Generic and Brand-Name l -Thyroxine Are Not Bioequivalent for Children With Severe Congenital Hypothyroidism

Abstract

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.