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.

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.

A case series analysis of serious exacerbations of viral hepatitis and non-viral hepatic injuries in tocilizumab-treated patients.

BACKGROUND AND AIMS: Reports of moderate to severe liver injury associated with tocilizumab, an interleukin-6 (IL-6) receptor antagonist, have been reported in the post-marketing setting. This case series aims to characterize cases of tocilizumab-associated clinically significant hepatic injury. METHODS: We analysed cases of severe acute liver injury associated with tocilizumab reported in the FDA Adverse Event Reporting System and the medical literature. RESULTS: We identified 12 cases in which tocilizumab was a suspected primary cause of liver injury and eight cases in which serious sequelae of underlying or coincident viral hepatitis were temporally associated with its use. Using the Drug-Induced Liver Injury Network (DILIN) severity scale, five of 12 cases were Grade 5 (two liver transplants, three deaths), one was Grade 4 (liver failure) and six were Grade 3 (serious events with elevated bilirubin). Two cases reported liver atrophy with low hepatocellular expression of Ki-67, a marker of cellular proliferation. Among the eight cases of tocilizumab-associated viral hepatitis exacerbation, three were scored as DILIN severity Grade 5 (one liver transplant, two deaths), one was Grade 4 (liver failure), and four were Grade 3. The reported viral hepatitis events were hepatitis B virus (HBV) reactivation (n = 3), hepatitis C virus (HCV) flare (n = 1), cytomegalovirus (CMV)-induced liver failure (n = 1), Epstein-Barr virus hepatitis (n = 1), acute hepatitis E (HEV, n = 1) and HEV-induced macrophage activation syndrome (n = 1). CONCLUSION: Tocilizumab may be a primary cause of severe liver injury, as well as exacerbate underlying viral hepatitis. The disruption by tocilizumab of IL-6-mediated immune protection and hepatocyte regeneration may aggravate clinical outcomes in some cases.

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.

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.

An Evaluation of Postmarketing Reports of Serious Idiosyncratic Liver Injury Associated with Ulipristal Acetate for the Treatment of Uterine Fibroids.

INTRODUCTION: Ulipristal acetate (ulipristal) is a selective progesterone receptor modulator that has been marketed for daily use in Europe and Canada to reduce symptoms caused by uterine fibroids. Long-term use of some other members of this class of 19-norprogesterone-derived agents has been associated with idiosyncratic hepatotoxicity. OBJECTIVE: We analyzed postmarketing reports of suspected drug-induced liver injury associated with the daily use of 5 mg of ulipristal to treat symptoms of uterine fibroids. METHODS: We searched for reports of serious liver injury associated with ulipristal, submitted to the US Food and Drug Administration through 31 January, 2020. Cases of liver injury temporally associated with long-term ulipristal exposure that reported combined increases of serum aminotransferases and bilirubin were individually assessed using a five-tier categorical scale of likelihood for a causal association with the drug by individuals with expertise in drug-induced liver injury evaluation. Individual cases that did not culminate in liver failure, death, or liver transplantation were also assessed for their causal association with ulipristal by the Roussel Uclaf Causality Assessment Method. RESULTS: We identified nine non-US cases that met the criteria for inclusion in our search for cases of serious liver injury associated with ulipristal. Five cases reported clinical outcomes of liver transplantation and/or death and all were assessed to have a probable causal association with ulipristal acetate. Evaluation of the other four cases reporting resolution of liver injury after treatment discontinuation revealed a possible or probable causal relationship with ulipristal. CONCLUSIONS: We identified postmarketing cases of serious acute drug-induced liver injury causally associated with ulipristal used to treat uterine fibroids, some with outcomes of liver transplant and/or death. The presence of common structural features identified with certain selective progesterone receptor modulators in the treatment of chronic conditions may indicate a liability for idiosyncratic drug-induced liver injury.

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.

Association of Noninfectious Pneumonia With Ustekinumab Use.

