Abstract
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We report a case series of clinically significant hyperthyroidism and hypothyroidism following exposure to CTPs, identified from the FDA Adverse Event Reporting System (FAERS) database and medical literature via Embase and PubMed through January 31, 2020.
The FDA identified 12 U.S. cases, including 4 literature cases (3 –5), that we categorized as having a probable or possible association between CTPs and clinically significant hyperthyroidism and hypothyroidism based on the World Health Organization–Uppsala Monitoring Centre's system for causality assessment. The median age was 53 years (range 20–75 years). The most common CTP was levothyroxine combined with liothyronine, followed by liothyronine alone. Table 1 summarizes these cases.
Summary of Cases Following Exposure to a Compounded Thyroid Product (N = 12)
Outcome of adverse event (e.g., improved, resolved) following cessation of the suspected product.
Case 1 was further investigated by the FDA, and the compounded product containing liothyronine and levothyroxine was tested. The result of liothyronine and levothyroxine was within label claim. However, this case was assessed as a probable causal association due to the positive dechallenge.
The units for TSH may be expressed as mU/L, mU/mL, μU/L, or μU/mL depending on the reference utilized; however, we use μU/L throughout to be consistent with the units and reference range described by Kratz et al. (7).
Case 2 reported the reason for use of a CTP was that the patient wanted to take a “natural product.” The FDA investigated this case further and tested the compounded product containing liothyronine and levothyroxine. The result of liothyronine was within label claim; however, levothyroxine was subpotent. A for-cause inspection of the compounding pharmacy resulted in the issuance of a Warning Letter to the compounder.
Case 3 reported “the pharmacy was contacted and noted they recently released compounded thyroid replacement medications with ‘increased amounts of thyroid hormone’.”
Case 4 reported the reason for use of a CTP was to improve T3 levels.
Cases 6, 7, and 8 reported that analysis of the CTP confirmed superpotent product: 10-fold the labeled amount of LT3 and LT4, more than 1000-fold the labeled amount of LT3, and 15-fold the labeled amount of T3 and T4, respectively.
Case 9 reported the reason for use of a CTP was because “Nature Throid” (an all-natural unapproved product) was unavailable at retail pharmacies; however, a compounding pharmacy offered to compound the product for the patient.
Case 10 reported concomitant use of Armour Thyroid and compounded liothyronine for 15 months.
Case 11 reported taking compounded liothyronine for “several years”; however, developed “thyroid toxicosis” 5 days following most recent refill.
Case 12 reported the reason for use of a CTP was to improve T3 levels because the patient's body was unable to convert T4 to T3.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; BPM, beats per minute; CK, creatine kinase; CT, computed tomography; CTP, compounded thyroid product; EF, ejection fraction; F, female; FDA, Food and Drug Administration; HR, heart rate; LT3, L-triiodothyronine; LT4, levothyroxine; M, male; MRI, magnetic resonance imaging; NR, not reported; RR, reference range; T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyroid stimulating hormone; WHO-UMC, World Health Organization–Uppsala Monitoring Centre.
The eight probable cases contained specific thyroid function test (TFT) results (e.g., thyroid stimulating hormone [TSH], thyroxine [T4], triiodothyronine [T3]) that confirmed either clinically significant hyperthyroidism or hypothyroidism, lacked confounding factors, were reported by a health care professional, and described adverse events that improved or resolved following cessation of the suspected product. Clinical outcomes included thyrotoxic crisis requiring hospitalization and plasmapheresis, and pituitary enlargement secondary to marked hypothyroidism. The latter case described incorrect dose conversion from levothyroxine to a CTP, resulting in undertreatment and significant elevation in TSH to 150 μU/mL (reference range 0.4–4.5 μU/mL) (3).
Of the four possible cases, three reported approximate TFT results. The remaining case reported an elevated T3 value; however, it was confounded by concomitant Armour Thyroid use. Clinical outcomes included tachycardia, delirium, and hospitalization.
Clinically significant symptoms associated with extremes in thyroid hormone levels may result from even small deviations in the potency of NTI products (1). Compounding errors are one way in which these deviations may occur. Inconsistent potency in the APIs may also contribute to these issues. Recently, the FDA alerted drug makers of a recall of porcine thyroid API due to inconsistent levels of levothyroxine and liothyronine and cited the potential clinical risks (1).
We believe that the cases described are representative of many that likely exist because traditional pharmacies compounding under Section 503A (6) of the Federal Food, Drug and Cosmetic Act generally do not report adverse events of CTPs to the FDA. Despite this limitation, the data presented provide evidence of significant harm associated with CTPs.
Although compounded drugs can serve an important medical need for some patients (e.g., those with excipient allergy), they can pose safety risks. Therefore, FDA-approved products should be used to treat hypothyroidism unless a compounded alternative is clinically necessary and permitted by law.
Footnotes
Acknowledgment
The authors do not have any acknowledgements.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.