Problems With Alternative Levothyroxine In France Force Merck To Switch Back To Original
Executive Summary
French patients who have experienced adverse reactions to a new formulation of Merck KGaA’s hypothyroidism drug Levothyrox are to be given temporary access to the original formulation, pending the availability of other brands of levothyroxine. Merck says the vast majority of patients have had no problems with the new version.
Merck KGaA is temporarily reintroducing the original formulation of its hypothyroidism product Levothyrox (levothyroxine sodium) in France after more than 9,000 reports were received of adverse reactions, including headaches, dizziness, unusual fatigue and gastrointestinal disturbances, following the introduction of a new formulation of the drug in March 2017.
The move, requested by the health authorities, is temporary pending the import of other brands of levothyroxine, which should arrive within four weeks and will “meet the needs of patients presenting with persistent undesirable effects associated with the new formulation of Levothyrox,” the French health minister Agnès Buzyn announced.
It’s not clear what might be causing the adverse reactions. Changes to the excipients in the product are unlikely to be the culprit. According to the regulatory agency ANSM, which OKd the new formulation on the basis of bioequivalence and other studies carried out by Merck, the only changes made were the replacement of lactose with mannitol and the addition of anhydrous citric acid as a preservative.
The changes made to Levothyrox “do not change the efficacy or the tolerance profile of the medicine,” and “no changes are expected for patients linked to the change in the formulation,” it said in March.
It is possible that the side-effects are related to dosage levels. ANSM noted that levothyroxine has a narrow therapeutic window and that the patient’s thyroid balance “can be sensitive to very small variations in dosage.”
“Most of the reported symptoms may suggest signs of hypothyroidism or hyperthyroidism” – Merck KGaA
A spokesman for Merck in France told the Pink Sheet that the reported symptoms were in line with those experienced on the old formulation and “most may suggest signs of hypothyroidism or hyperthyroidism, such as unusual fatigue, gastrointestinal symptoms (constipation, diarrhea), weight changes, hair loss, dizziness, palpitations, hot flushes and sleep disorders.”
For the “overwhelming majority of the three million patients treated with Levothyrox, the transition from the old to the new formulation has been successful without reported side effects,” the spokesman said. “For some patients, thyroid balance may take longer to reach. It is important to remember that the clinical symptoms of thyroid imbalance are not very specific and vary from one patient to another.”
The health minister said that the new formulation “suited the great majority of patients” but that there were some “who, despite taking the correct dosage, continue to have side-effects.”
New Formulation For Greater Stability
The new, more stable formulation of Levothyrox was developed to replace the existing one after the health authorities in a number of countries, including Brazil, China, France and the US, asked marketing authorization holders to tighten the specifications for levothyroxine content to 95-105%, “i.e., restricting the variability in levothyroxine content to ±5% of the stated dose over the product’s entire shelf-life,” the spokesman said.
Noting that small differences in doses may lead to a variation in efficacy or adverse effects, he said that the “objective of health authorities is to reduce this possible adverse effect over time.”
“Bioequivalence is the guarantee of efficacy and safety identical to those of the old formulation” – ANSM
In an updated Q&A document posted in August, ANSM said the new formulation was “shown to be bioequivalent to the old one on the basis of two pharmacokinetic studies.” It was “demonstrated that the new excipients did not modify the quantity of active substance passing into the blood, nor the speed with which it reached the target organ. This bioequivalence is the guarantee of efficacy and safety identical to those of the old formulation.”
At the minister’s request, ANSM has now published all the documentation relating to the quality of the product, including the bioequivalence studies conducted by Merck.
It also uploaded an article published last year in Current Medical Research and Opinion which said the new formulation “meets the most stringent potency specification guidelines, and has been demonstrated to be bioequivalent to the current formulation and to show dosage form proportionality.”
Access To Alternative Treatments
Packs of the old formulation, under the brand name Euthyrox, will be made available as soon as the company receives a licence from ANSM to import them, Merck said.
Asked where they would be sourced, the spokesman said the company’s supply chain “is confident that it can manage the transitory reintroduction of Levothyrox old formulation via the different production sites in Europe and balance the logistics to avoid any local shortage in the home country.”
He said the company was “working towards the deadline given by the French Minister of Health who announced that within 15 days (Sept. 30), European stocks of the old formulation will be made available upon medical prescription only for patients with persistent side effects.”
The older formulation will only be available for a transitional period, on medical prescription, and “only for patients meeting specific criteria on conditions and their response to the new formulation of levothyroxine sodium,” the spokesman added.
ANSM and Merck stressed that patients should not interrupt their levothyroxine treatment without taking medical advice and should consult their general practitioner or endocrinologist to adjust their dosage during the adaptation phase if they have any symptoms.
In the meantime, ANSM says it has been made aware of a case of a patient being switched to the only other thyroid drug available in France, L-Thyroxine Serb, made by the French company Laboratoires Serb. This product is only intended for children under eight years of age and those who have problems swallowing tablets. Any such switching could cause a shortage in supply of the drug and there is no alternative for these patients, the agency stresses.
UK 2016 Action on Teva Drug
Action regarding the stability of levothyroxine products has been taken elsewhere. In the UK, the Medicines and Healthcare products Regulatory Agency issued a statement in October last year regarding changes to the formulation and manufacture of Teva’s levothyroxine tablets, saying that the company had “demonstrated an acceptable level of efficacy and safety to allow their levothyroxine tablets to re-enter the market” and that additional tablet strengths had been introduced “to improve precision of dosing.”
In February 2012, the Commission on Human Medicines (CHM) had recommended the suspension of the marketing authorization for Teva’s levothyroxine 100mcg tablets following reports of reduced efficacy when patients switched to the product from other levothyroxine drugs.
Teva subsequently undertook an “extensive reformulation” of the 50mcg and 100mcg tablets, along with manufacturing process improvements “that provide assurance of product consistency,” the MHRA said at the time.
Merck recently inaugurated a new pharmaceutical production plant in China that among other things will manufacture Euthyrox, which last year was in short supply in the country because of high demand and a slow importation process. (Also see "Merck KGAA Invests €260m In Production Value Chain in China" - Scrip, 18 Nov, 2016.)
From the editors of Scrip Regulatory Affairs.