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.
concomitant use with cytochrome P450 (CYP) enzyme inhibitors
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.
Higher dosage strength oral and transmucosal opioid analgesic products
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.
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.
Dolutegravir (Tivicay and combination products Juluca, Triumeq)
exposure in pregnancy
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.