Side Effects Skyrocket in France With Levothyroxine Reformulation
Widespread reports of side effects linked to changes in the formulation of the hypothyroidism drug levothyroxine (Levothyrox, Merck) in France have forced the company to put its previous formulation — now in limited supply — back on the market and further sparked an investigation, accusations of fraud, and even a police raid of Merck's plant in Lyon, France.
The new formulation of the synthetic levothyroxine drug, used by approximately 3 million patients in France — largely women — was introduced in France in March. This was in response to concerns raised in 2012 by the French drug safety group National Agency for Medicines and Health Products Safety (ANSM) about variation in levels of active ingredients, potentially affecting the previous formulation's shelf life.
Changes to the formulation included removal of the nonactive ingredient, or excipient, lactose, and replacement with mannitol and citric acid, which are commonly used in tablet drug formulations and have not been linked to adverse effects.
But within 3 months of the new formulation's release, as reported by Medscape France, thousands of patients began reporting side effects, including dizziness, cramps, headaches, and hair loss — side effects that could be associated with either not getting enough or getting too much thyroid-hormone replacement.
Adverse-Event Reports Fueled by Media Reports?
According to ANSM, an estimated 9000 adverse-event reports had been filed by September, and, with substantial coverage of the issue in the French media, more than 150,000 calls have been reported to a help line.
More than 60 lawsuits have reportedly been filed and, in response to a petition of more than 300,000 signatures to restore the old formula, the French government made unprecedented move last month of asking Merck to bring back the old version of the drug — despite the original concerns over that formulation.
Supplies of the older formulation, being shipped from Germany under the name of Euthyrox, are limited, however, and doctors have been urged to prescribe it to patients only as a last resort if they complain of the side effects in response to the new formulation.
As negative press over the reports has intensified, accusations of fraud have been hurled, with a prosecutor in Marseilles launching an investigation into whether Merck deceived patients with regard to the formulation change, according to news agency Reuters. And French police searched Merck's plant in Lyon last week.
While ANSM is expected to release an account of the adverse-event reports later this month, the agency has said it currently knows of "no scientific explanation" for the effects and has publicly supported the new formulation's safety.
Merck has meanwhile conducted an open-label, randomized bioequivalence study of 216 patients showing nearly identical peak plasma concentrations and elimination rates of the old and new formulations.
French health minister Agnes Buzyn likewise asserted to the media, "There is no fraud, there is no conspiracy" relating to the new formulation and said many of the side effects were related to the reordering of Levothyrox but were corrected "when the treatment is well-dosed."
One expert told Medscape Medical News that levothyroxine does have a very narrow therapeutic index, so even small dose adjustments can result in easily detectable changes in thyroid-function tests.
In France, the ANSM has announced that an alternative to Levothyrox, L-Thyroxin Henning (Sanofi), will become available as an alternative to Levothyrox later this month.
Although not a leading levothyroxine drug in the United States, where the top-selling brand is Synthroid (AbbVie), Levothyrox is widely used in Europe and elsewhere in the world.
Not the First Reformulation Ruckus
The case isn't the first time a reformulation of a levothyroxine drug has resulted in an onslaught of side effect reports.
As reported in the BMJ, a switch in the formulation of the drug Eltroxin (GlaxoSmithKline) in New Zealand in 2007, despite no changes in active ingredients, was met with a nearly 2000-fold increase in adverse-event reporting, skyrocketing from just 14 reports over the previous 30 years that the drug had been available to more than 1400 reports in 18 months (BMJ. 2009;339:b5613).
There are numerous similarities between that case and the current situation: just as there have been rumors in France that Merck manufactured the new formulation with cheaper ingredients sourced in China, it was rumored in New Zealand that the new formulation of Eltroxin was being manufactured in India and contained genetically modified ingredients.
Likewise, key factors speculated to have boosted the sudden spike in adverse-event reports in both cases include intense media coverage and the misattribution of unrelated physical symptoms to the new formulation.
In the Eltroxin case, two additional brands of levothyroxine were approved in New Zealand in 2008, yet by 2009, the level of adverse-reaction reports for Eltroxin returned to the levels seen prior to the reformulation, and 80% of patients using levothyroxine were using the new form of Eltroxin by the end of 2009, the BMJ article notes.
Levothyroxine's Narrow Therapeutic Index
While new formulations of any type of drug may raise concerns about differences in responses, levothyroxine is of particular concern due to a narrow therapeutic index, meaning that even small dose adjustments can result in easily detectable changes in thyroid-function tests, James Hennessey, MD, director of clinical endocrinology in the division of endocrinology at Beth Israel Deaconess Medical Center, Boston, Massachusetts, explained to Medscape Medical News.
"The uniqueness of levothyroxine, in my opinion, is the narrow therapeutic window that we have to shoot for, with relatively small differences in drug absorption potentially resulting in clinically significant differences, not just in thyroid-function tests, but, one could assume, also in symptoms," he said.
And with the subjectivity of symptoms and the potential influence of other factors on symptoms, thyroid-function tests represent the more sensitive gauge of whether a drug is truly having an effect on the thyroid — and such simple tests could provide important insights into cases such as those reported in France.
"The bottom line is that when a [thyroid-drug] formulation changes, patients should have their thyroid function checked within 6 to 8 weeks after the change to make sure their thyroid function remains stable," Dr Hennessey said.
"If it is indeed stable, then we can start from there to look at what else might be causing the symptoms."
Dr Hennessey has consulted for Allergan and Abbvie.