Should thyroxine tablets be refrigerated? Have we got it wrong in Australia?

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.