Comparison of Safety Profiles of the New and Old Formulations of Levothyroxine in a First Global Introduction in France

Abstract

Background Levothyroxine sodium marketed in France was reformulated following a French National Agency for Medicines and Health Products Safety request for a more stringent potency specification. Despite previously established purity and bioequivalence of the new and old formulations, reports of adverse events substantially increased following reformulation. This analysis evaluated the nature and relevance of the medically confirmed safety reports. Methods Spontaneous and solicited individual case safety reports in France were retrieved from 26 March 2015 to 30 June 2016 (old formulation) and 26 March 2017 to 30 June 2018 (new formulation). Rates of reports and adverse events were calculated for the overall patient population and for at-risk subgroups. Adverse events delineated by thyroid-stimulating hormone levels were evaluated. Results A total of 295 and 42 775 reports for the old formulation and new formulation, respectively, were retrieved, with 149 and 5503 medically confirmed. The most common medically confirmed adverse events were consistent with the known safety profile of levothyroxine, with generally comparable rates between both formulations (range of differences, 1.8–4.1%). Most cases were not serious (old formulation, 65.8%; new formulation, 78.7%). Reporting rates were similar or higher for the old formulation within subgroups of at-risk patients. Nature/distributions of adverse events by thyroid-stimulating hormone levels as determined by both the marketing authorization holder of levothyroxine and the French National Agency for Medicines and Health Products Safety were similar. Conclusions The new formulation safety profile aligns with the established profile of the old formulation of levothyroxine. The benefit–risk profile is unchanged, such that the benefits of using the new formulation in the approved indications outweigh the risks associated with the treatment.

Real world clinical experience with a new formulation of levothyroxine engineered to meet new and stricter regulatory requirements

“…The comparable numbers of AE in the years before and after the switch in the present study contrasts with earlier findings in France, where the incidence of AE reports increased from 495 in the year before the switch to 42,775 in the year after. 6 It is important to note that the nature of those AE did not reveal any new and unknown safety issues with LT4 NF. 6 A similar phenomenon (~2,000fold increase in AE reports) had been observed in New Zealand in 2007 following reformulation of a different LT4 product.…”

“…6 It is important to note that the nature of those AE did not reveal any new and unknown safety issues with LT4 NF. 6 A similar phenomenon (~2,000fold increase in AE reports) had been observed in New Zealand in 2007 following reformulation of a different LT4 product. 8 Both of these situations featured intense media and social media interest that in itself was likely to have fuelled the growth in reports of AE associated with the switch.…”

“…An earlier report investigated the safety and tolerability of LT4 NF in France, the first country in which the product was launched, using data from a pharmacovigilance database maintained by its pharmaceutical sponsor. 6 LT4 NF is now available for prescription in many more countries. This article describes the incidence and nature of AE from the company's global safety database before and after the switch in 18 countries that have available 12 months of post-marketing experience for LT4 NF.…”