MHRA Response re Liothyronine Patient Information

[helvella]

The other day, after many months, I received the following response from the MHRA - edited only to remove personal identification:

GCEP-00128197: Liothyronine PIL and SmPC Advice - PUBLIC

Dear <helvella>,

Thank you for your enquiry. I am sorry that we have not been able to respond to you as quickly as we would like. Your questions and our responses are listed below. I hope that these are helpful; however do not hesitate to contact us again should you need further information or any clarifications.

Query:

The PILs and SmPCs for all three UK Liothyronine tablet products contain advice about doses lower than 20 micrograms. From the SmPC for Mercury Pharma Liothyronine, I quote:

Method of Administration: Oral

• For doses lower than 20 micrograms, the tablet should be allowed to dissolve/disperse in 20 mL of water for 10 minutes, in a small measuring cup.

• The patient should gently swirl the solution occasionally to aid the dissolution/dispersion. The patient should then swirl the solution for a few seconds prior to using a suitable oral syringe to withdraw the amount of liquid corresponding to the dose prescribed (5mL for a 5mcg dose; 10 mL for a 10mcg dose).

• The patient can then squirt the liquid directly into their mouth from the suitable oral syringe by gently pressing the plunger.

• Any remaining liquid should be discarded.

(10. Date of revision of the text 02/03/2018)

medicines.org.uk/emc/produc...

There are several issues with this advice.

1) The advice would apply to any dosage other than a multiple of 20 micrograms. For example, 25 or 30 micrograms. Why – seemingly arbitrarily – highlight only doses lower than 20 micrograms?

For liothyronine sodium, the 20 microgram (mcg) tablet is the sole oral solid dosage form currently authorised in the UK. The names, marketing authorisation numbers and marketing authorisation holders for Liothyronine Sodium 20 microgram Tablets are:

• Tertroxin Tablets 20 mcg / Liothyronine Sodium 20 microgram Tablets; PL 10972/0033; Mercury Pharma Group Limited

• Liothyronine Sodium 20 Microgram Tablets; PL 00289/2116; Teva UK Limited

• Iraksin 20 microgram Tablets / Liothyronine Sodium 20 Microgram Tablets; PL 20117/0270; Morningside Healthcare Limited

Note that not all of these medicines may currently be marketed.

The dosage (posology) of a medicine is described in the Summary of Product Characteristics (SmPC) and may vary depending upon the clinical condition for which it is prescribed (the indication) and the age, body weight or surface area of the patient or emergence of adverse events. A general overview of posology for Liothyronine Sodium 20 microgram Tablets is given below:

Adults:

Starting dose of 10 or 20 micrograms every 8 hours, increasing after one week, if necessary, to the usual recommended daily dose of 60 micrograms in two or three divided doses.

Myxedema Coma:

60 micrograms given by stomach tube, then 20 micrograms every 8 hours. It is more usual to start treatment with intravenous liothyronine.

Adjunct to carbimazole treatment of thyrotoxicosis:

20 micrograms every 8 hours.

Paediatric population:

Children below 12 years: 5 micrograms daily.

Adolescents: 12 – 17 years: Initially 10-20 micrograms daily; increased to 60 micrograms daily in 2-3 divided doses.

Elderly: 5 micrograms daily.

Based on the posology, the majority of patients may be treated with a single or with multiple 20 microgram tablets. The paediatric and elderly populations are exceptions, for which doses lower than 20 micrograms are required. As a result; instructions for preparation of doses less than 20 micrograms are included within the SmPC.

2) The discarding of remaining liquid is problematical. It should not be put into the drainage system but the advice appears to endorse doing just that - simply by offering no advice to do otherwise. My view is that any remaining liquid should be collected and returned to a pharmacy for safe disposal. However, even that has issues.

