Merck receives recommendation for approval in 21 EU countries for the new formulation of Euthyrox®

[helvella]

This press release seems to have been missed by everyone! After the debacle in France with the reformulated Euthyrox (levothyroxine) - not mentioned in this press release despite specifically mentioning it being introduced in France in 2017 - I had thought that the company might have stepped back from this rollout.

(I checked all more recent press releases - none is related to this Euthyrox rollout. I presume, therefore, that it is still going ahead.)

I find it interesting that they claim:

The new formulation came at the request of several health authorities worldwide.

Also, they claim that it is produced to tighter standards.

They do say that patients being switched to the new formulation should be monitored closely. But we all know that will rarely be honoured. Indeed, I imagine that majority of patients will simply find the new formulation has been supplied without their doctor having the slightest awareness.

Merck receives recommendation for approval in 21 EU countries for the new formulation of Euthyrox®

Merck today announced that the German Federal Institute for Drugs and Medical Devices has recommended to approve Merck’s new formulation of Euthyrox® (levothyroxine) in 21 EU countries.

26 Jul 2018 | Darmstadt, Germany

• German Federal Institute for Drugs and Medical Devices (BfArM) recommends new formulation of Euthyrox® for approval in 21 EU countries

• BfArM is acting as a representative of all 21 EU countries involved in the EU worksharing procedure

Darmstadt, Germany, July 26, 2018 – Merck, a leading science and technology company, today announced that the German Federal Institute for Drugs and Medical Devices has recommended to approve Merck’s new formulation of Euthyrox® (levothyroxine) in 21 EU countries. National approvals will be issued following this recommendation.

"The tighter specification of the active ingredient in the new formulation of Euthyrox® aims to help patients have better control over their individual levothyroxine dosage,” said Steven Hildemann, Global Chief Medical Officer at the Biopharma business of Merck. “Following the positive recommendation from BfArM, Merck will continue to collaborate closely with local Health Authorities, healthcare professionals and patient groups in preparation for the roll out of the new formulation in the 21 countries. Together with the respective stakeholders, and in full compliance with the local regulations, we aim to ensure that patients are appropriately informed. Therefore it is our first priority to support physicians and help them provide their patients with the best possible transition to the new formulation of Euthyrox®.”

The German BfArM decision to recommend the approval of the new formulation of Euthyrox® across 21 EU states was based on a study demonstrating bioequivalence between the old and new formulations.

Levothyroxine is a synthetically produced hormone that corresponds to the natural thyroid hormone Thyroxin (T4). It is used to treat hypothyroidism, goiter and to suppress TSH in the post-treatment of differentiated thyroid cancer.

The new formulation came at the request of several health authorities worldwide. It was introduced in France in March 2017 and Switzerland in April 2018. Turkish authorities have approved the new formulation and Merck expects to launch the medicine there in the course of 2018.

For thyroid drugs a small dosage variation might impact the patient’s thyroid balance. Prescribing doctors are therefore encouraged to monitor patients closely when prescribing the new formulation and to adjust the individual dosage if medically required. Along with Health Authorities, Merck recommends that all patients do not switch or stop their treatment without medical advice and refer to their prescribing physician to potentially adjust the medication dose to their individual need during the transition phase.

Web version of press release

merckgroup.com/en/news/euth...

PDF of press release

merckgroup.com/content/dam/...

[RedApple]

Is there any info on the site about the difference between the ingredients? Would be useful to have this listed so that people can compare what they have.

[helvella Administrator in reply to RedApple]

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.

sciencemag.org/news/2017/09...

Also noticed this:

thyroiduk.org/tuk/news_docs...

[Hidden in reply to helvella]

Isn't that a good thing since lactose binds thyroid hormone...?

[helvella Administrator in reply to Hidden]

If there weren't extremely serious issues with the Merck product in France and similar issues with the Teva product in the UK, then maybe.

There is also the problem that patients simply changing from a lactose-containing product to a lactose-free product, without they or their doctors understanding and monitoring, definitely not so good. If, as you suggest lactose tends to bind to levothyroxine, and we assume mannitol does not, then the switch would likely move patients in the direction of being over-dosed.

