions (EBGM, 12.1; 90% CI, 9.4-15.3), infections, vascular events, and transient ischemic attacks (EBGM, 2.9; 90% CI, 2.2-3.9) were reported disproportionately. Among 249 deaths for which relevant dates were available, 128 (51.4%) were reported within 30 days of a sipuleucel-T infusion, of which 81.2% included a specified cause of death; of these 104 deaths, there were 37 neoplasms (35.6%), 25 cardiac disorders (24.0%), 18 nervous system disorders (17.3%), and 9 infections (8.7%). Reported adverse events were generally consistent with the safety experience observed in prelicensure studies and described in the sipuleucel-T package insert. Off-label use among overtly symptomatic men with CRPC, reporting bias, or lack of product effectiveness may have influenced the reporting of deaths within 30 days of treatment initiation. With this overview of sipuleucel-T experience, the present study serves as a resource for health care professionals and patients as they weigh the risks and benefits of treatment in the context of all available therapeutic options for CRPC.

Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs.

Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia. To analyze serious adverse drug event reports about these impulse control disorders received by the US Food and Drug Administration (FDA) and to assess the relationship of these case reports with the 6 FDA-approved dopamine receptor agonist drugs. We conducted a retrospective disproportionality analysis based on the 2.7 million serious domestic and foreign adverse drug event reports from 2003 to 2012 extracted from the FDA Adverse Event Reporting System. Cases were selected if they contained any of 10 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) that described the abnormal behaviors. We used the proportional reporting ratio (PRR) to compare the proportion of target events to all serious events for the study drugs with a similar proportion for all other drugs. We identified 1580 events indicating impulse control disorders from the United States and 21 other countries:710 fordopamine receptor agonist drugs and 870 for other drugs. The dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR = 277.6, P < .001). The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001). Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with these specific impulse control disorders. At present, none of the dopamine receptor agonist drugs approved by the FDA have boxed warnings as part of their prescribing information. Our data, and data from prior studies, show the need for more prominent warnings.

Progressive multifocal leukoencephalopathy associated with efalizumab use in psoriasis patients

Progressive multifocal leukoencephalopathy (PML), a rare, potentially fatal demyelinating disease, affects primarily immunocompromised individuals. The Food and Drug Administration (FDA) received reports of PML associated with efalizumab (Raptiva), a biologic agent approved for psoriasis. In July 2009, efalizumab was voluntarily withdrawn from the US market because of the risk of PML. To describe 3 cases of PML in psoriasis patients treated with efalizumab. The FDA's Adverse Event Reporting System (AERS) database was searched for post-marketing reports of PML associated with biologic agents that are FDA approved for psoriasis (adalimumab, alefacept, efalizumab, etanercept, infliximab) from market approval to January 30, 2009. Twelve cases suggestive of PML were identified: adalimumab (1), efalizumab (4), etanercept (3), and infliximab (4). Efalizumab was the only drug with cases reporting PML in the setting of psoriasis. All cases of PML in efalizumab-treated patients presented 3 years or more after treatment initiation and resulted in death. Cases of PML in patients treated with adalimumab, etanercept, or infliximab occurred in patients treated for conditions other than psoriasis and were confounded by the use of other immunosuppressive therapies or were not confirmed PML cases. AERS data are limited because of an underreporting of spontaneous post-marketing adverse events and variable quality and quantity of information provided. These cases suggest that prolonged efalizumab therapy is a risk factor for PML. Although the cases reported treatment for longer than 3 years, a specific treatment duration that does not place patients at risk for PML has not been defined.

Statins and Interstitial Lung Disease: A Systematic Review of the Literature and of Food and Drug Administration Adverse Event Reports

Objective To systematically review all published case reports and the US Food and Drug Administration adverse event reporting (FDA-AER) database to examine the relationship between statins and interstitial lung disease (ILD). Data sources PubMed (1987 to September 2007) and the FDA-AER database (as of June 2007) were searched for reports of ILD in which a statin was listed as a causative suspect. Review methods Two authors (one author for Pub Med cases and one for FDA-AER cases) independently abstracted patient data. Given the paucity of information, all case reports and case series in English and French were included. All adverse event reports from the FDA-AER database in which a statin was listed as causative suspect were included. Results The literature search using PubMed yielded eight articles describing a total of 14 case reports of ILD in association with statin use. The FDA-AER system database contained 162 cases of reported statin-induced ILD as of June 2007. For every 10,000 reports of a statin-associated adverse event, approximately 1 to 40 reports were for ILD. Conclusions Statin-induced ILD is a possible newly recognized side effect of statin therapy. The mechanism of lung injury is not defined. The current review provides novel information from the FDA-AER that supports a possible, although unusual, pulmonary class effect of statins. To systematically review all published case reports and the US Food and Drug Administration adverse event reporting (FDA-AER) database to examine the relationship between statins and interstitial lung disease (ILD). PubMed (1987 to September 2007) and the FDA-AER database (as of June 2007) were searched for reports of ILD in which a statin was listed as a causative suspect. Two authors (one author for Pub Med cases and one for FDA-AER cases) independently abstracted patient data. Given the paucity of information, all case reports and case series in English and French were included. All adverse event reports from the FDA-AER database in which a statin was listed as causative suspect were included. The literature search using PubMed yielded eight articles describing a total of 14 case reports of ILD in association with statin use. The FDA-AER system database contained 162 cases of reported statin-induced ILD as of June 2007. For every 10,000 reports of a statin-associated adverse event, approximately 1 to 40 reports were for ILD. Statin-induced ILD is a possible newly recognized side effect of statin therapy. The mechanism of lung injury is not defined. The current review provides novel information from the FDA-AER that supports a possible, although unusual, pulmonary class effect of statins.

