Background:An association between certain immunomodulatory therapies (rituximab, ipilimumab, and other immune checkpoint inhibitors) and inflammatory (non-ischemic and non-infectious) colitis in oncologic and non-oncologic patient populations is well documented in the medical literature.Objective:The purpose of this case series is to describe adverse event reports of new onset, inflammatory colitis in association with ocrelizumab in patients with multiple sclerosis submitted to U.S. Food and Drug Administration (FDA) or published in the medical literature.Methods:The FDA Adverse Event Reporting System (FAERS) and medical literature were searched.Results:A review of postmarketing cases from FAERS and published medical literature identified 38 cases consistent with inflammatory, non-ischemic, and non-infectious colitis in association with ocrelizumab. The median time-to-onset was 8 months. Cases were reported using the following diagnostic terms: Crohn's disease (13), unspecified colitis (11), microscopic colitis (5), ulcerative colitis (5), medication-induced colitis (3), and autoimmune colitis (2).Conclusions:This case series highlights ocrelizumab induced immune-mediated colitis that can be clinically severe and potentially life-threatening. Based on the findings of this review, the ocrelizumab Prescribing Information was amended to include immune-mediated colitis in the Warnings and Precautions section.

The US Food and Drug Administration's (FDA's) routine postmarketing drug safety monitoring may lead to safety-related labeling changes for identified risks. Additionally, the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA) require the FDA to conduct postmarket pediatric-focused safety reviews of adverse events. The purpose of these pediatric reviews is to identify risks associated with drug or biological products 18 months after the FDA approves a pediatric labeling change pursuant to studies conducted under the BPCA or PREA. These reviews are presented to the FDA Pediatric Advisory Committee (PAC) or publicly posted on FDA's website. The aim of this study was to evaluate the impact of pediatric reviews prompted by BPCA/PREA from October 1, 2013, to September 30, 2019. The impact was quantified by the number of new safety signals identified and the subsequent safety-related labeling changes resulting from pediatric reviews relative to safety-related labeling changes triggered by other data sources. Among 163 products with at least one pediatric review completed, a new safety signal that resulted in a safety-related labeling change was found for 5 of these products (representing 3 active ingredients); none described risks specific to the pediatric population. Between October 2013 and September 2021, there were 585 safety-related labeling changes implemented for products with at least one completed pediatric review. Less than 1% of 585 safety-related labeling changes were the result of a mandated pediatric review. Our study suggests that mandated pediatric reviews conducted 18 months after a pediatric labeling change provided minimal value over other postmarket safety surveillance activities.

A drug’s risk profile is not fully delineated at regulatory approval as rare adverse drug reactions (ADRs) may be undetected during clinical trials and populations at risk are often unknown. ADRs may resemble natural disease and are challenging to recognize. In clinical practice, understanding ADR characterizations and mechanisms can facilitate detection, assessment, treatment and prevention. ADR monitoring and clinical assessment by prescribers and researchers can generate drug safety signals and suggest a new, potentially causal association between a drug and an adverse event (AE). Pharmacovigilance systems are designed to detect ADRs and surveillance tools including AE report data, published scientific literature, and preclinical, clinical, and pharmacologic knowledge of the drug are used to provide scientific and clinical evaluation of the safety signal. These evaluations can lead to regulatory actions such as revising the drug’s labeling and communicating new information on drug risks and benefits to alert prescribers and patients.

