TY - JOUR
T1 - Generic and brand-name L-thyroxine are not bioequivalent for children with severe congenital hypothyroidism
AU - Carswell, Jeremi M.
AU - Gordon, Joshua H.
AU - Popovsky, Erica
AU - Hale, Andrea
AU - Brown, Rosalind S.
PY - 2013/2
Y1 - 2013/2
N2 - Context: In the United States, generic substitution of levothyroxine (L-T4) 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-T4 (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-T4 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 T4 and total T3 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-T4 dose (P<.0004)andwereyounger (P<.003) butwerenot 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-T4 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-T4 is necessary.
AB - Context: In the United States, generic substitution of levothyroxine (L-T4) 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-T4 (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-T4 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 T4 and total T3 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-T4 dose (P<.0004)andwereyounger (P<.003) butwerenot 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-T4 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-T4 is necessary.
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U2 - 10.1210/jc.2012-3125
DO - 10.1210/jc.2012-3125
M3 - Article
C2 - 23264396
AN - SCOPUS:84873660997
SN - 0021-972X
VL - 98
SP - 610
EP - 617
JO - Journal of clinical endocrinology and metabolism
JF - Journal of clinical endocrinology and metabolism
IS - 2
ER -