Reassuring Findings About Switching Among Generic Versions of the Thyroid Drug Levothyroxine

Levothyroxine is one of the most commonly used prescription medications in the U.S.[1] It is primarily used as a replacement therapy in patients with various types of hypothyroidism (underactive thyroid).[2]

This drug is available in brand-name (EUTHYROX, LEVOLET, LEVO-T, LEVOXYL, SYNTHROID, THYQUIDITY, THYRO-TABS, TIROSINT, TIROSINT-SOL, UNITHROID) and less expensive generic products that are made by different drug manufacturers.

The range between therapeutic and toxic concentrations of levothyroxine in the blood is narrow,[3] which has historically raised concerns regarding whether various levothyroxine products differ in their potency. Therefore, the Food and Drug Administration (FDA) has tightened its requirements for all levothyroxine products to ensure that all approved generic levothyroxine products are just as safe and effective as brand-name ones and thus can be used interchangeably with them.[4],[5]

However, clinical practice guidelines from the American Thyroid Association that are based on low-quality evidence recommend the use of either a brand-name levothyroxine or a generic product of the drug from the same manufacturer from refill to refill in the general population of hypothyroidism patients.[6] Furthermore, these guidelines indicate that switching between levothyroxine products can possibly result in variations in the administered dose and should be avoided to the extent possible. For patients who switch levothyroxine products, the guidelines recommend that they be tested to make sure that the drug’s level in the blood remains within the normal range.

In current practice, however, pharmacists dispense the exact brand-name levothyroxine when the prescriber designates it as “dispensed as written.” Otherwise, pharmacists can substitute generic levothyroxine products from different manufacturers without notification or approval of prescribers.

Findings from a new retrospective, real-world observational study that assessed switching among the most common generic levothyroxine products made by different manufacturers in the U.S. suggest that switching among these products is unlikely to have a substantial impact on treatment effects.

The study was conducted by FDA scientists in collaboration with researchers from the Mayo Clinic, Yale University and OptumLabs. It was published in the April 1, 2022, issue of the Journal of American Medical Association (JAMA) Internal Medicine.

Basic information about levothyroxine

Levothyroxine is a synthetic (lab-made) but identical oral form of the inactive human thyroid hormone thyroxine (or T4), a hormone that is produced by the thyroid gland. It is available in various strengths. The body converts it to triiodothyronine hormone (or T3), which is the predominant active hormone used by the body.

Up to 80% of levothyroxine is absorbed after intake and is slowly processed by the body, which makes the drug ideal for once-daily dosing.[7] The starting dose depends on patient factors, such as age, the presence of heart disease and weight. Extra caution to avoid overdosing is necessary for patients with heart disease and for the elderly.

Levothyroxine’s initial dosage also must be tailored to individual patients, based on thyroid blood test results along with patient symptoms, until an optimal steady (maintenance) dose is reached. Once a stable effective dose is achieved, thyroid blood tests should be performed annually.[8]

The JAMA Internal Medicine study[9]

To identify study patients, the researchers used information from a large national administrative health insurance claims database (with data from commercial and Medicare Advantage plans) linked to laboratory test results. The overall study sample included 15,829 adult patients who filled generic prescriptions of levothyroxine from any of the three most common manufacturers (Lannett, Mylan and Sandoz) from January 2008 to June 2019. All patients had a stable dosage of a generic levothyroxine from the same manufacturer for at least three months before they either continued to take that same product or switched to another generic levothyroxine product of the same dosage from a different manufacturer. These patients also had a normal baseline level of thyroid-stimulating hormone (TSH), the single best screening test for primary thyroid function.[10]

The mean age for patients in the overall sample was 59 years, and 73% were women. Slightly more than half of these patients (56%) received a daily levothyroxine dosage of 50 micrograms (mcg) or less.

During the study period, 2,780 (18%) patients switched from one generic levothyroxine product to another from a different manufacturer (switchers) and the remaining 13,049 (82%) patients continued to take the same generic levothyroxine products (nonswitchers). The average duration of generic levothyroxine treatment among switchers and nonswitchers was 226 and 228 days, respectively.

To minimize baseline differences between patients in the two groups, the researchers matched all 2,780 switchers with 2,780 nonswitchers with similar characteristics. Therefore, for each matched pair, the switcher and nonswitcher patients were similar in terms of their demographic characteristics and underlying medical conditions (if any), as well as baseline TSH levels.

The researchers then compared matched pairs of levothyroxine switchers and nonswitchers in terms of changes in their TSH levels within six weeks to 12 months of follow-up.

