Association between generic-to-generic levothyroxine switching and thyrotropin levels among US adults.
Open accessAbstract
IMPORTANCE: Switching among generic levothyroxine sodium products made by different manufacturers typically occurs at the pharmacy and may affect serum thyrotropin (TSH) levels. OBJECTIVE: To compare TSH levels between patients who continued taking the same sourced generic levothyroxine product and those who switched. DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness research study with 1:1 propensity matching used data from OptumLabs Data Warehouse, a national administrative claims database linked to laboratory test results. Adults aged 18 years or older were included if they filled a generic levothyroxine prescription between January 1, 2008, and June 30, 2019, and had a stable drug dose, the same drug manufacturer, and a normal TSH level (0.3-4.4 mIU/L) for at least 3 months before either continuing to take the same product or switching among generic levothyroxine products (index date). Patients were excluded if they were pregnant, had diagnosed hypopituitarism or hyperthyroidism, or had a medical condition or used medications that could affect thyrotropin levels. They were also excluded if they filled a prescription for other forms of thyroid replacement therapy between 6 months before the index date and when the first TSH level was obtained 6 weeks to 12 months after the index date. Data were analyzed from December 1, 2019, to November 24, 2021. MAIN OUTCOMES AND MEASURES: Proportion of individuals with a normal (0.3-4.4 mIU/L) or markedly abnormal (<0.1 or >10.0 mIU/L) TSH level using the first available laboratory result 6 weeks to 12 months after the index date. A propensity score model was developed to minimize confounding using logistic regression with the binary outcome of continuing the same sourced levothyroxine product vs switching generic levothyroxine. Covariates were demographics, comorbidities, and baseline TSH level. The balance among the treatment groups was evaluated by comparing standardized mean differences of baseline covariates between the groups. RESULTS: A total of 15 829 patients filled generic levothyroxine (mean [SD] age, 58.9 [14.6] years; 73.4% [11 624] were women; 4.5% [705] were Asian, 10.2% [1617] were Black, 11.4% [1801] were Hispanic, and 71.4% [11 295] were White individuals); of these patients, 56.3% [8905] received a daily levothyroxine dose of 50 μg or less. A total of 13 049 patients (82.4%) continued taking the same sourced preparation, and 2780 (17.6%) switched among generic levothyroxine preparations. Among 2780 propensity-matched patient pairs, the proportion of patients with a normal TSH level after the index date was 82.7% (2298) among nonswitchers and 84.5% (2348) among switchers (risk difference, -0.018; 95% CI, -0.038 to 0.002; P = .07). The proportion of patients with a markedly abnormal TSH level after the index date was 3.1% (87) among nonswitchers and 2.5% (69) among switchers (risk difference, 0.007; 95% CI, -0.002 to 0.015; P = .14). The mean (SD) TSH levels after the index date were 2.7 (2.3) mIU/L among nonswitchers and 2.7 (3.3) mIU/L among switchers (P = .94). CONCLUSIONS AND RELEVANCE: Results of this comparative effectiveness research study suggest that switching among different generic levothyroxine products was not associated with clinically significant changes in TSH level. These findings conflict with the current guideline recommendation that warns clinicians about potential changes in TSH level associated with switching among levothyroxine products sourced from different manufacturers.
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The Brito et al. study was based on an administrative claims database linked to laboratory test results, which may conceal confounding issues, and was carried out on generic preparations widely used in US and much less in Europe.
“However, the study from Brito et al. was based on ‘an administrative claims database linked to laboratory test result’. Therefore, this approach may conceal several confounding issues, and this work was carried out on generic preparations, widely used in US and much less in Europe.”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [38]
Study Design and Data Source describes US administrative claims linked to laboratory results, and Limitations acknowledges that residual confounding may remain. Baseline Characteristics and Exposures identifies the studied generics as the most commonly prescribed in the US market. Our copy does not establish that generic preparations are used much less in Europe. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSwitching among generics is not associated with clinically significant changes in TSH level according to Brito et al. in a study of some 16,000 patients.
“Switching among generics is not associated with clinically significant changes in TSH level for Brito et al. in a study encompassing some 16,000 patients (38)”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [38]
In 2 comparative effectiveness studies, switching levothyroxine products was not associated with clinically significant changes in thyrotropin level; one study compared generic vs brand-name levothyroxine among 17,598 US adults and the other compared switching among different generic levothyroxine products in 15,829 US adults.
“However, in 2 comparative effectiveness studies, 64,65 switching was not associated with clinically significant changes in thyrotropin level; one of the studies included a comparison of generic vs brand-name levothyroxine among 17 598 US adults and the other study included switching among different generic levothyroxine products in 15 829 US adults.”
From Hypothyroidism: A Review (2025) · cites this paper as [64]
In 2022, a comparative effectiveness study using data from a national database found no significant difference in TSH levels between 2780 individuals who switched among generic LT4 preparations and 2780 propensity-matched controls.
“Interestingly, in 2022, a comparative effectiveness study using data from a national database provided conflicting results (120). By comparing 2780 individuals who switched among generic LT4 preparations with 2780 propensity-matched controls, no significant difference was detected in TSH levels.”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [120]
A 2022 study of 15,829 hypothyroid patients from 2008 to 2019 found that switching between different generic levothyroxine products did not produce clinically significant TSH changes.
“Conversely, in 2022, a study evaluating 15 829 hypothyroid patients undergoing LT4 treatment was published, covering the period from 2008 to 2019.This investigation elucidated that switching between disparate generic LT4 products did not yield clinically significant variations in TSH levels.”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [48]
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- Authors
- 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.
- Affiliations
- Mayo Clinic (US)
- Yale New Haven Hospital (US)
- United States Food and Drug Administration (US)
- Yale University (US)
- Corresponding author
- Brito, Juan P.
- ORCID
- Venue
- JAMA Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2022-04-01
- Volume
- 182
- Issue
- 4
- Pages
- 418
- ISSN
- 2168-6106 (ISSN-L)
- PMC
- PMC8886450
- OpenAlex
- W4214532034
- Cited by
- 29
- References
- 16
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 10
- FWCI
- 4.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Internal Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR001863)
- U.S. Food and Drug Administration (U01FD005938)
- Center of Excellence in Regulatory Science and Innovation
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Social Sciences › Economics, Econometrics and Finance › Economics and Econometrics › Pharmaceutical Economics and Policy
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- levothyroxine, generic drug switching, thyroid-stimulating hormone, TSH levels, thyroid hormone replacement, thyroid function monitoring, hypothyroidism, medication adherence, prescription refills, comparative effectiveness, United States, propensity score matching, standardized mean difference
- MeSH terms
- Adult, Aged, Female, Humans, Male, Middle Aged, Pregnancy, Retrospective Studies, Thyrotropin, Thyroxine, Drugs, Generic, Hormone Replacement Therapy, Drug Substitution
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