Importance: The US Food and Drug Administration (FDA) conducts ongoing public health safety surveillance for drug and therapeutic biologic products. Identifying cases of acute and subacute noninfectious pneumonia supports the public health mission of the FDA. Objective: To identify and analyze postmarketing cases of noninfectious pneumonia associated with ustekinumab use. Design, Setting, and Participants: This retrospective analysis of postmarketing (spontaneous) case reports reviewed the FDA Adverse Event Reporting System (FAERS) and the PubMed databases from September 25, 2009, through November 20, 2017. Twelve cases of new-onset acute and subacute noninfectious pneumonia were identified after general marketing of ustekinumab. Cases were excluded if the time to symptom onset was more than 2 years from ustekinumab initiation and if an alternative origin for the noninfectious pneumonia (other than drug-induced) was reported. Main Outcomes and Measures: Cases of noninfectious pneumonia associated with ustekinumab use were analyzed for baseline and demographic information, reason for ustekinumab use, symptoms, time to onset, dose sequence, laboratory and diagnostic information, and clinical outcome. Results: Of the 12 cases, 8 were identified from the FAERS database and 4 from PubMed. The 12 cases (7 men [58%] and 5 women [42%], with a median [range] age of 63 [27-80] years) included 7 interstitial pneumonia (58%), 3 eosinophilic pneumonia (25%), 1 organizing pneumonia (8%), and 1 hypersensitivity pneumonitis (8%) diagnoses. All 12 cases reported a serious outcome, including 7 hospitalizations (58%) and 1 respiratory failure requiring mechanical ventilation (8%). No outcome of death was reported. All 12 cases were supportive of a temporal association; specifically, in 9 cases (75%), the pulmonary symptoms appeared after 1 to 3 doses of ustekinumab. In addition, 7 cases (58%) of positive dechallenge were reported, including 1 case of a positive rechallenge. Conclusions and Relevance: The postmarketing cases suggest an association between noninfectious pneumonia and use of ustekinumab; these findings have led to the addition of a new warning for ustekinumab users regarding the risk of developing noninfectious pneumonia.

Acute acalculous cholecystitis: A new safety risk for patients with MS treated with alemtuzumab.

OBJECTIVE: To evaluate acute acalculous cholecystitis (AAC) as a potential safety risk for patients treated with alemtuzumab. METHODS: The Food and Drug Administration Adverse Event Reporting System and the medical literature were searched for cases of AAC in conjunction with alemtuzumab for all clinical indications. RESULTS: Eight spontaneously reported cases meeting the case definition of AAC in close temporal association with alemtuzumab use were identified. Based on established criteria within the Food and Drug Administration Division of Pharmacovigilance for causality assessment, 4 cases were assessed as probable while 4 were possible. All cases occurred in patients with relapsing-remitting multiple sclerosis. Seven of the 8 cases presented with AAC during or shortly after alemtuzumab treatment, thereby suggesting an acute cytokine release syndrome as a putative pathogenic mechanism. The cases identified in this review differ from the typical AAC cases described in the medical literature based on female preponderance, lack of concurrent critical illnesses, inconsistent presence of other risk factors, and resolution with conservative treatment in the majority of cases. CONCLUSIONS: AAC represents a new and potentially life-threatening adverse event associated with alemtuzumab use in relapsing-remitting multiple sclerosis. In cases seen to date, early and conservative treatment resulted in good clinical outcome, although the natural history of AAC in this population without critical illness is not well defined. Awareness of this safety risk by general and specialty neurologists is important for prompt recognition and optimal management.

Serious Liver Injury Associated with Macitentan: A Case Report.

Several endothelin receptor antagonists (ERAs) that were developed for the treatment of pulmonary arterial hypertension (PAH), including bosentan and sitaxentan, have been linked to clinically significant hepatocellular injury, as well as liver failure. We describe the first case of fulminant hepatitis to be reported in association with the ERA macitentan. This case was recently identified within the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and describes liver transplantation occurring 13 months after macitentan initiation in a young patient (23 years old) with idiopathic PAH New York Heart Association (NYHA) functional class III.

Etonogestrel implant migration to the vasculature, chest wall, and distant body sites: cases from a pharmacovigilance database.

