Levothyroxine: new prescribing advice for patients who experience symptoms on switching between different levothyroxine products

[helvella]

Am posting this as major news!

Will most likely come back and add some comments.

As I see it, if the issues described apply, any GP not only can but MUST prescribe by specific product.

Levothyroxine: new prescribing advice for patients who experience symptoms on switching between different levothyroxine products

If a patient reports persistent symptoms when switching between different levothyroxine tablet formulations, consider consistently prescribing a specific product known to be well tolerated by the patient. If symptoms or poor control of thyroid function persist (despite adhering to a specific product), consider prescribing levothyroxine in an oral solution formulation.

From:

Medicines and Healthcare products Regulatory Agency

Published

19 May 2021

Advice for healthcare professionals:

generic prescribing of levothyroxine remains appropriate for the majority of patients and the licensing of these generic products is supported by bioequivalence testing

a small proportion of patients treated with levothyroxine report symptoms, often consistent with thyroid dysfunction, when their levothyroxine tablets are changed to a different product – these cases are noted in UK professional guidelines

if a patient reports symptoms after changing their levothyroxine product, consider testing thyroid function

if a patient is persistently symptomatic after switching levothyroxine products, whether they are biochemically euthyroid or have evidence of abnormal thyroid function, consider consistently prescribing a specific levothyroxine product known to be well tolerated by the patient

if symptoms or poor control of thyroid function persist despite adhering to a specific product, consider prescribing levothyroxine in an oral solution formulation

report suspected adverse reactions to levothyroxine medicines, including symptoms after switching products, to the Yellow Card scheme

Background

Levothyroxine is authorised for the control of hypothyroidism. In the UK, prescribing of levothyroxine is usually generic, with no named product specified on the prescription. Patients may thus be changed between different levothyroxine products according to what is available at their local pharmacies, with the prescriber generally unaware of the specific product that the patient is taking at any particular time. This generic prescribing approach is supported by strict UK regulatory requirements for licensing to ensure compatibility (bioequivalence) between products.

Nevertheless, the MHRA receives reports of patients experiencing adverse events on switching between different levothyroxine products. The MHRA has conducted a review of the available data and sought advice from the Commission on Human Medicines (CHM) as to whether any regulatory action is needed to minimise the risk of adverse events on switching between different levothyroxine products.

Reports considered by the review

Levothyroxine is one of the most commonly prescribed medicines in the UK. Between 1 January 2016 and 31 December 2020 there were a total of nearly 260 million packs of levothyroxine dispensed against a prescription in UK retail and hospital pharmacies. [footnote 1]

For the 5-year period between 1 January 2015 and 31 December 2019, the MHRA received 335 Yellow Cards reporting one or more of the terms ‘product substitution issue’, ‘condition aggravated’ or ‘drug ineffective’ with levothyroxine. The majority of reports were received from patients rather than healthcare professionals, with 47 of the cases having a healthcare professional reporter. Associated symptoms were mostly consistent with hypothyroidism or hyperthyroidism, and included fatigue, headache, malaise, anxiety, palpitations, pruritus, nausea, myalgia, dizziness, arthralgia, feeling abnormal, alopecia, depression, abnormal weight gain, and insomnia.

Of the 335 cases, 12 reported a recurrence of their symptoms after a second trial with the medicine concerned. Only 27 of the 335 cases included reference to thyroid function test results. Of these, 9 suggested a hypothyroid state, with 4 hyperthyroid and 14 euthyroid. In most cases, thyroid function test data from before the product switch were not available to confirm that thyroid function was well controlled before the switch, or to indicate whether a substantial change in parameters within reference range had occurred.

