Immune-mediated colitis associated with ocrelizumab: A new safety risk.

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.

Acute Hyperkinetic Movement Disorders as a Multifactorial Pharmacodynamic Drug Interaction Between Methylphenidate and Risperidone in Children and Adolescents.

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.

Tumefactive multiple sclerosis in association with fingolimod initiation and discontinuation.

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.

Expanding spectrum of opportunistic infections associated with dimethyl fumarate.

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.

Hypertension: A new safety risk for patients treated with erenumab.

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.

Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases.

Background: Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors has been associated with Fournier gangrene (FG), a rare urologic emergency characterized by necrotizing infection of the external genitalia, perineum, and perianal region. Objective: To describe and compare reported cases of FG in diabetic adults receiving treatment with SGLT2 inhibitors or other antiglycemic agents. Design: Descriptive case series. Setting: U.S. Food and Drug Administration (FDA) Adverse Event Reporting System and published case reports. Patients: Adults receiving SGLT2 inhibitors or other antiglycemic agents. Measurements: Clinical and laboratory data. Results: The FDA identified 55 unique cases of FG in patients receiving SGLT2 inhibitors between 1 March 2013 and 31 January 2019. The patients ranged in age from 33 to 87 years; 39 were men, and 16 were women. Time to onset after initiation of SGLT2-inhibitor therapy ranged from 5 days to 49 months. All patients had surgical debridement and were severely ill. Reported complications included diabetic ketoacidosis (n = 8), sepsis or septic shock (n = 9), and acute kidney injury (n = 4). Eight patients had fecal diversion surgery, 2 patients developed necrotizing fasciitis of a lower extremity that required amputation, and 1 patient required a lower-extremity bypass procedure because of gangrenous toes. Three patients died. For comparison, the FDA identified 19 FG cases associated with other antiglycemic agents between 1984 and 31 January 2019: metformin (n = 8), insulin glargine (n = 6), short-acting insulin (n = 2), sitagliptin plus metformin (n = 2), and dulaglutide (n = 1). These patients ranged in age from 42 to 79 years; 12 were men, and 7 were women. Two patients died. Limitation: Inability to establish causality or incidence, variable quality of reports, possible underreporting, and confounding by indication. Conclusion: FG is a newly identified safety concern in patients receiving SGLT2 inhibitors. Physicians prescribing these agents should be aware of this possible complication and have a high index of suspicion to recognize it in its early stages. Primary Funding Source: None.

Liver injury associated with dimethyl fumarate in multiple sclerosis patients.

BACKGROUND: In pre-approval trials, there was an increased incidence of mild, transient elevations of liver aminotransferases in study subjects treated with dimethyl fumarate (DMF). OBJECTIVE/METHODS: To evaluate post-marketing cases of drug-induced liver injury associated with DMF. RESULTS: We identified 14 post-marketing cases of clinically significant liver injury. Findings included newly elevated serum liver aminotransferase and bilirubin levels that developed as early as a few days after the first dose of DMF. The pattern of liver injury was primarily hepatocellular. No cases resulted in liver failure. CONCLUSION: Health professionals should be alerted to possible serious liver injury in patients receiving DMF.

Adverse event detection using the FDA post-marketing drug safety surveillance system: Cardiotoxicity associated with loperamide abuse and misuse.

OBJECTIVE: The purpose of this investigation was to identify and characterize post-marketing reports of cardiotoxicity, including torsades de pointes (TdP), associated with loperamide use. METHODS: We searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database for post-marketing reports of serious cardiac adverse events associated with loperamide use from December 28, 1976 (U.S. drug approval date), through December 14, 2015. We also conducted a Pubmed and Google Scholar search to identify additional published reports of cardiotoxicity associated with loperamide in the medical literature through February 11, 2016. RESULTS: Forty-eight cases of serious cardiac adverse events associated with loperamide use composed the case series. The most frequently reported cardiac adverse events were syncope (n = 24), cardiac arrest (n = 13), QT-interval prolongation (n = 13), ventricular tachycardia (n = 10), and TdP (n = 7). There were 10 cases that resulted in death. Of the 48 cases, the most commonly reported reasons for use can be characterized as drug abuse (n = 22) and diarrhea treatment (n = 17). More than one-half of the 48 cases were reported after 2010. Of the 22 drug abuse cases, the median daily dose was 250 mg (range 70 mg to 1600 mg) and events occurred as early as 6 hours after a dose and as long as 18 months after initiation of loperamide. Thirteen of the 22 cases reported using loperamide for euphoric or analgesic effects, and 9 reported use to prevent opioid withdrawal symptoms. CONCLUSION: The FAERS case reports provide evidence to suggest that high doses of loperamide are associated with TdP and other serious cardiac adverse events. The majority of cases in this series occurred in the setting of drug abuse for the purpose of preventing opioid withdrawal or to produce euphoric effects. It is important for both clinicians and patients to be aware of this potential risk, because prompt therapy and discontinuation of the offending agent are often essential to management and prevention of loperamide-induced cardiac arrhythmias.

