British National Formulary - Confusion

[helvella]

In the British National Formulary, there is a section for each medicine headed Medicinal Forms.

You can see below that the lists start with the heading All products.

However, this is just plain misleading! The first five entries are all for 12.5 microgram levothyroxine tablets. But there is only one actual product – Teva! The entries for A A H, Alliance, DE and Medihealth are because they are distributors of the Teva product – not because there are any other actual products.

No-one just looking at the BNF could appreciate what this really means without additional understanding.

And, for 25 microgram tablets, it is even more confusing as there are multiple products and multiple distributors with no indication whatsoever which is which.

To further add to the confusion, Almus and Northstar are listed and they are own label suppliers. So not really another product but not just a distributor.

It isn’t only the BNF which pulls us into this trap, but they are such an obvious and frequently consulted site, they make a good example. (They have also recently re-worked their Medical Forms sections but have not addressed this issue.)

Levothyroxine

Tablet

All products

◦ Levothyroxine sodium 12.5microgram tablets A A H Pharmaceuticals Ltd

◦ Levothyroxine sodium 12.5microgram tablets Alliance Healthcare (Distribution) Ltd

◦ Levothyroxine sodium 12.5microgram tablets DE Pharmaceuticals

◦ Levothyroxine sodium 12.5microgram tablets Medihealth (Northern) Ltd

◦ Levothyroxine sodium 12.5microgram tablets Teva UK Ltd

◦ Eltroxin 25microgram tablets Advanz Pharma

◦ Levothyroxine sodium 25microgram tablets A A H Pharmaceuticals Ltd

◦ Levothyroxine sodium 25microgram tablets Advanz Pharma

◦ Levothyroxine sodium 25microgram tablets Alliance Healthcare (Distribution) Ltd

◦ Levothyroxine sodium 25microgram tablets DE Pharmaceuticals

◦ Levothyroxine sodium 25microgram tablets Medihealth (Northern) Ltd

◦ Levothyroxine sodium 25microgram tablets NorthStar Healthcare Unlimited Company

◦ Levothyroxine sodium 25microgram tablets Phoenix Healthcare Distribution Ltd

◦ Levothyroxine sodium 25microgram tablets Sigma Pharmaceuticals Plc

◦ Levothyroxine sodium 25microgram tablets Teva UK Ltd

◦ Levothyroxine sodium 25microgram tablets Wockhardt UK Ltd

◦ Levothyroxine sodium 25microgram tablets lactose free Imported (Germany)

◦ Eltroxin 50microgram tablets Advanz Pharma

◦ Levothyroxine sodium 50microgram tablets A A H Pharmaceuticals Ltd

◦ Levothyroxine sodium 50microgram tablets Accord Healthcare Ltd

◦ Levothyroxine sodium 50microgram tablets Advanz Pharma

◦ Levothyroxine sodium 50microgram tablets Alliance Healthcare (Distribution) Ltd

◦ Levothyroxine sodium 50microgram tablets Almus Pharmaceuticals Ltd

◦ Levothyroxine sodium 50microgram tablets DE Pharmaceuticals

◦ Levothyroxine sodium 50microgram tablets Medihealth (Northern) Ltd

◦ Levothyroxine sodium 50microgram tablets NorthStar Healthcare Unlimited Company

◦ Levothyroxine sodium 50microgram tablets Phoenix Healthcare Distribution Ltd

◦ Levothyroxine sodium 50microgram tablets Sigma Pharmaceuticals Plc

◦ Levothyroxine sodium 50microgram tablets Teva UK Ltd

◦ Levothyroxine sodium 50microgram tablets lactose free Imported (Germany)

◦ Levothyroxine sodium 75microgram tablets A A H Pharmaceuticals Ltd

◦ Levothyroxine sodium 75microgram tablets Alliance Healthcare (Distribution) Ltd

◦ Levothyroxine sodium 75microgram tablets DE Pharmaceuticals

◦ Levothyroxine sodium 75microgram tablets Medihealth (Northern) Ltd

◦ Levothyroxine sodium 75microgram tablets Teva UK Ltd

◦ Eltroxin 100microgram tablets Advanz Pharma

◦ Levothyroxine sodium 100microgram tablets A A H Pharmaceuticals Ltd

◦ Levothyroxine sodium 100microgram tablets Accord Healthcare Ltd

◦ Levothyroxine sodium 100microgram tablets Advanz Pharma

◦ Levothyroxine sodium 100microgram tablets Alliance Healthcare (Distribution) Ltd

