We have a short paper coming out very soon in Clinical Phamacokinetics (doi.org/10.1007/s40262-020-00887-x} which shows that switching formulations of T4 tablets is not as easy as manufacturers assume and leads to ADR's (complaints). This also shows that different formulations by different manufacturers make switching more problematic than is currently believed by the field. I summarise some of the points. (I can give more data out when the paper is published).
This commentary on reformulation makes several statements
1)When averaging bioequivalence (the same effect of dosage by two different formulations) a group of healthy volunteers are used and their responses to the two formulations measured. The bioequivalence shown by such methods ignores the individual variation both at the same time and in different volunteers shows the basic weakness of this approach,
1) Pharmacological bioequivalence and and clinical interchangeability (outcome of dosing in the body) therefore are linked but one does not forecast performance by the other.
2)In normal healthy subjects, T4 is made by the thyroid gland and subsequent distribution in the circulation is automatic through the bloodstream. In athyreotic patients with no thyroid, T4 must be taken by mouth. Therefore not all T4 ingested is retained – some is lost through the intestine and some is taken in by this route. The routes of utilisation are fundamentally different and uptake is affected by possible interfering substances (eg food).
3)The bioequivalence data was obtained using healthy volunteers, given a large dose of either of the two formulations and measuring the fall in T4 over 72 hours in ach case. There are many assumptions here that are not tested. One is that the massive overdose of T4 does not significantly affect the normal working of the healthy thyroid and of tissue deiodinases. One of the responses by the body will be to remove excess T4 by converting to rT3 and this response will be different person to person. Thus the decay of the extra T4 will come through a mixture of T4-T3 and T4-rT3 conversion – unique in size and relationship in each person.
4)It follows that each persons response to T4 therapy whether healthy or not is unique to them and that this is added to by the new formulation being used on patients with some or no thyroid – complicating things even more.
5)Statistically averaging results from studies like this is fundamentally wrong and explains why testing new formulations is not the easy thing it is believed to be. Each person has a different response and the responses of health subjects will not extrapolate to those lacking a sufficiently active or no thyroid gland.
6)New formulations are not the simple switchover that manufacturers believe in and as a corollary switching between products made by different manufacturers also fall under these problems.
Written by
diogenes
Remembering
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I emailed the MHRA about the inadequacy of testing bioequivalence and the fact that Northstar levothyroxine is now two different products (100 & 50 are Teva; 25 is Accord/Actavis).
My email:
From: <redacted email address>
Sent: 29 January 2020 20:53
To: MHRA Customer Services <MHRACustomerServices@mhra.gov.uk>
Subject: URGENT - Northstar Levothyroxine
Good evening,
The products known as Northstar Levothyroxine (supplied to the UK market via northstarrx.co.uk - part of McKesson Corporation) have, since launch onto the UK market, been manufactured by Accord Healthcare in Barnstaple (formerly Actavis) under product licences PL 0142/0104 and PL 0142/0105.
It appears that Northstar are now selling Teva Levothyroxine 25 micrograms in Northstar livery under Product Licence PL00289/1972.
(At time of writing, I do not know if there have been, or will be, any changes to the 50 and 100 microgram dosages.)
As you will know, a considerable number of patients have had issues with Teva Levothyroxine and many have put in Yellow Card reports.
Also, in the 2013 report, Levothyroxine Tablet Products: A Review of Clinical & Quality Considerations 07 January 2013, it is made clear that bioequivalence is an outstanding issue.
Further, the European (primarily French) issues with the change of Euthryox formula from lactose to mannitol demonstrated that existing bioequivalence testing is wholly unacceptable. The idea that healthy volunteers will experience the same issues as those with thyroid disease and, quite possibly, other diseases is wishful thinking and has never been proved.
We are now in the situation that patients may be dispensed a mixture of two different formulations in what appears the same packaging – albeit the MA Holder details do enable identification to those who are aware enough to notice.
(Even if Northstar is also switching over to Teva for 50 and 100 microgram products, there will be a long period in which patients will see both Actavis and Teva products in Northstar livery at the same time. Indeed, were pharmacies were to ensure a clean cutover, patients may well have remaining packets.)
