Introduction: The combination of BRAF and MEK inhibitors (BRAF/MEKi) has significantly improved survival in melanoma patients with BRAF V600 mutations. However, these agents can cause cardiovascular (CV) toxicity, compromising efficacy. This study evaluated the CV adverse events (cAEs) associated with BRAF/MEKi using the U.S. FDA Adverse Event Reporting System (FAERS) to identify new signals of disproportionate reporting (SDRs). Methods: Descriptive and disproportionality analyses were conducted on reports listing dabrafenib (D), vemurafenib (V), encorafenib (E), trametinib (T), cobimetinib (C), or binimetinib (B) as suspects in monotherapy or combination therapy (D + T, V + C, E + B), with melanoma as the indication and at least one cAE. Standardized MedDRA Queries (SMQs) related to cAEs, including bradyarrhythmias and tachyarrhythmias, cardiac failure, cardiomyopathy, thrombotic events, ischaemic heart disease, and myocarditis/pericarditis, were analyzed. Results: Of the 14,077,067 reports retrieved, 18,370 (0.1%) were linked to BRAF/MEKi, with 1591 (8.7%) reporting cAEs, primarily in combination therapy (n = 1268). Disproportionality analysis identified 64 clinically relevant SDRs, most of which were unexpected. Notable findings included bradyarrhythmias, such as QT prolongation with D + T (n = 59; Reporting Odds Ratio, ROR = 5.09, 95% Confidence Interval, CI = 3.94–6.58), cardiac failure with V + C (29; 3.76, 2.6–5.42), and tachyarrhythmias, particularly atrial fibrillation with D + T (99; 2.37, 1.94–2.89). Among embolic and thrombotic events, clinically significant SDRs were observed for disseminated intravascular coagulation with D + T (38; 10.22, 7.42–14.06) and pulmonary embolism with V + C (22; 2.79, 1.83–4.24). Conclusions: Our findings underscore the need for comprehensive CV monitoring in patients receiving BRAF/MEKi therapy to prevent or detect cAEs early and reduce treatment-related risks, particularly in high-risk populations.

Awareness related to the risk/benefit profile of therapies used in paediatric and elderly patients is limited. We carried out a study, called the MEAP 3.0 study, to collect and analyse evidence of adverse drug reactions (ADRs) and drug–drug interactions (DDIs) that occurred in frail populations under polypharmacy in a real-world setting. Data were retrieved from reports of ADRs and pharmacological counselling from patients treated in hospitals and territorial health services. We collected 2977 ADRs reports and identified ‘anti-infectives for systemic use’ and ‘cardiovascular system’ as the most frequently implicated pharmacological classes in under-18 and over-65 patients, respectively. We detected 2179 DDIs, of which 10.7% were related to at least one ADR: 22 were classified as ‘contraindicated’ (7 in the paediatric group and 15 in the elderly one), and 61 as ‘major’ (6 in the paediatric patients and 55 in the geriatric ones), while 151 DDIs were classified as ‘moderate’ (10 referred to paediatric population, and 109 to elderly patient) and as ‘minor’ (1 in paediatric patients, and 31 in the elderly ones). The MEAP 3.0 project demonstrates that pharmacovigilance surveillance and therapeutic reconciliation are valid strategies to avoid potential DDIs and the occurrence of ADRs, allowing for personalised medicine.