Generic and Brand-Name L-Thyroxine Are Not Bioequivalent for Children With Severe Congenital Hypothyroidism
Context:In the United States, generic substitution of levothyroxine (l-T(4)) by pharmacists is permitted if the formulations are deemed to be bioequivalent by the Federal Drug Administration, but there is widespread concern that the pharmacokinetic standard used is too insensitive.Objective:We aimed to evaluate the bioequivalence of a brand-name l-T(4) (Synthroid) and an AB-rated generic formulation (Sandoz, Princeton, NJ) in children with severe hypothyroidism.Design:This was a prospective randomized crossover study in which patients received 8 weeks of one l-T(4) formulation followed by 8 weeks of the other.Setting:The setting was an academic medical center.Patients:Of 31 children with an initial serum TSH concentration >100 mU/L, 20 had congenital hypothyroidism (CH), and 11 had autoimmune thyroiditis.Main Outcome Measures:The primary endpoint was the serum TSH concentration. Secondary endpoints were the free T(4) and total T(3) concentrations.Results:The serum TSH concentration was significantly lower after 8 weeks of Synthroid than after generic drug (P = .002), but thyroid hormone levels did not differ significantly. Subgroup analysis revealed that the difference in TSH was restricted to patients with CH (P = .0005). Patients with CH required a higher l-T(4) dose (P < .0004) and were younger (P = .003) but were not resistant to thyroid hormone; 15 of 16 CH patients had severe thyroid dysgenesis or agenesis on imaging. The response to generic vs brand-name preparation remained significant when adjusted for age.Conclusions:Synthroid and an AB-rated generic l-T(4) are not bioequivalent for patients with severe hypothyroidism due to CH, probably because of diminished thyroid reserve. It would therefore seem prudent not to substitute l-T(4) formulations in patients with severe CH, particularly in those <3 yr of age. Our results may have important implications for other severely hypothyroid patients in whom precise titration of l-T(4) is necessary.
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