Purpose/Background Acute hyperkinetic movement disorders have been reported with the concomitant use of attention-deficit/hyperactivity disorder (ADHD) stimulants and antipsychotics in children and adolescents. We analyzed postmarketing reports of suspected acute hyperkinetic movement disorder associated with concomitant use of ADHD stimulants and antipsychotics. Methods/Procedures We searched for postmarketing reports of acute hyperkinetic movement disorders associated with concomitant use of ADHD stimulants-antipsychotics in the US Food and Drug Administration Adverse Event Reporting System through December 6, 2019. PubMed and EMBASE were also searched for acute hyperkinetic movement reports with the concomitant use of ADHD stimulants-antipsychotics through January 13, 2020. Findings/Results We identified 36 cases resulting in acute hyperkinetic movement disorder associated with the concomitant use of ADHD stimulants-antipsychotics, 19 of which were also identified in the medical literature. From an ADHD stimulant perspective, methylphenidate products accounted for the largest number of cases (n = 23 [64%]), followed by amphetamine products (n = 9 [25%]) and atomoxetine (n = 4 [11%]). From an antipsychotic perspective, all 36 cases were reported with second-generation antipsychotics, particularly risperidone (n = 20 [56%]). Most of the cases were reported in boys (n = 31 [86%]) aged 6 to 12 years (n = 27 [75%]). Approximately 53% of the cases reported a time to onset within 24 hours of the drug change. Acute dystonic reactions (n = 27 [75%]) were the most frequently reported movement disorder. Implications/Conclusions As outlined in changes to the US prescribing information for all methylphenidate and risperidone products, health care professionals should be aware that changes to this combination may be associated with a pharmacodynamic drug-drug interaction resulting in acute hyperkinetic movement disorder.

Postmarket surveillance is critical for the identification of rare safety risks, which are unlikely to be identified during clinical trials and the drug development program. Rare adverse drug reactions with the potential for serious outcomes, including fatalities, include the severe cutaneous adverse reactions of Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Dermatologists play an important role in the diagnosis of these serious drug reactions and contribute to drug safety by reporting cases of suspected cutaneous adverse drug reactions.

The US Food and Drug Administration Adverse Event Reporting System (FAERS) contains over 24 million individual case safety reports (ICSRs). In this research project, we evaluated a natural language processing (NLP) tool’s ability to extract four demographic variables (gender, weight, ethnicity, race) from ICSR narratives. Specificity of the NLP algorithm was over 94% for all demographics, while sensitivity varied between the demographics: 98.6% (gender), 45.5% (weight), 100% (ethnicity), and 85.3% (race). Among ICSRs missing weight, ethnicity, and race in the structured field, few cases had this information in the narrative (>95% missing); consequently, the positive predictive value (PPV) for these three demographics had wide 95% confidence intervals. After NLP implementation, the total number of ICSRs missing gender was reduced by 33% (i.e., NLP identified 472 thousand reports having a gender value in the narrative that was not in the structured field), while the total number of ICSRs missing weight, ethnicity, or race was reduced by less than 4%. This study demonstrated that the implementation of an NLP tool can provide meaningful improvements in the availability of gender information for pharmacovigilance activities conducted with FAERS data. In contrast, NLP tools targeting the extraction of weight, ethnicity, or race from free-text fields have minimal impact largely because the information was infrequently provided by the reporter. Further gains in completeness of these fields must originate from increases in provision of demographic information from the reporter rather than informatic solutions.

This case series identifies cases reported in the US Food and Drug Administration Adverse Event Reporting System of acute cholecystitis associated with use of glucagon-like peptide-1 receptor agonists that did not have gallbladder disease warnings in their labeling.

INTRODUCTION:Missing age presents a significant challenge when evaluating individual case safety reports (ICSRs) in the FDA Adverse Event Reporting System (FAERS). When age is missing in an ICSR's structured field, it may be in the report's free-text narrative. OBJECTIVES:This study aimed to evaluate the performance and assess the potential impact of a rule-based natural language processing (NLP) tool that utilizes a text string search to identify patients' numerical age from unstructured narratives. METHODS:Using FAERS ICSRs from 2002 to 2018, we evaluated the annual proportion of ICSRs with age missing in the structured field before and after NLP application. Reviewers manually identified patients' age from ICSR narratives (gold standard) from a random sample of 1500 ICSRs. The gold standard was compared to the NLP-identified age. RESULTS:During the study period, the percentage of ICSRs missing age in the structured field increased from 21.9 to 43.8%. The NLP tool performed well among the random sample: sensitivity 98.5%, specificity 92.9%, positive predictive value (PPV) 94.9%, and F-measure 96.7%. It also performed well for the subset of ICSRs missing age in the structured field; when applied to these cases, NLP identified age for an additional one million ICSRs (10% of the total number of ICSRs from 2002 to 2018) and decreased the percentage of ICSRs missing age to 27% overall. CONCLUSIONS:NLP has potential utility to extract patients' age from ICSR narratives. Use of this tool would enhance pharmacovigilance and research using FAERS data.