Every medicine is the subject of an Environmental Risk Assessment, as part of assessment of the marketing authorisation application. The package leaflet makes clear that “Medicines should not be disposed of via wastewater or household waste.” The Package Leaflet signposts the patient to discuss disposal needs with their pharmacist who is in a position to offer advice and arrange disposal, according to the specific needs of the individual patient (“Ask your Pharmacist how to dispose of medicines no longer required.”)

3) Was any consideration given to the cost of complying with this advice? Obviously, for a 10 microgram dose, following this advice doubles the cost (compared to splitting tablets). For a low cost medicine, that might be acceptable. At something like £258 for 28 tablets, and the product already being withdrawn from numerous patients on the grounds of cost, it is unconscionable to expect patients to throw half the medicine away!

The MHRA is responsible for the regulation of medicines and medical devices in the UK. A medicine is only granted a marketing authorisation (product licence) once supporting data have been fully evaluated to assure its quality, safety and efficacy for the conditions it is intended to treat and to confirm that it has an acceptable balance of risk and benefit. The cost of the particular medicine cannot and does not feed into this assessment.

The pricing of medicines and the clinical commissioning decisions are not under the remit of MHRA. We advise you to contact the NHS Business Services Authority regarding pricing medication in the NHS. Please review the link below:

Email: [e-mail]

Telephone: [phone]

4) Was any consideration given as to how patients are expected to know they need oral syringes and measuring cups? Where they can be obtained from? (Just checked Boots and they don’t list them.) How much they cost (especially important for those of limited means)? That oral syringes should only be used once?

The need for preparation of a solution from Liothyronine Sodium 20 microgram Tablets will depend upon the prescribed dose, as illustrated by the dosage instructions in the SmPC. Should a dose of 5 or 10 micrograms be required, the dispensing pharmacist will provide an oral syringe and further support to the patient, as required.

5) What actual difference does it make to dose as advised rather than splitting tablets? If a tablet splits slightly unevenly does the patient suffer?

The need and appropriateness of sub-division of tablets is assessed as part of the evaluation of a marketing authorisation application. It is very important that tablets are not sub-divided (“split”) for dosing purposes unless this option is clearly described within the SmPC and package leaflet.

Liothyronine sodium 20 microgram Tablets are relatively small and contain a potent drug. For this reason, tablet sub-division for dosing purposes has not been authorised for these medicines. Doses of liothyronine sodium of less than 20 micrograms should be prepared by forming a solution/dispersion of a tablet in water, in accordance with the instructions in the SmPC and package leaflet.

6) Where is the research which shows that the advised method is better than splitting for liothyronine? (Given their different ingredients, this research needs to be repeated for each make.)

7) Where did this advice originate in respect to liothyronine? It does rather look as if the biggest beneficiaries of following the advice would be the three manufacturers.

Sub-division of liothyronine tablets is not appropriate as explained above. For each authorised liothyronine tablet product; data have been submitted to support the preparation of a solution / dispersion in water in line with the instructions in the SmPC and package leaflet. These data have been evaluated to assure their appropriateness and ability to provide an accurate and precise quantity of liothyronine sodium. These data and this method of sub-dividing the dose by dissolving or dispersing the tablet has been reviewed and endorsed by experts of the Commission on Human Medicines (CHM) and its Expert Advisory Committee for Chemistry and Pharmacy Standards who advised that tablet sub-division is inappropriate. Membership of these committees is published on the MHRA’s website (see link).

Kind Regards,

<YS>

Customer Services

Communications division

Medicines and Healthcare Products Regulatory Agency

10 South Colonnade, Canary Wharf, London E14 4PU

Telephone: [phone]

Email: [e-mail]

[Hennerton]

We cannot win this lunacy. I had much the same response from Morningside Health when I wrote after I was given their product and read the instructions on dispersing in water. When I replied, citing the financial waste involved each time and the impractical nature of their advice, they had absolutely no answer. I then asked my very knowledgeable Eastern European trained pharmacist what I should do. He was adamant that using the water method is more prone to inaccuracies in dose than splitting. I am happily still splitting.