Bleeding Complications With Warfarin Use

Warfarin sodium is widely used and causes bleeding; a review might suggest the need for regulatory action by the US Food and Drug Administration (FDA). We accessed warfarin prescriptions from the National Prescription Audit Plus database of IMS Health (Plymouth Meeting, Pennsylvania), adverse event reports submitted to the FDA, deaths due to therapeutic use of anticoagulants from vital statistics data, and warfarin bleeding complications from national hospital emergency department data. The number of dispensed outpatient prescriptions for warfarin increased 45%, from 21 million in 1998 to nearly 31 million in 2004. The FDA's Adverse Event Reporting System indicated that warfarin is among the top 10 drugs with the largest number of serious adverse event reports submitted during the 1990 and 2000 decades. From US death certificates, anticoagulants ranked first in 2003 and 2004 in the number of total mentions of deaths for drugs causing "adverse effects in therapeutic use." Data from hospital emergency departments for 1999 through 2003 indicated that warfarin was associated with about 29 000 visits for bleeding complications per year, and it was among the drugs with the most visits. These data are consistent with literature reports of major bleeding frequencies for warfarin as high as 10% to 16%. Use of warfarin has increased, and bleeding from warfarin use is a prevalent reaction and an important cause of mortality. Consequently, a "black box" warning about warfarin's bleeding risk was added to the US product labeling in 2006. Physicians and nurses should tell patients to immediately report signs and symptoms of bleeding. A Medication Guide, which is required to be provided with each prescription, reinforces this message.

Analysis of Severe Adverse Events Related to the Use of Mifepristone as an Abortifacient

The systematic analysis of morbidity and mortality for the Food and Drug Administration (FDA)-approved medical abortion regimen using mifepristone is possible using data from the FDA's Adverse Event Reporting System. To assess mifepristone's mortality, morbidity, sentinel events, and quality of postmarketing surveillance using mifepristone adverse event reports (AERs). Six hundred seven unique mifepristone AERs submitted to the FDA over a 4 year span were coded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. Coding was based only on data in AERs and may underestimate severity and treatment rendered. Two board-certified obstetrician/gynecologists, the authors, made individual evaluations, compared them, and agreed upon final coding. The most frequent AERs were hemorrhage (n = 237) and infection (66). Hemorrhages included 1 fatal, 42 life threatening, and 168 serious cases; 68 required transfusions. Infections included 7 cases of septic shock (3 fatal, 4 life threatening) and 43 cases requiring parenteral antibiotics. Surgical interventions were required in 513 cases (235 emergent, 278 nonemergent). Emergent cases included 17 ectopic pregnancies (11 ruptured). Second trimester viability was documented in 22 cases (9 lost to follow-up, 13 documented fetal outcome). Of the 13 documented cases, 9 were terminated without comment on fetal morphology, 1 was enrolled in fetal registry, and 3 fetuses were diagnosed with serious malformations, suggesting a malformation rate of 23%. Hemorrhage and infection are the leading causes of mifepristone-related morbidity and mortality. AERs relied upon by the FDA to monitor mifepristone's postmarketing safety are grossly deficient due to extremely poor quality.

An analysis of reports of depression and suicide in patients treated with isotretinoin

Background: The Food and Drug Administration (FDA) has received reports of depression and suicide in patients treated with isotretinoin. Objective: Our purpose was to provide the number and describe the cases of depression and suicide reported to the FDA in US patients treated with isotretinoin and to consider the nature of a possible association between isotretinoin and depression. Methods: An analysis was made of reports of depression, suicidal ideation, suicide attempt, and suicide in US isotretinoin users voluntarily submitted to the manufacturer and the FDA from 1982 to May 2000 and entered in the FDA's Adverse Event Reporting System database. Results: From marketing of isotretinoin in 1982 to May 2000, the FDA received reports of 37 US patients treated with isotretinoin who committed suicide; 110 who were hospitalized for depression, suicidal ideation, or suicide attempt; and 284 with nonhospitalized depression, for a total of 431 patients. Factors suggesting a possible association between isotretinoin and depression include a temporal association between use of the drug and depression, positive dechallenges (often with psychiatric treatment), positive rechallenges, and possible biologic plausibility. Compared with all drugs in the FDA's Adverse Event Reporting System database to June 2000, isotretinoin ranked within the top 10 for number of reports of depression and suicide attempt. Conclusion: The FDA has received reports of depression, suicidal ideation, suicide attempt, and suicide in patients treated with isotretinoin. Additional studies are needed to determine whether isotretinoin causes depression and to identify susceptible persons. In the meantime, physicians are advised to inform patients prescribed isotretinoin (and parents, if appropriate) of the possibility of development or worsening of depression. They should advise patients (and parents) to immediately report mood swings and symptoms suggestive of depression such as sadness, crying, loss of appetite, unusual fatigue, withdrawal, and inability to concentrate so that patients can be promptly evaluated for appropriate treatment, including consideration of drug discontinuation and referral for psychiatric care. (J Am Acad Dermatol 2001;45:515-9.)