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Drug Studies

The Office of Surveillance and Epidemiology in the Center for Drug Evaluation and Research (CDER) leads the Sentinel System. Sentinel was created to meet the mandate described in Section 905 of the Food and Drug Administration Amendments Act 2007 (FDAAA) to create an active postmarket drug safety surveillance system. CDER uses Sentinel to proactively assess the safety of FDA approved drugs under real-world conditions.


The Active Risk Identification and Analysis (ARIA) system is the largest and most developed component of Sentinel. ARIA uses state-of-the-art analysis tools and a distributed database of standardized claims and claims linked with electronic health records (EHR) data to monitor the safety of medications. The data undergo continuous quality checks and refreshes. With ARIA, safety analyses are conducted more efficiently compared to studies with fully customized analytics—often in a matter of months, rather than several years. 

How Drug Safety Studies Inform FDA’s Regulatory Process

FDA conducts safety studies in Sentinel for the following purposes, as described in Section 505(o)(3)(B) of FDAAA:

  • Assess a known serious risk related to the use of the drug
  • Assess signals of serious risk related to the use of the drug
  • Identify an unexpected serious risk

Sentinel drug safety studies can contribute to FDA’s regulatory process in a variety of ways. This includes:

  • Providing reassuring data to address new concerns about the safety of a medical product
  • Contributing evidence to support an FDA Drug Safety Communication or Label Change
  • Responding to a citizen's petition
  • Informing FDA’s risk management strategy for a drug
  • Becoming part of an Advisory Committee deliberation
  • Providing evidence that alleviates a drug safety concern

To learn more about how the FDA has used the Sentinel and ARIA Systems, please see the following assessment report. This assessment covers fiscal years 2018 through 2022, the period aligning with the Prescription Drug and User Fee Act (PDUFA) VI.

 

  • Signal Identification: analyses used to detect new and unsuspected potential safety concerns.
  • Level 1: analyses used to describe and characterize patterns of medication use or rates of health outcomes of interest. The Sentinel Query Builder application represents a subset of Level 1 functionality. Query Builder analyses are typically run on Merative™ MarketScan® Research Databases but some are also run on Sentinel's distributed database. 
  • Levels 2 and 3: analyses used to study whether a potential adverse health outcome is related to the use of drug and estimates the size of that risk.
     

Levels of ARIA Analyses

The graph below captures the total number of analyses conducted by the FDA since 2016 throughout the Sentinel System, including the Sentinel Distributed Database (SDD), IBM Watson Health, IBM Explorys, TriNetX, HCA Healthcare, PCORnet, and Veradigm. 

All Sentinel System Analyses by Quarter Graphic

Sentinel’s ARIA system is complemented by EHR data systems, enabling the selection of a data source that best fits a drug safety question of interest. There are 3 categories of EHR data sources:

  • Data Aggregators: Compiles EHR data from multiple, discrete healthcare organizations in a single platform.
  • Data Warehouse: Stores extracted, standardized data from transactional systems in a central repository.
  • Network: An integrated partnership of standardized EHR data among multiple data partners.

Sentinel's Multi-Modal Response System

All drug safety studies conducted in Sentinel are included below. The table is organized by the drug or population of interest and the health outcome(s) under study. When available, links are provided to the analytic code (package), results, communications and the study’s regulatory outcome.

Sentinel Study Status

Sentinel Study Purpose

FDA Sentinel Drug Studies: from ARIA and other Sentinel Data Sources

Drug/Population Safety Analysis Status Health Outcome(s) Impact(s) Posted Last Updated Purpose Original Posting Date Regulatory Determination / Use ARIA Results Analytic Code Regulatory Links Related Publications Meets requirements of FD&C Act Sec 505(o) prior to requiring a PMR
Glomerular Diseases
Complete
Complete Regulatory Outcome, Results Drug and Outcome Analysis

This study was conducted to assist the U.S. Food and Drug Administration (FDA) in reviewing several requests for orphan drug designations by estimating the number of individuals affected by several glomerular diseases in the United States.

Data from this study suggested glomerular diseases seemed to be rare in the United States. Based on the finding of this study in the FDA’s Sentinel System and Census data projections, numbers of individuals with focal segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), membranous nephropathy (MN), minimal change disease (MCD), membranoproliferative glomerulonephritis (MPGN), crescentic and necrotizing glomerulonephritis (CNGN), lupus nephritis (LN), and nephrotic syndrome (NS) in the United States were all below the 200,000 person threshold for orphan drug designation, for each year from 2016 to 2019.

Nevertheless, because algorithms used to estimate different glomerular diseases were not validated, estimates are subject to potential case misclassification, which may underestimate or overestimate the true disease prevalence.  

/studies/drugs/individual-drug-analyses/estimated-prevalence-glomerular-diseases-descriptive, /studies/drugs/individual-drug-analyses/estimated-prevalence-glomerular-diseases-updated-descriptive No
Mixed Amphetamine Salts
Complete
Complete Regulatory Outcome, Communication, Results Drug Use

Generic mixed amphetamine salt (MAS) products, particularly the immediate-release tablet products of specific generic MAS products, have been the subject of spontaneous reports to the Drug Quality Report System, a subset of the Food and Drug Administration's (FDA) MedWatch. Most complaints described lack of effectiveness and a need for a dose increase after switching to specific generic MAS products from other MAS products. The objective of these Sentinel analyses was to examine utilization and switching patterns among adults with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) and/or narcolepsy, treated with immediate release MAS formulations in postmarketing real world settings. Results from this descriptive analysis suggest that switching appeared to correlate with the number of dispensings and the patterns of switching did not suggest increased switching away or switching back after use of the generics of interest. Based on these data, FDA determined that no regulatory action is needed at this time.

/studies/drugs/individual-drug-analyses/utilization-and-switching-patterns-mixed-amphetamine-salt, /studies/drugs/individual-drug-analyses/mixed-amphetamine-salts-immediate-release-tablet-use No
Rinvoq (upadacitinib)
Ongoing
Ongoing
acute myocardial infarction (Crohn's disease)
acute myocardial infarction (ulcerative colitis)
deep vein thrombosis (Crohn's disease)
deep vein thrombosis (ulcerative colitis)
pulmonary embolism (Crohn's disease)
pulmonary embolism (ulcerative colitis)
thrombotic stroke (Crohn's disease)
thrombotic stroke (ulcerative colitis)
Drug and Outcome Analysis No
Brintellix (vortioxetine) and Brilinta (ticragelor)
Complete
Complete Regulatory Outcome, Communication, Results Drug Use

In July 2015, FDA released a drug safety communication regarding prescribing or dispensing errors due to brand name confusion with the antidepressant Brintellix (vortioxetine) and the antiplatelet Brilinta (ticagrelor). In May 2016, FDA approved a brand name change for the antidepressant Brintellix to Trintellix.

 

This study was intended to explore Sentinel’s ability to detect potential drug name confusion errors using Brintellix-Brilinta as a feasibility use case. We developed a claims-based algorithm for identifying potential drug name confusion errors. In combination with claims profile review, we identified likely errors in both Brintellix and Brilinta users. This study demonstrated that a claims‐based algorithm combined with manual review of claims profiles could be used to identify potential drug name confusion errors.

 

/studies/drugs/individual-drug-queries/prevalent-dispensings-ticagrelor-brilinta-and-vortioxetine, /studies/drugs/individual-drug-queries/brintellix-and-brilinta-medication-errors-due-name-confusion No
Long-Acting Injectable Antipsychotics
Ongoing
Ongoing Analytic Code, Results Drug and Outcome Analysis /studies/drugs/individual-drug-analyses/counts-and-characteristics-long-acting-injectable No
Dupixent (dupilumab)
Complete
Complete Regulatory Outcome, Results Drug Use

In 2017, the FDA approved Dupixent (dupilumab), an interleukin-4 receptor alpha agonist. Dupixent is currently indicated for atopic dermatitis for patients aged six months and older, asthma for patients aged six years and older, chronic rhinosinusitis with nasal polyposis in adult patients, eosinophilic esophagitis in patients one year old and older, and prurigo nodularis in adult patients. FDA sought to understand whether Dupixent was being used off-label prior to the eosinophilic esophagitis approval, and if so, to what extent.

An analysis was completed in Sentinel in 2021 to investigate utilization patterns of Dupixent by varying cohort inclusion requirements with broad and narrow definitions of eosinophilic esophagitis. Overall, findings suggested that very few patients used Dupixent to treat eosinophilic esophagitis. As this analysis was conducted for informational purposes only, FDA did not take regulatory action.

