To the Editor: In May 2004, Sigma, the sole Australian supplier of l-thyroxine sodium, instructed pharmacists that thyroxine tablets should be stored refrigerated, both in pharmacies and after dispensing. Thyroxine bottles now carry explicit labels: “keep refrigerated” or “refrigerate at all times”. This instruction seems to have been accepted by health professionals, but patient-support groups immediately questioned the refrigeration directive. In response, Sigma conceded that thyroxine tablets can be stored at room temperature (< 25°C) for up to 4 weeks, with refrigeration still the preferred option.

There are major unresolved issues about the potency, stability and bioavailability of various thyroxine preparations that are marketed competitively in the United States.1 With a single supplier in Australia, we can avoid between-preparation variations, provided that stability and consistency are maintained.

The instruction to refrigerate thyroxine tablets seems to be uniquely Australian. None of my co-authors of the website <www.thyroidmanager.org>2 is aware of a refrigeration directive in any other country. The local instruction seems to have followed interaction between the Therapeutic Goods Administration and the manufacturer, so that unopened bottles could be marketed with a longer shelf life.

Is the rest of the world missing out on something important? Is there something peculiar about the Australian formulation that makes it unstable at room temperature? Could this directive be without firm basis, or even dangerous?

There is currently no evidence on whether thyroxine in already-opened, unsealed bottles is more or less stable at 4°C than at room temperature, but the need to keep the tablets dry has been widely emphasised.3 Consider the condensation that will occur during 200 daily openings of a refrigerated glass bottle, whatever it contains. If damp tablets lose potency, this would lead to apparent under-treatment. In the months since refrigerated storage was recommended in Australia, preliminary observations suggest that apparent under-dosage (ie, unexpected rises in serum TSH) may indeed occur in previously compliant patients (personal observation). If dosage were increased, the adjustment could result in over-treatment after a change to a fresh preparation. Thyroxine has a narrow therapeutic window, and excessive dosage can have serious effects, especially if there is associated cardiac ischaemia.

While refrigeration of sealed bottles of thyroxine might extend the shelf life, the instruction to refrigerate unsealed bottles seems ill-advised. When an existing formulation is modified, it is generally the obligation of a manufacturer to demonstrate safety. The stability of tablets in sealed bottles and those in current use are quite separate issues. To establish how tablets in current use are influenced by refrigeration, it is necessary to measure the thyroxine content of remaining tablets from bottles of 200, opened and used daily for up to 6 months. Without such data, it is preferable to instruct patients not to store currently used bottles of thyroxine at refrigerator temperature.

In reply: Sigma Australia acquired Oroxine (thyroxine sodium) from the original manufacturer in 1999, and launched Eutroxsig, an identical product, in 2002. During 2002–03, as a result of advances in analytical technology for some pharmaceutical products, product specifications, including shelf life and storage conditions, were updated, so that the product’s quality, safety and efficacy could be maximised or maintained throughout the claimed shelf life.

For Oroxine and Eutroxsig, the new stability data showed a loss of up to 10% of thyroxine sodium in the first 6 months when stored below 25°C, with some plateauing thereafter. As an interim measure, Sigma, in agreement with the Therapeutic Goods Administration (TGA), decided to immediately reduce the shelf life from 24 to 12 months (“store below 25°C”) and set the lower release to 98.0% (up from 92.5%), while investigating reasons behind the loss in potency.

The manufacturing process was confirmed to consistently yield tablets with very reproducible chemical and physical attributes in accordance with the release criteria. During manufacturing, however, about 2% of the thyroxine sodium is lost, with a corresponding similar increase in degradants.

To limit the degradants responsible for the reduction in potency of thyroxine at room temperature, it was agreed with the TGA that thyroxine should be stored at 2°– 8°C (“Refrigerate. Do not freeze”), based on good stability data generated at this temperature. Consumer Medicine Information (CMI) and Product Information (PI) were updated in May/June 2004 to reflect this change.

The new stability studies support the storage of Oroxine and Eutroxsig in the refrigerator; however, repeated in-use handling may result in an increase in condensation and microbial contamination. This may lead to changes in the physical characteristics of these products, including the growth of mould. There may be a further increase in condensation if the lid is not tightly closed. One possible solution is for patients to place up to 4 weeks’ supply of tablets in a spare, previously used, Oroxine or Eutroxsig amber-coloured bottle and store out of the fridge (below 25°C) for current use, while keeping the remaining stock in the fridge. Sigma is looking at options to improve the packaging so that the above problems are minimised or eliminated.

Oroxine and Eutroxsig, manufactured by Sigma, are sold in Australia only. Sigma does not have access to formulation details, stability results and justification for the storage conditions used in other countries; therefore, we are unable to comment on such issues. As an Australian company, we are obliged to follow the regulatory guidelines of the Therapeutic Goods Act 1989 (Cwlth).

Sigma recommends that the label instructions regarding storage conditions after opening be strictly followed to maximise the quality, safety and efficacy of the product.