You may remember that when there were issues with Mercury Pharma Levothyroxine and Eltroxin, the question was raised as to why the formulations differed by dosage. This was, I believe, addressed by adjusting the formulations. It was, though, accepted as an issue.
Now we are back to having different dosages having not just slightly but wholly different formulations.
1) Patients will be unaware of the change to formulation.
2) Patients who might already have found themselves unable to tolerate Teva Levothyroxine will inadvertently be subject for a second time to whatever side effects they have already suffered.
3) Patients who notice any changes will very likely not readily understand the underlying issue.
4) Because there is a lack of bioequivalence, patients could find themselves unable to achieve a stable dose. After all, if they are not bioequivalent two 25s will not be the same as one 50. Just changing tablet dosage (without changing the numerical dose) is likely to have an effect.
Indeed, there are questions over the use of mannitol, sorbitol and lactose in levothyroxine tablets.
Ledeți I, Romanescu M, Cîrcioban D, et al. Stability and Compatibility Studies of Levothyroxine Sodium in Solid Binary Systems-Instrumental Screening. Pharmaceutics. 2020;12(1):E58. Published 2020 Jan 10. doi:10.3390/pharmaceutics12010058
Finally, I have been unable to locate any approved Northstar Levothyroxine packaging. I can find the PARs for many products but not these. Does this mean that you do not approve, or have not approved, the packaging for these repackaged products? Or just that I cannot find the approvals?
I volunteer as an administrator of a large online thyroid forum, and would appreciate an URGENT response so that we can, to the best of our ability, warn patients before they have any problems due to these issues.
Thank you for contacting us and raising your concerns.
As you have correctly highlighted - Northstar is an ‘own label supplier’ (OLS) for Levothyroxine tablets 25mcg, 50mcg and 100mcg for the following licences: PL00289/1972, PL 00142/0104, PL 00142/0105.
An own label supplier relates to situations where a medicinal product is marketed in the livery of a company which is different to that of the Marketing Authorisation Holder (MAH) and possibly under a different product name. In these situations, in addition to the details of the MAH, the product information will also include details of the own label supplier/distributor. It is up to the MAH to propose an own label supplier and request a change to their licence to add this supplier. The MHRA will approve the addition to the licences and the artwork for the own label supplier.
There is no requirement in law for a product range to have a common or quantitatively proportional formulation over a range of dosage strengths. When considering the situation with OLS, commonly, where the product range includes a range of strengths, the OLS will source these from the same MAH; however, this is not mandatory, and it is possible for an OLS to be registered to licences held by different MAHs. Notwithstanding this, we have written to the MAHs for the concerned licences to draw their attention to the design of the OLS packaging and your concern about differentiation with a request to consider these.
The details of the MAH and the PL number must be included in the product information by the OLS. In addition, any additional warnings that are included in the MAH’s product information must also be included for the OLS. This includes listing of excipients of known effect, e.g. lactose. For your information, the approved packaging for Levothyroxine tablets by OLS Northstar are attached.
MHRA is aware of the ongoing discussions regarding interchangeability between Levothyroxine tablets in Europe and are following these closely. However, we are unable to comment specifically on the Euthyrox product as this is not a UK licensed product. It is currently standard practice in the UK to prescribe levothyroxine on a generic basis. This means that the prescriber does not specify the brand /named supplier when prescribing this medicine. The choice of supplier is left to the dispensing pharmacist and they can switch between different suppliers. Please be assured that, as with all medicines and vaccines, the MHRA continues to routinely monitor the safety of levothyroxine tablets in the UK. Should any important safety signals be identified, appropriate regulatory action will be taken and communicated to healthcare professionals and patients alike.
Regarding your concern about bioequivalence studies in healthy volunteers: It is usual to conduct bioequivalence studies in healthy volunteers for a number of reasons, one being that this is usually the best way to show up differences in absorption of a medicine that may be due to formulation. There are additional reasons why a healthy volunteer population is preferred for levothyroxine bioequivalence studies. The absorption of levothyroxine into the bloodstream is not affected by thyroid status. This will therefore be the same whether someone has normal thyroid function or an underactive thyroid. If the bioequivalence studies were to be conducted in hypothyroid patients, the patient would need to be taken off their levothyroxine medicine for a sufficient period to ensure none of the drug was left in the body as this would interfere with the blood levels for the bioequivalence study. Levothyroxine lasts for a long time in the bloodstream and therefore a patient would need to be taken off their tablets for more than one month in order to ensure that there was none of their previous medicine in their body. This could have detrimental consequences on their health. It would also be unethical to withhold levothyroxine treatment from a newly diagnosed patient for similar reasons.