The underlying causes for the symptoms experienced by patients switching between levothyroxine products are generally unclear. Potential causative factors could include:

gastrointestinal comorbidities potentially affecting levothyroxine absorption [footnote 2]

concomitant use of medication reducing gastric acidity, which can also affect levothyroxine absorption[footnote 3]

very low thyroid reserve[footnote 4]

intolerance or allergy to an excipient in a particular brand

specific genotypes relating to thyroid hormone synthesis or thyroid receptor function [footnote 5] [footnote 6] [footnote 7]

For the most part, the symptoms experienced on switching levothyroxine tablet formulations could indicate the need for dose adjustment. However, some patients experience symptoms despite thyroid function testing showing them as biochemically euthyroid.

These symptoms experienced by a minority of patients are acknowledged in UK professional guidelines. These guidelines note that although generic prescribing of levothyroxine is appropriate for the vast majority of patients, in rare cases a patient may require a specific levothyroxine brand to be prescribed.[footnote 7] In some patients, better control of thyroid function may be achieved with oral solution forms of levothyroxine than with tablets.[footnote 8] [footnote 9] [footnote 10]

Management of symptoms after product switching

CHM considered the reports in the UK and advised that levothyroxine should continue to be prescribed generically for most patients. If a patient reports symptoms after their brand of levothyroxine is changed, healthcare professionals are advised to consider testing of thyroid function and follow the ‘Advice for healthcare professionals’ section above.

The product information for levothyroxine tablets is being updated to include this advice for prescribers – see example Summary of Product Characteristics and Patient Information Leaflet.

Report on a Yellow Card

Please continue to report suspected adverse drug reactions to the Yellow Card scheme.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

the Yellow Card website

the Yellow Card app; download from the Apple App Store or Google Play Store

some clinical IT systems for healthcare professionals (EMIS, SystmOne, Vision, MiDatabank, and Ulysses)

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines or medical device and diagnostic adverse incidents used in coronavirus (COVID-19) using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

Article citation: Drug Safety Update volume 14, issue 10: May 2021: 1.

gov.uk/drug-safety-update/l...

[SlowDragon Administrator]

At last!

Just shows.....it’s is EXTREMELY important to put in a yellow card if you get adverse results changing brands ....and they were counting them!

Surprised it’s only 335 reports - but it’s 335 reporting one or more of the terms ‘product substitution issue’, ‘condition aggravated’ or ‘drug ineffective’ with levothyroxine

Of the 335 cases, 12 reported a recurrence of their symptoms after a second trial with the medicine concerned. Only 27 of the 335 cases included reference to thyroid function test results.

Between 1 January 2016 and 31 December 2020 there were a total of nearly 260 million packs of levothyroxine dispensed against a prescription in UK retail and hospital pharmacies.

That’s a lot of prescriptions

[helvella Administrator Thyroid UK in reply to SlowDragon]

If someone is even suspicious that there is a side effect or interaction, it is right to put in a Yellow Card report.

The MHRA do not expect 100% cast iron proof. All they expect is that we do reports as honestly and carefully as we can.

We patients are often not in a position to be certain. Simple suspicion is enough to justify putting in a Yellow Card report.

If the MHRA receive multiple similar reports, each one will back up the others. But if we don't put in the reports, they won't be there to do so.

There are similar schemes in many other countries. If you are not in the UK, look for your country's scheme.

[nellie237 in reply to helvella]

I started filling in a yellow card form (not Levo).....I got to the box where it asked if my GP had submitted a yellow card.....I didn't know. The next time I spoke to him I asked him......

GP "It's a known side effect"

Me "Well, they won't know how common/dangerous if its not reported, and I think it carries more weight if you do it"

GP "Sigh"....but I could hear him tapping it out on his keyboard..........

[helvella Administrator Thyroid UK in reply to nellie237]

It is quite clear that doctors are dreadful at making reports.

Some appear to think that they will be making fools of themselves if they put in a report that doesn't stand up. Others, as yours, that there is no point.

Of course, it's probably for the best if both patients and doctors report everything!

[shaws Administrator in reply to helvella]

I agree with your comment helvella.