/studies/drugs/individual-drug-analyses/dupixent-dupilumab-utilization-patterns-descriptive-analysis No
Provigil (modafinil) and Nuvigil (armodafinil)
Ongoing
Ongoing
cardiac congenital malformations
non-cardiac congenital malformations
Analytic Code, Results Drug and Outcome Analysis /studies/drugs/individual-drug-analyses/risk-congenital-cardiac-malformations-following-0, /studies/drugs/individual-drug-analyses/risk-congenital-cardiac-malformations-following-armodafinil, /studies/drugs/individual-drug-analyses/risk-non-cardiac-congenital-malformations-following No
Pre-Pen Plus (benzylpenicilloyl polylysine)
Complete
Complete
skin test antigen utilization
Regulatory Outcome, Results Drug Use

A U.S. Food and Drug Administration (FDA) Advisory Committee (AC) meeting was planned to discuss the application for a new Penicillin Allergy Skin Test Kit (Pre-Pen Plus) product in March 2019. In preparation for the AC meeting, FDA used Sentinel to consider background information on trends in the recent use of penicillin allergy skin testing generally. The Sentinel analysis provided an estimate of the increasing trend in Pre-Pen penicillin allergy testing between 2008 and 2018. Ultimately, for reasons unrelated to the Sentinel analysis, FDA canceled the planned AC meeting.

/studies/drugs/individual-drug-analyses/trends-penicillin-allergy-testing No
Olumiant (baricitinib) and Actemra (tocilizumab)
Complete
Complete
emergency use authorization (EUA) utilization
Regulatory Outcome, Results Other Regulatory

In November 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for baricitinib to be used in combination with remdesivir to treat COVID-19 in hospitalized patients on respiratory support (i.e., supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation). In June 2021, the FDA issued an EUA for tocilizumab to treat COVID-19 in hospitalized patients receiving systemic corticosteroids and on respiratory support. To understand the scope of utilization and characteristics of users of baricitinib and tocilizumab in the context of COVID-19, FDA conducted a descriptive analysis among patients with inpatient baricitinib or tocilizumab use in the Sentinel System. Both products were commercially available prior to FDA issuance of the EUAs, and the study period for this analysis (April 1, 2020, to March 31, 2021) included time prior to FDA issuance of these EUAs. Specific characteristics assessed included evidence of COVID-19, use of respiratory support, concomitant drug use, and medical conditions.

Results indicated that most patients who received inpatient baricitinib/remdesivir therapy had evidence of COVID-19. However, about half of patients who received inpatient baricitinib therapy did not appear to have concurrent remdesivir use, and few patients with inpatient baricitinib therapy appeared to have documented respiratory support at drug therapy initiation. Results also indicated that most patients with inpatient tocilizumab therapy had evidence of COVID-19 and a majority had concurrent systemic corticosteroid therapy. Additionally, around 25% of patients with tocilizumab therapy had documented mechanical ventilation at drug therapy initiation.  This analysis informed the FDA’s active safety monitoring efforts for products authorized or used for the treatment of COVID-19. FDA approved these products for the treatment of adults with COVID-19 in May 2022 (baricitinib) and December 2022 (tocilizumab), and EUAs remain in place for use in pediatric patients as of August 2023.
 

/studies/drugs/individual-drug-analyses/baricitinib-or-tocilizumab-use-hospitalized-patients-covid No
Dupixent (dupilumab)
Ongoing
Ongoing
signal identification
Analytic Code Signal Identification No
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors
Complete
Complete
diabetic ketoacidosis (DKA)
use in type 1 diabetes mellitus (T1DM)
Regulatory Outcome, Communication, Results Drug and Outcome Analysis

In response to clinical trials showing an increased risk of DKA with sotagliflozin in T1DM, FDA assessed off-label use of SGLT2 inhibitors (approved for use in T2DM) and real-world rates of DKA when used in patients with T1DM. Elevated rates of DKA with off label SGLT2 inhibitor use among patients with T1DM were seen compared to clinical trials. These findings were presented at the Advisory Committee meeting for sotagliflozin, and this helped inform the committee member discussion on the benefit-risk assessment.

Yes /assessments/drugs/sglt-2-inhibitor-use-and-incidence-diabetic-ketoacidosis-patients-type-1-diabetes, /studies/drugs/individual-drug-analyses/sodium-glucose-cotransporter-2-sglt2-inhibitor-use-patients No
Xofluza (baloxavir)
Ongoing
Ongoing
signal identification
Analytic Code, Results Signal Identification /studies/drugs/individual-drug-analyses/baloxavir-and-oseltamivir-utilization-descriptive-analysis No
Glucagon-Like Peptide-1 Receptor Agonists
Ongoing
Ongoing
intentional self-harm
Communication Drug and Outcome Analysis No
Ilumya (tildrakizumab)
Ongoing
Ongoing Results Drug and Outcome Analysis Yes /studies/drugs/individual-drug-analyses/follow-time-guselkumab-risankizumab-and-tildrakizumab-users, /studies/drugs/individual-drug-analyses/utilization-guselkumab-risankizumab-tildrakizumab-and Yes
Siliq (brodalumab)
Ongoing
Ongoing
hospitalized neutropenia
myocardial infarction and stroke
serious infection
Results Drug and Outcome Analysis Yes /studies/drugs/individual-drug-analyses/utilization-brodalumab-descriptive-analysis, /studies/drugs/individual-drug-analyses/utilization-guselkumab-risankizumab-tildrakizumab-and Yes
Skyrizi (risankizumab)
Ongoing
Ongoing Results Drug and Outcome Analysis Yes /studies/drugs/individual-drug-analyses/follow-time-guselkumab-risankizumab-and-tildrakizumab-users, /studies/drugs/individual-drug-analyses/utilization-guselkumab-risankizumab-tildrakizumab-and Yes
Tremfya (guselkumab)
Ongoing
Ongoing Results Drug and Outcome Analysis Yes /studies/drugs/individual-drug-analyses/follow-time-guselkumab-risankizumab-and-tildrakizumab-users, /studies/drugs/individual-drug-analyses/utilization-guselkumab-risankizumab-tildrakizumab-and Yes
Neupogen (filgrastim), Remicade (infliximab), and Neulasta (pegfilgrastim)
Complete
Complete Regulatory Outcome, Communication, Results Methods and Development

Following the new regulatory pathway for approval of biosimilar and interchangeable products, FDA needs to be able to evaluate their post-marketing experience. However, how biosimilars are coded for reimbursement, and therefore appear in claims data, is unknown. Since accurate identification of biologics and biosimilars in claims data is a fundamental need for future studies of these products, this study was conducted to examine how patient exposure to biologics and biosimilars can be identified in claims data. Use of filgrastim and infliximab was identified primarily via Healthcare Common Procedure Coding System (HCPCS) codes (filgrastim: 86.4%-97.7%; infliximab: 87.8%-100%) although some use was identified via National Drug Codes (NDCs) (filgrastim: 2.2%-13.5%; infliximab: <0.1%-6.5%). The median exposure episode gap ranged from 1 to 3 days for filgrastim and 48 to 50 days for infliximab. Data on identification of biosimilars in claims data and observed gaps between exposure episodes can be used to support future drug safety studies of biosimilars.

/studies/drugs/individual-drug-analyses/characterization-use-biologics-and-biosimilars-sentinel, /studies/drugs/individual-drug-analyses/utilization-dispensing-and-coding-patterns-biologics-and No
Ablysinol (dehydrated alcohol)
Complete
Complete
atrioventricular block
heart failure
myocardial infarction
permanent pacemaker placement
septal myectomy
ventricular arrhythmia
Regulatory Outcome, Analytic Code, Communication, Results Drug and Outcome Analysis

Percutaneous transluminal septal myocardial ablation (PTSMA) is an alternative to surgery for left ventricular outflow tract obstruction in patients with hypertrophic obstructive cardiomyopathy. PTSMA involves injection of dehydrated alcohol into the coronary artery, inducing a localized basal septal myocardial infarction which remodels the outflow tract. Ablysinol, a dehydrated alcohol product, was approved by FDA on June 21, 2018. FDA wanted to understand how approval of this new dehydrated alcohol product would impact the number of PTSMA procedures conducted and subsequent post-procedural complications. 

FDA conducted a study in the Sentinel System to evaluate changes in the frequency of PTSMA procedures conducted and changes in the occurrence of potential post-procedural complications after approval. After Ablysinol approval in 2018, the frequency of PTSMA procedures per year, the proportion of potential post-procedural complications such as heart failure, atrioventricular block, and permanent pacemaker placement observed, and the proportion of PTSMA procedures requiring a repeat PTSMA procedure, increased only slightly in this study. Evaluation of death was not pursued in this analysis due to under capture in the assessed data. The FDA determined that no regulatory action is needed at this time.

