Generic Substitution of Levothyroxine in Practice
The active ingredient levothyroxine is found in a significant number of medicinal products (MP) in the Czech Republic. The question of its generic substitution remains current, primarily because the previously published data tend to call for caution due to possible adverse effects on the patient.
Generic substitution and its limitations
There is a large number of MPs containing levothyroxine on the Czech market, which are not entirely properly considered fully bioequivalent. Their interchange is not recommended due to the narrow therapeutic range of levothyroxine. With MPs having a narrow therapeutic range, it is crucial to adhere to proper dosing and avoid slight deviations in absorption or the content of the active ingredient in the dosage form, which can lead to patient decompensation. Generics are generally allowed a range of active ingredient content of 80–120 %, whereas for MPs with a narrow therapeutic range it is 90–110 %.
FDA Recommendations
A few years ago, based on recommendations from the U.S. Food and Drug Administration (FDA) from 2007, the composition of excipients was changed − lactose was replaced with mannitol and citric acid was added. The innovative formulation guarantees increased stability of levothyroxine content in the range of 95–105 % throughout its shelf life (3 years), contributing to the safety and efficacy of treatment.
The removal of lactose primarily increased the stability of levothyroxine in the product formulation. The amount of lactose in the tablets was so low that it was unlikely to cause gastrointestinal problems in individuals with lactose intolerance.
Modified formulation
Based on adverse effects (AEs) reported in France, where MPs with the new formulation were among the first to be issued, a recommendation was issued to monitor the levels of thyroid-stimulating hormone (TSH) and free thyroxine in the blood for 1–2 weeks after switching to the new product and, if necessary, to perform individual dose titration of the drug.
In other countries, including the Czech Republic, the product with the new formulation was always supplied with an accompanying Information Letter for healthcare professionals. This step − thanks to good information and communication with doctors, pharmacists, and patients − prevented an increase in the incidence of AEs. Currently, TSH control is recommended 6–8 weeks after the change.
Context and consequences of generic substitution
A survey published in 2010 (Hennessey et al.) examined the causes of reported adverse events (n = 199) during levothyroxine treatment and found a high rate of causation to generic substitution. The vast majority (88.9 %; n = 177) of adverse events were associated with product substitution and manifested as higher or lower drug efficacy.
The circumstances of the drug interchange were known in 167 out of 177 cases. Only in one case (0.6 %) was the substitution performed by the prescribing physician, whereas in other cases, it happened at the pharmacy, either with the knowledge of the prescribing physician (13 out of 167 cases; 7.8 %), or more often without the physician's knowledge (153 out of 167 cases; 91.6 %).
Of the total of 54 cases of serious adverse events, 96.3 % (n = 52) were associated with generic product substitution.
Inconsistency of obtained data
According to the results of a systematic review (Qian et al.) published in 2021, the results of studies examining the effectiveness and safety of product substitution with levothyroxine in real clinical practice are limited and bring conflicting findings. The data from the collected studies were so diverse that a meta-analysis could not be conducted. Generic levothyroxine products in several studies were associated with lower costs for the healthcare system, but also with lower adherence to therapy with a risk of patient decompensation.
Conclusion
Substituting prescribed levothyroxine with a generic product may be associated with an increase in adverse effects and reduced patient adherence to therapy. If a change is necessary, the patient's condition should be objectively assessed by a physician after a certain period and the drug dose should be adjusted if necessary.
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Sources:
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