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.
RCT Entities:
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 hypothyroidpatients in whom precise titration of L-T(4) is necessary.
Authors: C A Spencer; J S LoPresti; A Patel; R B Guttler; A Eigen; D Shen; D Gray; J T Nicoloff Journal: J Clin Endocrinol Metab Date: 1990-02 Impact factor: 5.958
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Authors: F Monzani; N Caraccio; M Kozàkowà; A Dardano; F Vittone; A Virdis; S Taddei; C Palombo; E Ferrannini Journal: J Clin Endocrinol Metab Date: 2004-05 Impact factor: 5.958
Authors: D S Cooper; B Specker; M Ho; M Sperling; P W Ladenson; D S Ross; K B Ain; S T Bigos; J D Brierley; B R Haugen; I Klein; J Robbins; S I Sherman; T Taylor; H R Maxon Journal: Thyroid Date: 1998-09 Impact factor: 6.568
Authors: Jacqueline Jonklaas; Antonio C Bianco; Andrew J Bauer; Kenneth D Burman; Anne R Cappola; Francesco S Celi; David S Cooper; Brian W Kim; Robin P Peeters; M Sara Rosenthal; Anna M Sawka Journal: Thyroid Date: 2014-12 Impact factor: 6.568