URGENT - Northstar Levothyroxine

[helvella]

I have just heard back from the MHRA regarding the issue that Northstar Levothyroxine products now include 25 microgram tablets supplied by Teva (as well as 50 and 100 microgram tablets supplied by Accord/Actavis).

I shall respond but wanted to keep you aware.

(This dovetails into diogenes post re Euthyrox healthunlocked.com/thyroidu... )

Note the sentence starting: Notwithstanding this,…

From: MHRA Customer Services <[e-mail]>

Sent: 13 February 2020 14:50

To: <helvella email>

Subject: RE: GCEP-00141623: URGENT - Northstar Levothyroxine

Dear <helvella>,

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 MHRA respondent>

Customer Services

Communications division

Medicines and Healthcare Products Regulatory Agency

10 South Colonnade, Canary Wharf, London E14 4PU

Original email to the MHRA:

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.

Regards

<helvella>