Use of FDA’s Sentinel System to Quantify Seizure Risk Immediately Following New Ranolazine Exposure
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Neurological complications including seizures have been reported with ranolazine. We sought to quantify the risk of seizure-related hospitalizations or emergency department events following ranolazine exposure in the Sentinel System (2006–2015).
Study Design and Setting
Eligibility criteria were new use of ranolazine after 183 days washout period and absence of seizure diagnoses, anti-epileptic drugs, or seizure-related disorders during the baseline period.
Among 52,155 ranolazine users, we identified 28 seizures in the 1–32 days after new ranolazine dispensing: 12 occurring in days 1–10 (high-risk window), 11 in days 11–20 (moderate-risk window) and 5 in the control window (days 21–32). Assuming an equal likelihood of seizure events across the 32-day observation window, we estimate an attributable risk of 0.9 excess cases per 10,000 exposed users. Using a self-controlled risk interval design with exact logistic regression, seizures were elevated in the high-risk window (relative risk [RR] 2.88 (95% confidence interval [CI] 1.01–8.33) compared with the control window. No significant increased risk was observed in the moderate window. Half of the seizure cases had a diagnosis of renal disease, although seizure risk was not significant (RR 3.20 [CI 0.82–14.01]). A majority of patients in both risk windows were 75 years or older.
Our study suggests risk among younger ranolazine patients is rare. Given the imprecision of the risk estimates, we interpret the elevated seizure risk following ranolazine exposure with caution. Further analysis in a larger elderly population is warranted.
The views expressed in this paper are those of the authors and are not intended to convey official US Food and Drug Administration policy or guidance. Many thanks to the Data Partners who provided data used in the analysis: Aetna, Blue Bell, PA; Blue Cross Blue Shield of Massachusetts, Boston, MA; Harvard Pilgrim Health Care Institute, Boston, MA; HealthCore, Inc., Translational Research for Affordability and Quality, Alexandria, VA; HealthPartners Institute, Minneapolis, MN; Humana, Inc., Comprehensive Health Insights, Miramar, FL; Kaiser Permanente Colorado Institute for Health Research, Denver, CO; Kaiser Permanente Center for Health Research Hawai’i, Honolulu, HI; Kaiser Permanente Mid-Atlantic States, Mid-Atlantic Permanente Research Institute, Rockville, MD; Kaiser Permanente Northern California, Division of Research, Oakland, CA; Kaiser Permanente Northwest Center for Health Research, Portland, OR; Kaiser Permanente Washington Health Research Institute, Seattle, WA; OptumInsight Life Sciences Inc., Boston, MA; Vanderbilt University Medical Center, Department of Health Policy, Nashville, TN, through the Tennessee Division of TennCare of the Department of Finance and Administration, which provided data. Many thanks to Andrew Petrone for programming support and Nicole Haug for analytic support.
Compliance with Ethical Standards
Conflict of interest
Efe Eworuke has no conflicts of interest that are directly relevant to the content of this study. Emily C. Welch has no conflicts of interest that are directly relevant to the content of this study. Anne Tobenkin has no conflicts of interest that are directly relevant to the content of this study. Judith C. Maro has no conflicts of interest that are directly relevant to the content of this study.
This project was supported by Task Order HHSF22301012T under Master Agreement Health and Human Services: HHSF223201400030I from the US Food and Drug Administration (FDA).
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