Bristol-Myers Squibb Co and Sanofi, the manufacturers of Plavix (clopidogrel) have been ordered to pay over $834 million to the state of Hawaii after failing to warn about the drug’s potential health risks to patients with combinations of CYP2C19 variants which result in a CYP2C19 poor metabolizer status.
Clopidogrel is metabolized to its active metabolite by CYP2C19, as shown in the PharmGKB clopidogrel pathway. Patients carrying CYP2C19 no function alleles (e.g. CYP2C19*2) have reduced or no conversion of clopidogrel to the active metabolite, which puts them at an increased risk of cardiovascular events. The CPIC guideline for clopidogrel recommends that CYP2C19 intermediate and poor metabolizers receive alternative antiplatelet therapy.
The companies were found to have violated Hawaii’s consumer protection laws by not disclosing that Plavix would be ineffective for as many as 30% of patients in Hawaii, many of whom are of Asian and Pacific Islander descent. Some CYP2C19 no function variants, such as CYP2C19*2, are found at higher frequencies in Asian and Pacific Islander populations compared to their frequency in European populations (see the CYP2C19 allele frequency table).
Judge Dean Ochiai ruled that Bristol-Myers Squibb Co and Sanofi “knowingly placed Plavix patients at grave risk of serious injury or death in order to substantially increase their profits” over a 12-year period from 1998 to 2010. Information about the effect of CYP2C19 no function alleles on the efficacy of Plavix was added to the drug label in 2009, and a Black Box warning to consider alternate therapy for CYP2C19 poor metabolizers was added in 2010. PharmGKB has annotated the Plavix label and highlights pharmacogenomic information found within the label.
Hawaii Attorney General Clare Connors emphasized the growing impact of pharmacogenomics on the pharmaceutical industry: “The order entered by the court today puts the pharmaceutical industry on notice that it will be held accountable for conduct that deceives the public and places profit above safety”.
In a joint statement, the companies said that “the overwhelming body of scientific evidence demonstrates that Plavix is a safe and effective therapy, including for people of Asian descent.” and that they plan to appeal.