ESA News

Issues of Thyroxine Stability and Storage: Current Status

In May 2004, Sigma, the sole Australian supplier of L-thyroxine sodium informed pharmacists that thyroxine tablets should henceforth be stored refrigerated, before and after dispensing. No reason, other than concern about shelf-life, was given for this instruction which appears to be uniquely Australian; no similar suggestion has been made for any of the multiple international preparations of thyroxine, regardless of source. Since that time, the “keep refrigerated” direction on the dispensed product has been explicit in Australia. (Some pharmacists follow the instruction with such zeal that they insist on transport in a refrigerated pack.)

It soon became apparent that daily opening and closing of a refrigerated bottle for up to six months appeared to have an adverse effect on tablet stability, probably as a result of dampness. Adverse drug reaction reports were filed. It was of particular concern that a dose increase, as a result of diminishing potency, could be a potential cause of dangerous overdosage after change to a fresh preparation. (www.mja.com.au/public/issues.182_12_200605/contents_2006505.html).
In response, Sigma conceded that unsealed bottles of tablets in current use might be better stored at room temperature, but this modification has not been widely communicated to pharmacists.

In a more recent development, letters from Sigma to doctors and pharmacists in June and August 2005, foreshadow a change to a formulation to five bottles of 40 tablets each, to be stored refrigerated, except for the bottle in current use. In support of this change, Sigma refer to “new stability studies”, but the data have not been made available for review.

Failure to disclose this information appears to be contrary to current aims to achieve more open communication between the pharmaceutical industry, healthcare professionals and consumers. On that basis, a formal request for this information was sent to Sigma on 26 September 2005. The reasons for seeking this information were set out in a letter of the same date to Dr Leonie Hunt of the Drug and Safety Evaluation Branch of the Therapeutic Goods Administration, as follows:

This letter accompanies a formal request to Dr Ovais Siddiqui of Sigma Pharmaceuticals that he make available the data to support his statement in his letters of 27 June and 15 August 2005 to medical practitioners and pharmacists that “new stability studies support the storage of these products in the fridge” in reference to revised storage conditions for thyroxine. My reasons for this request are set out below. While some may regard the issue as trivial, it can be viewed as a test case that questions openness of disclosure and evidence-based practice in the relationship between the pharmaceutical industry, regulatory authority, pharmacists, prescribers and over 200,000 Australians consumers who use thyroxine.

I am sure that you are aware that it is many decades since pharmacy progressed away from confidential formulations, towards a professional ethos of more open disclosure. That principle is at stake here and is especially pertinent in relation to the reported view of Dr David Graham, that he favours greater transparency in medicines decisions.

The reasons for my request are as follows:

It is rational to question the anomalous storage conditions for thyroxine in Australia, in relation to thyroxine storage recommendations in the rest of the world.

If there are data to show that thyroxine stability is improved by refrigeration, it would be important to make the facts known, in view of current doubts about the bioavailability of various thyroxine preparations, particularly in the US market. If storage temperature is an additional variable that affects shelf-life, that fact should be made known outside Australia.

Because precise treatment of hypothyroidism is especially critical in the first trimester of pregnancy and in the long-term management of differentiated thyroid cancer, those who prescribe this treatment need to have access to relevant data about the preparation that they prescribe.

With Sigma as a monopoly supplier of thyroxine in Australia, consumers are absolutely dependent on this single product. That alone makes it obligatory for medical professionals to seek and obtain relevant facts about the formulation that is marketed here.

If the data to which Dr Siddiqui refers cannot be made available, there are some who will hold the view that there may be no such data. It would then follow that the Australian directive of May 2004 to refrigerate thyroxine may have been in error, based only on the hope that shelf-life might be improved by refrigeration.

I would be most grateful if you would do all that you can to bring the relevant facts to the fore. Alternatively, I would value your views as to what action could potentially be taken by various consumer groups to obtain this information.

It is my hope that Sigma will make relevant data known, in a spirit of free and open biomedical communication, based on the wish to achieve the best outcome for many people whose health depends on thyroid hormone replacement. That is the reason why I am sending this communication as an open letter to other stakeholders.

Sigma have since offered access to the data under a confidentiality agreement that precludes evaluation or discussion of the data. That offer has been declined and the issue remains unresolved.

Jim Stockigt