Per the Food and Drug Administration (FDA), findings from several recent studies (see Tables 1 and 2) found no difference in clinical response between brand or generic levothyroxine products. The FDA classifies levothyroxine as a narrow therapeutic index agent and emphasized its current, rigorous bioequivalence standards. In response to growing concerns regarding levothyroxine bioequivalences, however, the FDA formed a task force to investigate, requesting and receiving stability data from manufacturers of all the approved, marketed levothyroxine 2003 and 2005 to examine the stability profile of each drug. They found a trend toward a loss of potency, with some preparations showing potency approaching 90 percent of labeled potency by the expiration date. While approved levothyroxine sodium products fall within the current potency specification 90-110%, the stability data showed that some products rapidly degrade over their labeled shelf life. This loss in potency varied drastically between different manufacturers. For example, some levothyroxine sodium tablets remained "very stable," losing less than 5% of labeled potency within 24 months, while other products lost approximately 10% of labeled potency in 9 months. In 2007, the FDA tightened the potency window for levothyroxine products from 90-110% to 95-105% potency specification until the expiration date. [1], [2]
In a 2004 position statement on the interchangeability of levothyroxine products, the American Thyroid Association (ASA), the Endocrine Society, and the American American Association of Clinical Endocrinologists (AACE) expressed concern over the FDA's bioequivalence process. They recommended patients should be maintained on the same brand name levothyroxine product. If the brand of levothyroxine medication is changed, either from one brand to another brand, from a brand to a generic product, or from a generic product to another generic product, patients should be retested by measuring serum thyroid-stimulating hormone (TSH) in six weeks. Minute changes in levothyroxine administration may contribute to significant changes in TSH serum concentrations, and thus precise and accurate TSH control is crucial in avoiding potential adverse iatrogenic effects. [3]
The ASA’s 2014 clinical guidelines for the treatment of hypothyroidism recommend a prescription of brand name levothyroxine or alternative maintenance of the same generic preparation (i.e., maintenance of an identifiable formulation of levothyroxine). Switches between levothyroxine products could potentially result in variations in the administered dose and should generally be avoided for that reason (weak recommendation, low-quality evidence [for general populations]; strong recommendation, low-quality evidence [frail patients, high-risk thyroid cancer patients, pregnant patients]; strong recommendation, moderate-quality evidence [early childhood hypothyroidism]). The ASA also states the use of different levothyroxine products may sometimes be associated with altered serum TSH values, a change in an identifiable formulation of levothyroxine (brand name or generic) should be followed by re-evaluation of serum TSH at steady state. (weak recommendation, low-quality evidence). [4]
The European Thyroid Association (ETA) and Thyroid Federation International (TFI) have also released a joint position statement in 2018 on the interchangeability of levothyroxine products. Though not specific to Synthroid and instead focused on European levothyroxine products, the statement notes that switching between levothyroxine brands has been correlated with an increase in health issues and medication-related adverse effects, and that testing bioequivalence does not necessarily correlate with continued euthyroidism if a patient receives a levothyroxine formulation change. Thus, the statement recommends that patients should be maintained on the same formulation or brand name of levothyroxine, with blood testing conducted at a follow-up of 6 weeks to determine if dosage adjustments are required. [5]