Regarding the reference on compatibility between excipients and levothyroxine, we are also aware of this study. Such compatibility studies, based on binary mixtures (50:50 drug substance:excipient) are useful to guide the formulator, e.g. by flagging gross instability or an interaction between that drug substance and excipient. For a specific product however, the suitability of the formulation through its shelf-life is supported by regulatory stability data.
We hope that this information is helpful and you are welcome to come back if you require further assistance.
Kind regards
<redacted individual name>>
Customer Services
Communications division
Medicines and Healthcare Products Regulatory Agency
Thank you diogenes and your team. I especially think the following is very important:
26)New formulations are not the simple switchover that manufacturers believe in and as a corollary switching between products made by different manufacturers also fall under these problems.
"The absorption of levothyroxine into the bloodstream is not affected by thyroid status. This will therefore be the same whether someone has normal thyroid function or an underactive thyroid."
That would be true if it were directly injected into bloodstream. The fact is that thyroid disfunction frequently affects the gut which in turn will affect absorption. Gut flora may be altered by excipients or variety of gut flora may influence how tablets disintegrate and are absorbed so any changes are likely to disrupt expected absorption.
The MHRA needs to stop treating levothyroxine as generic and interchangeable because it is not.
My experience is that because it behaves like a low index drug though it is not technically a low index drug, then very small changes make a very big difference.
There is so much potential for alteration in potency effect from the start to end of process such as the choice of ingredients, storage of bulk ingredients, excipients, the molecular size and proportions of the solvents, manufacturing processes, packaging, storage of final prodect, ingestion, gut health, food and medicines.
This makes it extremely challenging for patients to maintain stability over the long term.
Sticking to a formulation is about the only aspect of the numerous variations mentioned that patients can control - and should control - to reduce disfunction, doctor visits and unnecessary additional medications in my opinion.
Regarding your concern about bioequivalence studies in healthy volunteers: It is usual to conduct bioequivalence studies in healthy volunteers for a number of reasons, one being that this is usually the best way to show up differences in absorption of a medicine that may be due to formulation. There are additional reasons why a healthy volunteer population is preferred for levothyroxine bioequivalence studies. The absorption of levothyroxine into the bloodstream is not affected by thyroid status. This will therefore be the same whether someone has normal thyroid function or an underactive thyroid. If the bioequivalence studies were to be conducted in hypothyroid patients, the patient would need to be taken off their levothyroxine medicine for a sufficient period to ensure none of the drug was left in the body as this would interfere with the blood levels for the bioequivalence study. Levothyroxine lasts for a long time in the bloodstream and therefore a patient would need to be taken off their tablets for more than one month in order to ensure that there was none of their previous medicine in their body. This could have detrimental consequences on their health. It would also be unethical to withhold levothyroxine treatment from a newly diagnosed patient for similar reasons.
Reply:
I am afraid that I cannot accept your argument here.
Is there any solid evidence that thyroid status does not affect absorption?
And I propose an enhancement to the testing protocols.
The process of delivering a product to market appears currently to consist of:
1. Develop product within the company;
2. Test product on healthy human volunteers;
3. Supply product to anyone prescribed levothyroxine.
At that point, not one single hypothyroid person has taken even one single tablet of this new formulation.
In effect the testing has been shifted from what I would like (a selected group of informed consenting hypothyroid patients, properly monitored in a formal trial) to everyone who doesn’t notice the new formulation when they next get their prescription dispensed. In a trial, if any of the patients doesn’t feel well, they know they can bail out and get help and support.
I suggest that doing this is itself unethical.
At the very least, this should add hypothyroid patient testing:
1. Develop product within the company;
2. Test product on healthy human volunteers;
3. Test product on hypothyroid volunteers;
4. Supply product to anyone prescribed levothyroxine.
(I suggest a completely different protocol for testing on hypothyroid volunteers. A very simple approach would likely suffice. Switch to the new product at the same dose. Continue for at least three months. Do lots of tests including at least those done on healthy volunteers. Do lots of assessment such as maintaining diaries and inventories.)