/studies/drugs/individual-drug-analyses/frequency-percutaneous-transluminal-septal-myocardial, /studies/drugs/individual-drug-analyses/cardiovascular-outcomes-following-percutaneous-transluminal, /studies/drugs/individual-drug-analyses/cardiovascular-outcomes-following-percutaneous Yes
Ozempic (semaglutide)
Complete
Complete
signal identification
Regulatory Outcome, Analytic Code, Results Methods and Development

FDA initiated this pilot study in Sentinel to explore the use of TreeScanTM for routine drug safety surveillance, using a use case of Ozempic (a specific form of semaglutide). TreeScan is a signal identification approach that scans thousands of health outcomes simultaneously while adjusting for multiple scenarios that can be used to monitor the underlying assumption of no clinical differences.

The study specifically sought to monitor non-pregnancy and non-cancer outcomes among new users of Ozempic compared to new users of sitagliptin among patients with type 2 diabetes. FDA determined the statistical alerts generated by the TreeScan analysis do not warrant further evaluation or action. This pilot demonstrated that tree-based scan statistics can be applied to the Sentinel Distributed Database using an active comparator design to simultaneously evaluate thousands of safety outcomes for medicines as an additional safety surveillance tool.

/studies/drugs/individual-drug-analyses/outcome-monitoring-following-ozempic-use-patients-type-2 No
Aimovig (erenumab)
Complete
Complete
signal identification
Regulatory Outcome, Analytic Code, Results Signal Identification

FDA initiated this pilot study in Sentinel to explore the use of TreeScanTM for routine drug safety surveillance, using a use case of Aimovig (erenumab). TreeScan is a signal identification approach that scans thousands of health outcomes simultaneously while adjusting for multiple scenarios that can be used to monitor the underlying assumption of no clinical differences.

The study specifically sought to monitor non-pregnancy and non-cancer outcomes among new users of Aimovig using a self-controlled risk interval analysis and tree-based scan statistics. FDA determined the statistical alerts generated by the TreeScan analysis do not warrant further evaluation or action. This pilot demonstrated that tree-based scan statistics can be applied to the Sentinel Distributed Database (SDD) using a self-controlled risk interval design to simultaneously evaluate thousands of safety outcomes for medicines as an additional safety surveillance tool.

/studies/drugs/individual-drug-analyses/utilization-select-products-migraine-treatment-and, /studies/drugs/individual-drug-analyses/outcome-monitoring-following-erenumab-use-signal No
Proton Pump Inhibitors
Ongoing
Ongoing
COVID-19 hospitalization
Severe COVID-19
Analytic Code Drug and Outcome Analysis No
Brexafemme (ibrexafungerp)
Ongoing
Ongoing Results Drug Use /studies/drugs/individual-drug-analyses/utilization-ibrexafungerp-pregnant-patients-descriptive, /studies/drugs/individual-drug-analyses/utilization-ibrexafungerp-pregnant-patients-descriptive-0 No
Corticosteroids
Complete
Complete
outpatient utilization
Regulatory Outcome, Communication, Results Drug Use

In June 2020 the United Kingdom Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, reported benefit from dexamethasone use in severely ill hospitalized patients with COVID-19, but potential harm in patients not requiring oxygen supplementation. As a result, in October 2020, the National Institutes of Health (NIH) issued guidelines advising against the use of systemic corticosteroids in non-hospitalized COVID-19 patients. The Rapid Sentinel Distributed Database (SDD) was used to describe the demographic and clinical characteristics of U.S. non-hospitalized patients with COVID-19 who initiated systematic corticosteroids and those who did not from April 2020 to July 2021. Additionally, descriptive information was generated on the proportion of corticosteroid initiators who were hospitalized within 30 days of initiation.*  

There were 766,105 eligible COVID-19 patients (median age 48.5 years [standard deviation, 19.9 years]), 9.4% of whom received corticosteroids in an outpatient setting within 14 days of COVID-19 diagnosis. Treatment often started on the day of COVID-19 diagnosis (51.3%), largely through pharmacy dispensings rather than during medical encounters. Corticosteroid use increased over time from 2.2% initiating in April 2020 to 13.8% initiating in July 2021. Among those who received corticosteroids in an outpatient setting, 11.1% were hospitalized (COVID-19 in any diagnostic position) within 30 days of initiation.  

An early version of these analyses was presented to the NIH COVID-19 Treatment Guidelines Panel (April 2021). Later, updated analyses were published in the Journal of the American Medical Association (JAMA) (April 2022). The Centers for Disease Control and Prevention (CDC) subsequently issued a health advisory citing these data and alerting physicians and the public that systemic corticosteroids are not recommended for patients with mild to moderate COVID-19 who do not require supplemental oxygen.  

 

*In addition to the Rapid SDD, the FDA conducted parallel analyses in three other data sources. Results here pertain only to Sentinel.

/studies/drugs/individual-drug-analyses/outpatient-corticosteroid-use-patients-covid-19-descriptive, /studies/drugs/individual-drug-analyses/outpatient-corticosteroid-use-patients-covid-19-updated No
Simponi (golimumab)
Complete
Complete Regulatory Outcome, Results Drug Use

In May 2013, the FDA approved golimumab for ulcerative colitis with a post-market required (PMR) study to assess risk of lymphoma. In response to concerns about low enrollment in this study, the FDA conducted an analysis in Sentinel's Merative™ MarketScan® Research Databases using the Query Builder tool to understand if golimumab utilization in patients with ulcerative colitis (UC) was contributing to low patient enrollment. From January 2017 – December 2019, the relative frequency of anti-TNFα new-use episodes for UC in adults was 56%, 39%, and 5% for adalimumab, infliximab (including biosimilars), and golimumab, respectively. These data confirmed low utilization of golimumab and supported the FDA’s decision to discontinue further enrollment in the PMR study.

/studies/drugs/individual-drug-analyses/biologics-use-adults-ulcerative-colitis-descriptive-analysis No
Eliquis (apixaban), Pradaxa (dabigatran), and Xarelto (rivaroxaban)
Complete
Complete
cutaneous small-vessel vasculitis
Regulatory Outcome, Analytic Code, Communication, Results Drug and Outcome Analysis

Cases of cutaneous small-vessel vasculitis (CSVV) associated with direct oral anticoagulants (DOACs) were reported in DOAC premarket trials and to the FDA Adverse Events Reporting System (FAERS) post approval. FDA conducted a study in Sentinel to characterize CSVV cases among patients with atrial fibrillation treated with DOACs. Additional studies in Sentinel explored incidence rates for DOACs, warfarin, and allopurinol as positive control and compared adjusted CSVV risk in new users of DOACs and warfarin. No statistically significant differential CSVV risk was observed among new users of DOACs and warfarin. FDA did not take regulatory action at this time, based on available information.

Yes /assessments/drugs/individual-drug-queries/cutaneous-small-vessel-vasculitis-following-dabigatran, /studies/drugs/individual-drug-analyses/cutaneous-small-vessel-vasculitis-following-direct-oral, /studies/drugs/individual-drug-analyses/direct-oral-anticoagulants-doacs-warfarin-allopurinol-or, /studies/drugs/individual-drug-analyses/cutaneous-small-vessel-vasculitis-and-acute-kidney-injury, /studies/drugs/individual-drug-analyses/incident-utilization-allopurinol-hydralazine-and No
Anti-obesity medications (benzophetamine, bupropion/naltrexone, diethylpropion, liraglutide, lorcaserin, orlistat, phendimetrazine, phentermine, phentermine/topiramate)
Complete
Complete
duration of use
patient characteristics
Regulatory Outcome, Communication, Results Drug Use

The Bipartisan Budget Act of 2018 (P.L. 115-123) included a provision for the Government Accountability Office (GAO) to review the prevalence of obesity and the use of obesity drugs. GAO requested that FDA assess utilization patterns and treatment duration for the nine available prescription used to treat obesity. FDA used the Sentinel System to assess the baseline characteristics of patients initiating weight management drugs and evaluate the duration of treatment of the first treatment episode and cumulative duration across all treatment episodes. These results were incorporated into the GAO report entitled, “Few Adults Used Prescription Drugs for Weight Loss and Insurance Coverage Varied.”

Yes /studies/drugs/individual-drug-analyses/utilization-sodium-glucose-co-transporter-2-sglt-2-inhibitor, /studies/drugs/individual-drug-analyses/utilization-obesity-drugs-descriptive-analysis, /studies/drugs/individual-drug-analyses/incident-utilization-patterns-obesity-drugs-descriptive No
Invokana (canagliflozin)
Ongoing
Ongoing Results Drug and Outcome Analysis Yes /studies/drugs/individual-drug-analyses/renal-cell-carcinoma-following-canagliflozin-use-patients Yes
Zarxio (filgrastim-sndz)
Complete
Complete
signal identification
Regulatory Outcome, Analytic Code, Results Methods and Development

FDA initiated this pilot study in Sentinel to explore the use of TreeScanTM for routine drug safety surveillance of biosimilars, using a use case of Zarxio (Filgrastim-sndz). Biosimilars are biologic medications that are highly similar to existing approved biologics with no identified clinically meaningful differences in safety, effectiveness, and quality. However, the complex nature of biologics generally means a biosimilar is not identical to the reference product. TreeScan is a signal identification approach that scans thousands of health outcomes simultaneously while adjusting for multiple scenarios that can be used to monitor the underlying assumption of no clinical differences.

