Growing Pains: Controversies of Levothyroxine

Growing Pains: Controversies of Levothyroxine
Madeleine Davies, PharmD, M Health Fairview Smiley’s Clinic

Background: For decades, leading organizations for thyroid-related conditions have warned against switching between levothyroxine formulations, from brand to generic or even between different generic formulations. In 2004, the American Thyroid Association, Endocrine Society, and the American Association of Clinical Endocrinologists issued a joint statement decrying the Food and Drug Administration’s (FDA) decision to label certain levothyroxine preparations as therapeutic equivalents. Their concerns stem from levothyroxine’s narrow therapeutic window, their recommendations for small dose adjustments (typically 12.5-25 mcg every 6 weeks), and from the FDA’s definition of bioequivalence. Bioequivalence is met when a new drug’s Cmax and AUC is within 80-125% of the reference drug’s ≥90% of the time. With this definition of bioequivalence, a 100 mcg tablet of levothyroxine could contain 80-125 mcg of active ingredient, a range that spans 4 tablet strengths.

Evidence: Despite the concerns of professional organizations, several studies have documented that the large bioequivalence window has minimal clinical relevance. The first of these studies, published in 1997 by Dong et al., showed both the bioequivalence and therapeutic equivalence of Synthroid®, Levoxyl®, and two generic formulations of levothyroxine. This 4-way cross-over study was conducted in 22 women with hypothyroidism; each woman took each levothyroxine formulation for 6 weeks with no washout period. There was no difference in reported symptoms between formulations, and all formulations met FDA bioequivalence standards with each other.

A recent retrospective study of 2780 patients published by Brito et al. in JAMA Int Med studied the implications of switching between generic levothyroxine products based on information obtained from a national database of commercially insured or Medicare Advantage patients. Patients were included in the study if they continued to receive the same stable dose of levothyroxine for three months prior to and at least six weeks after switching manufacturers, they had at least one thyroid stimulating hormone (TSH) value in normal range (defined as 0.3-4.4 mIU/L) prior to the switch, and TSH was recorded six weeks to 12 months after the switch. These patients were compared to a matched cohort of patients who were maintained on the same levothyroxine generic. There was no significant difference in patients who maintained normal TSH values between those who were maintained on the same manufacturer of levothyroxine and those who switched (82.7% vs 84.5%, P=0.07). A subgroup analysis of patients on ≥100 mcg/day of levothyroxine showed similar rates of normal TSH levels between those who did not switch and those who did (70.9% vs. 76.6%, P=0.08).

Discussion & Clinical Impact: Controversy of levothyroxine product interchangeability has existed for decades. According to King’s 1996 article, Dong et al.’s paper was originally pulled from publication due to the study sponsor threatening legal action if it was published. The sponsor, then-maker of Synthroid®, had selected Dong as lead investigator since she had previously published articles on the lack of bioequivalence between levothyroxine products. The results of the study defied expectations, and multiple studies have since indicated bioequivalence between multiple levothyroxine products. Although guidelines are slow to change, prescribers and dispensers of levothyroxine can reassure their patients that a change in manufacturer is unlikely to warrant close monitoring of thyroid levels.

References:

  1. American Thyroid Association, Endocrine Society, American Association of Clinical Endocrinologists joint statement on the U.S. Food and Drug Administration’s decision regarding bioequivalence of levothyroxine sodium. Thyroid. 2004;14:486.
  2. Brito JP, Deng Y, Ross JS, et al. Association between generic-to-generic levothyroxine switching and thyrotropin levels among US adults. JAMA Int Med. 2022;182(4)418-425. doi:10.1001/jamainternmed.2022.0045.
  3. Dong BJ, Hauck WW, Gambertoglio JG, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA. 1997;277(15);1205-1213. doi:10.1001/jama.1997.03540390035032.
  4. King R. How drug firm paid for study by university, then yanked it. Wall Street Journal. April 25, 1996. Accessed May 11, 2022. https://www.wsj.com/articles/SB83038763545145500?reflink=desktopwebshare_permalink.