Impact of a Forced Dose-Equivalent Levothyroxine Brand Switch on Plasma Thyrotropin: A Cohort Study

Linda E. Flinterman, Josephina G. Kuiper, Joke C. Korevaar, Liset van Dijk, Karin Hek, Eline Houben, Ron Herings, Anton A. M. Franken, Johan P. de Graaf, Annemieke Horikx, Marijke Janssens, Rietje Meijer, Anneke Wijbenga, Eugène van Puijenbroek, Bruce H. R. Wolffenbuttel, Thera P. Links, Peter H. Bisschop, Eric Fliers

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Background: Patients with primary hypothyroidism are treated with levothyroxine (LT4) to normalize their serum thyrotropin (TSH). Finding the optimal dosage is a long-lasting process, and a small change can have major impact. Currently, limited data are available on the impact of dose-equivalent substitution between brands. This study aimed to determine the effect of the shortage of the LT4 brand Thyrax® in the Netherlands and the resulting dose-equivalent switch to another brand on plasma TSH concentrations in a large cohort of patients. Methods: Observational cohort study. Two registries representative for the Dutch population containing prescription and laboratory test data: the Nivel Primary Care Database and the PHARMO Database Network. Patients using at least 25 μg Thyrax daily for one year or longer were included. Two cohorts were formed: a switch cohort consisting of patients who switched from Thyrax to an alternative brand, and a Thyrax cohort including patients who continued to use Thyrax. Patients in the switch cohort did switch from Thyrax to a different brand of LT4 in 2016 and had two consecutive TSH measurements on the same dose of LT4, one before and one 6 weeks after the switch. Patients in the Thyrax cohort had two consecutive TSH measurements on the same dose of Thyrax that were 6 weeks apart. Results: In the Thyrax cohort, 19% of euthyroid patients using ≤100 μg had a TSH level outside the reference range at the subsequent measurement compared with 24% in the switch cohort (p < 0.0001). For patients using >100 μg Thyrax, these figures were 24% and 63%, respectively (p < 0.0001). Furthermore, patients using >50 μg Thyrax were four to five times more likely to become hyperthyroid after a dose-equivalent switch to a different brand compared with patients who stayed on Thyrax. Conclusions: In euthyroid patients continuing the LT4 product Thyrax at the same dose, TSH was out of range in 19-24% at least 6 weeks later. A dose-equivalent switch from Thyrax to other LT4 brands induced biochemical signs of overdosing in an even larger proportion (24-63%) of patients. The results indicate that a dose-equivalent LT4 brand switch may necessitate a dose adjustment in a large number of patients.
Original languageEnglish
Pages (from-to)821-828
Number of pages8
Issue number6
Publication statusPublished - 1 Jun 2020


  • Adult Aged Aged, 80 and over Databases, Factual *Drug Substitution Female *Hormone Replacement Therapy Humans Hypothyroidism/blood/*drug therapy Male Middle Aged Thyrotropin/*blood Thyroxine/*therapeutic use Treatment Outcome *change of brand *hypothyroidism *levothyroxine *natural experiment *overdosing
  • change of brand
  • hypothyroidism
  • levothyroxine
  • natural experiment
  • overdosing

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