MHRA issues alert but Clexane will not be recalled
MHRA: precautionary advice |
Batches of Clexane (enoxaparin sodium; Sanofi-Aventis)
containing low-levels of a contaminant called over-sulphated chondroitin
sulphate (OSCS) have been distributed in the UK, the Medicines and Healthcare
products Regulatory Agency announced last week.
OSCS has been suspected
by the US Food and Drug Administration to be the contaminant contained
in
other heparin products, used in the US, Australia, China and some European
countries, which have been associated with a rise in serious adverse
events, including deaths.
From 1 January 2007 to 13 April 2008, the FDA received reports of 131
deaths of patients receiving heparin. Of the 81 deaths with one or more
allergic symptoms or symptoms of hypotension and death, 78 were reported
to the FDA on or after 1 January 2008. By comparison, 55 deaths were
reported in patients receiving heparin for the whole of 2006. At the
beginning of this year a number of heparin products were recalled abroad
and, in February, the FDA launched an investigation into heparin products.
In the UK, the MHRA is not recalling the contaminated Clexane batches
but has issued a Class 4 drug alert (caution in use). The MHRA says that
the affected batches contain “a very low level of impurity” and
that there is no evidence that the low levels of OSCS found in the contaminated
batches, which have been on the UK market for several months, have led
to an increase in the number of adverse drug reactions as seen in other
countries with other heparin products.
The Commission on Human Medicines
has advised that the product can continue to be used and has recommended
continued supply despite the contamination.
The MHRA says that withdrawal of the contaminated Clexane could lead
to a shortage of low molecular weight heparins and has issued precautionary
advice to minimise any risk of adverse reactions. “Intravenous
and arterial administration of enoxaparin should be avoided if possible.
If given by these routes, suitable emergency treatment should be available
and patients should be closely observed for signs of possible hypotensive
or allergic reactions.”
Commenting on an article published in The New England Journal of
Medicine,
which suggests that the OSCS contaminant in US batches of heparin is
responsible for adverse reactions that have been reported elsewhere (see Panel),
a spokesman for the MHRA said: “[The MHRA is] currently
seeking expert advice on the relevance of these findings to the UK situation.
At present, this does not change the precautionary advice we have already
given.”
Sanofi-Aventis has used both capillary electrophoresis
and nuclear magnetic resonance to both quantify and identify the contaminant
and the results have been confirmed by the MHRA for samples of some
batches.
Research papers published
In the same week as the MHRA’s drug alert, the results of a
study published
online in Nature Biotechnology confirmed that the
contaminant suspected to be contained in batches of heparin associated
with an acute, rapid onset of serious side effects was OSCS.
Ram Sasisekharan, from the Massachusetts Institute of Technology,
Massachusetts, and colleagues analysed six heparin preparations
that correlated with adverse reactions and four control preparations.
They point out that the “highly unusual” repeating tetrasulphated
disaccharide found in the contaminant’s structure has not been
isolated to date from animal tissue and is highly unlikely to have
been produced naturally.
In a related study published
online in The New England Journal
of Medicine (23 April 2008), Dr Sasisekharan and
colleagues demonstrate a potential biological link between the
presence of
OSCS
in suspect batches of heparin and the anaphylactoid reactions seen
in affected patients. They found that OSCS directly activates the
kinin-kallikrein pathway in human plasma, which can lead to the
generation of bradykinin. |
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