Background: Only progressive multifocal leukoencephalopathy (PML) is currently described in the dimethyl fumarate (DMF) prescribing information. Objectives: To describe opportunistic infections (OIs), other than PML, reported in association with DMF. Methods: The FDA Adverse Event Reporting System (FAERS) and medical literature were searched. Results: We retrieved 34 cases of serious OIs with a causal association with DMF, including 11 central nervous system (CNS) infections and 23 extra-CNS infections. Six OIs occurred with normal circulating absolute lymphocyte counts. The median latency from DMF initiation was 13 months and was variable. Conclusion: DMF is associated with the development of OIs that require invasive diagnostic and/or therapeutic procedures. Patients should be monitored for OIs when treated with DMF regardless of circulating absolute lymphocyte counts.

Objective To identify and analyze postmarketing case reports of elevated blood pressure (BP) associated with erenumab use. Methods A retrospective analysis of postmarketing (spontaneous) case reports of erenumab-associated elevated BP submitted to the FDA Adverse Event Reporting System from May 17, 2018 through April 30, 2020. A case of elevated BP was defined as (a) an initiation of a pharmacological intervention or emergency department visit or hospitalization for emergent de novo or worsening of preexisting hypertension, or (b) BP measurement of >= 140 mm Hg systolic or >= 90 mm Hg diastolic with or without baseline BP measurement reported. Reports of elevated BP associated with erenumab use were analyzed for baseline and demographic information, latency, drug-event causal association, and clinical outcome. Results Sixty-one cases of elevated BP were identified, 86% (49/57) were women and the median age was 56 [range 24-88] years. Forty-one cases were associated with a serious outcome per regulatory criteria, including seven that specified hospitalization. No case reported an outcome of death. The median systolic BP increase was 39 (interquartile range (IQR) 32, 59) mm Hg and median diastolic BP increase was 28 (IQR 18, 41) mm Hg. A total of 27/61 (44%) cases reported treatment for elevated BP (i.e., pharmacologic intervention or emergency department visit/hospitalization). Elevated BP occurred most frequently (28/61, 46%) within a week of the first dose of erenumab. Nineteen cases (19/61, 31%) reported a history of preexisting hypertension. Conclusions This case series suggest an association between elevated BP and use of erenumab. In light of our findings, the erenumab (Aimovig) prescribing information was amended to include hypertension in the Warnings and Precautions section.

Background: Tumefactive multiple sclerosis (TMS) is a rare multiple sclerosis (MS) form that usually manifests as the initial presentation or in the early stages of MS. Objective: The aim of this study is to evaluate reports of TMS associated with fingolimod use. Methods: The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and the medical literature were searched for cases of TMS occurring during or after fingolimod treatment. Results: We identified 29 TMS cases, 19 following fingolimod initiation and 10 following fingolimod discontinuation. In these cases, a TMS diagnosis occurred at a median of 7 years after MS diagnosis, and a median of 7 and 3 months following initiation and discontinuation of fingolimod, respectively. Twenty-two cases were assessed as possible and seven as probable from a causal association perspective. A much larger crude number of TMS reports was observed for fingolimod compared to other disease-modifying therapies. Conclusion: TMS should be considered when a severe or atypical MS relapse occurs shortly after fingolimod initiation or discontinuation, and should prompt imaging evaluation and appropriate treatment initiation. Prescribers' awareness of the association between TMS and fingolimod may avoid unnecessary diagnostic procedures. In light of our findings, fingolimod (Gilenya) prescribing information was amended to include TMS in the Warnings and Precautions section.

