Thyroxine: anatomy of a health scare

This article blames the 'health scare' (sic) for reported reactions
to introduction of re-formulated Eltroxin on the media and the involvement
of a 'champion' small-town pharmacist. Surely the authors have missed the
point. Regulatory authorities have a duty of care to investigate concerns
over drug product safety and efficacy over and above simply checking that
all the usual procedures have been carried out. Demonstrating their
adherence to the rule rather than the spirit of regulation is more about
defending their honour and reputation.

The key issues that need investigation in such cases are on the
product side:- ingredient quality, ingredient changes, manufacturing
changes and bioavailability; and on the affected patient side:- adverse
reactions/side-effects, toxicity and interactions with other drugs and
conditions.

Product issues

Changes in taste and colour (from 'white' to 'white to off-white')
will upset some patients but usually reassurance that the main ingredient
is exactly the same will satisfy most people. The new formulation's
twofold 1. increase in rate of dissolution - not on the tongue as stated
but in the stomach - could arguably make a difference to the reaction of
patients to taking this drug.
Levothyroxine sodium, the 'active ingredient' remained the same as did the
excipient Magnesium stearate. Other excipients changed namely Lactose
monohydrate to Microcrystalline cellulose, Maize starch to Pre-gelatinized
maize starch. Another excipient Acacia was also dropped and replaced by
both Purified talc and Silicon dioxide (Colloidal anhydrous silica). The
manufacturing method also changed in the order of blending and the
addition of ingredients.

GlaxoSmithKline's (GSK) own bioequivalence study between the old and
new formulations was carried out on 35 healthy male and female volunteers
from 17 December 2002 - 26 February 2003 basically showed no differences
but points out that its bioequivalence study is not designed to compare
adverse reactions in medicines.

Patient issues

When investigating patients and their reactions (changed or not) to
taking the new product we should listen to and examine patients and take
their concerns seriously not simply re-check regulatory procedures. Even
if bioavailability of Eltroxin to individual patients was reduced or
increased in individual patients it is unlikely that the effects of this
would be noticed for several weeks or even months of taking a changed
formulation. Re-testing individual's thyroid stimulating hormone (TSR)
could provide evidence of reduced bioavailablity although there is often
little correlation between a patient's symptoms or their lack (e.g.
slowness, dry or falling hair, thickening of the skin, deepening of the
voice, weight gain, cold intolerance, and constipation)bradycardia and
constipation). Clinical examination (confirmation of symptoms and checking
for bradycardia), seeking biochemical evidence of adequate thyroid
hormone replacement and looking for possible interactions between all the
ingredients of all the products taken by the patient.

Side-Effects

The authors reference to ingredients excluding levothyroxine as inert
is wrong. Helium in an inert gas but if I inhale some my speech sounds
like Donald Duck. Nor should it should be assumed that ingredients such as
excipients, preservatives and colouring - intended as inactive - have no
action other than contributing to product form, appearance and shelf life.
Indeed when new products are tested they are treated as single unified
entities in trials using adequate numbers of volunteers to reveal expected
and unexpected effects or lack of these.
The authors' attribution of the symptoms (side effects in my book)
reported such as 'weight gain, lethargy, muscle pain, joint pain, and
depression' to the disease being treated - Hypothyroidism - simply does
not stand up to scrutiny as the majority of the New Zealand patients would
not have been new but would have been on treatment for some time.
Side effect of drugs for replacement therapy are usually indicative of
excessive dosage and for Levothyroxine these include: anginal pain,
cardiac arrhythmias, palpitations, cramps in skeletal muscles.
tachycardia, diarrhoea, vomiting, tremors, restlessness, excitability,
insomnia, headache, flushing, sweating, excessive loss of weight, and
muscular weakness. The question is not - can some of the reported symptoms
be ascribed to idea that 'hypothyroid patients, even those taking
thyroxine replacement therapy, have been found to have greater levels of
emotional distress and more physical symptoms than people without
hypothyroidism'? - but rather - does this essentially new product have the
propensity to cause the reported side effects of 'conjunctivitis, eye
pain, headache, itching, skin rash, abnormal or blurred vision, nausea,
and indigestion'?. Only thorough investigation can answer this question -
certainly these side-effects are common with nearly all drugs - could this
be to do with excipients?
So what should regulators do to fully meet their remit for drug safety. A
clue lies in the authors third reference to a study by Saravanan et al 2.
on psychological well-being in patients on "adequate" doses of L-
thyroxine. This was done by searching the computerised prescribing records
of patients of five general practices who had been on thyroxine. Nowadays,
with the increased used of coded data entry in the full (not just
prescribing) electronic patient record (EPR) not only can the patients
taking thyroxine be identified but all their other medications, diseases,
laboratory tests and results, symptoms signs and so on can be collected,
analysed, audited and researched.

Lessons

In my view the real lessons to be learned from this affair are:

1) Consideration be given to the idea that re-formulated drug
products should be subjected to the same regulatory test procedures as new
products;

2) Medicines regulators should access and commission detailed
analyses from anonymised coded Primary Care (GP) Electronic Care Records
(ECRs)

1. http://www.medsafe.gov.nz/hot/alerts/EltroxinInfo.asp

2. Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM.
Psychological well-being in patients on "adequate" doses of L-thyroxine:
results of a large, controlled community-based questionnaire study. Clin
Endocrinol (Oxf) 2002;57:577-85

Competing interests:
Roger Weeks is the Chairman of the charity Doctors' Independent Network (DIN) which collects anonymised data from GP's Electronic Patient Records for the advancement of patient care through research and audit.