The researchers found no statistically significant differences in TSH levels between the two groups. Specifically, the proportion of patients with normal TSH levels (from 0.3 to 4.4 milli-international units/liter [mIU/L]) was similar for matched switchers and nonswitchers: 85% and 83%, respectively. Likewise, the proportion of patients with markedly abnormal TSH levels (less than 0.1 or greater than 10 mIU/L) during follow-up was comparable for both groups: 2.5% for switchers and 3.1% for nonswitchers. In addition, the average TSH levels and change in these levels were identical for the two groups: 2.7 and 0.5 mIU/L, respectively.

The researchers also conducted additional analyses that showed no statistically significant differences in TSH levels between matched switchers and nonswitchers for various patient subgroups, including those pertaining to patients who received a levothyroxine dose of more than 100 mcg per day.

Overall, this study concluded that there is no evidence that switching between generic levothyroxine products has a significant clinical impact on TSH levels. Its findings challenge the American Thyroid Association’s recommendation against switching among generic levothyroxine products from different manufacturers.

Notably, the study had some limitations. Mainly, due to its observational nature, it may have been biased by factors that were not examined in the study. Therefore, its findings need to be confirmed in future studies, ideally in a randomized control trial. If confirmed, the findings may help curb the underuse of generic levothyroxine products in the U.S.,[11] which would be associated with cost savings.

Importantly, because the study did not include brand-name levothyroxine products, it remains unclear whether generic-to-brand-name or brand-name-to-generic levothyroxine switching may affect TSH levels.

What You Can Do

If you are taking levothyroxine for hypothyroidism and have concerns about being switched by your pharmacy between different generic levothyroxine products, discuss this article with your doctor. Note that all levothyroxine products should be taken on an empty stomach — at least 30 minutes before breakfast — and should not be taken within four hours of taking certain drugs including antacids or supplements that contain calcium or iron.[12] Absorption of levothyroxine is increased by fasting and decreased by grapefruit products and certain foods (such as dietary fiber, cottonseed meal, soybeans and walnut).

Never stop taking the drug, skip a dose or take a higher dose without medical supervision. Taking too much levothyroxine can cause serious problems, such as atrial fibrillation (a common heart-rhythm disorder), osteoporosis (bone thinning) or worsened blood-sugar control in diabetic patients.
 

References

[1] Wallach O. Ranked: The most prescribed drugs in the U.S. November 1, 2021. https://www.visualcapitalist.com/ranked-the-most-prescribed-drugs-in-the-u-s/. Accessed May 2, 2022.

[2] AbbVie Inc. Label: levothyroxine (SYNTHROID). July 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1e11ad30-1041-4520-10b0-8f9d30d30fcc&type=display. Accessed May 2, 2022.

[3] Food and Drug Administration. Draft guidance on levothyroxine sodium. December 2014. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Levothyroxine%20sodium_draft_Oral%20tab_RLD%20021116%20%20%20%20%20%20%20%20%20%20%20%20%20%20021210%20%20%20%20%20%20%20%20%20%20%20%20%20%20021301%20%20%20%20%20%20%20%20%20%20%20%20%20%20021342%20%20%20%20%20%20%20%20%20%20%20%20%20%20021402_RC12-14.pdf. Accessed May 2, 2022.

[4] Benvenga S, Carlé A. Levothyroxine formulations: pharmacological and clinical implications of generic substitution. Adv Ther. 2019;36(Suppl 2):59-71.

[5] Food and Drug Administration. FDA acts to ensure thyroid drugs don’t lose potency before expiration date. October 3, 2007. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-acts-ensure-thyroid-drugs-dont-lose-potency-expiration-date. Accessed May 2, 2022.

[6] Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: Prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-1751.

[7] AbbVie Inc. Label: levothyroxine (SYNTHROID). July 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1e11ad30-1041-4520-10b0-8f9d30d30fcc&type=display. Accessed May 3, 2022.

[8] American Thyroid Association. Hypothyroidism. 2017. http://www.thyroid.org/wp-content/uploads/patients/brochures/ata-hypothyroidism-brochure.pdf. Accessed May 3, 2022.

[9] Brito JP, Deng Y, Ross JS, et al. Association between generic-to-generic levothyroxine switching and thyrotropin levels among US adults. JAMA Intern Med. 2022;182(4):418-425.

[10] Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: Prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-1751.

[11] Ross JS, Rohde S, Sangaralingham L, et al. Generic and brand-name thyroid hormone drug use among commercially insured and Medicare beneficiaries, 2007 through 2016. J Clin Endocrinol Metab. 2019;104(6):2305-2314.

[12] AbbVie Inc. Label: levothyroxine (SYNTHROID). July 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1e11ad30-1041-4520-10b0-8f9d30d30fcc&type=display. Accessed May 3, 2022.