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.