The study specifically sought to monitor non-pregnancy and non-cancer outcomes among new users of Zarxio compared to new users of Neupogen. FDA determined the statistical alerts generated by the TreeScan analysis do not warrant further evaluation or action. This pilot demonstrated that tree-based scan statistics can be applied to the Sentinel Distributed Database to simultaneously evaluate thousands of safety outcomes for biosimilar medicines as an additional surveillance tool.

/studies/drugs/individual-drug-analyses/utilization-select-biological-products-descriptive-analysis, /studies/drugs/individual-drug-analyses/outcome-monitoring-following-zarxio-use-signal, /studies/drugs/individual-drug-analyses/outcome-monitoring-following-zarxio-use-updated-signal No
New Molecular Entities (NMEs)
Ongoing
Ongoing
utilization characterization
Communication, Results Drug Use /studies/drugs/individual-drug-analyses/new-molecular-entities, /studies/drugs/individual-drug-analyses/duration-follow-new-molecular-entities-approved-2005-2006, /studies/drugs/individual-drug-analyses/duration-follow-new-molecular-entities-approved-2008-and, /studies/drugs/individual-drug-analyses/duration-follow-new-molecular-entities-approved-2010-2012, /studies/drugs/individual-drug-analyses/duration-follow-new-molecular-entities-approved-2011, /studies/drugs/individual-drug-analyses/duration-follow-new-molecular-entities-approved-2014-and, /studies/drugs/individual-drug-analyses/duration-follow-new-molecular-entities-approved-2016, /studies/drugs/individual-drug-analyses/duration-follow-new-molecular-entities-approved-2017, /studies/drugs/individual-drug-analyses/duration-follow-new-molecular-entities-approved-2017-updated, /studies/drugs/individual-drug-analyses/duration-follow-new-molecular-entities-approved-2018, /studies/drugs/individual-drug-analyses/duration-follow-new-molecular-entities-approved-2019 No
Gonadotropin-Releasing Hormone (GnRH) Agonists
Complete
Complete
utilization characterization
Regulatory Outcome, Results Drug Use

FDA conducted an analysis to assess the feasibility of studying the long-term safety of gonadotropin-releasing hormone (GnRH) agonist use in adolescents through Sentinel. The primary objective was to characterize GnRH agonist use in adolescents and to examine possible diagnoses associated with their use. Sentinel findings demonstrated that a small cohort of adolescents with GnRH agonist use was identified. Most of this use appeared to be short term: half of patients had less than 5 months of GnRH agonist therapy and three-quarters of patients had less than 11 months of therapy. Diagnosis codes occurring in proximity to a claim for a GnRH agonist included those related to puberty disorders and gender dysphoria. Sentinel findings suggest that safety studies of GnRH agonist use among adolescents may be feasible, depending on the outcome of interest.

No /studies/drugs/individual-drug-analyses/use-gonadotropin-releasing-hormone-gnrh-agonists-patients No
Epidiolex (prescription cannabidiol)
Complete
Complete Regulatory Outcome, Results Drug Use

Epidiolex (prescription cannabidiol) was approved in June 2018 for the treatment of seizures associated with Lennox Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients 1 year of age and older.

As a part of FDA’s mission to perform surveillance of cannabidiol-containing products, a utilization analysis was conducted in Sentinel’s Merative™ MarketScan® Research Databases to inform feasibility of future studies.

Based on the available findings, FDA determined that no regulatory action was needed.

 

/studies/drugs/individual-drug-analyses/epidiolex-prescription-cannabidiol-utilization-patterns No
Insulin
Complete
Complete Regulatory Outcome, Communication, Results Drug Use

In March 2020, insulins were transitioned from being regulated as drugs to being regulated as biological products. This transition allows for the introduction of biosimilars, which are highly similar to, and have no clinically meaningful differences from, their reference biological medication. To facilitate pharmacovigilance, an analysis was conducted to characterize how insulin was captured in electronic healthcare data sources, specifically via National Drug Codes (NDC) or Healthcare Common Procedure Coding System (HCPCS) codes. This analysis demonstrated that over 98% of the 107 million insulin claims in Sentinel between 2013 and 2018 were identified using NDC codes, supporting the use of NDCs to identify insulin exposure in drug safety studies using electronic healthcare data. Having a variety of different tools to identify products for pharmacovigilance is of high value. We have demonstrated that a large fraction of insulin use in Sentinel can be identified using NDCs. That, in addition to other identifiers, supports effective pharmacovigilance.

Yes /assessments/drugs/individual-drug-queries/patterns-insulin-product-use-and-billing-codes, /studies/drugs/individual-drug-analyses/insulin-coding-practices-descriptive-analysis No
Entresto (sacubitril/​valsartan)
Complete
Complete Analytic Code, Communication, Results Drug and Outcome Analysis Yes /studies/drugs/individual-drug-analyses/utilization-sacubitrilvalsartan-descriptive-analysis, /studies/drugs/individual-drug-analyses/sacubitrilvalsartan-angiotensin-converting-enzyme-ace, /studies/drugs/individual-drug-analyses/angioedema-following-sacubitrilvalsartan-use-patients-heart, /studies/drugs/individual-drug-analyses/angioedema-following-sacubitrilvalsartan-use-patients-0 Yes
Pediatric patients
Complete
Complete Regulatory Outcome, Communication, Results Methods and Development

The objective of this study was to identify and compare clinical and claims-based pediatric hypertensive patients in the FDA Sentinel System. FDA sought to determine the feasibility of using blood pressure values for identifying hypertension in the pediatric population. Pediatric hypertension in claims-based data sources is under-captured but also serves as a marker for greater disease severity. Investigators should understand coding practices when using real world data (RWD) sources for identification of pediatric hypertension in future work. This study compared and examined overlap between the two methods for identification of pediatric hypertensive patients (claims-based and clinical electronic health record [EHR]-based) over a 36-month period in the Sentinel System. Furthermore, it provided guidance for the use of RWD in future pediatric hypertension studies.

/studies/drugs/individual-drug-analyses/hypertension-pediatric-patients-descriptive-analysis, /methods-data-tools/methods/pilot-test-vital-signs-and-laboratory-results-table-descriptive-modules No
Gilenya (fingolimod)
Ongoing
Ongoing
all congenital malformations
congenital cardiac malformations (primary)
congenital urinary malformations (primary)
Analytic Code Drug and Outcome Analysis No
Olumiant (baricitinib)
Ongoing
Ongoing
acute myocardial infarction
deep vein thrombosis
pulmonary embolism
stroke
Drug and Outcome Analysis Yes No
Taltz (ixekizumab)
Complete
Complete Regulatory Outcome, Results Drug Use

In response to a sponsor’s reported difficulty in accruing patients for a postmarket required study (PMR) using administrative healthcare data to retrospectively assess pregnancy outcomes in a cohort of women exposed to ixekizumab, the FDA conducted a Sentinel analysis to obtain contemporary information about the utilization of ixekizumab in pregnancy. Specifically, the study estimated the number of pregnancies with a pharmacy dispensing for ixekizumab and comparator drugs, overall and among patients with approved indications for ixekizumab. Between March 2016 and June 2021, there were 29 ixekizumab-exposed pregnancies, of which 19 had no concomitant exposure to comparators. For the 19 uniquely exposed pregnancies, use increased from no pregnancies in 2016 and 2017 to three pregnancies in 2018 (15.8%), two (10.5%) in 2019, and 10 pregnancies in 2020 (52.6%). Although the number of pregnancies exposed to ixekizumab is low, the analysis showed that the number of pregnancies exposed to ixekizumab is increasing over time. This contributed to FDA’s decision to continue evaluating potential risks associated with ixekizumab use during pregnancy via the pregnancy safety PMR.