OBJECTIVE: To describe clinical outcomes of etonogestrel implant patients with migration to the vasculature, chest wall and other distant body sites spontaneously reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. STUDY DESIGN: We performed a standardized Medical Dictionary for Regulatory Activities (MedDRA) query in the FAERS database (through November 15, 2015), with reports coded with one or more MedDRA preferred terms that indicate complications with device placement or migration of the device from the original site of insertion to the vasculature, chest wall and other distant body sites. We excluded any cases previously described in the medical literature. RESULTS: We identified 38 cases of pronounced etonogestrel implant migration. Migration locations included the lung/pulmonary artery (n=9), chest wall (n=1), vasculature at locations other than the lung/pulmonary artery (n=14) and extravascular migrations (n=14) to other body sites (e.g., the axilla and clavicle/neck line/shoulder). The majority of cases were asymptomatic and detected when the patient desired implant removal; however, seven cases reported symptoms such as pain, discomfort and dyspnea in association with implant migration. Three cases also describe pulmonary fibrosis and skin reactions as a result of implant migration to the vasculature, chest wall and other distant body sites. Sixteen cases reported surgical removal in an operating room setting. CONCLUSIONS: Our FAERS case series demonstrates etonogestrel implant migration to the vasculature, chest wall and other body sites distant from the site of original insertion. IMPLICATIONS STATEMENT: As noted by the sponsor in current prescribing information, a key determinant in the risk for etonogestrel contraceptive implant migration appears to be improper insertion technique. Although migration of etonogestrel implants to the vasculature is rare, awareness of migration and education on proper insertion technique may reduce the risk.

Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus: A Review of Cases Reported to the U.S. Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Direct-acting antiviral agents (DAAs) are used increasingly to treat hepatitis C virus (HCV) infection. Reports were published recently on hepatitis B virus (HBV) reactivation (HBV-R) in patients with HBV-HCV co-infection. Hepatitis B virus reactivation, defined as an abrupt increase in HBV replication in patients with inactive or resolved HBV infection, may result in clinically significant hepatitis. OBJECTIVE: To assess whether HBV-R is a safety concern in patients receiving HCV DAAs. DESIGN: Descriptive case series. SETTING: U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). PATIENTS: 29 patients with HBV-R receiving HCV DAAs. MEASUREMENTS: Clinical and laboratory data. RESULTS: The FDA identified 29 unique reports of HBV-R in patients receiving DAAs from 22 November 2013 to 15 October 2016. Two cases resulted in death and 1 case in liver transplantation. Patients in whom HBV-R developed were heterogeneous regarding HCV genotype, DAAs received, and baseline HBV characteristics. At baseline, 9 patients had a detectable HBV viral load, 7 had positive results on hepatitis B surface antigen (HBsAg) testing and had an undetectable HBV viral load, and 3 had negative results on HBsAg testing and had an undetectable HBV viral load. For the remaining 10 patients, data points were not reported or the data were uninterpretable. Despite provider knowledge of baseline HBV, HBV-R diagnosis and treatment were delayed in 7 cases and possibly 7 others. LIMITATIONS: The quality of information varied among reports. Because reporting is voluntary, HBV-R associated with DAAs likely is underreported. CONCLUSION: Hepatitis B virus reactivation is a newly identified safety concern in patients with HBV-HCV co-infection treated with DAAs. Patients with a history of HBV require clinical monitoring while receiving DAA therapy. Studies would help determine the risk factors for HBV-R, define monitoring frequency, and identify patients who may benefit from HBV prophylaxis and treatment. DAAs remain a safe and highly effective treatment for the management of HCV infection. PRIMARY FUNDING SOURCE: None.

Chemical Leukoderma Associated with Methylphenidate Transdermal System: Data From the US Food and Drug Administration Adverse Event Reporting System.

