Maintaining Therapeutic Doses of Levothyroxine Throughout Shelf Life

Narrow Therapeutic Range

Levothyroxine is now available in 9 strengths – from 50 to 200 µg (50, 75, 88, 100, 112, 125, 137, 150, and 200 µg), which allows for, in most cases, administration in one tablet once daily. The bioavailability of the drug is influenced by many factors (drug and food interactions, liver and gastrointestinal function, smoking, age, gender), and moreover, during the shelf life, the active ingredient in the tablet can degrade, which may lead to insufficient dosing and patient decompensation. Also, the substitution of one product for another can cause differences in drug absorption.

Treatment Control is Necessity

For drugs with a narrow therapeutic range, it is advisable to use either monitoring of plasma drug concentrations (TDM; e.g., for some antibiotics or antiepileptics) or monitoring the pharmacological effect of the drug (e.g., determining INR during warfarin treatment or TSH during levothyroxine treatment). This is particularly important when starting therapy and titrating to the optimal dose but also during significant changes in the patient's clinical condition, when substituting one product for another (e.g., from the original to a generic) or when changing the formulation of a product (e.g., after excipient innovation).

When treating with levothyroxine, special attention should be paid to risk groups such as pregnant women, children, elderly patients, patients with thyroid cancer or cardiovascular disease, where even a small change in dose can have a significant clinical impact. When there is a change in therapy, it is recommended to check the effect and thus the dosing after 6–8 weeks by examining the level of thyroid stimulating hormone (TSH).

Generic Substitution and Its Limitations

There are many products containing levothyroxine on the Czech market, and although they are considered bioequivalent from a regulatory perspective, their substitution (generic substitution) is not recommended due to the narrow therapeutic range.

Guaranteed Active Ingredient Content

The product Euthyrox^® contains a formulation of levothyroxine with lower variability in the active ingredient content (95–105%) throughout the shelf life of the drug (3 years). The innovation that reached the Czech market in the fall of 2019 has a positive impact on maintaining a constant dose in the tablets throughout the shelf life and was achieved by changing the excipients. Lactose was replaced by mannitol, which ensures better stability of the active ingredient. This change allows the use of the drug by patients with lactose intolerance. A newly added excipient to this formulation is citric acid as a stabilizer, which prevents the degradation of levothyroxine over time by adjusting and maintaining pH and has antioxidant effects.

Conclusion

For drugs with a narrow therapeutic range, great emphasis is placed on correct dosing. Even slight deviations in absorption or the content of the active ingredient in the dosage form can impact patient compensation. The innovative formulation of levothyroxine guarantees the stability of the active ingredient content in the range of 95–105% for the entire 3 years, thus contributing to the safety and efficacy of the treatment.

(lexi)

Sources:

1. Gottwald-Hostalek U., Uhl W., Wolna P. et al. New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials. Curr Med Res Opin 2017; 33 (2): 169–174, doi: 10.1080/03007995.2016.1246434.
2. FDA acts to ensure thyroid drugs don’t lose potency before expiration date. U.S. Food and Drug Administration, 2007 Oct 3. Available at: www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-acts-ensure-thyroid-drugs-dont-lose-potency-expiration-date
3. Information letter – Euthyrox. State Institute for Drug Control, 23. 9. 2019. Available at: www.sukl.cz/leciva/informacni-dopis-euthyrox