Generic and Brand-Name L-thyroxine Are Not Bioequivalent for Children With Severe Congenital Hypothyroidism

J Clin Endocrinol Metab. 2013 Feb;98(2):610-7. doi: 10.1210/jc.2012-3125. Epub 2012 Dec 21.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Child
  • Child, Preschool
  • Congenital Hypothyroidism / blood
  • Congenital Hypothyroidism / drug therapy*
  • Cross-Over Studies
  • Drugs, Generic / pharmacokinetics*
  • Drugs, Generic / therapeutic use
  • Female
  • Humans
  • Male
  • Severity of Illness Index
  • Therapeutic Equivalency
  • Thyrotropin / blood
  • Thyroxine / blood
  • Thyroxine / pharmacokinetics*
  • Thyroxine / therapeutic use
  • Treatment Outcome
  • Triiodothyronine / blood

Substances

  • Drugs, Generic
  • Triiodothyronine
  • Thyrotropin
  • Thyroxine