[Hidden in reply to helvella]

I am certainly no expert, especially since I take NDT myself, but I remember from my "T4 only years" that it was recommended to avoid taking calcium with levo, and leave at least four hours between levo and calcium supplements. So why would not calcium used as a filler bind some of the thyroid hormone in levo...?

[helvella Administrator in reply to Hidden]

Perhaps it does? Indeed quite likely but it could depend on the precise form of the calcium. There doesn't seem to be much published information.

ncbi.nlm.nih.gov/pubmed/129...

But I am a bit confused why you mentioned calcium? Lactose and mannitol (and citric acid) do not contain calcium.

[Hidden in reply to helvella]

Well, no longer sure myself...I just remember being told not to eat any dairy right after taking levo as the calcium in milk, yoghurt etc would bind some of the thyroid hormone...but maybe I am actually talking about calcium and not lactose which, I believe, you also find in milk...?!

[helvella Administrator in reply to Hidden]

Yes - you do indeed get lactose and calcium in milk and most other dairy products. (But there is none, for example, in clarified butter. All the calcium should have been removed.)

[helvella Administrator in reply to RedApple]

Another paragraph to comment on:

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.

Healthy volunteers are NOT the same as thyroid patients. If this is standard practice, then it is one of those standards that needs to change.

216 people is a rather small group. There are many, many differences among humans which occur with far lower frequency. And the selection of those 216 necessaries misses out on anyone who has ongoing issues which are making them ill - hence not healthy. From 216 to millions? Not acceptable.

Also, "almost identical" is not a scientifically defined term. Just how different? Numbers, full statistics.

Just imagine if thyroid disease, maybe being hypothyroid, specifically tends to affect the biochemistry of mannitol in our bodies?

[greygoose in reply to helvella]

Or maybe, given the similar problems with Teva, we just need lactose to help the thyroxine work?

[helvella Administrator in reply to helvella]

An old paper, from 1966, with lots of question marks.

Abstract

Thyroid cancer has less avidity for iodide than normal thyroid tissue, thus limiting the use of I131 for inoperable thyroid malignancy. Methods to overcome this problem have relied primarily upon TSH either directly or indirectly (i.e., after antithyroid drug withdrawal). Frequently the response to TSH is minimal. That iodide deficiency can increase I131 uptake in normal thyroid tissue prompted an investigation of methods of iodide depletion in the preparation of thyroid cancer patients for I131 therapy. Iodine-deficient diets alone, and the use of NaCl and mercurial diuresis however were unsuccessful. Seven patients with residual thyroid cancer after thyroidectomy have been subjected to combined iodine-deficient diets and intravenous mannitol. This produced two- to three-fold increases in 24-hour uptakes in 5 of these patients. This augmentation in uptake is achieved without the stimulation of I131 release that is produced by TSH. The use of intravenous mannitol seems to be a valuable adjunct in the I131 therapy of inoperable thyroid cancer.

metabolismjournal.com/artic...

Obviously, intravenous mannitol will be in massively higher doses than is present in the new formulation Levothyrox (or Teva). Nonetheless, could mannitol be having an impact on iodine/iodide uptake? And, for that matter, on kidney function?

[MissGrace in reply to helvella]

216!!! That’s shocking! And not hypos!!! That’s doubly shocking! I’m horrified, it’s unbelievable! So the ‘new formula’ that is, paradoxically, ‘just the same’ is making people ill, but it must be in their heads because 216 healthy people stayed healthy? And surely giving ‘healthy people’ Levo would make them unhealthy???

I’m baffled. The medical world harp on and on about T3 and lack of studies and evidence - but this is okay apparently.

Sometimes I think the whole world is barking mad.

Thanks for finding and posting this information.

🤸🏿‍♀️🥛

[Wantie]

Just a bit of background on the back of this story.

