New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials

Rather a shame that the products mentioned are not usually available in the UK. Also interesting that a company has seen fit to put in the effort, and bear the cost, of reformulating.

(Is it possible that the products were on the brink of being criticised for not being within official tolerances?)

Also, I'd note, the range 95-105%, whilst pretty much standard, still allows a difference of about one tenth in the potency. I reckon that if those of us on stable doses were to increase (or reduce) our doses by a tenth, we would notice. And the change would at least sometimes build-up so that we end up moving very much further away from out optimums.

Also interesting that they make a 200 microgram tablet, and talk about 600 microgram doses (at least in testing) - when we often see anyone taking as much as 200 micrograms treated as some sort of over-dosing junkie.

New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials

Ulrike Gottwald-Hostalek , MD, Wolfgang Uhl , MD, Peter Wolna , PhD & George J. Kahaly , MD, PhD

Pages 1-21 | Received 07 Sep 2016, Accepted 05 Oct 2016, Accepted author version posted online: 08 Oct 2016

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Objective: Small levothyroxine (L-T4) dose changes can lead to significant clinical effects. To ensure thyroid hormone levels are safely maintained, authorities are increasingly adopting stricter potency specifications for L-T4, the most stringent of these being 95–105% of the labeled dose over the whole shelf-life. Levothyroxine sodium (Euthyrox®, Eutirox®, Lévothyrox®) has been reformulated, and two studies performed to ensure bioequivalence to the currently marketed formulation and dosage form proportionality of the new formulation.

Methods: The bioequivalence study was open-label, randomized, single-dose, two-period, two-sequence crossover comparing the highest dosage strengths of the currently marketed and the new L-T4 formulation at a total dose of 600 µg. The dosage form proportionality study was open-label, randomized, three-period, six-sequence crossover, comparing 50 µg, 100 µg, and 200 µg L-T4 tablets, at a total dose of 600 µg. Blood samples were taken at predefined time intervals. Primary outcomes were area under curve (AUC) and maximum concentration (Cmax) of thyroxine (T4) in plasma.


In the bioequivalence study, comparing the T4 profiles for the new and current formulation of L-T4, the geometric least square mean ratio of the baseline-adjusted AUC0-72,adj was 99.3% (90% confidence interval [CI]: 95.6–103.2) and the Cmax,adj was 101.7% (90% CI: 98.8–104.6). Bioequivalence was established as the 90% CI lie within the predefined 0.9–1.11 limits. In the dosage form proportionality study, pairwise comparisons ranged from 99.3–104.8%, and all 95% CI were within the predefined CI range (0.8–1.25): The three dose strengths were dosage form proportional.


The new formulation of L-T4 meets the most stringent potency specification guidelines, has been demonstrated to be bioequivalent to the current formulation and to show dosage form proportionality. The new formulation will enable patients to receive a dose fine-tuned to their medical needs, contributing to improved safety in the use of L-T4.

Keywords: Levothyroxine, specification, bioequivalence, dosage form proportionality, pharmacokinetic trials,


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Hopefully the full, final paper might be accessible at some point.

2 Replies

  • Helvella,

    Don't all UK Levothyroxine brands have to meet 95-105% spec over their entire shelf life?

  • From memory, no. 90-105% - the MHRA report says they considered tightening the specifications but decided against.