/studies/drugs/individual-drug-analyses/utilization-ixekizumab-pregnant-patients-descriptive No
Lupron Depot PED (leuprolide acetate)
Complete
Complete
any fracture
hip replacement
major fracture (primary)
temporomandibular joint replacement
Regulatory Outcome, Analytic Code, Communication, Results Drug and Outcome Analysis

In response to case reports describing musculoskeletal adverse events, including decreases in bone density, in young adults who had been exposed to leuprolide acetate during childhood, the FDA further evaluated the risk of fracture with the use of gonadotropin-releasing hormone (GnRH) agonists indicated for the treatment of central precocious puberty (CPP), including leuprolide acetate. The Sentinel analysis estimated the risk of major fractures among individuals with CPP who initiated leuprolide acetate during childhood and compared them with leuprolide acetate-unexposed age- and sex-matched reference populations with and without CPP. Compared separately to the leuprolide-unexposed children with or without CPP, the study observed a lower risk of fracture in female leuprolide users with CPP, but no statistically significant difference in fracture risk for male leuprolide users with CPP. Results from the post hoc analysis were consistent with the findings from the main analysis. Because results from this study provided no evidence for an increased risk of fracture following leuprolide use during childhood, FDA determined that no regulatory action is needed at this time.

Yes /studies/drugs/individual-drug-analyses/new-pediatric-users-leuprolide-acetate-depot, /studies/drugs/individual-drug-analyses/lupron-depot-ped-use-among-patients-central-precocious, /studies/drugs/individual-drug-analyses/fractures-following-leuprolide-acetate-use-multiple-factor-matched-analysis, /studies/drugs/individual-drug-analyses/fractures-following-leuprolide-acetate-use-multiple-factor No
Women with heart failure
Complete
Complete Regulatory Outcome, Analytic Code, Communication, Results Drug and Outcome Analysis

In the development program, vericiguat showed embryo-fetal toxicities in animal studies which may be associated with the soluble guanylate cyclase stimulator class.  The FDA review team sought information to inform whether a Risk Evaluation and Mitigation Strategies (REMS) program should be required for vericiguat. A retrospective cohort study was conducted in the Sentinel System to assess prevalence of heart failure (HF) in women of childbearing age and the number of live birth pregnancies among these women. A second analysis described characteristics and outcomes of pregnancies in women with HF, and compared them to age-matched pregnant women without HF. 

From January 2010 to February 2020, 144,162 women with HF were identified (prevalence, 0.5%) among 29.5 million women of childbearing age in the Sentinel System. Within this HF cohort, there were 813 women with 822 pregnancies ending in live birth deliveries (5.5 deliveries per 1,000 women with HF). Applying the prevalence of HF to the 2019 Census estimates, we projected there were 310,613 women of childbearing with HF in the U.S. in 2019 and among these women, there were an estimated 808 pregnancies ending in live birth deliveries.  

In the second analysis, 489 live birth deliveries were identified (mean maternal age, 32.4 years) in 487 women with HF. These women had more comorbidities and used more health services than pregnant women without HF but were healthier than age-matched non-pregnant women with HF. Beta-blockers (21.5%), diuretics (15.3%), and ACE inhibitors (10.2%) were the commonly used HF medications during the pre-pregnancy period. Utilization of beta-blockers remained unchanged throughout and after pregnancy. Use of ACE inhibitors dropped to 5.3% in the first trimester, to less than 1% in the second and third trimesters but increased to 8.0% after pregnancy. Use of other HF medications, such as aldosterone antagonists, angiotensin receptor blockers, and ivabradine, were rare.

HF is rare among women of childbearing age and pregnancies only occurred in a small number of these women. Among women with HF, the use of potentially embryo-fetal toxic HF medications was low and decreased during pregnancy, in accordance with recommendations in drug labeling. Based on the low use of HF medications generally, and the population for which vericiguat is indicated (subtype of HF patients [symptomatic chronic heart failure with reduced ejection), vericiguat exposure is expected to be low. This information contributed to the review team’s determination that labeling would provide sufficient information to ensure the benefits of vericiguat outweigh its risks.  

 

No /studies/drugs/individual-drug-analyses/pregnancy-among-women-heart-failure-descriptive-analysis, /studies/drugs/individual-drug-analyses/characterizing-pregnant-women-and-without-evidence-heart No
Gadolinium-based contrast agents
Complete
Complete Regulatory Outcome, Analytic Code, Communication, Results Drug and Outcome Analysis

Gadolinium-based contrast agents (GBCA) are used in magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) diagnostic imaging procedures to aid in the visualization of abnormalities. GBCAs have a warning for hypersensitivity reactions, and seizure risk is listed as a postmarketing adverse event. The FDA identified cases of seizures shortly following GBCA exposure in the FDA Adverse Event Reporting System (FAERS) case reports and initiated a Sentinel study to better understand the magnitude of seizure risk associated with exposure to GBCAs during MRI and MRA procedures. An increased risk of seizure was not observed comparing contrast to non-contrast MRI in this study (RR=1.04, 95% CI 0.62-1.61). FDA determined that current labeling was sufficient to communicate that seizures have been observed in the post-market setting.

/studies/drugs/individual-drug-analyses/mri-and-gbca-procedures, /studies/drugs/individual-drug-analyses/same-day-seizures-following-gadolinium-based-contrast-agents, /studies/drugs/individual-drug-analyses/seizures-following-gadolinium-based-contrast-agents-exposure, /methods-data-tools/health-outcomes-interest/coding-trend-analyses-epilepsy-inpatient-care-setting, /methods-data-tools/health-outcomes-interest/coding-trend-analyses-epilepsy-emergency-department, /methods-data-tools/health-outcomes-interest/coding-trend-analyses-convulsions-inpatient-care, /methods-data-tools/health-outcomes-interest/coding-trend-analyses-convulsions-emergency-department No
Makena (hydroxyprogesterone caproate injection) and its generics
Complete
Complete Regulatory Outcome, Communication, Results Drug Use

FDA initiated this analysis to better understand utilization of hydroxyprogesterone caproate (HPC) injection, including Makena® and its generics, among pregnant women in the United States. We identified a total of 3,445,739 live-birth pregnancies (among 2.9 million women) between 2008 and 2018 in the Sentinel Distributed Database (SDD). Of these pregnancies, 6.5 per 1,000 pregnancies used injectable HPC, showing modest use of injectable HPC during the second and/or third trimesters among all live-birth pregnancies in the SDD. The majority (73%) of pregnancies with injectable HPC use had at least one of three obstetrical indications of interest recorded before or during the pregnancy. Sentinel analysis results were presented at an FDA Advisory Committee Meeting for consideration in assessing the potential public health impact of withdrawing Makena’s accelerated drug approval. Following the FDA Advisory Committee Meeting, the FDA’s Center for Drug Evaluation and Research (CDER) recommended withdrawing Makena’s accelerated approval.

No /studies/drugs/individual-drug-analyses/hydroxyprogesterone-caproate-and-progesterone-use-during No
Sinuva (mometasone furoate)
Ongoing
Ongoing
cataracts
diminished visual acuity
glaucoma
nasal septal perforation
Analytic Code, Communication, Results Drug and Outcome Analysis Yes /assessments/drugs/individual-drug-queries/sinus-stents-mometasone-and-diminished-visual-acuity, /methods-data-tools/health-outcomes-interest/coding-trend-analyses-nasal-septal-perforations, /methods-data-tools/health-outcomes-interest/coding-trend-analyses-glaucoma, /methods-data-tools/health-outcomes-interest/coding-trend-analyses-cataracts, /methods-data-tools/health-outcomes-interest/coding-trend-analyses-visual-acuity, /studies/drugs/individual-drug-queries/glaucoma-cataracts-diminished-visual-acuity-and-nasal-septal, /studies/drugs/individual-drug-queries/mometasone-furoate-mf-sinus-implant-use-patients-nasal-polyps Yes
Stelara (ustekinumab)
Ongoing
Ongoing
serious infection (Crohn’s disease)
serious infection (ulcerative colitis)
Results Drug and Outcome Analysis Yes /studies/drugs/individual-drug-queries/serious-infections-following-ustekinumab-use-descriptive, /studies/drugs/individual-drug-analyses/serious-infection-following-ustekinumab-use-patients-crohn-s Yes
Aldactone (spironolactone)
Complete
Complete Regulatory Outcome, Communication, Results Drug Use

In October 2019, FDA pursued a study in the Sentinel System to describe utilization patterns for spironolactone in patients with heart failure (HF) with preserved ejection fraction (HFpEF). The study was initiated as the FDA Center for Drug Evaluation and Research (CDER) Division of Cardiology and Nephrology was considering data from a clinical trial sponsored by the National Institutes of Health (NIH) that found a significantly lower incidence of heart failure (HF) hospitalization among HFpEF patients treated with spironolactone compared to placebo. To characterize the real-world utilization of spironolactone in patients with HFpEF, and in patients with HF with reduced ejection fraction (HFrEF), FDA conducted a study in the Sentinel System. The study identified 2,009,529 patients with HFrEF and 9,257,514 HFpEF patients. The proportion of patients initiating spironolactone was 20.7% after HFrEF diagnosis versus 7.6% after HFpEF diagnosis. The median time (days) to initiation of spironolactone after HFrEF diagnosis was 90 (IQR: 19–385) and after HFpEF diagnosis was 286 (IQR: 57–851). The median duration (days) of first treatment episode in HFrEF patients was 120 (IQR: 44–321) and for HFpEF patients was 114 (IQR: 32 – 301). The median dose was similar (25mg/day) for both HF cohorts. This study characterized the use of spironolactone in a large database with demographically and geographically diverse patients. While there was lower initiation of spironolactone following HFpEF compared to HFrEF diagnosis, the dosing and duration of the first continuous spironolactone episode were similar. As a result of this study, no regulatory action was taken.

