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Interchangeability of name brand vs. generic levothyroxine questionable
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Two studies published in the Journal of Clinical Endocrinology & Metabolism offer conflicting results regarding the interchangeability of brand-name and generic levothyroxine in patients with congenital hypothyroidism.
“Despite widespread concern about the validity of current FDA methodology in determining [levothyroxine] bioequivalence, there is a paucity of clinical data in which the question has been assessed directly in patients, and those results that have been obtained are conflicting and controversial,” Jeremi M. Carswell, MD, of Boston Children’s Hospital and Harvard Medical School, and colleagues wrote in the Journal of Clinical Endocrinology & Metabolism.
Comparing generic, brand-name formulations
For their study, Carswell and colleagues randomly assigned 31 children with thyroid-stimulating hormone concentrations greater than 100 mU/L to treatment with a brand-name levothyroxine (Synthroid, Abbott Laboratories) or an AB-rated generic (Sandoz). After 8 weeks, the patients switched treatment formulations for another 8 weeks. Twenty children had congenital hypothyroidism and 11 had autoimmune thyroiditis.
TSH concentrations appeared to be significantly lower after treatment with branded levothyroxine when compared with the generic formulation (P=.002). However, there was no substantial difference in thyroid hormone levels. The researchers also found that the difference in TSH was limited to patients with congenital hypothyroidism (P=.0005). These patients also were younger (P=.003) and needed a higher dose of levothyroxine (P<.0004), although they were not resistant to thyroid hormone, according to study results. The responses to the brand-name vs. generic formulations also remained significant even after adjustment for age.
In a second study, Jefferson P. Lomenick, MD, of Vanderbilt University School of Medicine, and colleagues compared treatment with brand-name levothyroxine (n=35) with a generic formulation (n=27) in children aged 0 to 36 months with congenital hypothyroidism.
Analysis with the Wilcoxon rank-sum test revealed no difference in TSH standard deviation (SD) in patients using branded levothyroxine vs. the generic (3 vs. 2.2; P=.27). A linear mixed model also showed that children treated with the generic had lower TSH estimated SD (1.35; 95% CI, 1.194-1.526) compared with those treated with the brand-name formulation (1.66; 95% CI, 1.536-1.803). The researchers also noted no difference between the generic and brand-name groups in free thyroxine SD using the Wilcoxon rank-sum test (0.29 vs. 0.36; P=.11). The generic group, however, had lower free T4 in the linear mixed model (0.216; 95% CI, 0.187-0.249) than the branded levothyroxine group (0.298; 95% CI, 0.273-0.326). Frequency of levothyroxine dosing adjustments was comparable between treatment groups in total (P=.097) and after adjustment for number of TSH checks (P=.45).
Clinical implications
Although these studies yielded conflicting results, the differences may be attributable to the study designs, James V. Hennessey, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center in Boston, wrote in an accompanying editorial.
James V. Hennessey
For instance, he noted that the retrospective, parallel treatment study conducted by Lomenick and colleagues “did not address the interchange of the name brand product with the AB2 (Synthroid referenced) rated generics listed.”
“To assess interchangeability, the best bet would be to evaluate what little interchange of generic (AB1 [Unithroid referenced]) products occurred,” he wrote. “This would need to be analyzed separately to gain insight into the question of interchange among the named AB1 generics because no subjects were treated with both name brand and a corresponding generic product.”
In terms of the study conducted by Carswell and colleagues, Hennessey said the design and results justify the conclusion that branded and AB-rated generic formulation were not bioequivalent but suggested different wording.
“I would consider this better phrased as ‘… are not clinically interchangeable …’ because FDA definitions of bioequivalence and therapeutic equivalence in this case are both based on pharmacokinetic data that appear insensitive to exposed clinically significant differences in these products,” Hennessey wrote.
Until further evidence becomes available, Hennessey wrote, following the American Association of Clinical Endocrinologists/American Thyroid Association/The Endocrine Society recommendations on levothyroxine therapy remains the best option.
For more information:
Carswell JM. J ClinEndocrinolMetab. 2013;98:610-617.
Hennessey JV. J ClinEndocrinolMetab. 2013;98:511-514.
Lomenick JP. J ClinEndocrinolMetab. 2013;98:653-658.
Disclosure: The researchers report no relevant financial disclosures. Hennessey reports receiving consulting honoraria from Akrimax Pharmaceuticals and Abbott Labs.