The furore in France came about because the government and the drug company went into denial. The packaging changed and patients were told there was no difference to the formulation. Only after thousands of patients complained of symptoms caused by the new formulation, and a legal action which resulted in an independent assessment of the drug, did both the government and Merck admit that the formulation had changed. These patients are now suing for compensation. I live in France and take the Merck Levo and didn’t notice any change but then I take cynomel with it. My endo was always ruthless about prescribing Merck and not allowing the pharmacy to revert to generics as in her mind these were the inferior products.

[RedApple in reply to Wantie]

Wantie, is the new formulation still being supplied or have Merck reverted to the old formulation now?

[Wantie in reply to RedApple]

As far as I know and I take the Merck Levo they have stuck with the new formulation. At the height of the controversy in 2017 / 18 the government went over the heads of the medical bodies and bought in a huge supply of the old formulation.....these were gone in days ! Since then it’s been the new product and a continuing legal battle for those that were badly affected. See this article from a french monthly newspaper for Brits in France connexionfrance.com/French-...

[helvella Administrator in reply to Wantie]

Fully understand that there was denial that product would not work exactly the same. But this is what I do not understand.

Did the leaflets packed in with the product not identify a change of ingredients?

I appreciate that if they did not blazon "New Formulation" (or, perhaps, "Nouvelle formulation") across the box, many might not notice that there had been a change.

What little I have read, the company said that the active ingredient is the same and that it was regarded as bioequivalent. Not that there had been absolutely no change at all.

(As in the press release, the company is quite clearly now admitting that the new formulation is NOT bioequivalent. Otherwise there would be no need to recommend close monitoring. So I agree some very unsatisfactory disinformation/misinformation which must be followed up.)

[greygoose in reply to Wantie]

Are there any generics in France? I was never given any when I was on levo, just the Merck.

[helvella Administrator in reply to greygoose]

So far as I am aware, not as such. Used to be only Levothyrox. But with the fallout from the reformulation, we have seen varied reports as to what is available. And I am not up to date with it all.

[greygoose in reply to helvella]

No, me neither. I haven't taken levo for about 15 years or more. But, at that time, I'm pretty certain there was only Levothyrox available.

[Wantie in reply to greygoose]

There must have been something because my endo used to tell me to make sure I didn’t get given generics and at the start she used to specify Merck on the prescription. To be fair that was about 12 years ago ! For that reason I never had anything other than Merck.

[greygoose in reply to Wantie]

When I was first diagnosed, 19 years ago, I didn't get on with levo at all. I asked my endo if there was 'anything else' I could take - I didn't specify another brand or T3 or whatever, because I didn't know anything about it at the time. And she said no, Levothyrox is all there is. And, of course, went on to add that she'd never had a patient that didn't do well on levo, blah blah blah, you know the story! So, I've often wondered if she was just a liar, or really that ignorant - or perhaps a mixture of the two! But, I was certainly never given a generic at the pharmacy, so I don't really know.

[Wantie in reply to greygoose]

connexionfrance.com/French-... Have you seen this article? There’s a more recent one Which is even more troubling.

[helvella Administrator in reply to Wantie]

No - I had not seen that. Thank you.

French Levothyrox case forced to open in concert hall

A Lyon court hearing into the ongoing case of controversial thyroid medication Levothyrox has opened in a concert hall after the city’s Palais de Justice proved too small to host the 4,113 plaintiffs present.

The hearing opened this week (Monday 3 December), with the plaintiffs suing drug manufacturer, German laboratory Merck, over a “lack of information” over the medication’s controversial new formula, which was first introduced in France in 2017.

So many plaintiffs showed up at the hearing that it was forced to decamp from the Lyon Palais de Justice to the “Double Mixte” concert hall in Villeurbanne. This is normally the site of concerts, festivals and conventions.

The Lyon hearing into Levothyrox is just one of many set to take place across France, with another high-profile hearing expected imminently in Marseille.

There, a Toulouse-based lawyer - who indicted Merck - is seeking €10,000 in compensation for each of his plaintiffs.

The new formula has been the subject of a long-running medical scandal, with patients who rely on the drug claiming that since the introduction of the new version, the medicine no longer works.

