Comparative pharmacovigilance assessment of mortality with pimavanserin in Parkinson disease-related psychosis

BACKGROUND: Pimavanserin is approved for treatment of Parkinson disease (PD)-related psychosis, but its use has been associated with an increased risk of death during clinical trials, as well as during postmarketing surveillance. Previous reports on the association between pimavanserin and mortality have not taken into account limitations of data sources nor included comparable populations or comparisons to relevant treatment alternatives. OBJECTIVE: To conduct a comparative pharmacovigilance assessment of pimavanserin vs treatment alternatives and by restricting surveillance data to more representative populations. METHODS: This was a retrospective analysis of adverse event case reports submitted to the FDA’s Adverse Event Reporting System (FAERS) from 2016 through 2019 quarter 3 (Q3). FAERS data are collected from the full population, were further restricted to only those with PD, and were based on PD medication use. Reports were assessed for exposure to pimavanserin, clozapine, quetiapine, haloperidol, and other atypical antipsychotics. The outcome of interest was all-cause death. A proportional reporting ratio (PRR) and 95% confidence limits were calculated for each 2 by 2 contingency of outcome (death) and exposure (pimavanserin and others). For each outcome/exposure pair, the baseline population was altered to include the full FAERS sample, only reports with PD, reports with PD treated with levodopa, and reports with PD treated with multiple PD medications. The sample was also stratified by time period before April 2018 and after September 2018 to capture periods of public knowledge and federal response. A lower 95% CI (Lower95CI) ≥ 2 for the PRR was considered as the accepted threshold for a drug safety signal. RESULTS: As of 2019 Q3, there were 2,287 reports of death associated with pimavanserin. Compared within the full FAERS base population, pimavanserin yielded a PRR Lower95CI = 2.08 but was smaller when restricted to comparison among only a base population with PD (Lower95CI = 1.09), PD treated with levodopa (Lower95CI = 1.15), or PD treated with multiple PD medications (Lower95CI = 1.63). Metrics for quetiapine, clozapine, and other atypical antipsychotics were similar in magnitude. Stratification by time showed a possible reporting bias associated with pimavanserin, since no safety signal was detected before April 2018; however, a signal was present thereafter. CONCLUSIONS: Compared in context with treatment alternatives for patients with PD, pimavanserin was not associated with excess reports of death in the FAERS data. This information should be used in shared decision making between physicians and PD patients to balance the risks and benefits of pimavanserin and other treatments for PD psychosis.