The Medicines and Healthcare products Regulatory Agency (MHRA) have issued advice to healthcare professionals about heparin enoxaparin sodium (Clexane®) pre-filled syringes. The manufacturer of this low molecular weight heparin (LMWH), Sanofi Aventis , have informed the MHRA that some batches distributed in the UK over a period of 4 to 6 weeks, contain low levels of the impurity, over-sulphated chondroitin sulphate (OSCS).
The MHRA advise that there is no evidence these low levels of OSCS have led to adverse reactions. It is expected that new and uncontaminated Clexane® stock will become available from June 2008.
Withdrawal of the contaminated Clexane® products could lead to a shortage of low molecular weight heparins. The Commission on Human Medicines (CHM) has considered the matter and recommended the continued supply of this product despite the low level contamination. There are currently no similar concerns with other heparin products in the UK, but the MHRA will continue to review the situation.
The context is that earlier this year, the Food and Drug Administration (FDA) in the U.S. announced that a significant number of adverse events, including deaths, have been associated with the use of contaminated unfractionated heparin (UFH) manufactured by Baxter Healthcare Corporation that contained much higher levels of OSCS. The adverse events were associated with intravenous use and included allergic or hypersensitivity-type reactions, with symptoms such as hypotension, shortness of breath, nausea, vomiting, diarrhoea, and abdominal pain. It should be stressed that this unfractionated heparin is not available in the UK and no such cases have been reported in association with the batches of contaminated Clexane® on the UK market.
A recent study has suggested a scientific rationale for a potential biologic link between the presence of OSCS contaminated heparin and the observed adverse events. Work by regulatory authorities is continuing to both investigate the contamination issues and in pharmacovigilance.
The MHRA advise prescribers that:
Enoxaparin is a very important therapy and it is essential that patients continue to receive it as prescribed by their doctor
As there is no evidence of any specific risks, and to maintain supplies, product on the UK market should continue to be used
Purely as a precaution, 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.
All healthcare professionals should be aware of this advice and report all suspected adverse reactions relating to any Heparin and Enoxaparin Sodium (Clexane®) products via the Yellow Card Scheme.
Kishimoto TK, et al. Viswanathan K, Ganguly T, et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 2008; 358 published on-line on 23rd April 2008.