◦ Levothyroxine sodium 100microgram tablets Almus Pharmaceuticals Ltd

◦ Levothyroxine sodium 100microgram tablets Aristo Pharma Ltd

◦ Levothyroxine sodium 100microgram tablets DE Pharmaceuticals

◦ Levothyroxine sodium 100microgram tablets Medihealth (Northern) Ltd

◦ Levothyroxine sodium 100microgram tablets NorthStar Healthcare Unlimited Company

◦ Levothyroxine sodium 100microgram tablets Phoenix Healthcare Distribution Ltd

◦ Levothyroxine sodium 100microgram tablets Sigma Pharmaceuticals Plc

◦ Levothyroxine sodium 100microgram tablets Teva UK Ltd

◦ Levothyroxine sodium 100microgram tablets lactose free Imported (Germany)

Capsule

All products

◦ Tirosint 25microgram capsules Imported (United States)

◦ Tirosint 50microgram capsules Imported (United States)

◦ Tirosint 100microgram capsules Imported (United States)

bnf.nice.org.uk/drugs/levot...

Liothyronine

Tablet

All products

◦ Liothyronine 5microgram tablets A A H Pharmaceuticals Ltd

◦ Liothyronine 5microgram tablets Alliance Healthcare (Distribution) Ltd

◦ Liothyronine 5microgram tablets DE Pharmaceuticals

◦ Liothyronine 5microgram tablets Medihealth (Northern) Ltd

◦ Liothyronine 5microgram tablets Morningside Healthcare Ltd

◦ Liothyronine 10microgram tablets Alliance Healthcare (Distribution) Ltd

◦ Liothyronine 10microgram tablets DE Pharmaceuticals

◦ Liothyronine 10microgram tablets Medihealth (Northern) Ltd

◦ Liothyronine 10microgram tablets Morningside Healthcare Ltd

◦ Liothyronine 20microgram tablets A A H Pharmaceuticals Ltd

◦ Liothyronine 20microgram tablets Accord Healthcare Ltd

◦ Liothyronine 20microgram tablets Advanz Pharma

◦ Liothyronine 20microgram tablets Alliance Healthcare (Distribution) Ltd

◦ Liothyronine 20microgram tablets DE Pharmaceuticals

◦ Liothyronine 20microgram tablets Medihealth (Northern) Ltd

◦ Liothyronine 20microgram tablets Morningside Healthcare Ltd

◦ Liothyronine 20microgram tablets Teva UK Ltd

◦ Cytomel 25microgram tablets Imported (United States)

Capsule

All products

◦ Liothyronine 5microgram capsules Alliance Healthcare (Distribution) Ltd

◦ Liothyronine 5microgram capsules Roma Pharmaceuticals Ltd

◦ Liothyronine 10microgram capsules Alliance Healthcare (Distribution) Ltd

◦ Liothyronine 10microgram capsules Roma Pharmaceuticals Ltd

◦ Liothyronine 20microgram capsules Alliance Healthcare (Distribution) Ltd

◦ Liothyronine 20microgram capsules Roma Pharmaceuticals Ltd

bnf.nice.org.uk/drugs/lioth...

(These lists were copied on 12/09/2022 and will change over time.)

[nightingale-56]

You can quite understand why Doctors and Pharmacists are confused about prescribing when reading this! Thanks for posting . Only hope I can carry on getting my NDT privately - much simpler!

[helvella Administrator in reply to nightingale-56]

Speaking to my own GP, I said that I would not accept 12.5 microgram tablets as only Teva is available. He replied that there are five products to choose from. I explained... He didn't seem very pleased... (I suspect he was seeing the same information through the GP surgery software, EMIS or whatever.)

As so often, I do not blame GPs for being confused by this.

I do blame GPs for seeing these things and not complaining, making it into an issue that needs resolving. They appear more willing to accept them as ongoing issues than do anything about them.

[nightingale-56 in reply to helvella]

GPs really could help their patients more, and ultimately make their job easier, if they put in a complaint about this sort of thing.

[Aurealis]

Why? 🤦‍♀️

[helvella Administrator in reply to Aurealis]

I really don't know.

As every product has a Product Licence number, that could have been used to identify the products.

There is a big database called DM+D which sits behind a very large part of the NHS' medicine information. And, as it appears to me, there is bit of poor design and/or implementation which means there is no obvious way of getting all products rather than products from all suppliers, if you see what I mean!

What I don't want to do is point a finger of blame at any one person or body because it needs better analysis of what happened than I can muster. Otherwise it's just general shouting rather than adding to our understanding.

