Background/Objectives: Biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) have expanded treatment options for inflammatory rheumatic diseases, highlighting the need for continuous pharmacovigilance. This study evaluated changes in prescribing patterns and safety profiles of b/tsDMARDs between 2018–2019 and 2023–2024 in routine clinical practice. Methods: A retrospective observational study was conducted in patients with rheumatoid arthritis (AR), psoriatic arthritis (PsA), ankylosing spondylitis (AS), or juvenile idiopathic arthritis (JIA) treated at a rheumatology outpatient clinic in Southern Italy. Demographic and clinical characteristics, prescribed therapies, treatment switches/swaps, therapeutic failures, and adverse events (AEs) were collected through a structured pharmacovigilance program. Prescribing trends between the two study periods were compared using chi-square analysis. Results: A total of 342 patients were included (202 in 2018–2019 and 140 in 2023–2024). Prescribing patterns changed significantly over time (χ² = 83.24, p < 0.0001), with increased use of newer therapeutic classes and biosimilars, while tumor necrosis factor (TNF) inhibitors remained the most frequently prescribed drugs. The proportion of biologic-naïve patients increased from 52.0% to 66.4%, whereas AEs decreased from 31.7% to 15.0%, with no serious adverse events (SAEs) reported. Conclusions: Prescribing strategies for inflammatory rheumatic diseases evolved substantially between 2018 and 2024, reflecting the availability of new therapeutic options and a more personalized treatment approach. b/tsDMARDs showed a favorable real-world safety profile, supporting the importance of ongoing pharmacovigilance.