In an unprecedented U-turn, the French government has asked drug manufacturer Merck to return to the market a thyroid hormone replacement drug named Levothyrox that the company had phased out and replaced with a new formulation just 6 months ago. The move, which overturns a decision by France's National Agency for Medicines and Health Products Safety (ANSM), comes after thousands of patients complained about side effects from the new drug, creating a media storm and a political problem for the French government.
The old formulation will once again become available in pharmacies on Monday, under a new name, Euthyrox; the two versions will coexist for an undetermined period of time.
About 3 million French people, 80% of them women, take Levothyrox, which replaces the hormone thyroxine in patients with hypothyroidism. Among their complaints over the past few months: hair loss, weight gain, extreme fatigue, headaches, diarrhea, and heightened heart rates.
But their problems are a bit of a medical mystery, because Merck hasn't changed the active ingredient in Levothyrox; what's new are the excipients, ingredients that help stabilize and bulk up the drug. And some experts say the scare has less to do with pharmacology than with consumer distrust, poor communication, and media pressure.
Merck introduced the new Levothyrox formulation in March, at the request of ANSM, which said there was too much variation in the amount of active ingredient over the drug's shelf life and between individual tablets. The new version contains mannitol and citric acid—both innocuous and widely used as excipients—instead of lactose. The amount of active ingredient in each of the new tablets is between 95% and 105% of the target, which is better than commonly accepted standards, says Luciano Rossetti, global head of research and development at Merck, who is based in Billerica, Massachusetts. Rossetti says the United States, Brazil, China, and other countries have also asked the company to change its formulation.
But in France, the backlash has been intense. Patients began reporting side effects in June; as dramatic stories appeared in the press, a petition asking for a return to the old formulation gathered nearly 300,000 signatures and some 9000 reports of adverse events poured into ANSM's website. A dedicated telephone line received more than 150,000 calls in the first week.
Rumors started flying as well. Patients accused Merck, which has a monopoly on thyroxine replacement treatments in France, of trying to boost profits by making the new drug on the cheap in China—though Levothyrox is actually produced in Europe—while the government turned a blind eye. Patients have filed more than 60 lawsuits accusing the company and the government of "failure to assist a person in danger," "causing danger to life," and other crimes. Prosecutors in Paris are investigating.
On 15 September, Minister of Solidarity and Health Agnés Buzyn gave in to the pressure and announced she had asked Merck to bring back the old formulation.
Merck says there is nothing wrong with the new version. Before introducing it, the company did a randomized "bio-equivalence" study in 216 healthy volunteers that showed that peak blood levels and elimination rates of the old and the new formulation were almost identical. Although it had some limitations, the study “complies fully with the standard procedure for reformulations, and actually shows good performance,” says Régis Bouquié, a pharmacologist at the Leon-Jean Gregory Hospital in Thuir, France. Replacing lactose, which seemed to limit the tablets' shelf life, was an improvement, he adds.
“Here we have a crisis, and in every crisis undesirable effects get overreported.”
So why did the change cause so many problems? ANSM says it is analyzing the adverse event reports; conclusions are not expected before October. There is “no scientific explanation at this point for the surge in observed effects,” a press officer says.
Experts say at least some of the problems were likely caused by fluctuations in patients' thyroxine levels as a result of the switch—despite the bio-equivalence study. It's well-known that small changes in thyroxine blood levels can have big effects. And the drug is eliminated very slowly from the bloodstream, which is why it can take months for doctors and patients to find the optimal dose. If lactose reduced the hormone's effective concentration in the old formulation, many patients likely received less hormone than assumed; a new, more stable, formulation may have generated a small wave of hyperthyroidism.
In addition, patients may have attributed problems that had nothing to do with their medication to the switch. And some may have suffered from the "nocebo effect, in which the mere expectation that they were taking a harmful compound caused physical symptoms. “Here we have a crisis, and in every crisis undesirable effects get overreported,” Violaine Guérin, a Parisian endocrinologist, recently said on public television. (She also wrote a reassuring open letter to patients.) Guérin pointed out that 9000 reports of side effects among 3 million users—a rate of 0.3%—is actually very low.
Communication missteps may have exacerbated the problem, however. Merck notified doctors and pharmacists of the switch in a letter that many didn't notice amid the flurry of professional mail; there was no warning about potential side effects. The company and ANSM initially refused to publish the bio-equivalence study; once they did, it actually had a “positive” and “reassuring” effect, Rossetti says. Merck is eager to prevent a repeat of the affair: It has invested €32 million in the transition and plans to introduce the new version of Levothyrox in other countries.
A similar scare a decade ago could have been a warning sign, however. New Zealand saw a big jump in reported side effects in 2007 and 2008—along with the same explosive mix of anxiety, distrust, and media interest—after the only approved thyroxine replacement drug there, made by GlaxoSmithKline, was reformulated. "As countries look to reduce the cost of healthcare, reformulations and switches to generic drugs will become more common," scientists wrote in an analysis of the affair in The BMJ. "Switches provide more opportunities for health scares to develop."
Buzyn’s announcement has eased the tensions in France somewhat, but it has also created an odd situation. “First, the authorities explained to us that the old Levothyrox was a bad, unstable drug," says Muriel Londres, a spokesperson for Living Without a Thyroid, a patient association, in Paris. "Now they reauthorize it, without telling us under what criteria it will be made available, or for how long. No wonder our patients are angry and upset.”