Objective  To mine and analyze the adverse drug event (ADE) signals of ezetimibe monotherapy and its single tablet compound preparation, to provide a basis for clinical medication safety.

Methods  Extract reports of ADE for the specified medications from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, covering the period from the first quarter of 2004 to the fourth quarter of 2024. Signal detection and analysis will be conducted using the following methods: the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the UK Medicines and Healthcare products Regulatory Agency’s (MHRA) algorithm, the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS).

Results  A total of 17,674 ADE reports associated with ezetimibe were included, comprising 12,660 reports for the monotherapy formulation and 5,014 reports for the single tablet compound preparation. The ADE signal numbers for monotherapy formulation and single tablet compound preparation were 234 and 142, involving 27 system-organ classes (SOC), with musculoskeletal and connective tissue disorders being the most frequently reported SOC. Among the top ten ADE by report count, myalgia, muscle spasms, arthralgia, limb pain, blood creatine phosphokinase increase, and rhabdomyolysis were identified as positive signals. ADE such as dyspnea, gait disturbance, and acute kidney injury were not documented in the drug labeling. The risk signal profiles of ezetimibe monotherapy and its single tablet compound preparation were generally consistent overall. However, compared to the monotherapy, the single tablet compound preparation showed an additional positive signal for acute kidney injury, while gastrointestinal ADE (e.g., abdominal pain, upper abdominal pain, and abdominal discomfort) did not emerge as signals for the compound preparation.

Conclusion  The overall safety profile of ezetimibe monotherapy and its single tablet compound preparation is comparable. In clinical practice, it is essential to remain vigilant for the potential cumulative risk of muscle toxicity when ezetimibe is co-administered with statins, and to enhance active monitoring for unlabeled adverse drug events such as dyspnea, gait disturbance, and acute kidney injury.

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