[phenelope]

What a list! I used Eltroxin. It was the only one that worked for me. Then the formula was changed and it became useless. I became hopelessly weary.

I SAW ABOUT THE DEMONSTRATIONS IN FRANCE AND WENT AND BOUGHT EUTHYROX FROM THERE. OLD FORMULA. IT WORKS OKAY.

However, I have concluded that I need T3. I do not believe that the T4 is converting to T3. I take T3 for energy.

Reading up on all the medicines, and what happened in France when the government ordered Merck to continue some of the old formula, I believe that the addition of MANNITOL is the culprit. It makes pills glossy and slightly slimy.

I believe that it, like sorbitol, causes medicine to be bio-unavailable for some of us..

I believe it has been added to all Levo's, and Premarin, Thiroid S, Armour, and a number of Ritalin medications as an unlisted 'excipient.' I believe it is being used to replace lactose.

I believe that I am not alone with this contrary metabolism. I would love to hear from other people for whom medicines suddenly become glossy and cease working. Mannitol should be a listed ingredient.

Help please! Are you out there fellow Mannitol sufferers? Can we do anything about it?

[helvella Administrator in reply to phenelope]

I don't think there is any evidence it has been added as an unlisted ingredient to any medicine.

I did not react well to the reformulated Teva which does contain mannitol. But I do not get any of the same effect from Accord, Mercury Pharma or Wockhardt.

It would be necessary to do a proper analysis in order to be sure. I have no idea how much analysis of this sort costs but I can't think you'll get anywhere without.

[phenelope in reply to helvella]

It takes a lot of reading using an incognito mode. I spent hours. The big sales meeting with Merck and all the large pharmaceutical companies. The French demonstrations. The record about Sorbitol, another sugar alcohol, sometimes making drugs bio-unavailable., . The visible effect it has on the pills. The fact that suddenly the pills look glossy.

There is a website that lists all the excipients, but sometimes they are out of date and precede the changes.

Chemists are not given lists of excipients. They are unlisted, as being irrelevant and harmless. Lactose has to be a listed excipient. If it disappears, it has probably been replaced with Mannitol.

I have a lot of reports on it. long and boring. From the French demonstrations by families who were getting ill from the reformulated thyroid medicine no longer working it is clear that a sizeable number of people have the same metabolism as I have.

Bananas make me ill! Is that a clue to our metabolism? For some people they are poisonous, did you know?

Enuff sed, in the words of Molesworth Minor...

[phenelope in reply to helvella]

Levothyrox FYI

Levothyrox case: confirmation of the condemnation of the laboratory for lack of information

Paris, Saturday March 19, 2022 – This is the end of the first civil part of the Levothyrox affair. In 2017, the Merck laboratory put on the market, without warning anyone, a new formula of their drug treating hypothyroidism and taken daily by three million people in France. One of the excipients, lactose had indeed been surreptitiously replaced by mannitol and citric acid.

Attacked by 3,300 patients among all those sickened by the new formula, the Merck company claimed to have acted in accordance with the legislation and the public health code, by showing the modification of excipients in the context of the leaflet and the labeling boxes.

But for the Court of Cassation, if the leaflet meets the regulatory requirements (in that it gives the new composition of the drug), the only mention of mannitol and citric acid, in a dense text "and printed in small type is insufficient to show an evolution of the formula.

The condemnation of the manufacturer and the operator is therefore confirmed. If this extensive procedure is now closed, the Levothyrox file is the subject of a criminal investigation against X for alleged acts of aggravated deception, homicide and involuntary injuries and endangering the lives of others.

[helvella Administrator in reply to phenelope]

I am well aware of what happened in France. It was very badly done.

However, in subsequent rollouts, Merck made it very much clearer.

There are still issues with what they did.

But I still am not convinced that ingredients have been changed and not identified on the official documents.

[phenelope in reply to helvella]

Thanks for replying. I hope you are right about the ingredients and excipients.

There is this:

"The Pharmacopoeias (US Pharmacopoeia, British Pharmacopoeia) contain monographs for many excipients. However, not all excipients reach these texts due to companies withholding data because of concerns about releasing proprietary information."

The only declared changes in France, as you know, were citric acid and mannitol.

Mannitol was apparently used instead of lactose to increase shelf life and avoid allergies. For a lot of people it made the thyroxine bio-unavailable. But there must be another answer......

[helvella Administrator in reply to phenelope]

If a medicine contains, say, Magnesium Stearate, Maize starch, or whatever, those will have to conform to BP, PhEur, USP or other relevant monograph.

