The present study describes a comprehensive analysis of the Adverse Drug Reactions (ADRs) documented in the Database of the Spanish Pharmacovigilance System (FEDRA) concerning the use of biological medications used for severe refractory asthma, specifically omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and tezepelumab. Emphasis was placed on ADRs not documented in the Technical Sheet (Summary of Product Characteristics, SmPC) of the respective specialties (Xolair®, Nucala®, Cinqaero®, Fasenra®, Dupixent®, and Tezspire®), which could potentially trigger a warning signal in Pharmacovigilance, indicating previously unidentified risks. The analysis encompassed data from the inception of each drug ́s marketing until January 22, 2024, including cases originating from various sources: direct submissions to the Spanish Pharmacovigilance System, communications from the Pharmaceutical Industry, and findings from literature review. Notifications were analyzed independently of their origin, so a complete review of all ADRs associated with these medications was ensured. In essence, this investigation highlights the critical role of post-marketing safety information, emphasizing the relevance of comprehensive reporting by healthcare professionals to facilitate a robust Pharmacovigilance system, ultimately advancing patient care and safety.