[helvella Administrator Thyroid UK in reply to Hennerton]

I shall be responding to the MHRA asking for chapter and verse references to their assertion.

I have just this minute sent an email to the pricing people mentioned (paragraph 3) )

If anyone else feels like communicating with any of the involved organisations, please feel free to do so. There is absolutely nothing special or proprietary about my emails or involvement.

[m7-cola in reply to helvella]

Thanks for your work on this.

[m7-cola in reply to Hennerton]

Thanks for this reassurance

[Angel_of_the_North in reply to Hennerton]

Me too.

[amala57]

Complete madness!

[jimh111]

Thanks for this. I got a reply from the MHRA in May:

You further expressed your concerns around liothyronine being hydrophobic and that an accurate dose cannot be dispensed by dispersing in water. At present liothyronine 20 micrograms is the lowest strength of liothyronine tablet available on the UK market. To administer doses lower than 20 micrograms, the patient is instructed to dissolve a whole tablet in 20 ml water and to take a portion of the volume according to the dose required, as advised in the Teva SmPC and PIL. The solubility of liothyronine is sufficient that 20 micrograms can be readily dissolved in 20 ml water, which has been verified by the company through testing prior to granting of the medicinal license. The cloudiness with some products is due to the excipients – the non-active ingredients - and not the liothyronine which dissolves. This contrasts with levothyroxine which has lower solubility, which you may have in mind. Liothyronine tablets should not be broken to obtain a lower dose due to a serious risk of administering an incorrect dose. This is due to the low amount of liothyronine per tablet which may not be evenly distributed throughout the tablet. Therefore, to ensure accuracy of dosing, it is advised for all liothyronine products that a whole tablet should be dissolved where a lower dose is required; once again, this has been validated by testing prior to granting of the license.

I also challenged some other details on the PIL: “Liothyronine is triiodothyronine NOT thyroxine” and is “not long lasting”. They are going to look into this, they say they will review whether to change it, the wording is written to avoid complexity.

I later checked out the solubility of liothyronine (11.4 mcg/ml pubchem.ncbi.nlm.nih.gov/co... ) and it is better than levothyroxine. The stuff about the amount of liothyronine not being evenly distributed is a red herring. Either they mix up an homogenous preparation and press it into tablets or they individually pop 20 mcg liothyronine into each tablet. Of course it is the latter, so splitting tablets will work although perhaps they can't guarantee a perfectly split tablet will contain 10 mcg L-T3 to the same level of precision a full tablet will contain 20 mcg. This is splitting hairs, the fraction of a percent difference will be compensated when we take the other half.

"NHS Business Services Authority" Another useless quango burning up NHS money.

[SilverAvocado]

Helvella, thank you for bringing this technical issues to my attention. I would never have the mental energy to look into this myself, but it's fantastic to hear about other people doing it.

[m7-cola]

I totally agree with you.

[Hpbr]

Oh my goodness. It just gets worse and worse. My gp is trying to wean me off lio. My previous dose of 150 levo and 20 lio is now 200 levo and 10 lio. I'm not messing around and chucking away valuable medicine. I half them with a pill cutter. That said I'm not giving them up. I feel awful even on half dose. Throwing away half a dose. That's madness.

[BootsOn]

At what age are we considered to be elderly? 5 mcg a day would condemn me to a slow painful death.

[JGBH]

Thank you helvella.

[helvella Administrator Thyroid UK]

I have now sent a Freedom of Information request to the MHRA for the actual information on which the decision was made to insist on dissolving over splitting.

(With the additional request that if they are not the right ones to reply, tell me who is.)

[Zephyrbear in reply to helvella]

In the meantime, I shall just continue splitting them... You might like to add the question: if they weren't meant to be split, why do they have a score line...?

[helvella Administrator Thyroid UK in reply to Zephyrbear]

The “official” answer is so that people who cannot swallow whole tablets can take them in two parts. That is why they are often called break lines...