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Atosiban Clinical Experience – Efficacy and Safety
channel blockers. We will consider claims that calcium channel contractility in pre-term labour and that they can be safely
blockers are more effective and cheaper, the unlicensed status of manufactured to a particular standard (toxicity and pharmacokinetic
nifedipine – recent data suggest that it has more side effects – and studies have been performed in animals and humans, including
the quality of the nifedipine trials and review some new trials that pregnant ones). Of course, they have not demonstrated that they can
have not yet been included in the systematic reviews. reduce peri-natal mortality.
Nifedipine is licensed for the treatment of hypertension outside
pregnancy, but not for use as a tocolytic. The manufacturers have
The oxytocin antagonist atosiban
never sought a licence; the trials are not of sufficient quality to
has been evaluated in two
support one and neither the dose nor route of administration is
agreed. The trials used both the oral and sublingual routes, with
placebo-controlled trials and a larger
doses ranging from 30 to 160mg per day. Therefore, doctors using
number of trials against other
nifedipine as a tocolytic are using the drug off-label. This is
reasonable for effective drugs for diseases in pregnancy for which no
tocolytics, mainly beta-mimetics.
licensed drug exists. Examples include syntocinon plus ergometrine
for preventing post-partum haemorrhage, or the anticonvulsant
magnesium for eclampsia. In such situations, doctors faced with a
The Relative Effectiveness of sick patient have to do their best, and using an evidence-based drug
Nifedipine and Atosiban off label is justified. It is a rather different situation when a licensed
The suggestion of the systematic reviewers that while atosiban is of drug is already available for the same indication. A doctor choosing
comparable efficacy to beta-mimetics, nifedipine may be more so has to use the unlicensed drug off-label has to argue not only that the
tempted some authors to make a formal ‘indirect comparison’.
9
So unlicensed drug is effective, but that it is so much more effective
long as such comparisons are based only on randomised groups this than the licensed one that it is worth taking the risk. This could
is scientifically valid and preserves the benefits of randomisation in conceivably happen, particularly if the manufacturers of a well-
the original trials. These authors concluded that nifedipine might be studied drug had decided it was not economically justified to seek a
more effective than atosiban in delaying delivery by 48 hours and in licence, but it hardly applies to nifedipine.
reducing respiratory distress syndrome. However, indirect comparison
is only as good as the trials on which it is based. It will be misleading Nifedipine tablets are cheaper than ritodrine or atosiban infusions,
if bias differs between the two sets of trials. This is probably the case but this does not prove that using the former will save money in the
with the nifedipine trials, which were of considerably poorer quality long run. The price of nifedipine does not include the costs of
than either the atosiban or the beta-mimetic studies. Most of the licensing studies for use in pregnancy, or the costs of preparing a
latter were double-blind, national or international trials with pre- special pre-term labour preparation. Even if one drug remained
determined sample size calculations, formal protocols, independent slightly cheaper than another after licensing and special
third-party randomisation and relatively low rates of loss to follow-up. manufacturing costs were included, the drug costs of treating pre-
The nifedipine trials were smaller, often single-centre, run informally term labour are dwarfed by other treatment costs, both acutely in
using ad hoc systems of envelope randomisation, were without
clearly published protocols, pre-determined sample sizes or primary
end-points and often failed to report the rate of loss to follow-up. A doctor choosing to use the
These differences in trial quality are objective and based on the
unlicensed drug off-label has to argue
judgements of the authors of the relevant Cochrane reviews.
10
not only that the unlicensed drug is
A more recent meta-analysis
11
combined disaggregated data from all
effective, but that it is so much more
of the randomised trials. This removes the benefits of randomisation
and makes the comparison groups susceptible to all of the biases effective than the licensed one that it is
that affect observational cohort studies, as well as causing the
worth taking the risk.
additional problem of incomplete recruitment of eligible patients
because of consent issues. The conclusion that prostaglandin
inhibitors are superior to other agents is thus highly unreliable. the labour ward and neonatal unit and in caring for the resulting
children in the long term. No full analysis of these costs has been
The Unlicensed Status of Nifedipine in performed, and nor is one likely to appear in the near future
Contrast to Atosiban because the treatment effectiveness uncertainties are too great.
Drug licensing is important. It reassures doctors and patients that
the drug, when given at a particular dose and formulated, There may also be remote harms from avoiding licensed drugs in
manufactured and stored in a particular way, has been tested and pregnancy. There is already a long-standing dearth of new chemical
found to be both effective and safe for a specific indication in formulations in obstetrics, and this will only be exacerbated if the
studies that were conducted to a certain minimum standard. ones that do appear are not used.
12,13
Ritodrine and atosiban have been licensed in the EU for the Recent Side-effect Data
treatment of premature labour because the regulatory authorities Since the latest update of the Cochrane reviews and the publication
have been convinced that they are effective in reducing uterine of the RCOG guidelines there have been a number of case reports
EUROPEAN OBSTETRICS & GYNAECOLOGY 47
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