[tattybogle]

WOW !'‘product substitution issue’' / ‘'condition aggravated’' / ‘'drug ineffective’'

I did a Yellow Card for Teva last year , but don't think i used any of those specific terms ... think i just waffled vaguely about feeling bleurgh.

I wonder how may more reports they would have found if they included ''bleurgh''

[nellie237 in reply to tattybogle]

🤪🤣🤣It's hard to be articulate when feeling bleurgh

[tattybogle in reply to nellie237]

[mourneadventurer]

Perhaps a direct link on the ThyroidUK site to the Yellow Card app might be useful with some suggestions for keywords?

[helvella Administrator Thyroid UK in reply to mourneadventurer]

Do you use the Yellow Card app? Do you find it significantly better than doing things in a web browser? From the description, it doesn't appear to be that helpful. However, allowing an alert list for specific medicines might be helpful for many. (I just subscribed to all alerts and get regular emails.)

Yellow Card Mobile App: You can now receive news updates from the MHRA and report side effects to medicines via the Yellow Card app. Please download it from the Apple App Store or Google Play Store. Key features of the app include the ability to create a ‘watch list’ of medications for which you can receive news and alerts from the MHRA. You can view numbers of Yellow Cards reported to the MHRA for medicines of interest and see previous Yellow Cards you have submitted through the app. At the moment account details are not syncronised between this website and the app, so you need to create separate accounts. We are also considering ways to report medical device adverse incidents, defective medicines and counterfeit products through the app.

yellowcard.mhra.gov.uk/the-...

There has long been a pinned post here on the forum:

healthunlocked.com/thyroidu...

And the Thyroid UK web site has this:

thyroiduk.org/help-and-supp...

[mourneadventurer in reply to helvella]

Thanks Helvella,I personally have never used the Yellow Card scheme as I was unaware of T4 hormone replacement contraindications.

When battling with GP regarding hypothyroid symptoms yet apparently euthyroid. Anything to empower anyone in that situation is worthwhile.

Thankyou for your contribution Helvella!

[MMaud]

I just logged on this morning to mention this change.

Like many, I have issues with TEVA brand and did have it on my record that it should not be prescribed, which was all fine, until the Endo changed my dose. From that point forth, it took me several prescription rounds of requests and letters to have my prescribing notes amended again. Hopefully, this guidance will make things a bit easier.

[Mugs19 in reply to MMaud]

It doesn’t appear to include the right to specify which brand of oral solution you should have.

[helvella Administrator Thyroid UK in reply to Mugs19]

Inevitably there will be things not covered. But even as it stands, it represents a significant shift which we should be very pleased to see.

(There have been several posts identifying that some individual patients very much care which levothyroxine oral solution they take. But I'm not sure any are obvious cases of different absorption between products - which seems very likely for some tablets.)

[MMaud in reply to Mugs19]

To be honest, Mugs, I would be approaching it on the basis of the halo effect. If my GP argued against, I'd be asking him to document his rationale, including the science to back it up, so that I could understand.

Writing "stuff" down often softens stances - particularly those on the extremes.

[Jaydee1507 Administrator]

Well hallelujah!

[CapnM]

When my pharmacist switched brands on me the other day I queried it and she said they just got what they got (except where TEVA concerned she seemed to imply she could request this- though I was a bit brained fogged at the time). Do you know if this is correct for most pharmacists - that they cant choose the brand on ordering ------ or am I being led on by their personal desire not to stock too many brands?

[helvella Administrator Thyroid UK in reply to CapnM]

Afraid it might be true that they get what they get. But it is likely to depend on the ordering system in each pharmacy. Difficult to know except that the large chains almost certainly use the same ordering system in each of their own branches. Some systems might allow specifying make; others not.

Trouble is, it ends up being our responsibility to check and to find a pharmacy which will get what we want.

(I think the pharmacy contracts with the NHS imply they cannot be selective about which products they supply. But this halfway house - sometimes it matters, sometimes it doesn't - leaves them and us in an invidious situation.)