Currently on the Issue of Interchangeability of Preparations with Levothyroxine in Practice
Levothyroxine (LT4) in oral form is the standard therapy for patients with hypothyroidism. Given the legislative possibility of generic substitution and the number of original and generic preparations containing LT4, its substitution is possible, though not recommended. What are the practical conclusions?
Generic Substitution – Yes or No
Legislation allows the interchangeability of preparations with the same active substance, route of administration, and dosage form, provided that the prescribed preparation is not available in the pharmacy and neither the doctor nor the patient has expressed disapproval of the substitution.
From a scientific perspective, only drugs with documented direct bioequivalence are interchangeable. Some preparations, typically those containing LT4, were not registered as the original brand and subsequent generics (using the original preparation as a reference), but as several independent original preparations. Among them, bioequivalence studies are lacking, their SPCs may differ, and each such original can have its own generics. This fact complicates the overview of the possible interchangeability of individual preparations during dispensing.
Interchangeability of Preparations with Levothyroxine
LT4 is known for its narrow therapeutic range, which is associated with an increased risk of overdose or underdosing, especially in high-risk groups. In the Czech Republic, it is available in several medicinal preparations from different manufacturers of varying strengths. The published data to date advise caution, and the preparations are generally not recommended to be interchanged due to various undesirable complications that may arise from the substitution.
Inevitable substitutions occurred, for example, in the Netherlands, where during a short supply disruption of one LT4 preparation and subsequent generic substitution, an increased incidence of adverse effects was observed. The substituted preparations had most of the excipients different, and overall, 53% of patients taking LT4 doses > 100 µg/day exhibited signs of excessive supplementation. In response to these experiences, general recommendations were issued to check serum TSH 6 weeks after the necessary substitution of an LT4 preparation.
Changes in Excipient Composition in Practice
A few years ago, based on the recommendations of the U.S. Food and Drug Administration (FDA), the excipient composition of some LT4 preparations was changed to limit the degradation of the active substance during the 3-year shelf life of the preparation. The new formulation demonstrated bioequivalence with the original composition.
However, after transitioning to the new composition, an unexpectedly increased incidence of adverse effects was observed in France, for example. They were reported in patients, of whom 60% had normal TSH levels, and 15–20% had levels indicative of hypothyroidism or hyperthyroidism. A similar phenomenon occurred following reformulation in other countries around the world (e.g., USA, New Zealand). There was no scientific explanation for this range of adverse effects following the reformulation. It is assumed they could have been caused by insufficient communication about the change in preparation (new appearance, composition) with the patient, the influence of social media, and the nocebo effect. In response to this phenomenon, it was subsequently recommended to check the patient's status 1−2 weeks after conversion, specifically the levels of thyrotropin (TSH) and thyroxine in the blood, and adjust the dose if necessary.
Conclusion
Even small differences between individual preparations can lead to significant changes in TSH levels, which is concerning for groups of patients such as the elderly, pregnant women, pediatric patients, or oncology patients. Therefore, ideally, patients should always receive the same LT4 preparation. In cases where a change is justified for some reason, it is necessary to evaluate TSH levels after an interval and adjust the LT4 dose in correlation with the results.
The formulation of LP with levothyroxine without lactose, containing mannitol and citric acid, is bioequivalent to the previous formulation and meets the bioequivalence criteria for drugs with a narrow therapeutic index. Due to the removal of lactose, the preparation is also suitable for patients with lactose intolerance.
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Sources:
1. Benvenga S., Carle A. Levothyroxine formulations: pharmacological and clinical implications of generic substitution. Adv Ther 2019; 36 (Suppl. 2): 59−71, doi: 10.1007/s12325-019-01079-1.
2. Suchopár J. Therapeutic interchangeability of drugs, perspectives from the manufacturer, doctor, and pharmacist. Diabetology, Metabolism, Endocrinology, Nutrition 2022; 25 (2): 77−79.
3. 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
4. Information letter – Euthyrox. State Institute for Drug Control, 23. 9. 2019. Available at: www.sukl.cz/leciva/informacni-dopis-euthyrox
5. SPC Euthyrox. Available at: www.sukl.cz/download/spc/SPC21491.pdf
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