Mining Safety Signals of Letermovir Drug Combinations: Real-World Pharmacovigilance Analysis

Letermovir (LMV) is vital for cytomegalovirus prevention in transplant recipients, but its safety and drug-drug interactions (DDI) related adverse event (AE) risks require further investigation. This study conducted a pharmacovigilance analysis to identify novel AE signals of LMV and assess DDI-related AEs with commonly co-administered drugs. AE reports from 29 quarters, from the launch of LMV to the fourth quarter of 2024, were collected from the Food and Drug Administration Adverse Event Reporting System for analysis. Two statistical models (reporting odds ratio [ROR] method and medicines and healthcare products regulatory agency) were used to identify AEs meeting the threshold, which were then compared with LMV drug labels and designated medical event (DME) risk signals. Four models were applied to detect potential AE signals related to LMV combination use, and DDI-related AEs and DMEs were analyzed in conjunction with single-drug mining results. Finally, 54 LMV AE signals were identified, of which 4 AE signals had appeared in the LMV drug labels, namely edema (ROR = 3.69), acute heart failure (ROR = 14.48), pericardial effusion (ROR = 4.77), and atrial fibrillation (ROR = 3.61). Among the remaining new AE signals, AEs with stronger ROR values included herpetic gastritis (ROR = 23,772.49), human herpesvirus 6 encephalitis (ROR = 214.17), and acute graft-versus-host disease (aGVHD) in skin (ROR = 190.2). Eight DME signals of LMV were determined, such as hepatic failure, drug-induced liver injury, renal failure, and acute kidney injury (AKI). In the DDI analysis, 279 DDI-related AE signals meeting all four model criteria were identified. Among 28 drugs commonly co-administered with LMV, immunomodulatory agents contributed the highest proportion of signals (34.4%, 96/279), with cyclosporine associated with the most AE types (10.4%, 29/279). The most frequent AEs included aplastic anemia (4.3%), esophagitis (3.9%), and renal failure (3.6%). There was a positive AE signal difference when LMV was combined with cyclosporine or tacrolimus. When used in combination with cyclosporine, in addition to cardiac events and peripheral edema listed in the LMV drug label, DME signals such as pancytopenia, febrile neutropenia, AKI, and hepatic failure may also occur; when used in combination with tacrolimus, one needs to be alert to the occurrence of aGVHD in skin/intestine. LMV use may induce cardiac AE signals such as acute heart failure, pericardial effusion, and atrial fibrillation, and may increase the risk of herpes virus reactivation. When LMV is used in combination with drugs such as cyclosporine or tacrolimus, it may exacerbate hepatic and renal toxicity. Acute heart failure and atrial fibrillation AE signals were detected when combined with cyclosporine. Future efforts should focus on the safety of LMV in clinical practice and real-world settings, with optimized medication strategies to minimize risks and enhance therapeutic outcomes.