If, for a minute, we were to accept the argument that a healthy volunteer trial is sufficient, then doing a hypothyroid subject trial would be expected to have absolutely no impact on those volunteers. What it would do is ensure that if any issues were identified, despite the assertion there wouldn’t be any, that observation could prevent many thousands of hypothyroid patients suffering.
Given that patients regularly send in Yellow Card reports when they have switched levothyroxine products, there is at least that much evidence they do not need to come off levothyroxine for a month in order to identify possible adverse effects. Indeed, going through a period of potentially severe hypothyroidism would invalidate every aspect of such an approach. As well as being deeply unethical.
A switch of make without any period off levothyroxine would likely identify many issues.
Effect of Health Status on Levothyroxine Absorption
I think you make a mistake at the first stage of saying that levothyroxine absorption is not affected by thyroid status. It is affected. I put forward some ideas as to what might cause alterations in absorption profiles.
1 Acidity/Alkalinity of the gut
As one simple aspect, consider that stomach acidity is dependent on thyroid status. In someone who is hypothyroid, there can be insufficient stomach acidity. What effect does that have?
I suspect, but have not yet found good evidence, that if the stomach is insufficiently acidic, the intestine is likely to be less alkaline than in a normal healthy subject.
We are all well aware that levothyroxine is poorly soluble in neutral and acidified water. But is rather more soluble in alkaline solutions. (This is, of course, how come oral levothyroxine exists.) If the small intestine is less alkaline we should suspect that this will affect the absorption profile quite possibly including the total absorption achievable. (Even if it were found to be more alkaline, it is likely to produce a different absorption profile.)
2 Genetic Causes
Patients who are hypothyroid through genetic causes are automatically un- or under-represented in pools of healthy volunteers.
3 Gut motility
Slowed gut is a widely reported issue in those who are hypothyroid. This can affect absorption. There are several reports of different absorption in cases of gastroparesis.
4 Hyperthyroidism
You appear to ignore hyperthyroid patients on black and replace. Any interaction between anti-thyroid medicines and the new formulation would be missed.
5 Athyreotic patients
You assume that athyreosis has exactly the same effect as any other cause of hypothyroidism. See Clinical Phamacokinetics (doi.org/10.1007/s40262-020-00887-x).
6 Gut biome
It is often believed, on good grounds, that the gut of those who are or have been hypothyroid has a distinct shift in composition of the biome.
7 Temperature
Low body temperature is one of the most common signs of hypothyroidism. The rate of all reactions changes with temperature and it is feasible that absorption profiles will be affected by being taken in someone with low body temperature.
You could respond that those who are properly treated will have “normal” body temperature. Which ignores the fact that it can take many months, or longer, to increment levothyroxine dose to reach that level. Throughout that time, they will most likely have low body temperature.
8 Co-morbidities
There would be absolutely no identification of issues with other diseases. Obvious examples being hypoglycaemia in hypothyroidism. Low iron. Low vitamin B12. Low vitamin D. Hypertension.
9 Sex
It is, I believe, quite usual for all healthy volunteers be male. As hypothyroidism is considerably more common in females, that alone ignores all aspects of female health. It is very well known that the menstrual cycle affects thyroid binding proteins.
10 General Medicine Interactions
Using healthy volunteers entirely avoids any testing in patients who are taking medicines other than levothyroxine. Many take anti-depressants, anti-hypertensives, anxiolytics, pain relief.
Personal Experience
When I was first prescribed levothyroxine, I was utterly confident that I would take whatever make was dispensed. Although I obviously knew some people preferred one make to another, I assumed it would not be an issue for me.
Within a fairly short time I was affected by the effective failure to deliver claimed dose by old formulation Teva. I was going backwards - not forwards – as my dose was being slowly incremented. After that unpleasant experience, I was much more observant and detected differences among the products I took.
My own experience of new formulation Teva is that even taking as little as 12.5 micrograms (alongside 100 micrograms of Actavis), for just a few days, I suffered stomach issues. Not a dose increase, just the small change from splitting 25 microgram Mercury Pharma tablets.
