UPDATED 5/19/12: Just as Sanofi-Aventis loses its exclusivity for its blockbuster drug Plavix (clopidogrel) this month, several generic formulations of the antiplatelet agent have been approved, the Food and Drug Administration announced on May 17.
In the FDA statement announcing the approval, Keith Webber, Ph.D., deputy director of the Office of Pharmaceutical Science in the FDA’s Center for Drug Evaluation and Research, referred to the importance of having effective and affordable medications available for people with chronic health conditions. “The generic products approved today will expand those options for patients,” he said.
The anticipated reduction in cost is expected to keep the drug on its perch as the leading non-aspirin antiplatelet agent, experts agree.
Dr. Sanjay Kaul said that the availability of generic clopidogrel was welcome news “especially for cost-prohibitive environments, where affordability is a major detriment to long-term treatment adherence and, consequently, an optimal benefit-risk balance,” in an interview,
Dr. Sanjay Kaul
“It must, however, be acknowledged that for a drug that never got the claim of superiority over aspirin, its rise to be the second highest selling pharmaceutical agent speaks more to the miracle of marketing than the miracle of medicine,” added Dr. Kaul, director of the cardiovascular diseases fellowship training program at Cedars-Sinai Heart Institute, Los Angeles. “Nonetheless, clopidogrel will continue to be the dominant oral antiplatelet agent (besides aspirin) that will be used for a broad spectrum of cardiovascular disease indications in the foreseeable future.”
Dr. Eric R. Bates, professor of internal medicine at the University of Michigan, Ann Arbor, said that it will be interesting to follow pricing trends over the next 1-2 years and to see how the availability of generic clopidogrel affects the market shares of the new entrants to the antiplatelet field, prasugrel (Effient) and ticagrelor (Brilinta). “It is possible that the large payers will require genetic or platelet function testing proof of poor clopidogrel responsiveness before they agree to pay for prasugrel or ticagrelor,” he said in an interview.
Dr. Peter Kowey, professor of medicine at Thomas Jefferson University in Philadelphia, noted that the availability of generic clopidogrel will help many patients who have a difficult time paying for the proprietary formulation, but said he has two concerns. First, “generic reproduction of cardiac drugs can expose patients to risk if the quality of the generic is compromised in any way,” he said. And second, “the availability of cheaper clopidogrel will discourage doctors from using prasugrel or ticlopidine, even though we know that those drugs are superior for the indication and may have real advantages for some of our patients.”
“As with so many things in medicine these days, economics may become the most compelling issue in drug selection and patient care – and that is not something any doctor desires,” added Dr. Kowey.
Dr. Eric Bates
Clopidogrel, a P2Y12 platelet inhibitor taken orally once a day, is approved for the treatment of acute coronary syndrome and for patients who have had a recent myocardial infarction, recent stroke, or established peripheral artery disease. The approved indication includes the statement that clopidogrel "has been shown to reduce the combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death."
Clopidogrel was initially approved by the FDA in 1997, and has been marketed as Plavix by Sanofi-Aventis. The agent generated $5 billion in sales in 2010 alone.
Generic formulations of both the 75-mg daily dose and the 300-mg loading dose have been approved, according to the FDA.
The manufacturers of the approved 300-mg generic formulations are Dr. Reddy’s Laboratories, Gate Pharmaceuticals, Mylan Pharmaceuticals, and Teva Pharmaceuticals. The manufacturers of the approved 75-mg doses are Mylan, Teva, Apotex Corporation, Aurobindo Pharma, Roxane Laboratories, Sun Pharma, and Torrent Pharmaceuticals.
The clopidogrel prescribing information includes a boxed warning about the smaller effect of clopidogrel on platelet function in people who are poor metabolizers of CYP2C19, and the higher rate of cardiovascular events in this population, when treated with recommended doses after acute coronary syndrome or percutaneous coronary intervention.
The FDA statement also points out the interactions with omeprazole (Prilosec) and esomeprazole (Nexium), which reduce the antiplatelet activity of clopidogrel, and says that these drugs should be avoided in people taking clopidogrel.
Dr. Kaul had no relevant disclosures. Dr. Bates receives advisory board honoraria from all antiplatelet manufacturers. Dr. Kowey said he serves as a consultant for Sanofi and Bristol Myers Squibb, which markets Plavix with Sanofi; he has no equity interest in those companies or any other drug company.