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Lévothyrox° (levothyroxine): a change in formulation results in thousands of reports of adverse effects

In France, the lactose in Lévothyrox° (levothyroxine) tablets was replaced by mannitol and citric acid was added as a preservative. According to France's national medicines agency (ANSM), two pharmacokinetics studies demonstrated that the old and the new tablets were bioequivalent. A pharmacovigilance investigation is underway to look into thousands of reports from patients signalling various disorders following the change in formulation. On 15 September 2017, the Agency made various documents available online.

In late March 2017, Merck introduced in France a new formulation of Lévothyrox° (levothyroxine) tablets: lactose was replaced by mannitol, and citric acid was added as a preservative (1).

This change had been requested in 2012 by the French medicines agency (ANSM) because "there could be differences in the levothyroxine content, not only from one batch to another (…) but also over time within the same batch. These fluctuations in the active ingredient being a source of disturbances in thyroid balance in patients" (our translation) (1).

Since then, thousands of patients taking Lévothyrox° have reported various ailments which they considered to be directly linked to the drug (2). A pharmacovigilance investigation has been launched, and is still ongoing as of mid-September 2017.

Levothyroxine is an essential medicine in hormone replacement therapy for hypothyroidism. Its narrow therapeutic index means that small variations in the dosage can have clinical consequences. The optimal dosage needs to be established for each patient on the basis of symptoms and TSH levels, and needs to be monitored regularly.

Levothyroxine's half-life is around 6 to 7 days, possibly longer in the case of hypothyroidism, with full therapeutic effect achieved after several weeks, including after a change of dosage. Similarly, its effects linger for several weeks after stopping the drug (3).

When the change in formulation was announced, the French medicines agency ANSM confirmed the bioequivalence between the old and the new Lévothyrox° tablets, based on two pharmacokinetics studies, and called for closer monitoring of patients. However, as of 14 September 2017, neither the Agency nor the pharmaceutical company had accompanied this announcement with a publication of the results of these studies (1).

On 15 September 2017 the ANSM made various documents available online (in French):

In view of the numerous signals and the questions raised concerning the pharmaceutical qualities of the new tablets, a careful analysis by the medicines agency of the pharmacovigilance data is called for.

A further analysis will be published in the November issue of Prescrire's French edition.

©Prescrire 18 September 2017

1- ANSM "Point d'Information - Lévothyrox (lévothyroxine) : changement de formule et de couleur des boîtes" 2 mars 2017 + "Questions/Réponses - Lévothyrox : changement de formule et de couleurs des boîtes et blisters" version 2 updated in August 2017: 8 pages.
2- APM "Thyroïde : le changement de formulation de lévothyroxine fait polémique" 23 August 2017 + "Lévothyrox : au moins 1 500 cas d'effets indésirables graves depuis deux mois (presse)": 2 pages.
3- Prescrire Rédaction "4-2. Patients hypothyroïdiens" Rev Prescrire 2017; 37 (401 suppl. Interactions médicamenteuses).

Source : "Lévothyrox° : des milliers de signalements en lien avec un changement de formulation" Rev Prescrire 2017; 37 (408): 756.

See also :
Hypothyroidism in adults
Prescrire Int 2015 ;
24 (164): 241-246.
Pdf, subscribers only

Hypothyroidism in adults:
treat patients exhibiting
(October 2015)