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.

Figures

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).