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.