/studies/drugs/individual-drug-queries/spironolactone-use-patients-reduced-ejection-fraction-heart No
Prenatal Tests
Complete
Complete Communication, Results Methods and Development /studies/drugs/individual-drug-analyses/prenatal-tests-women-potential-stillbirths, /studies/drugs/individual-drug-analyses/algorithms-estimate-start-pregnancy-using-vitro No
Zoloft (sertraline)
Complete
Complete
hospitalized depression
intentional self-harm
Analytic Code, Communication, Results Methods and Development /assessments/drugs/individual-drug-queries/intentional-self-harm-and-hospitalized-depression, /assessments/drugs/individual-drug-queries/intentional-self-harm-and-hospitalized-depression-0 No
Medications for attention deficit hyperactivity disorder
Complete
Complete
heart failure or cardiomyopathy
Regulatory Outcome, Communication, Results Drug and Outcome Analysis

Follow up investigation of case reports of cardiac events after long term stimulant use. FDA decided that no action is necessary at this time, based on available information.

Yes /drugs/assessments/adhd-medications-and-heart-failure No
Gimoti (metoclopramide)
Complete
Complete Regulatory Outcome, Results Drug Use

Tardive dyskinesia (TD) is a known safety risk with use of metoclopramide. During the review of an application for a nasal spray formulation of metoclopramide for use in diabetic gastroparesis, FDA wanted to understand the duration of use, since the risk of developing TD increases with duration of treatment and cumulative dosage. To understand real-world use patterns of metoclopramide, FDA conducted an analysis on the treatment episode duration, number, frequency, and cumulative dose among users of other available metoclopramide dosage forms, which had labeled recommended durations of use of 8 weeks or less. Among women ages ≥ 40 years identified in the Sentinel Distributed Database between January 1, 2009 and September 30, 2015, there were over 1.4 million users of metoclopramide. Of the 3.7% of these women with diabetic gastroparesis, approximately 25% had metoclopramide treatment episodes longer than 4 weeks. These data provided context for FDA’s assessment of the application by providing information about the potential for the target population to use a nasal metoclopramide product outside the parameters supported by the available safety data.

/assessments/drugs/individual-drug-queries/use-metoclopramide-among-patients-diabetic-gastroparesis No
Reglan (metoclopramide)
Complete
Complete Regulatory Outcome, Results Drug Use

This Sentinel analysis was initiated to determine length of therapy for oral metoclopramide among pediatric patients aged 0-17 years. Metoclopramide includes a boxed warning for increased risk of tardive dyskinesia (TD) for use > 12 weeks and is not recommended in pediatric patients due to risk of central nervous system complications. Based on the prescription claims data from 2012-2015, an estimated 10% of pediatric patients aged 0-17 years received prescriptions for oral metoclopramide for > 12 weeks, potentially increasing their risk of developing TD. These data provided context for FDA’s assessment of proposed pediatric use by providing information about the potential utilization outside the parameters supported by the available data.

/assessments/drugs/individual-drug-queries/oral-metoclopramide-use-descriptive-analysis No
Methotrexate, oral
Complete
Complete
wrong frequency dosing errors
Regulatory Outcome, Communication, Results Methods and Development

Low-dose oral methotrexate is associated with wrong frequency dosing errors, when taken once daily instead of the intended once weekly schedule. The Institute for Safe Medication Practices (ISMP) has classified methotrexate (oral, nononcologic use) as a high alert medication that can cause fatal and serious adverse events when mistakenly taken daily. However, the incidence of wrong frequency dosing errors with methotrexate is unknown. A chart confirmed analysis was conducted in one Sentinel Data Partner (Kaiser Permanente Northern California) and found the incidence of low-dose oral methotrexate wrong frequency dosing errors to be 0.4%. FDA used these findings to revise the methotrexate labeling in 2019, which included adding a new Warnings and Precautions section on the risk of improper dosing, removing an option for doses given every 12 hours for 3 days each week, and recommending that patients and caregivers be instructed to take methotrexate as directed as dosing errors have led to fatal toxicity. In July 2020, ISMP highlighted the labeling revision in their Medication Safety Alert! newsletter.

Yes /assessments/drugs/wrong-frequency-errors-low-dose-oral-methotrexate No
Brilinta (ticagrelor)
Complete
Complete
concomitant use with Lipitor (atorvastatin) or Crestor (rosuvastatin)
Regulatory Outcome, Communication, Results Drug Use

This analysis provided information on concomitant utilization of ticagrelor and moderate/high-intensity statins. FDA received postmarket reports of statin-induced myopathy/rhabdomyolysis in elderly patients taking atorvastatin or rosuvastatin with ticagrelor. Considering that use of high-intensity statins is advised in secondary prevention following a myocardial infarction, FDA initiated this analysis to understand utilization patterns for patients concurrently taking ticagrelor and a statin and provide context for postmarket case reports. Our Sentinel analysis found that out of all ticagrelor 90mg exposures in patients ≥75 years, the proportion of concomitant use with high-intensity statins increased from 57% in 2012 to 66% in 2016. Based upon these data and analyses from other sources, FDA decided that no regulatory action was needed at this time.

/assessments/drugs/individual-drug-queries/concurrent-use-ticagrelor-atorvastatin-or-rosuvastatin No
Eliquis (apixaban), Pradaxa (dabigatran), and Xarelto (rivaroxaban)
Complete
Complete Regulatory Outcome, Analytic Code, Communication, Results Drug and Outcome Analysis

Cases of severe uterine bleeding associated with use of novel oral anticoagulants (ACs) have been reported in the FDA Adverse Event Reporting System (FAERS) and the medical literature. FDA conducted a Sentinel study to examine severe uterine bleeding events requiring medical intervention in women treated with oral ACs. Among 1,050,192 new users of oral ACs, the incidence rates of severe uterine bleeding with medical, transfusion, and surgical (e.g., hysterectomy, myomectomy) management were 0.6, 1.7, and 5.0 per 1000 person-years, respectively. These findings contributed to the following class-wide label change for oral ACs in Section 8.3, “The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including [PRODUCT name] should be assessed in females of reproductive potential and those with abnormal uterine bleeding.”

Yes /assessments/drugs/incidence-severe-uterine-bleed-following-novel-oral-anticoagulants-use-descriptive, /assessments/drugs/severe-uterine-bleed-following-novel-oral-anticoagulants-use-propensity-score, /assessments/drugs/individual-drug-queries/incidence-rate-severe-uterine-bleeding-among-new-users No
Uloric (febuxostat)
Complete
Complete
duration of use
user characteristics
Regulatory Outcome, Communication, Results Drug Use

FDA conducted a study to further investigate a post-market clinical trial that identified an elevated risk of cardiovascular events. Sentinel was used to describe the real-world utilization of urate lowering therapies to help inform the committee’s determination that a population exists for whom the benefit-risk is favorable.

Yes /studies/drugs/individual-drug-analyses/characteristics-gout-patients-and-use-urate-lowering, /studies/drugs/individual-drug-analyses/counts-individuals-gout-using-urate-lowering-therapy-ult-and No
Eliquis (apixaban), Pradaxa (dabigatran), and Xarelto (rivaroxaban)
Ongoing
Ongoing
gastrointestinal bleeding
intracranial hemorrhage
major extracranial bleeding
thromboembolic stroke
Analytic Code Drug and Outcome Analysis Yes /studies/drugs/individual-drug-queries/stroke-intracranial-hemorrhage-and-bleeding-following, /studies/drugs/individual-drug-queries/thromboembolic-stroke-major-extracranial-bleeding-0, https://views.sentinelsystem.org/#/SingleAnalysisDashboards/Details/DAE649C8-1794-428F-A54F-FF0E6389EB2D No
Infed (iron dextran), Venofer (iron sucrose), Feraheme (ferumoxytol), Injectafer (ferric carboxymaltose), Monoferric (ferric derisomaltose)
Complete
Complete
exposure in pregnancy
Regulatory Outcome, Results Drug Use

This analysis characterized the frequency of IV iron utilization by week relative to live birth and stillbirth deliveries. Information from this analysis contributed to a class-wide labeling update for parenteral iron products to add new safety information to the Use in Specific Populations, Pregnancy section of the label. This update describes the risk of severe adverse reactions to pregnant women and their fetus.

