MHRA publishes a report on levothyroxine tablet products

[helvella]

I report this exactly as on the MHRA web site - without comment. I encourage you to both read what is below and the actual report (link to PDF):

MHRA publishes a report on levothyroxine tablet products: A review of the clinical and quality considerations

In response to concerns expressed by patients and healthcare professionals regarding potential inconsistencies in the quality and effectiveness of levothyroxine products, the MHRA conducted a review. Recommendations from this review were endorsed in March 2012 by the Commission on Human Medicines, an independent panel of experts who advise the licensing authority. These include more stringent controls of quality, including the introduction of a discriminatory dissolution test in the British Pharmacopoeia (BP) Monograph and tighter regulatory controls.

Levothyroxine tablet products: A review of clinical and quality considerations

mhra.gov.uk/home/groups/pl-...

Questions and answers

General

1. Why is the MHRA publishing this report?

Over recent years, the MHRA has received reports from prescribers and patients of problems with levothyroxine tablets, mostly concerning the quality or effectiveness of the product. The numbers of reports were very small in relation to the number of patients taking this medicine, nevertheless they were persistently received. In January 2011 the MHRA decided to undertake a detailed investigation into possible underlying reasons for these reports that might be connected to the known sensitivity of the drug substance, levothyroxine. The findings were presented to the Commission of Human Medicines for their consideration.

2. Who are the Commission on Human Medicines (CHM) and in what situations does it make recommendations to the MHRA?

The Commission on Human Medicines is an independent panel of experts with whom the licensing authority (MHRA) consults to obtain advice on the safety, quality and efficacy of medicines. The CHM may make recommendations to the licensing authority on particular medicines under consideration. Further information about the CHM is published on the MHRA’s website:

Commission on Human Medicines

mhra.gov.uk/Committees/Medi...

3. What recommendations did the CHM make for levothyroxine products?

The CHM made several recommendations aimed at improving the quality and consistency of levothyroxine products. A key recommendation was the introduction of a new discriminatory dissolution test that all products will have to meet when tested.

4. Why is the levothyroxine dissolution test important?

Dissolution is a way of testing that the levothyroxine drug is able to adequately dissolve out of the tablet and be available in solution for absorption from the gut. If the drug doesn’t completely dissolve, then it may not be fully absorbed by the body to give an optimal clinical effect. A dissolution test was developed by the MHRA. Although we cannot be certain that this test is predictive of what will happen in the body, all levothyroxine tablets on the UK market were shown by this test to have satisfactory dissolution apart from one make (Teva levothyroxine 100 microgram tablets). Teva levothyroxine 100 microgram tablets have since been withdrawn from the UK market.

5. Where can I get more information about the Teva levothyroxine 100 microgram tablet?

The MHRA consulted with the CHM over the Teva levothyroxine 100 microgram tablet on 9 February 2012 and this led to the suspension of the marketing authorisation of this product on 19 February 2012. The MHRA expects to publish a report on this CHM review by end February 2012.

6. When will the new dissolution test be applied to levothyroxine products?

The dissolution test will shortly be included in the BP monograph for Levothyroxine Tablets. This will become a legal requirement once published by the BP. The timescale for this is expected to be about January 2014. More information about the revised monograph for levothyroxine tablets is available on the BP website:

Revised Monographs (external link)

pharmacopoeia.gov.uk/custom...

Prescribers

7. In the recommendations it states: ‘…brand or named supplier prescribing is not considered necessary at this stage, but should be kept under review.’ Will the CHM be keeping this under review and issuing further guidance? And if so when is this likely to be?

All the recommendations made by the CHM to improve the quality of levothyroxine tablets have been taken forward by the MHRA and the BP Commission. Earlier this year, the MHRA met with each manufacturer of levothyroxine tablets to give them notice of these recommendations to ensure they are implemented. CHM did not recommend named or brand prescribing because the recommendations were considered to be adequate measures to ensure the quality and consistency of levothyroxine tablets that remain on the UK market. The MHRA are closely monitoring all reports of adverse events following suspension of the Teva Levothyroxine 100 microgram Tablet. Since removal of this product from the market, there are no clear signals suggesting that the levothyroxine products that remain on the UK market are inequivalent.

The MHRA will continue to review reports and consult with the CHM when necessary.

Patients

8. What should patients on levothyroxine do now?

If you are taking levothyroxine you do not need to take any action. Most patients on levothyroxine will have regular blood test to inform their GP that their hypothyroidism is controlled and whether any adjustment is needed to their treatment.

However, if you have any concerns over your treatment you should discuss these with your GP, practice nurse or pharmacist.

9. Where can I get more advice on this subject?

If you have any other questions regarding this review you should discuss them with your GP, practice nurse or pharmacist.

Please also continue to visit the MHRA website.

mhra.gov.uk/Safetyinformati...

Rod

[Hidden]

Hmmm. Thanks Rod. My only comment is that as with any investigation/research/questionnaire they will only get useful answers if they ask the right questions!

Jane x

[helvella Administrator Thyroid UK in reply to Hidden]

I couldn't help thinking that at least one question was properly asked, considered and resulted in a specific recommendation which will be much appreciated by many here:

Levothyroxine should be prescribed and dispensed in quantities covering three months supply, where appropriate, in order to address issues of continuity of supply and also to improve convenience to patients.

[shaws Administrator in reply to helvella]

I agree. If you have any chronic condition why supply 28days only? More expensive too.

