How Drug–Drug Interaction Studies Inform Drug Labeling: A Survey of US Food and Drug Administration‐Approved New Molecular Entities from 1998 to 2022

Drug-drug interactions (DDIs) are a major cause of adverse drug events and drug inefficacy. To mitigate their clinical burden, it is essential for drug labeling to provide actionable DDI recommendations to clinicians. This investigation analyzed DDI information included in US Food and Drug Administration (FDA) labeling over the past two decades, focusing on DDI management recommendations and the information sources that served as their basis. Data elements were extracted from drug labels and clinical pharmacology reviews for new molecular entities (NMEs) approved by the FDA between 1998 and 2022. Drug labels for 76.2% of NMEs contained ≥1 DDI recommendation, yielding a total of 8,992 unique DDI pairs. Actionable management strategies were recommended for 48.5% of DDI pairs. The most common sources informing DDI recommendations were predictions based on disposition pathways (43.5%) and clinical pharmacokinetic (PK) DDI studies (36.7%). Antivirals (39.2), psychiatry (24.2), and reproduction (23.1) were the therapeutic areas with the most average recommendations per approval, while oncology (71.9%), nephrology (71.4%), and medical imaging (63.6%) were the therapeutic areas with the highest percentages of actionable recommendations. The underlying mechanisms for 75.2% of DDI recommendations involved drug-metabolizing enzymes or drug transporters, with the most common being CYP3A inducers/inhibitors (38.8% of interactions), CYP3A substrates (24.4%), and CYP2C19 inducers/inhibitors (15.8%). The extent of drug exposure changes in PK DDI studies was positively associated with actionable labeling recommendations (P < 0.001). In conclusion, our findings identify considerations to enhance the efficiency and completeness of studying DDIs and communicating DDI management recommendations in drug labeling.