Yes /assessments/drugs/intravenous-iv-iron-utilization-among-pregnant-women No
Phosphodiesterase type 5 (PDE5) inhibitors
Complete
Complete
exposure in pregnancy
Regulatory Outcome, Communication, Results Drug Use

Use of PDE5 inhibitors was assessed among reproductive age women, including among pregnant women, to investigate a concern arising from an international clinical trial.  FDA decided that no action is necessary at this time, based on available information.

Yes /assessments/drugs/individual-drug-queries/phosphodiesterase-type-5-pde-5-inhibitor-utilization No
Hydrochlorothiazide
Complete
Complete
non-melanoma skin cancer
Regulatory Outcome, Analytic Code, Communication, Results Drug and Outcome Analysis

In response to observational studies showing an elevated risk of non-melanoma skin cancer associated with hydrochlorothiazide (HCTZ) use, FDA assessed the risk of non-melanoma skin cancer for patients treated with HCTZ-containing products compared to non-HCTZ angiotensin-converting-enzyme inhibitor (ACEI)-containing products in the Sentinel System. FDA found HCTZ is associated with an increased risk of non-melanoma skin cancer. In the Sentinel study, increased risk was predominantly for squamous cell carcinoma and in white patients taking large cumulative doses. These findings informed additions to the Adverse Reactions and Information for Patients sections of the label.

Yes /studies/drugs/individual-drug-analyses/non-melanoma-skin-cancer-following-hydrochlorothiazide-use-0, /studies/drugs/individual-drug-analyses/duration-use-among-new-users-hydrochlorothiazide-hctz, /studies/drugs/individual-drug-analyses/non-melanoma-skin-cancer-following-hydrochlorothiazide-use No
Eliquis (apixaban)
Complete
Complete
gastrointestinal (GI) bleed
intracranial hemorrhage
stroke
Analytic Code, Results Drug and Outcome Analysis Yes /assessments/drugs/individual-drug-queries/stroke-gastrointestinal-bleeding-and-intracranial, /studies/drugs/individual-drug-analyses/ischemic-stroke-intracranial-hemorrhage-and-gastrointestinal No
Zantac (ranitidine)
Complete
Complete Regulatory Outcome, Results Drug Use

This analysis provided information on use patterns of prescription ranitidine in patients with Medicare and private health care insurance. These data, in addition to data from other sources, were used to provide context for CDER’s Nitrosamine Impurities Task Force to better understand the use patterns among U.S. individuals. These data also informed the feasibility of a Sentinel analysis to evaluate clinical outcomes associated with prescription ranitidine use.

Yes /assessments/drugs/ranitidine-drug-utilization-patterns No
Gimoti (metoclopramide nasal spray)
Ongoing
Ongoing
adverse central nervous system reactions
tardive dyskinesia
Drug and Outcome Analysis Yes Yes
Singulair (montelukast)
Complete
Complete Neuropsychiatric adverse events consisting of:
inpatient depressive disorder
outpatient depressive disorder
self-harm
suicide
Regulatory Outcome, Analytic Code, Results Drug and Outcome Analysis

FDA presented a Sentinel study at a 2019 Advisory Committee of the risk of mental health side effects with montelukast compared to inhaled corticosteroids (ICS). In this study, FDA did not identify an elevated risk of hospitalized and treated outpatient depressive disorders, self-harm, and suicides among patients aged 6 years and older with asthma using montelukast compared to ICS. FDA also found no evidence that the risk of mental health side effects was modified by the 2008 FDA Early Communication. However, after reviewing the available information and convening a panel of outside experts, FDA strengthened the existing warnings about serious behavior and mood-related changes with montelukast by requiring a Boxed Warning because the benefits of montelukast may not outweigh the risks in patients with mild symptoms who could be adequately treated with other medicines.

Yes /drugs/assessments/neuropsychiatric-events-following-montelukast-use-propensity-score-matched, /studies/drugs/individual-drug-analyses/neuropsychiatric-events-following-montelukast-use No
Opioid analgesics (excluding fentanyl products)
Complete
Complete
duration of follow-up
duration of use
Regulatory Outcome, Results Drug Use

FDA held an Advisory Committee (AC) meeting to discuss the definition of opioid-sparing and opioid-replacement analgesics, with particular attention to acute pain in the post-surgical setting. A Sentinel analysis was conducted to understand the variation in opioid use based upon surgical type. Sentinel data indicated that opioid exposure could be reduced among select surgical populations, particularly those undergoing less invasive procedures. However, the analysis also suggested that longer initial prescription durations might be appropriate in some cases and maintaining flexibility in prescribing options is essential to account for variation in opioid analgesic needs by patient as well as procedure.

Yes /drugs/assessments/optimal-initial-length-opioid-prescription, /drugs/assessments/estimating-optimal-quantities-initial-opioid-analgesic-prescriptions-acute-pain No
Zydelig (idelalisib)
Complete
Complete Regulatory Outcome, Results Drug Use

Because the use of Zydelig in certain treatment regimens led to unacceptable levels of toxicity (pneumonitis, hepatitis, colitis), FDA evaluated the use of Zydelig concomitantly with other antineoplastic agents, in association with the labeled indication as well as other indications. The Sentinel analysis showed low observed rates of Zydelig concomitantly used with therapies which the labeled prescribing information describes as not indicated or not recommended. Based upon these data and analyses from other sources, FDA decided that no regulatory action was needed at this time.

Yes /drugs/assessments/concomitancy-and-indications-idelalisib-use No
Ibsrela (tenapanor)
Ongoing
Ongoing
inflammatory bowel disease (IBD)
Drug and Outcome Analysis Yes Yes
Oxymorphone
Complete
Complete
concomitant use with cytochrome P450 (CYP) enzyme inhibitors
Regulatory Outcome, Communication, Results Drug Use

Drug-drug interactions are an important clinical concern. In a March 2017 Advisory Committee, briefing documents raised the possibility that oxymorphone may be used for a particular niche - patients taking multiple medications - because its metabolism did not involve the hepatic cytochrome P450 system. FDA conducted an analysis to assess whether oxymorphone’s metabolism influenced prescriber practices. Results revealed that similar proportions of patients were dispensed oxymorphone combined with other CYP modifiers relative to reference products, suggesting that drug metabolism differences did not influence prescribing behavior.

Yes /assessments/drugs/individual-drug-queries/concomitant-use-opioid-analgesics-and-cytochrome-p450-cyp No
Higher dosage strength oral and transmucosal opioid analgesic products
Complete
Complete
patient characteristics
utilization patterns
Regulatory Outcome, Results Drug Use

FDA held an Advisory Committee (AC) meeting to better understand the use of higher dose opioid analgesics in the outpatient setting to inform a discussion of potential risk management strategies due to increasing public concern that these products may be more harmful in cases of accidental exposure and overdose, and may be more sought out for misuse and abuse. A Sentinel analysis was conducted to understand the current clinical use of higher dosage strength opioid analgesic products for pain management. Sentinel data indicated that patients on higher dosage strength opioid analgesic products had a higher prevalence of comorbidities, mental health disorders or substance abuse compared to patients on lower dosage strength opioid analgesic products. Moreover, the data showed that use of higher dosage strength products comprised a small proportion of all opioid use and has declined in recent years.

Yes /studies/drugs/individual-drug-analyses/use-higher-dosage-strength-oral-and-transmucosal-opioid, /studies/drugs/individual-drug-analyses/total-enrollment-medical-and-drug-coverage No
Qsymia (phentermine and topiramate extended release)
Complete
Complete
patient characteristics
Regulatory Outcome, Results Drug Use

Contributed important information regarding potentially viable sources of information to evaluate cardiovascular risk.

Yes /drugs/assessments/utilization-patterns-qsymia-phenterminetopiramate No
Non-insulin antidiabetics
Complete
Complete
duration of follow-up
duration of use
Regulatory Outcome, Results Methods and Development

Feasibility assessment that supported an ARIA sufficiency determination to replace a sponsor postmarketing requirement (PMR) safety study for canagliflozin and renal cell carcinoma.

