A sampling of levothyroxine (LT4) liquid formulations obtained from compounding pharmacies and student pharmacists using state-of-the-art equipment, shows substantial variation in the active drug components of such products, potentially posing health risks, new research shows.

"The results [of our study] were dramatic and it was a surprise to see this level of variation," Charles A. Carter, PharmD, said when presenting the findings here at the American Thyroid Association (ATA) 89th Annual Meeting. The study was funded by an educational grant from IBSA Pharma, the makers of Tirosint-SOL (levothyroxine sodium) solution.

"The compounded liquid formulation products are unlikely to provide precision in the prescribed dose, and reliable product performance is not likely to occur when administered to patients," said Carter, of the Department of Clinical Research, Campbell University, Buies Creek, North Carolina.

Whether it's poorly mixed formula or concentrations significantly different from those expected in the prescription, the consequences could affect patient health, Jacqueline Jonklaas, MD, PhD, told Medscape Medical News, when asked to comment.

"I think the main significance [of the study] is the risk of patients being undertreated or overtreated if they rely on compounded products that have this degree of variation in their LT4 content," stressed Jonklaas, who is assistant professor, Division of Endocrinology and Medicine, Department of Medicine, Georgetown University Medical Center, Washington, DC.

She told Medscape Medical News that she can't quantify how widespread the issue is. "I cannot really give you hard data about the frequency of compounding. I just see more compounding pharmacies being advertised and see more individuals who come to me taking compounded thyroid hormones," said Jonklaas.

Importantly, the ATA guidelines do not recommend compounded formulations for thyroid replacement.

"Within the United States, there are no liquid formulations and there are no compounding recipes that produce a stable concentration of LT4 in suspension," the recommendations state. "Efforts to create suspensions should be avoided and are associated with marked extremes in dosing."

Study Found Considerable Variation From Stated Label Strength

Carter explained that clinical situations arise where the use of liquid formulations of LT4 is warranted. With consideration of the growth in compounding pharmacy services, the objective of this study was to investigate the stability and consistency of such products.

The authors approached 12 pharmacies with compounding services and presented a prescription for liquid LT4 at a dose of 25 µg/mL.

Six of the pharmacies declined, citing concerns about the drug's narrow therapeutic index, however the other six agreed to fill the prescription.

Carter and colleagues also sought samples from student pharmacists in the Campbell College of Pharmacy in order to obtain samples from a well-controlled setting where state-of-the-art equipment was used. Those pharmacists were required to have successfully completed all of their academic training in compounding.

The compounded products were assayed in a US Food and Drug Administration (FDA)-registered pharmaceutical sciences lab for percentage of labeled strength. Each compounding pharmacy and student pharmacist subsequently prepared a second product sample 30 days later to simulate a refill prescription. All samples were stored according to the labeled instructions.

Among the 12 samples, including six from pharmacies and six from student pharmacists, the authors found that, in individual product assays on days 3, 6, 13, 20, 27, and 34, there was considerable variation, ranging from 12% to 47% (mean 26%), from the stated label strength.

One of the samples contained liothyronine (T3) and was labeled as such, and therefore was excluded. "There was just a misinterpretation of the prescription, but that's real-world, so I decided to report it," Carter said.

Among the samples obtained from the compound pharmacies, the concentrations on day 1 were 10% or lower than what was represented on the label, and on day 3, they ranged from 77% to 93% of what the label stated. At day 34, the range was from just 30% strength to 97%.

For the samples from student pharmacists, the numbers were not much better, ranging on the first day from 98% to 113% of the labeled dose, and at the end of the month, five of the six samples were more than 10% lower than the stated dose, varying from 75% to 89%.

"When we compared the initial prescription with the refill, there was no pattern between one compound versus another," Carter noted. "Essentially, the range was 58%, yet it was supposed to be the exact same dosage."

Levothyroxine Has a Narrow Therapeutic Index

A key concern in compounding LT4 is that the drug is characterized by the FDA as having a narrow therapeutic index, Carter explained.

"With a narrow therapeutic index, healthcare professionals are cautioned that even very small variations in active drug can create large variations in efficacy and safety," he stressed.

And Carter noted that "the literature shows that compounded LT4 has a stability issue in which the product degrades over time, and this may be reflected in this group."

These factors — the sampling of a suspension and/or product degradation — could explain some of the differences in concentration, he added.

"For most products, a suspension formulation is appropriate, but when you have a product with a narrow therapeutic index it becomes challenging because of the disparity of particulate matter you can draw with each dose," Carter noted.

"In our analysis, we probably did a very good job of shaking it up, but the concern is how well a patient would do it," he said.

Carter also noted that 11 of the formulations were water-based and one was oil-based, and there were important variations in the added excipients (flavoring) — including one specifying "grilled chicken miso" flavoring and another with Ora-Sweet flavoring.

"This is important because excipients and flavoring do have an impact in terms of absorption in patients with hypothyroidism," he noted.

Approved Formulations of Liquid LT4 Preferable to Compounding

Jonklaas explained the impact using an incorrect dose of levothyroxine could have.

"If a compounded LT4 has less LT4 content than it should have, patients may have hypothyroid symptoms and, for example, worsening cholesterol or less than ideal management of their thyroid cancer," she said.

Likewise, "If a compounded LT4 has more LT4 content than it should have, patients may have hyperthyroid symptoms or be at risk for cardiac arrhythmias or decreased bone density," she explained.

A case report from 2012, for instance, describes a woman who developed thyroid storm because of inappropriately administered compounded thyroid.

Although one reason for compounding could be to avoid ingredients to which patients are allergic, Jonklaas noted there are now approved formulations of liquid LT4 that can be used instead.

And despite a lack of research on the issue, "most physicians are increasingly encountering patients who are using products supplied by compounding pharmacies," Jonklaas said.

"So it appears to be a relevant and growing concern."

American Thyroid Association (ATA) 89th Annual Meeting. Abstract #7. Presented October 31, 2019.

For more diabetes and endocrinology news, follow us on Twitter and Facebook.