What seems to happen is that when I am on a good dose and product, I swallow my tablets and forget about it until the next ones are due. When I am not doing so well, I go through periods of feeling under- and/or over-dosed (sometimes both within 24 hours).
Over the years, I have tried many makes and have distinctly different impressions of many of them.
Aliud – excellent.
L-Thyroxin Henning – excellent.
UniPharma Levothyroxine – excellent.
Mercury Pharma – leaves me feeling unevenly treated. I feel over-dosed shortly after taking it but under-dosed by the next dose.
Wockhardt – seems to slightly under-dose me but have never taken a full dose.
Euthryox (non-mannitol) – good.
Actavis – the best of the UK products I have tried.
I appreciate that the resources of the MHRA may have other focus at the present time. For that reason, I am not expecting a fast response. However, I would like to know that representations such as this will not be ignored despite arriving at an inopportune time.
Great, thank you for your response to the MHRA. Your suggestion for testing is definitely an improvement on current practise. I didn't know most 'testees' were male. That's pretty ignorant of female hormonal health then.
I've not tried all the levos. Only TEVA, Mercury Pharma, Eltroxine and Actavis. Got badly underdosed on TEVA and horribly ill. Badly overdosed on Eltroxine and manic. Fine and stable on Actavis, back to my normal self. Only problem is osteoporosis which getting intermittently badly overdosed due to lack of bioequivalence may have contributed.
I note that this is in regards to levothyroxine, but presume the same can be said for liothyronine?
I have no thyroid gland and last June started self medicating on T3.... brilliant improvement in health.
Last November got picked up by NHS and got prescribed T3 a different brand. Since then have changed brands twice and simply cannot find equilibrium. I am still better than no T3 but still not optimum. Not helped by pills being convex and therefore not easy to cut uniformly.
So I presume 20mcgs in one brand is not the same in another?
The absorption issues of liothyronine are usually ignored. I suggest you start another thread as your response here is likely to be missed.
It appears that, mostly, absorption is much less variable and less likely to be affected by the things we know affect levothyroxine. But there is a lot of assumption there as so little proper research has taken place.
Other than Henning Thybon, all we really know is that they all contain liothyronine sodium and is is very unlikely that the quantities will vary significantly.
Henning Thybon has liothyronine hdyrochloride. No-one seems to know whether or not that makes any difference. Quite possibly, next to none.
this is all very worrying. i came off levo as i didnt feel well on it, with various symptoms, i went on ndt and felt a lot better, more normal. however, i cannot get it now and my doc agreed to try combo levo/t3. it has been nearly six weeks and i have had a lot of gut issues and headaches, bloating etc. i have came off the combo and it after the third day without, i feel better, bloating has gone and the headaches also. i dont know what to do now as i know i will eventually feel ill without meds. i wa hyper for a long time before receiving RAI and am now hypo
I've been a medicated hypothyroid for 7-8 years now. And if I've learnt nothing from the experience, it's that Thyroid supplementation should be done on symptoms not blood tests. That wayit doesnt matter what the manufacturer does. You take what you need each day. If the new brand is 3/4 strength and you feel cold, take a little more. If you get a head ache try a little less and if that doesn't work try a little more. The thing is everyone responds differently to thyroid drugs and they need more and less at different times of the year etc.
I'm sitting here and my fingers and tongue are a little buzzy - I'm a touch over medicated. I'm going to take half or maybe even none tomorrow and start back on it the day after.
Before the blood tests were introduced, all doctors diagnosed upon our clinical symptoms alone and we were given NDT (natural dessicated thyroid hormones) - even on a trial basis. Dr Gordon Skinner and Dr Peatfield were the very last doctors to take more interest in clinical symptoms than blood tests although these were still taken.
One of TUK's Advisors (deceased) stated that Big Pharma could see the potential to increase their profits enormously i.e. blood tests and that doctors were paid to prescribe and introduce levothyroxine initially in the USA.
How much do the NHS pay for blood tests for thyroid hormones instead of a trial of hormones to the patient? How many additional prescriptions are given which are supposed to relieve lingering or other symptoms that levo doesn't relieve.(I am also aware that many do well on levo but I'm not one of them).
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