[helvella Administrator Thyroid UK in reply to shaws]

Certainly for things like levothyroxine, it is madness.

I'd also like to suggest that, without a NICE statement, this MHRA recommendation is probably "trumps" over some jumped up PCT which demands that 28-day prescribing is necessary. Or, indeed, an individual doctor in most cases.

[Hidden]

Very interesting Rod - thanks!

Louise

xx

[Hidden]

I get two months. Should I ask for three?

[helvella Administrator Thyroid UK in reply to Hidden]

I too get two months supply.

I had already had a correspondence with our PCT who have been pushing 28-day prescribing but allowing GPs to give 56 days. So I have re-awakened that and asked if they will be re-considering their policy in the light of the specific MHRA recommendation for levothyroxine.

It would be wrong to push too hard, too soon and at the wrong gate! We do, in general, have to allow some time for this to trickle through to PCTs, doctors, etc. But maybe print it off and ask quietly next appointment?

I feel that the MHRA have failed to say what might have been in their minds. Surely we need to have three-month prescriptions AND get the repeat while we still have a month to go?

[Hidden]

It seems to me that reasoning behind it -- consistency of product -- reveals a rather more disturbing picture. I know that when my pharmacy gave me a different brand, it affected rather badly but how do you prove it was the product?

[helvella Administrator Thyroid UK in reply to Hidden]

You don't. And you don't need to prove it to report the issue. All that is required is your honest concern that such might be the case. And a bit of time filling in the report.

This MHRA report says that they were concerned by an increase in Adverse Drug Reactions - which reached around 50 a year for levothyroxine. Clearly, they were concerned that the numbers were that high.

If everyone who truly believes they suffer a reaction to levothyroxine and say so here were to report the issue, that number would not have been 50 but more likely 500 or more.

mhra.gov.uk/Safetyinformati...

At the same time, when everything is whirling around in your head, "What is causing which symptom?", it can make even this reporting more difficult.

[helvella Administrator Thyroid UK]

J Clin Endocrinol Metab. 2012 Dec 21. [Epub ahead of print]

Generic and Brand-Name L-Thyroxine Are Not Bioequivalent for Children With Severe Congenital Hypothyroidism.

Carswell JM, Gordon JH, Popovsky E, Hale A, Brown RS.

Source

Division of Endocrinology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115.

Abstract

Context:

In the United States, generic substitution of levothyroxine (l-T(4)) by pharmacists is permitted if the formulations are deemed to be bioequivalent by the Federal Drug Administration, but there is widespread concern that the pharmacokinetic standard used is too insensitive.

Objective:

We aimed to evaluate the bioequivalence of a brand-name l-T(4) (Synthroid) and an AB-rated generic formulation (Sandoz, Princeton, NJ) in children with severe hypothyroidism.

Design:

This was a prospective randomized crossover study in which patients received 8 weeks of one l-T(4) formulation followed by 8 weeks of the other.Setting:The setting was an academic medical center.Patients:Of 31 children with an initial serum TSH concentration >100 mU/L, 20 had congenital hypothyroidism (CH), and 11 had autoimmune thyroiditis.Main Outcome Measures:The primary endpoint was the serum TSH concentration. Secondary endpoints were the free T(4) and total T(3) concentrations.

Results:

The serum TSH concentration was significantly lower after 8 weeks of Synthroid than after generic drug (P = .002), but thyroid hormone levels did not differ significantly. Subgroup analysis revealed that the difference in TSH was restricted to patients with CH (P = .0005). Patients with CH required a higher l-T(4) dose (P < .0004) and were younger (P = .003) but were not resistant to thyroid hormone; 15 of 16 CH patients had severe thyroid dysgenesis or agenesis on imaging. The response to generic vs brand-name preparation remained significant when adjusted for age.

Conclusions:

Synthroid and an AB-rated generic l-T(4) are not bioequivalent for patients with severe hypothyroidism due to CH, probably because of diminished thyroid reserve. It would therefore seem prudent not to substitute l-T(4) formulations in patients with severe CH, particularly in those <3 yr of age. Our results may have important implications for other severely hypothyroid patients in whom precise titration of l-T(4) is necessary.

PMID:

23264396

05/11/2015 Edited to add link to full paper in pubMed Central:

ncbi.nlm.nih.gov/pmc/articl...

[Lintably]

I stumbled on this report about dissolution tests when looking for info about my Sandoz Liothyronin after having such a good result. Although this was about the dissolution test for Levothyroxine rather than Liothyronin I found it interesting that the Sandoz brand Levothyroxine was 12.5% more bioavailable than the benchmark.

I am making enquiries about getting the Sandoz Levothyroxine instead of the pointless Actavis/Almus product.

[Lintably]

After the dissolution tests Doctors in America were warned that Sandoz Levothyroxine was more potent.

Interesting that they choose to use a less potent product in preference because it was the original brand.

My Sandoz Liothyronine is miles better as it is more potent than the Mercury product.

I'm very interested in trying the Sandoz Levothyroxine.

thyroid.org/thyroid-experts...

[helvella Administrator Thyroid UK in reply to Lintably]

The whole of the USA reference products issue is somewhat odd. When levothyroxine products were forced to get full licence/approval, the first product to achieve that was Unithroid. Only later (and, if I remember right, past the official deadline) did Synthroid get approved. That resulted in Unithroid being the official reference product - but then there were all sorts of further arguments, and I simply do not remember how the dust settled.

[Lintably]

It's a mess frankly!