Background: Levothyroxine (LT4) is the standard treatment for hypothyroidism and is generally required lifelong. As a narrow therapeutic index medication, relatively small variations in LT4 exposure may result in clinically relevant changes in thyroid-stimulating hormone (TSH) concentrations. Switching between branded and generic products or between different manufacturers may occur because of drug availability, procurement policies, formulary changes, or cost considerations. Although switching appears clinically acceptable for many patients at the population level, individual variability remains a concern, particularly in patients requiring tight biochemical control. In Saudi Arabia, differences in procurement systems, formularies, and medication availability across healthcare sectors create a need for standardized national recommendations on LT4 replacement, switching, and monitoring. Objective: To develop multidisciplinary, evidence-based, and context-specific Saudi consensus recommendations for optimizing levothyroxine replacement therapy, with particular emphasis on formulation consistency, safe switching, post-switch monitoring, high-risk populations, and pharmacy-level substitution. Methods: A structured review of international guidelines, regulatory documents, systematic reviews, clinical trials, observational studies, and pharmacological evidence addressing LT4 pharmacology, bioequivalence, formulation switching, and thyroid-function variability was undertaken. A multidisciplinary Saudi expert panel comprising endocrinologists, internal medicine physicians, pharmacists, methodologists, and healthcare policy, regulatory, and pharmaceutical-services leaders reviewed the evidence and developed consensus statements relevant to the Saudi healthcare setting. Consensus was established using a modified Delphi process with sequential anonymous electronic voting on a 9-point Likert scale. Statements were revised based on panel feedback when required, and a strong consensus was predefined as ≥ 80% agreement. Results: The panel developed recommendations addressing LT4 formulation consistency, indications for switching, biochemical monitoring, management of high-risk populations, and pharmacy substitution. The consensus recommends maintaining patients on the same LT4 product once biochemical stability has been achieved and limiting switching to clinically or operationally justified circumstances, such as product unavailability, intolerance to excipients, or relevant cost considerations. When switching is unavoidable, serum
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