However, if a medicine states Opadry White, Eudragit (followed by a number), etc., I agree that we sometimes cannot find the ingredients of that proprietary product. (I have nit checked which specific products are covered by monographs and which are not.)

I'd go further and say that even for excipients for which there are monographs, we do not have general access to the monographs. There must be things like the required purity and levels of specific impurities.

(I believe all monographs should be freely accessible. Though, if they want to continue being able to charge for them, they could restrict access to some of the extreme technical details that are needed to prove conformity.)

The change to mannitol in France was at the request of the French health ministry! As you say, to improve shelf-life/stability. They did test the change. However that testing process has been questioned and I have previously posted a paper on precisely that question - and will add that text below.

And another advantage of mannitol was for those who wish to avoid all dairy products.

I really don't think all pharmaceutical companies would have chosen to reformulate all their thyroid hormone products.

A paper which questions the trial of new formulation Merck Euthyrox (from lactose to mannitol).

Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?

Concordet D1,

Gandia P1,

Montastruc JL2,

Bousquet-Mélou A1,

Lees P3,

Ferran A1,

Toutain PL1

Clinical Pharmacokinetics, 01 Jul 2019, 58(7):827-833

DOI: 10.1007/s40262-019-00747-3 PMID: 30949873 PMCID: PMC6584220

Abstract

In France, more than 2.5 million patients are currently treated with levothyroxine, mainly as the marketed product Levothyrox®. In March 2017, at the request of French authorities, a new formulation of Levothyrox® was licensed, with the objective of avoiding stability deficiencies of the old formulation. Before launching this new formulation, an average bioequivalence trial, based on European Union recommended guidelines, was performed. The implicit rationale was the assumption that the two products, being bioequivalent, would also be switchable, allowing substitution of the new for the old formulation, thus avoiding the need for individual calibration of the dosage regimen of thyroxine, using the thyroid-stimulating hormone level as the endpoint, as required for a new patient on initiating treatment. Despite the fact that both formulations were shown to be bioequivalent, adverse drug reactions were reported in several thousands of patients after taking the new formulation. In this opinion paper, we report that more than 50% of healthy volunteers enrolled in a successful regulatory average bioequivalence trial were actually outside the a priori bioequivalence range. Therefore, we question the ability of an average bioequivalence trial to guarantee the switchability within patients of the new and old levothyroxine formulations. We further propose an analysis of this problem using the conceptual framework of individual bioequivalence. This involves investigating the bioavailability of the two formulations within a subject, by comparing not only the population means (as established by average bioequivalence) but also by assessing two variance terms, namely the within-subject variance and the variance estimating subject-by-formulation interaction. A higher within individual variability for the new formulation would lead to reconsideration of the appropriateness of the new formulation. Alternatively, a possible subject-by-formulation interaction would allow a judgement on the ability, or not, of doctors to manage patients effectively during transition from the old to the new formulation.

Concordet D, Gandia P, Montastruc JL, et al. Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients? Clinical Pharmacokinetics. 2019 Jul;58(7):827-833. DOI: 10.1007/s40262-019-00747-3. PMID: 30949873; PMCID: PMC6584220.

Freely accessible here:

europepmc.org/article/PMC/P...

There were several letters published concerning this paper. However, they are not all freely accessible. This is one from the original authors as a response!

Note that it is very even-handed and expressly dismisses bad faith from any party. More a case of the rules not properly covering the situation about being applied as if they did.

Authors’ Reply to Coste et al.: “Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?”

link.springer.com/article/1...

[Salslowthyroid]

I have recently been issued with 25mcg liothyronine capsules from Nova Laboratories Ltd. There are no details further other than shelf life and contact details.

[helvella Administrator in reply to Salslowthyroid]

That would appear to be odd!

Are you aware of any reason they'd be prescribing 25 micrograms rather than the usual standard for the UK of 20 micrograms?

Or is there some special reason like avoiding corn, lactose, etc.?

Even if you need 25 micrograms, I'd be surprised if a "specials" company would charge less than even adding a 20 and a 5 from Roma - which would be £110.

[Salslowthyroid]

O I'm so very sorry! I meant 5mcg 🥴! I was just intrigued as they weren't on the NICE list.

[helvella Administrator in reply to Salslowthyroid]

They are not in the BNF because they are "specials" - made to order. Maybe your prescriber is not aware that 5 microgram capsules are now a fully licensed product?

I suspect that will be costing many times as much as Roma capsules.