Levothyroxine Sodium – An Overview of Challenges Related to Interchangeability and Stability of Different Formulations

Abstract

Since the early 1950s, oral levothyroxine sodium (L-T4) has been the primary form of treatment for hypothyroidism. There are currently several brands and generic options available to patients, some of which are considered bioequivalent. In the last two decades, however, several reports have shown loss of therapeutic control in patients after switching to a different, albeit bioequivalent, L-T4 product. Such observations can partly be explained by L-T4’s narrow therapeutic index, which means small changes in the dose can lead to therapeutic failure or adverse events. Thyroxine (T4) is also a labile compound and several products have been recalled due to stability or potency issues. These recalls have led regulatory agencies, such as the FDA, to revise the methods used to determine bioequivalence. Notwithstanding, several professional organizations have suggested that the current methods of determining bioequivalence are inadequate for establishing the therapeutic equivalence of levothyroxine sodium products. In addition to bioequivalence concerns, L-T4 tablets have been subject to several recalls due to stability and potency issues. This article examines how formulation properties, excipients, and tablet handling practices can influence the stability of L-T4 tablets. In addition, it provides a summary of L-T4 interchangeability in North America and provides an overview of L-T4 tablets recalls due to sub potency. Finally, it explores some of the challenges with the current method of establishing bioequivalence and discusses some of the risks associated with unintended dose changes of levothyroxine sodium.