Yes /assessments/drugs/duration-follow-and-treatment-non-insulin-antidiabetic-drugs No
Onglyza (saxagliptin) and Januvia (sitagliptin)
Complete
Complete
acute myocardial infarction (AMI)
heart failure
Analytic Code, Results Methods and Development Yes /drugs/assessments/acute-myocardial-infarction-and-hospitalized-heart-failure-following-saxagliptin No
Dolutegravir (Tivicay and combination products Juluca, Triumeq)
Complete
Complete
exposure in pregnancy
Regulatory Outcome, Communication, Results Drug Use

Based on preliminary results from an observational study suggesting a higher risk of neural tube defects among offspring of pregnant women using dolutegravir (see the FDA Drug Safety Communication below), FDA conducted a descriptive analysis of the prevalence and timing of dolutegravir use among HIV-infected women of childbearing age and HIV-infected women who had pregnancies with live birth deliveries. Prevalence of dolutegravir use among HIV-infected women of childbearing age was substantial, but the absolute number of dolutegravir-exposed pregnancies was very low. Although there was insufficient product exposure in pregnant women to support a robust safety assessment and the Sentinel mother-infant linkage was not yet available, the Sentinel analysis provided broader context regarding dolutegravir use among HIV-infected women who are of childbearing age or who had pregnancies with live birth deliveries.

Yes /assessments/drugs/individual-drug-queries/dolutegravir-use-during-pregnancy No
Ranexa (ranolazine)
Complete
Complete Regulatory Outcome, Analytic Code, Communication, Results Drug and Outcome Analysis

Combined with evidence from the Centers for Medicare & Medicaid Services, risk of seizure was determined to be driven primarily by underlying comorbidities. FDA decided that no action is necessary at this time, based on available information.

Yes /studies/drugs/individual-drug-analyses/seizure-following-ranolazine-use, /studies/drugs/individual-drug-analyses/prevalent-and-incident-dispensings-ranolazine No
Multiple sclerosis (MS) drugs
Complete
Complete
exposure before, during, and after pregnancy
Regulatory Outcome, Communication, Results Drug Use

Contextualized enrollment and recruitment in MS pregnancy registries. Described patterns of drug use before, during, and after pregnancy.

Yes /studies/drugs/individual-drug-analyses/use-multiple-sclerosis-drugs-among-pregnant-women, /studies/drugs/individual-drug-analyses/use-multiple-sclerosis-drugs-among-pregnant-women-live-birth No
Interleukin-1/-6 inhibitors
Complete
Complete
interstitial lung disease
pulmonary arterial hypertension
Regulatory Outcome, Results Drug and Outcome Analysis

Feasibility assessment of ARIA to conduct a postmarket safety study. FDA decided that no action is necessary at this time, based on available information.

Yes /assessments/drugs/individual-drug-queries/pulmonary-arterial-hypertension-and-interstitial-lung No
Forteo (teriparatide)
Complete
Complete Regulatory Outcome, Results Drug Use

Contributed to the decision regarding continuation of sponsor Postmarket Requirement for teriparatide

Yes /assessments/drugs/individual-drug-queries/duration-use-teriparatide No
Annovera (segesterone acetate and ethinyl estradiol vaginal system)
Ongoing
Ongoing Early Detection of:
arterial thromboembolism (ATE)
venous thromboembolism (VTE)
Results Drug and Outcome Analysis Yes /assessments/drugs/individual-drug-queries/venous-and-arterial-thromboembolism-among-new-users Yes
Actemra (tocilizumab)
Complete
Complete
exposure in pregnancy
Regulatory Outcome, Results Drug Use

This study provided information to evaluate reported difficulties in enrollment in ongoing pregnancy registry.

Yes /assessments/drugs/individual-drug-queries/actemra-tocilizumab-utilization-among-pregnant-women No
Multiple
Complete
Complete
drug utilization in pregnancy to evaluate enrollment in pregnancy registries compared with spontaneous reports
Regulatory Outcome, Communication Mini-Sentinel

FDA is using these findings, in addition to input received from the 2014 FDA Public Meeting, to evaluate safety data collection in pregnant women

No
Continuous or extended cycle oral contraceptives
Complete
Complete
venous thromboembolism (VTE)
Regulatory Outcome, Analytic Code, Communication, Results Drug and Outcome Analysis

FDA decided that no action is necessary at this time, based on available information.

Yes /assessments/drugs/individual-drug-queries/combined-oral-contraceptives-containing-ethinyl-estradiol, /assessments/drugs/individual-drug-queries/venous-thromboembolism-following-continuous-or-extended No
Intravenous iron products
Complete
Complete Regulatory Outcome, Results Mini-Sentinel

FDA decided that no action is necessary at this time, based on available information.

No /drugs/assessments/parenteral-iron-and-anaphylactoid-reactions
Onglyza (saxagliptin) and Januvia (sitagliptin)
Complete
Complete
Hospitalized heart failure
acute myocardial infarction (AMI)
Regulatory Outcome, Communication, Results Mini-Sentinel

Advisory Committee Presentation 

No /assessments/drugs/individual-drug-queries/anti-diabetes-drugs-and-acute-myocardial-infarction
Second generation antipsychotic agents
Complete
Complete
Achilles tendon rupture (ATR)
Metabolic effects in children (Type 2 diabetes, metabolic syndrome, weight gain)
Regulatory Outcome, Communication, Results Mini-Sentinel

FDA decided that no new action on behalf of pediatrics is necessary at this time, based on available information.

No /drugs/assessments/metabolic-effects-second-generation-antipsychotics-youth-subprojects-1-2-and-3
None
Complete
Complete
respiratory syncytial virus-associated illness
Regulatory Outcome, Results Other Regulatory

Epidemiological assessment of RSV-AI and patterns of health care utilization to help inform development of novel RSV therapeutics

Yes /studies/drugs/individual-drug-analyses/characterization-pediatric-medical-conditions-respiratory, /studies/drugs/individual-drug-analyses/respiratory-syncytial-virus-pediatric-population, /studies/drugs/individual-drug-analyses/epidemiology-pediatric-respiratory-syncytial-virus No
olmesartan medoximil
Complete
Complete Regulatory Outcome, Results Mini-Sentinel

Safety Labeling Change, Warnings and Precautions; Drug Safety Communication

No /assessments/drugs/individual-drug-queries/drugs-act-renin-angiotensin-aldosterone-system
Pradaxa (dabigatran etexilate)
Complete
Complete
gastrointestinal (GI) bleed
intracranial hemorrhage
Regulatory Outcome, Communication, Results Mini-Sentinel

FDA decided that no action is necessary at this time, based on available information.

No /studies/drugs/individual-drug-analyses/dabigatran-pradaxa-warfarin-and-gastrointestinal-bleed
Xarelto (rivaroxaban)
Complete
Complete
gastrointestinal (GI) bleed
intracranial hemorrhage
ischemic stroke
Regulatory Outcome, Communication, Results Mini-Sentinel

FDA decided that no action is necessary at this time, based on available information.

No /assessments/drugs/individual-drug-queries/prompt-rivaroxaban-surveillance
TNF-alpha inhibitors
Complete
Complete Regulatory Outcome, Communication, Results Drug Use

As part of FDA’s routine review of postmarketing studies, FDA conducted a drug utilization analysis of TNF alpha inhibitors in pregnant women in the Sentinel System. The study found that among pregnant women with a chronic inflammatory condition (ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis, psoriasis, rheumatoid arthritis), there was a preference to use etanercept compared to other TNF alpha inhibitors. For most TNF alpha inhibitors, use during pregnancy decreased after the first trimester. This assessment was one source of evidence considered for the Pregnancy and Lactation Labeling Rule (PLLR) Conversion Safety Labeling Change for Enbrel (etanercept).

Yes /assessments/drugs/individual-drug-queries/anti-tumor-necrosis-factor-tnf-utilization-among-pregnant No
Gadolinium-based contrast agents
Complete
Complete
exposure in pregnancy
Regulatory Outcome, Communication, Results Drug Use

Advisory Committee Presentation & FDA Drug Safety Communication

Yes /drugs/assessments/gadolinium-based-contrast-agents-gbcas-use-pregnancy No
Antipsychotic agents (including haloperidol injection)
Complete
Complete Regulatory Outcome, Analytic Code, Communication, Results Drug and Outcome Analysis

Sentinel data was used to support decisions around potential labeling changes for antipsychotics and stroke risk. FDA decided that no action is necessary at this time, based on available information.

Yes /drugs/assessments/antipsychotics-and-stroke, /assessments/drugs/individual-drug-queries/stroke-following-typical-or-atypical-antipsychotic-use, /assessments/drugs/individual-drug-queries/stroke-following-atypical-antipsychotic-or-z-hypnotic-use No
Ketoconazole oral tablets
Complete
Complete
drug use trends after safety label change and use in labeled indications
Regulatory Outcome, Results Drug Use

Citizen Petition Response

Yes /assessments/drugs/individual-drug-queries/indications-use-among-oral-antifungal-drug-users No
Keppra (levetiracetam)
Complete
Complete
anaphylaxis
angioedema
Regulatory Outcome, Results Mini-Sentinel

Drug Safety Label Change, Warnings and Precautions

No /drugs/assessments/aeds-and-angioedema No