Risks of reformulation: French patients complain after Merck modifies levothyroxine pillsBMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k714 (Published 16 February 2018) Cite this as: BMJ 2018;360:k714
All rapid responses
This feature on Pharmacovigilance by Ms Casassus (Paris) and the Rapid Response from Prof Glossmann ( Innsbruck) ought to make us all sit up and take notice.
On the face of it, the change of excipient resulted in unforeseen side-effects. We, the consumers assume the European Medicines Agency takes care of the quality and safety. Prof Glossmann suggests that gut metabolites had a role in production of the side-effects. This may well be the case. What we do know for sure is that excipients were changed ( lactose out, mannitol and citric acid in ) .
Lactose and mannitol provide different nutrients to gut flora.
It would seem safer and wiser to conduct safety audits whenever the drug formulation is altered. This applies to all drugs - immunological products ( these days commonly called vaccines.)
Has NICE any thoughts?
I for one appreciate Ms Casasdus and Prof Glossmann’s contributions to therapeutic safety debate.
Competing interests: No competing interests
Side Effects of a new Thyroxine Formulation: Metabolites from the Gut?
Sir, we are very much intrigued by the spectrum of side effects reported to the French national safety agency when the new formulation of Merck´s levothyroxine was introduced in March 2017. The French agency´s director-general had no explanation as the patients had normal levels of TSH. The reported problems included fatigue, memory loss, palpitations, weight gain, dizziness and nausea ,which improved for 65% of 1745 patients who switched to a competitor drug or Merck´s old version. Some of the side effects have a striking similarity to what is observed in rodent experiments with a novel metabolite of thyroxine,3-monoiodothyronamine ( T1AM),discovered in 2004 (1) .T1AM is a potent blocker of alpha 2 adrenoceptors and noradrenaline uptake but also activates a trace amine receptors(2). Where and how this metabolite is formed in vivo is still an enigma. Conversion of thyroxine into T1AM by an ex-vivo everted gut sac model (jejunum) from mice is proven by mass spectrometry and deiodinases as well as ornithine decarboxylase play an important role(3).The latter authors were stimulated to search for a gut-mediated ( extrathyroideal ) mechanism for formation of T1AM,as they observed very high serum concentrations ( up to 240 nM) of this metabolite only in thyroid cancer patients substituted with TSH suppressing oral thyroxine(4). Unsubstituted, healthy controls have levels around 8 nM (5) . The clearance of elevated T1AM, apparently formed by oral thyroxine substitution, seems to be low: When thyroxine- substituted patients were taken off the hormone for six days, levels remained essentially the same ( Hoefig et al. 2011). If the active ingredient of a drug is identical but the oral formulation is changed, concentrations in different sections of the gastrointestinal system may differ. Oral thyroxine appears not to be completely inert. Recent evidence points to changes in the gut flora(6) and, as suggested by us , increased formation of T1AM may be a possibility.
1. Scanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich PJ, et al. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med. 2004;10(6):638–42.
2. Glossmann HH, Lutz OMD. Torpor: The Rise and Fall of 3-Monoiodothyronamine from Brain to Gut-From Gut to Brain? Front Endocrinol (Lausanne) [Internet]. 2017;8(2016):118. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28620354
3. Hoefig CS, Wuensch T, Rijntjes E, Lehmphul I, Daniel H, Schweizer U, et al. Biosynthesis of 3-iodothyronamine from T4 in murine intestinal tissue. Endocrinology. 2015;156(11):4356–64.
4. Hoefig CS, Köhrle J, Brabant G, Dixit K, Yap B, Strasburger CJ, et al. Evidence for extrathyroidal formation of 3-iodothyronamine in humans as provided by a novel monoclonal antibody-based chemiluminescent serum immunoassay. J Clin Endocrinol Metab. 2011;96(6):1864–72.
5. Langouche L, Lehmphul I, Perre S V, Kohrle J, Van den Berghe G. Circulating 3-T1AM and 3,5-T2 in Critically Ill Patients: A Cross-Sectional Observational Study. Thyroid [Internet]. 2016;26(12):1674–80. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27676423%0Ahttp://online.liebertpub....
6. Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature [Internet]. Nature Publishing Group; 2018 Mar 19;(accepted). Available from: http://dx.doi.org/10.1038/nature25979
Competing interests: No competing interests