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.

Figure 1.

Serum TSH concentration after 8 weeks of brand-name l-T₄ vs generic formulation. Closed circles denote patients with congenital hypothyroidism; open circles indicate patients with acquired hypothyroidism. Lines connect paired data. The horizontal bar indicates the median value. The serum TSH concentration was significantly greater after generic vs brand-name product, but subgroup analysis revealed that this difference was seen only in patients with CH.

Figure 2.

Serum free T₄ and total T₃ concentration after 8 weeks of brand l-T₄ vs generic formulation. Closed circles denote patients with congenital hypothyroidism; open circles indicate patients with acquired hypothyroidism. Paired analysis showed no significant difference between groups; pairing of data is not illustrated.

Figure 3.

Serum TSH vs free T₄ concentration in patients with CH (closed circles) vs acquired hypothyroidism (open circles). Diagonal lines represent the normal range (35).