The new formula first hit pharmacy shelves in France in 2017, with reports of problems emerging as early as August that year.

Over three million people in France suffer from hypothyroidism and take some kind of medication to treat the condition.

Health minister Agnès Buzyn initially sought to appease complaints by making the old formula of Levothyrox available, with almost half of the 130,000 boxes selling out within two days.

Further laboratory tests of the new drug - including those by French medical safety authority Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) - have confirmed what they call the “good quality of the new formula”.

Yet, those taking the new formula have said that it has caused severe side-effects and problems associated with the return of their thyroid problems, including depression, fatigue, coldness, hair loss, shaking, headaches, vertigo, and even the resurgence of thyroid cancers.

Victims association l'Association Française des Malades de la Thyroïde (AFMT) ran its own laboratory tests, and said that it had found “anomalies in the composition” of the drug, but these tests were dismissed as unreliable by ANSM.

In September, French senator Laurence Cohen (Val-de-Marne; Ile-de-France) called for a new inquiry into the scandal to “get a real view of the situation”.

Despite the controversy, Merck has confirmed that it plans to roll out the new formula across 21 European countries from 2019.

[greygoose in reply to Wantie]

No, I hadn't read that particular one, but I've read similar. What is worrying is that they are so reluctant to believe patients when they say it causes side-effects! Surely the people taking the medication are the best placed to judge!

[helvella Administrator in reply to greygoose]

Online automatic translation of original. Page dated 13 February 2019.

The Week: Where are the alternatives to Levothyrox?

Fabienne Monquignon: Since April 2018, 5 alternatives to Levothyrox are on the market: L-Thyroxin Henning scored tablet; T soft capsule caps; Unbreakable compressed thyrofix; L-Thyroxine Serb oral solution drops and Euthyrox scored tablet. Many of us from the collective opted for Tcaps, a medicine with only two excipients and very well tolerated. It is issued only on prescription and its price varies. He is still not reimbursed. What is lamentable is that pharmacies take the opportunity to increase their rates. When I started it in April, it was at 10.20 euros. I find myself today at 12.5 €. Pharmacists are very nice to tell me that they have loads and employees to pay. We were told that it should not be more expensive than 11 euros. There are people who manage to pay almost € 15, which is shameful. So I went around the pharmacy sector and it is the pharmacy opposite Lafayette galleries is the cheapest.

asso-malades-thyroide.fr/wo...

[greygoose in reply to helvella]

Pharmacies in France are terrible places! All the pharmacists think they are doctors and know better than everyone else. They are ready to stage demonstrations to give themselves more power at the drop of a hat! I avoid them as much as possible!

[MissGrace]

Merck are no strangers to the courts on these kind of issues. You only have to google to find a number of other cases. Issues with the painkiller Vioxx being one the more recent ones.

google.co.uk/amp/s/mobile.r...

🤸🏿‍♀️🥛

[Nanaedake]

I definitely think levothyroxine should be tested on hypothyroid volunteers before declaring it fine. Also it should be tested on volunteers who've had thyroidectomy too. There could be all sorts of reasons why it doesn't work well in people with antibodies or without a thyroid gland.

[Ismaja]

When I was in Germany I had so bad side effects with my old thyroid medication.The GP was putting me on Euthyrox ( November 2018) within 2 days all the bad symptoms were gone. I was able to lose some weight and feel good as never before on thyroid medication. I am puzzled a bit about this thread, but as we all know we are often unique regarding thyroid medication.

[EllieTa in reply to Ismaja]

It was the same for me. All my bad symptoms disappeared when I took Merck Euthyrox and not my usual brand. It was amazing.

[EllieTa]

I took the new Euthyrox in Germany (I had left my Levothyroxine at home in the UK and was prescribed by a German doctor) and I felt wonderful - so much more energy. Then when I came back to the UK my pharmacy gave me Northstar and I started to feel really terrible. `I swelled up, my throat swelled up and I felt lethargic and couldn't go to my Pilates class.

Euthyrox is amazing and I wish it was available in the UK. It made such a difference to my health.