Drug shortages as a medication-safety problem: clinical impact, therapeutic substitutions, and mitigation strategies

Abstract

Drug shortages have become a recurrent feature of modern pharmacotherapy and should be conceptualised as a medication-safety problem rather than a purely logistical supply issue. I synthesised PubMed-indexed evidence (search and verification date: 10 February 2026) spanning scoping reviews, systematic reviews, pharmacovigilance analyses, observational outcome studies, and policy analyses to evaluate clinical consequences of shortages, safety risks from therapeutic substitutions, and mitigation strategies at clinical and system levels. The evidence indicates that shortages frequently involve high-consequence drug classes (generic sterile injectables, antibiotics, oncology agents) and generate harm through delayed/omitted therapy, forced substitution with unfamiliar agents or concentrations, and increased system complexity. Patient-important outcome signals include higher mortality during the US norepinephrine shortage in septic shock care (absolute risk increase 3.7%; adjusted OR 1.15) and worsened oncology outcomes during an intravenous etoposide shortage (increased hospitalisation and shorter progression-free survival). Pharmacovigilance studies demonstrate that shortages are associated with adverse drug reactions, medication errors, disease worsening, and serious outcomes including deaths or life-threatening events, with replacement drugs commonly implicated. Mitigation strategies with the strongest practical support are structured therapeutic interchange protocols led by pharmacists and stewardship teams (notably antimicrobial stewardship for antibiotic shortages), standardised order sets and concentration controls, active monitoring for substitution-related ADRs and errors, and transparent prioritisation frameworks for scarce curative therapies. India/LMIC evidence highlights that prolonged public-sector stock-outs and variable availability of essential medicines shift patients towards private procurement and informal substitution, requiring governance, procurement and distribution reforms alongside local inventory and digital visibility tools. Overall, shortage preparedness should be integrated into medication-safety programmes with explicit contingency pathways, audit of shortage-driven adverse events, and system-level supply resilience policies.