Drug Assessments

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.

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.

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.

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 as a risk medication that can cause fatal and harmful errors in patients, despite warnings.  However, the incidence of wrong frequency errors 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 is using these findings to determine appropriate regulatory action. 

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.

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.

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.

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

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.

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.

Drug Safety Label Change, Pregnancy and Lactation

Advisory Committee Presentation & FDA Drug Safety Communication

Feasibility assessment of ARIA sufficiency to replace a sponsor postmarketing requirement (PMR) safety study for Sinuva (mometasone furoate)

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