Progressive multifocal leukoencephalopathy after natalizumab discontinuation.

OBJECTIVE: To identify cases of laboratory- or biopsy-confirmed progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) who previously discontinued natalizumab (NTZ) for reasons unrelated to suspected or proven PML and assess PML risk factors in these cases. METHODS: We searched the US Food and Drug Administration Adverse Event Reporting System and MEDLINE for reports submitted from 2006 to 2012 of laboratory-confirmed PML with symptom onset ≥30 days following NTZ withdrawal. We only analyzed cases where NTZ discontinuation was unrelated to suspected PML. RESULTS: Seventeen patients discontinued NTZ for reasons unrelated to PML but were subsequently diagnosed with the disease. The median NTZ duration was 47 monthly doses (range = 9-59 doses). All patients presented with compatible clinical symptoms within 6 months following withdrawal, and PML was confirmed by brain biopsy or by identifying JC virus in the cerebrospinal fluid by polymerase chain reaction. Immune reconstitution inflammatory syndrome (IRIS) was reported in 11 patients. Eleven patients (65%) received new MS treatments between NTZ discontinuation and PML confirmation. No deaths were reported. At NTZ withdrawal, 16 patients (94%) had ≥1 PML risk factor, including NTZ duration ≥2 years (n = 13), prior immunosuppressive agents (n = 8), and reported anti-JC virus seropositivity (n = 13). INTERPRETATION: NTZ-treated patients presenting clinically with PML within 6 months after NTZ withdrawal frequently have pre-existing PML risk factors. Clinicians need heightened awareness for new onset PML, IRIS, and MS relapse in evaluating neurological decline following NTZ discontinuation. Ann Neurol 2014;75:108-115.

Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients.

We report on 20 natalizumab-treated patients with multiple sclerosis who developed laboratory-confirmed central nervous system (CNS) herpesvirus infections. In addition to progressive multifocal leukoencephalopathy, other CNS opportunistic infections have been rarely reported during natalizumab treatment. We encourage heightened awareness due to the risk for serious outcomes.

Assessment of the Impact of Mandated Postmarketing Pediatric-Focused Safety Reviews on Safety-Related Regulatory Actions 2013-2019.

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.

Postmarket Assessment for Drugs and Biologics Used in Dermatology and Cutaneous Adverse Drug Reactions.

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.

Leveraging Case Narratives to Enhance Patient Age Ascertainment from Adverse Event Reports.

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.

Towards Automating Adverse Event Review: A Prediction Model for Case Report Utility.

INTRODUCTION: 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. OBJECTIVES: The aim of this study was to develop and validate a model predictive of an ICSR's pharmacovigilance utility (PVU). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

An Evaluation of Postmarketing Reports with an Outcome of Death in the US FDA Adverse Event Reporting System.

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.

Hemophagocytic lymphohistiocytosis associated with the use of lamotrigine.

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.

Evaluation of Postmarketing Reports from Industry-Sponsored Programs in Drug Safety Surveillance.

INTRODUCTION AND OBJECTIVE: Adverse event reports from industry-sponsored programs, such as patient support programs, have contributed to a rise in the number of individual case safety reports in the US Food and Drug Administration Adverse Event Reporting System database. This study aimed to characterize individual case safety reports from industry-sponsored program and non-industry-sponsored program sources and compare their usefulness in safety signal detection. METHODS: Individual case safety reports of six drug and biological products were identified in the Food and Drug Administration Adverse Event Reporting System database between the date of Food and Drug Administration product approval and the first quarter of 2017. A random subset of industry-sponsored program and non-industry-sponsored program individual case safety reports were then compared to identify differences in reporters, outcomes, data completeness, and usefulness. The 'usefulness' of individual case safety reports was assessed by manually reviewing the availability of key information in the narrative (e.g., temporality, comorbidities). RESULTS: Compared with non-industry-sponsored program reports, more industry-sponsored program reports were associated with a serious outcome (51.4% vs. 58.8%, p = 0.02) and were reported by consumers (35.5% vs. 50.4%, p < 0.01). Industry-sponsored program reports tended to contain more data elements than non-industry-sponsored program reports (i.e., age, sex, indication for use), but completeness was variable across products. No significant difference in usefulness was identified between non-industry-sponsored program and industry-sponsored program individual case safety reports (30.6% vs. 28.5%, p = 0.42). Useful reports that contained at least one serious, unlabeled adverse event represented only 4% and 6.2% of the non-industry-sponsored program and industry-sponsored program report cohorts, respectively. CONCLUSIONS: Our study suggests that reports obtained from industry-sponsored programs in the Food and Drug Administration Adverse Event Reporting System database contain more data elements but are similar to non-industry-sponsored program reports with regard to 'usefulness' in signal detection.