Levothyroxine (also known as synthroid) is a synthetic T4 analog commonly used in the treatment of primary, secondary, and tertiary hypothyroidism, and a medication that is often encountered in the Emergency Department. As an NTI (narrow therapeutic index) medication, levothyroxine can have clinically serious side effects if sub- or supratherapeutic doses are taken by the patient including cardiovascular, neurological, gastrointestinal, dermatologic and endocrinological effects. So, what should we know as providers about this commonly used, and potentially dangerous, medication that could influence our ability to treat patients appropriately?

The FDA (Food and Drug Administration) monitors and studies bioequivalence among generic and brand-name oral levothyroxine products produced by different pharmaceutical companies to minimize variability in stability profiles. Per the FDA, “two products are considered to be bioequivalent when they are equal in the rate and extent to which the active pharmaceutical ingredient (API) becomes available at the site(s) of drug action”[5]. Bioequivalence studies compare the efficacy of brand name vs new generic versions of the drug. Initial guidelines in the early 2000s put forth by the FDA recommended a bioequivalence interval of 0.8 to 1.25 with a > 90% confidence interval between comparative levothyroxine products. In other words, two different preparations of levothyroxine (brand name vs. Generic, e.g.) can vary in the amount of active drug by as much as 20% more or less, and still be considered “bioequivalent”[1]. This conclusion hinged on the fact that multiple pharmaceutical manufacturers and professional endocrinologic associations were concerned for endogenous effects and overall T4 and TSH background effects with no regard for dosage adjustments. In outpatient settings, TSH levels are commonly used as the marker for initiating and adjusting levothyroxine dosages in hypothyroid patients.

Thus, multiple studies were performed by the FDA determining whether endogenous TSH (thyroid stimulating hormone) or T4 levels more accurately reflect levothyroxine bioequivalence between brand and generic formulations. All studies ensure that each formulation contains the same amount of active ingredients, and all are rapid-release formulations[2].

In 2005, a systematic review article questioned whether TSH was a better biomarker of levothyroxine bioequivalence. Studies concluded that TSH levels are not an accurate reflection of levothyroxine dosage[2]. Mova Laboratories submitted unpublished data to the FDA in support of this finding, revealing that the baseline variability levels for TSH were 25-26% to that of levothyroxine 10-11% thus confirming TSH levels do not accurately reflect variation in levothyroxine oral formulations[2]. Thus, routine monitoring of both TSH and free T4 levels continue to be the mainstay of both starting and adjusting levothyroxine dosages to avoid clinically poor outcomes for patients. In addition, these studies helped the FDA to find an acceptable range of bioequivalence between oral formulations that should not lead to any clinically significant changes in hypothyroid patients.

Levothyroxine continues to be labeled as an NTI (narrow therapeutic index) drug by the FDA. NTI is defined by the Code of Federal Regulations (CFR) as “There is less than 2-fold difference in median lethal dose (LD50) and median effective dose (ED50), or there is less than 2-fold difference in minimum toxic concentrations and (LD50) and median effective concentrations in the blood.[4]” As an NTI drug, studies have continued to question the concern for clinically poor outcomes in patients not only switching from brand to generic formulations but even between different generic formulations.

In a large comparative effectiveness research study published in JAMA of internal medicine in Feb 2022, researchers compared the proportion of individuals who maintained normal TSH levels in patients continuing with the same generic levothyroxine formulations vs those who switched between generic products. Amongst the 15829 patients enrolled in the study from 2008-2019, the proportion of individuals with normal TSH levels in the control group vs the experimental group was 82.7% vs. 84.5% (p > 0.05) thus suggesting that switching among different generic levothyroxine products was not associated with clinically significant changes in TSH level[3].

Although the FDA continues to tighten the guidelines of bioequivalence of brand vs general oral formulations of levothyroxine, a small number of patients may experience clinically significant side effects of switching formulations. As you continue to develop your clinical decision making, remember to ask the questions if you suspect thyroid-related symptoms:

– Are you on levothyroxine (brand on generic)?

– When did you last fill your prescription of levothyroxine?

– Any recent changes in brand to generic or vice versa of the medication?

– When did you last have your TSH and T4 levels checked?

Written by: Alexandra Sheriff, MD

Peer reviewed and edited by: Dylan Kellogg, MD

References:

[1] Benvenga, S., & Carlé, A. (2019). Levothyroxine Formulations: Pharmacological and Clinical Implications of Generic Substitution. Advances in Therapy, 36(S2), 59–71. https://doi.org/10.1007/s12325-019-01079-1

[2] Bolton, S. (2005). Bioequivalence studies for levothyroxine. The AAPS Journal, 7(1), E47–E53. https://doi.org/10.1208/aapsj070106

[3] Brito, J. P., Deng, Y., Ross, J. S., Choi, N. H., Graham, D. J., Qiang, Y., Rantou, E., Wang, Z., Zhao, L., Shah, N. D., & Lipska, K. J. (2022). Association Between Generic-to-Generic Levothyroxine Switching and Thyrotropin Levels Among US Adults. JAMA Internal Medicine. https://doi.org/10.1001/jamainternmed.2022.0045

[4] Sam Habet, Narrow Therapeutic Index drugs: clinical pharmacology perspective, Journal of Pharmacy and Pharmacology, Volume 73, Issue 10, October 2021, Pages 1285–1291, https://doi.org/10.1093/jpp/rgab102

[5] U.S. Food and Drug Administration. 2022. Bioequivalence. [online] Available at: <https://www.fda.gov/animal-veterinary/abbreviated-new-animal-drug-applications/bioequivalence&gt; [Accessed 23 March 2022].