OBJECTIVE: To identify and characterize cases of chemical leukoderma, an underrecognized adverse event, associated with the methylphenidate transdermal system (MTS) reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS). STUDY DESIGN: We searched the Food and Drug Administration Adverse Event Reporting System for reports of chemical leukoderma associated with MTS, received by the Food and Drug Administration from April 6, 2006 to December 23, 2014. RESULTS: We identified 51 cases of chemical leukoderma reported with the use of MTS. The median age was 11 years; 43 cases reported leukoderma at or near the application site only, and 7 reported leukoderma at other parts of the body in addition to the application site; 1 case did not provide enough information to confirm the affected site. The time to onset ranged from 2 months to 4 years after the initiation of MTS. MTS was discontinued in 31 cases. Thirteen patients were prescribed treatment for repigmentation. Three cases reported continued spread of leukoderma after MTS was discontinued. Nineteen cases were diagnosed as vitiligo, including 5 cases reporting histologic features consistent with vitiligo. Leukoderma was persistent in all cases. The median follow-up interval after the discontinuation of MTS in 23 cases was 14 months. CONCLUSIONS: As outlined in recent changes to the prescribing information for MTS, health care professionals need to be aware of the potential risk of chemical leukoderma caused by MTS, especially given that chemical leukoderma is often misdiagnosed as idiopathic vitiligo. MTS should be discontinued at the earliest sign of pigment loss and other treatment options considered.

Profiling cumulative proportional reporting ratios of drug-induced liver injury in the FDA Adverse Event Reporting System (FAERS) database.

BACKGROUND: Early prediction and accurate characterization of risk for serious liver injury associated with newly marketed drugs remains an important challenge for clinicians, the pharmaceutical industry, and regulators. To date, a biomarker that specifically indicates exposure to a drug as the etiologic cause of liver injury has not been identified. OBJECTIVES: Using cumulative proportional reporting ratios (PRRs), we investigated 'real-time' profiles of a set of pharmaceuticals, over the first 3 years of US marketing, for the signaling of clinically serious drug-induced liver injury (DILI) in a large spontaneous-reporting database. METHODS: Using report counts of hepatic failure or clinically serious liver injury obtained from the FDA Adverse Events Reporting System (FAERS) database, PRRs of adverse drug event terms were calculated by division of counts of domestic reports of these events by counts of all serious adverse events for each of 13 selected drugs associated with a broad range of hepatotoxic risk (including three linked to only rare instances of clinically apparent liver injury) with reference to all other drugs in the database. Drug-specific cumulative PRRs were measured at successive intervals (calendar quarters) using cumulative tallies of FAERS reports to generate time-based profiles over the initial 3 years of US marketing. RESULTS: In the set of drugs analyzed, those with no known hepatotoxic risk demonstrated time-based cumulative PRR profiles that approximate the background rates of hepatic failure and serious liver injury reported in the entire FAERS database. In contrast, those that were removed from marketing or subjected to marketing restrictions due to their potential to cause liver injury were associated with profiles of rapidly rising cumulative PRRs that were greater than 5 within the first 10 million domestic prescriptions or the first four quarters of US marketing. The systematic tracking and identification of rising PRRs for DILI associated with newly marketed pharmaceutical and biological agents is a valuable tool for identification of safety signals within the FAERS database. LIMITATIONS: Disproportionality profiling of spontaneous reports in FAERS (e.g., cumulative PRR measurements), which signals an association between a recently marketed drug and liver injury, is not a method to quantitatively measure drug-related risk. Regulatory actions in response to emerging drug safety concerns often depend on an accurate assessment of risks using multiple sources of data and the consideration of overall benefits and risks of the agent. Causality must be determined through analysis of individual cases to exclude other etiologies of liver injury. CONCLUSION: The FAERS database can be used to advance empiric hepatotoxicity time-trending reporting levels for newly marketed agents in order to rapidly identify recently launched potential hepatotoxic agents and initiate further evaluation.

Progressive multifocal leukoencephalopathy associated with efalizumab use in psoriasis patients.

BACKGROUND: 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. OBJECTIVE: To describe 3 cases of PML in psoriasis patients treated with efalizumab. METHODS: 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. RESULTS: 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. LIMITATIONS: AERS data are limited because of an underreporting of spontaneous post-marketing adverse events and variable quality and quantity of information provided. CONCLUSIONS: 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.