Drug Studies

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.

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.

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.  

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.”

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.

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.

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.

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.

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.

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.

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.

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.”

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.

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.

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.

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.

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

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

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.

FDA assessed the feasibility of conducting a postmarket study in Sentinel to further investigate preliminary results from an observational study suggesting a higher risk of neural tube defects among offspring of pregnant women using dolutegravir (see the related FDA Drug Safety Communication below). The Sentinel query identified insufficient product exposure in pregnant women to support a robust safety assessment.

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.

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

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

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

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

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

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

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

Advisory Committee Presentation 

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

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

Safety Labeling Change, Warnings and Precautions; Drug Safety Communication

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

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

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).

Advisory Committee Presentation & FDA Drug Safety Communication

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.

Citizen Petition Response

Drug Safety Label Change, Warnings and Precautions