Regulators in the USA have hit Sanofi-Aventis and Bristol-Myers Squibb with a new black box warning about the reduced effectiveness of their anti-clotting blockbuster Plavix in potentially a sizeable chunk of patients.

The US Food and Drug Administration has added a boxed warning to the label for Plavix (clopidogrel), for patients who do not effectively metabolises the drug, the second best-seller in the world with turnover of over $9 billion. These "poor metabolisers" have a low activity of the CYP2C19 gene which affects the enzyme that converts Plavix to its active form.

The FDA’s new warning states that in these patients, Plavix has less effect on platelets, and therefore “less ability to prevent heart attack, stroke and cardiovascular death”. It is estimated that 2%-14% of the population are poor metabolisers, depending on racial background ie 2% white, 4% black and 14% Chinese. The black box comes after a warning about poor metabolisers was added to the label in May 2009 and in November, the FDA issued a note citing new data which showed that when Plavix and AstraZeneca's Prilosec (omeprazole) and some other proton pump inhibitors are taken together, the effectiveness of the former is reduced.

The agency told healthcare professionals that tests are available, priced at about $500, to determine patients' CYP2C19 status. The FDA notes that patients should continue taking Plavix unless told to do otherwise and tells doctors to be aware that “although a higher dose regimen (600mg loading dose followed by 150 mg once daily) in poor metabolisers increases antiplatelet response”, an appropriate dose regimen for the latter group has not been established in a clinical trial.

How big an impact the black box warning will have on sales of Plavix, which is already suffering from generic competition in Europe and loses patent protection in the USA in 2012, remains to be seen. However some observers believe this represents an opportunity for Eli Lilly/Daiichi Sankyo’s rival bloodthinner Effient (prasugrel), sales of which have not set the world alight since its launch last summer.

In October, Medco Health Solutions launched a head-to-head trial of Plavix and Effient. looking at whether patients who were born with a normally functioning CYP2C19 gene, and are hence ‘extensive metabolisers’ of clopidogrel, have comparable outcomes to patients on prasugrel.