Drug strengths, stability of compounded levothyroxine suspensions vary widely
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CHICAGO — Compounded oral liquid levothyroxine products vary in stability, potency and consistency and present risks for patients, according to data presented the American Thyroid Association annual meeting.
“Compounded liquid levothyroxine products are unlikely to deliver precise prescribed dosage and reliable product performance when administered to patients,” Charles A. Carter, PharmD, MBA, BS, interim chairman and associate professor in the College of Pharmacy and Health Sciences, Department of Clinical Research, at Campbell University in Buies Creek, North Carolina, told Endocrine Today. “Our findings support the guidelines for the treatment of hypothyroidism [from the] ATA Task Force on Thyroid Replacement that efforts to create suspensions should be avoided.”
The FDA classifies levothyroxine as a narrow therapeutic index drug, indicating that small variations in the active drug can greatly affect efficacy and safety, Carter said during the presentation. No recipes exist for reliably compounding a levothyroxine suspension, and ATA guidelines recommend against creating such products, he said.
“However, with the growth of personalized medicine and the rise in the number of pharmacies that offer compounding services ... indeed pharmacies are compounding liquid formulations of levothyroxine,” Carter said.
To assess consistency and stability of the compounded medication under typical, real-world conditions, Carter and colleagues sourced oral levothyroxine suspension (25 mcg/mL) from six commercial compounding pharmacies and from six pharmacy students who had completed training for compounding medications. To simulate a prescription refill, each of the 12 sources submitted a second sample 30 days later. The researchers had each original product analyzed by an FDA-registered pharmaceutical sciences laboratory to determine the percentage of the labeled strength of levothyroxine at days 3, 6, 13, 20, 27 and 34. All products were stored as indicated on the product labels and were allowed to reach ambient temperature and then well-shaken prior to aliquot sampling.
Six compounding pharmacies that were originally presented with prescriptions for liquid levothyroxine rejected them citing the narrow therapeutic index of the drug, Carter said.
Among the first set of products received, 11 were suspensions in water and one in oil, and they had different flavorings and excipients listed on the labels. One product contained no levothyroxine and was accurately labeled liothyronine; it was not included in the analysis.
The percentage of levothyroxine measured across the samples ranged from 77% to 113% of the labeled strength at day 3 and from 30% to 97% at day 34. Percentage of levothyroxine in each individual sample also varied over time, by a mean of 26% with a range of 12% to 47%, and between each sample and its compounded “refill,” from 19% to 58%.
“We concluded that the compounded liquid formulation products that are being made extemporaneously are very much unlikely to deliver any precision in terms of the prescribed dosage, and reliable product performance is not likely to occur when these are administered to patients,” Carter said. - by Jill Rollet
Reference:
Carter CA. Oral 17. Presented at: 89th Annual Meeting of the American Thyroid Association; Oct. 30-Nov. 3, 2019; Chicago.
Disclosure: Carter reports that the study was funded by an unrestricted educational grant from IBSA Pharma.
Perspective
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Diana Isaacs, PharmD, BCPS, BC-ADM, CDE
Levothyroxine is the standard of care treatment for hypothyroidism. It is a drug with a narrow therapeutic index, and so there are even differences between brand name and generic tablets that can have a clinical impact on thyroid levels. It is recommended for a person to consistently take the same formulation to maintain target TSH levels. Levothyroxine also has many food and drug interactions, and so guidelines recommend separating from food and other medications, taking it either 60 minutes before eating in the morning or 3 hours after the last meal in the evening.
Many pharmacies are offering compounded formulations of levothyroxine to meet patients’ individual needs. For example, this can help people who have allergies to certain dyes or excipients. It can allow specific types of flavoring to be added or offer a dose that is not commercially available.
Unfortunately, there is a lack of consistency and standardization from these compounded products. Even two products from the same pharmacy could differ depending on who compounded them. They are more likely to have stability changes with the strength of active ingredient dissipating over time. Since levothyroxine has a narrow therapeutic index, this can have a profound clinical effect making it difficult to regulate thyroid hormones and achieve a euthyroid state.
There are certain instances when a standardized formula may not work for a person, such as in the case of extreme allergies to excipients. These compounded formulations should be reserved for those situations, and most people will do best with traditional levothyroxine products.
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