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Abstract Purpose: Older adults are vulnerable to adverse drug reactions (ADRs) and drug-drug interactions (DDIs). Evidence on clinically-manifest DDIs in older outpatients is scanty. The present study aims to report clinically-manifest DDIs, their risk factors, and preventive measures. Methods: This was a subgroup analysis of a six-year (2015–2021) long prospective study conducted in a tertiary hospital in North India. Older outpatients with ADRs constituted the study participants. Results Among 933 ADRs reported in 10400 patient registrations, clinically-manifest DDIs occurred in 199 (21.3%). DDIs accounted for 29.9%, 26.5%, and 21.3% of drug-related metabolic, vascular, and nervous system disorders respectively. Movement disorders (n = 18), hypotension (n = 16), and hypoglycemia (n = 15) were the common manifestations. 86% of DDIs were pharmacodynamic type and 13.1% were immune-mediated. Around 35% of DDIs required hospitalization with hyponatremia, movement disorders, and acute kidney injury as the common reasons. Older adults with Parkinsonism, acute infection, coronary artery disease, neuropsychiatric illness, and diabetes respectively had 3.14, 2.78, 1.97, 1.82-, and 1.77 times higher odds of DDIs. Those receiving ≥ 10 drugs had 5.33 times higher odds of DDIs compared to individuals receiving 1–4 drugs. ‘Avoiding the causative drug’, ‘optimal monitoring of the patient’, and ‘start-low and go-slow’ policy together, could prevent 85% of DDIs. Conclusions Every-fifth case of ADRs and nearly one-third of ADR-related hospitalizations in older adults are related to DDIs. Movement disorders, hypotension, and hypoglycemia are the common manifestations. A holistic approach with drug omission, optimal patient monitoring, and slow titration of therapy can prevent significant DDIs in the old.

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