A new formulation of Levothyrox® has been launched in France to replace an existing formulation, which is no longer marketed, and it is anticipated that this new formulation will be also marketed in the near future in all European Union countries, i.e. it will then be prescribed to several million further patients. |
Shortly after this compulsory substitution, adverse drug reactions were reported to the French network of pharmacovigilance centres, involving several thousand patients. |
It was shown that more than 50% of 204 healthy volunteers, enrolled into a successful European Union regulatory average bioequivalence trial, were actually outside the a priori bioequivalence range. |
It is suggested that the appropriate conceptual framework to document switchability between the old and the new Levothyrox® formulations is individual bioequivalence. |
1 Introduction
2 Precisely What is Indicated by an Average European Union or US Food and Drug Administration Bioequivalence Trial?
3 Formulation Substitution is Subject to National Regulation and is Not Dealt with by European Union Guidelines
4 Appropriate Conceptual Framework to Document Switchability Between Two Formulations is Individual Bioequivalence
5 For Levothyrox®, More Than 50% of Subjects Enrolled in a Large European Union Regulatory Average Bioequivalence Trial were Actually Outside the a Priori Bioequivalence Range
Class intervals | Unadjusted T4a AUCnew/AUCold ratio | Baseline-adjusted T4a AUCnew/AUCold ratio |
---|---|---|
< 0.8 | 2 1.0 (0.1–3.5) | 40 19.6 (14.4–25.7) |
0.8–0.9 | 17 8.3 (4.9–13.0) | 32 15.7 (11.0–21.4) |
0.9–1.11 (a priori regulatory interval) | 170 83.3 (77.5–88.2) | 67 32.8 (26.4–39.7) |
1.11–1.25 | 15 7.4 (4.2–11.8) | 26 12.7 (8.5–18.1) |
> 1.25 | 0 0.0 (0–1.8) | 39 19.1 (14.0–25.2) |