The rapidly expanding size of the Food and Drug Administration’s (FDA) Adverse Event Reporting System database requires modernized pharmacovigilance practices. Techniques to systematically identify high utility individual case safety reports (ICSRs) will support safety signal management. The aim of this study was to develop and validate a model predictive of an ICSR’s pharmacovigilance utility (PVU). PVU was operationalized as an ICSR’s inclusion in an FDA-authored pharmacovigilance review’s case series supporting a recommendation to modify product labeling. Multivariable logistic regression models were used to examine the association between PVU and ICSR features. The best performing model was selected for bootstrapping validation. As a sensitivity analysis, we evaluated the model’s performance across subgroups of safety issues. We identified 10,381 ICSRs evaluated in 69 pharmacovigilance reviews, of which 2115 ICSRs were included in a case series. The strongest predictors of ICSR inclusion were reporting of a designated medical event (odds ratio (OR) 1.93, 95% CI 1.54–2.43) and positive dechallenge (OR 1.67, 95% CI 1.50–1.87). The strongest predictors of ICSR exclusion were death reported as the only outcome (OR 2.72, 95% CI 1.76–4.35), more than three suspect products (OR 2.69, 95% CI 2.23–3.24), and > 15 preferred terms reported (OR 2.69, 95% CI 1.90–3.82). The validated model showed modest discriminative ability (C-statistic of 0.71). Our sensitivity analysis demonstrated heterogeneity in model performance by safety issue (C-statistic range 0.58–0.74). Our model demonstrated the feasibility of developing a tool predictive of ICSR utility. The model’s modest discriminative ability highlights opportunities for further enhancement and suggests algorithms tailored to safety issues may be beneficial.

INTRODUCTION:Adverse reactions with an outcome of death are inherently important for pharmacovigilance organizations to evaluate. Prior efforts to systematically evaluate individual case safety reports (ICSRs) with an outcome of death have been limited to high-level summaries.OBJECTIVE:The aim of this study was to characterize ICSRs with an outcome of death contained in the US FDA Adverse Event Reporting System (FAERS) database.METHODS:All ICSRs received through 31 December 2017 reporting an outcome of death were characterized by patient demographics, suspect product(s), adverse events, and reporter type. Using the ICSR's narrative and reporter information, we classified ICSRs by source to include those from industry-sponsored programs, poison control centers, specialty pharmacies, and litigation. Additionally, a random sample of ICSRs was evaluated for completeness of structured data fields and manually reviewed for the availability of key information in the narrative (i.e. cause of death, medical history, and causality assessment).RESULTS:Overall, 1,053,716 ICSRs with a death outcome were received in the study period. Ten medications treating conditions for malignancies, pain, and kidney disease accounted for nearly 20% of all fatal ICSRs. ICSRs originating from industry-sponsored programs, poison control centers, litigation, and specialty pharmacies accounted for 14%, 6.5%, 5.0%, and 3.3% of all fatal ICSRs, respectively. ICSRs in which the only adverse event coded was 'death' were more likely to be missing structured data and less likely to include key information in the narrative.CONCLUSION:Understanding the origins and characteristics of ICSRs with an outcome of death supports meaningful evaluations and interpretations of FAERS data. A wide variability in ICSR quality exists, even in those reports with the most serious outcome.

Objective To describe adverse event reports of hemophagocytic lymphohistiocytosis (HLH) reported in association with lamotrigine. Methods The Food and Drug Administration Adverse Event Reporting System database of spontaneous adverse event reports and medical literature databases were searched for cases of HLH reported in association with lamotrigine. Cases were included if they met the case definition of suspected or confirmed HLH and if causal association was assessed as robust or supportive. Results Eight cases met the case definition for HLH and were deemed causally associated with lamotrigine. These 8 cases of HLH had a plausible temporal relationship because they occurred within a 24-day interval from lamotrigine initiation. The doses ranged from 25 mg every other day to 250 mg once daily in the 6 cases that reported this information. Seven patients improved with drug discontinuation and one patient died after drug discontinuation and receiving an unspecified chemotherapy. Conclusions Lamotrigine is associated with immune-related adverse reactions including HLH. HLH is a potentially fatal event; prompt recognition and early therapeutic intervention to mitigate the event is important in improving patient outcomes.

4.5% to 10.4%; interstitial cystitis had the highest use among all the disorders analyzed [Figure].Pharmacy claims for opioids most commonly followed visits to primary care providers (PCPs) (23-58%), accounting for nearly one-third of opioid prescriptions, irrespective of the type of disorder, followed by gastroenterologist (GE) visits (8-40%) for GI disorders [Table].Conclusions: PCPs represented the most common provider type of opioids for the majority of the disorders analyzed; GEs were the second leading provider type for 6 of the 9 painful GI disorders.This database analysis is limited as it cannot absolutely identify the opioid prescriber or duration and reasons for opioid use.Writing assistance by Complete HealthVizion.