By Turna Ray
The US Food and Drug Administration this week issued a new warning to healthcare providers and patients against the concomitant use of the anti-platelet agent Plavix (clopidogrel) and CYP2C19-inhibiting agents, but the agency simultaneously acknowledged that there are many unanswered questions about the link between Plavix response and CYP2C19 metabolism pending results from ongoing studies.
The "Drug Interactions" section of the new label informs: "Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant use of drugs that inhibit CYP2C19, including omeprazole, esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine."
In its communication with doctors and the public, however, the agency focused specifically on the diminished response associated with co-administration of Plavix and the proton pump inhibitor Prilosec (omeprazole), based on results of a new study submitted by clopidogrel-developer Sanofi-Aventis. The FDA highlighted "new data show[ing] that when clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced.
"Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole," the agency said.
Instead of a CYP2C19-inhibiting heartburn treatment, the FDA recommends patients use H2 blockers, such as ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid), or over-the-counter antacids. However, the agency warns against simultaneously using Plavix and cimetidine (Tagamet and Tagamet HB) as it is a CYP2C19 inhibitor. It also discourages the use of antacids that interfere with the anti-clotting activity of clopidogrel.
The labeling change this week follows an earlier update from the agency that informed healthcare providers of studies indicating that poor CYP2C19 metabolizers have limited response to Plavix. At the time, the agency also said it was awaiting results from ongoing studies before making pharmacogenetically guided dosing recommendations for Plavix [see PGx Reporter 06-17-2009].
"When we make these recommendations we look at totality of evidence," Mary Ross Southworth, deputy director for safety in FDA's Division of Cardiovascular and Renal Products, said in a call announcing the labeling update. Although this update is only for Plavix, Ross Southworth noted that the FDA is mulling whether to update the labeling for CYP2C19-inhibiting drugs about the risks associated with co-administration with Plavix.
Another open question for the FDA in this regard is whether this diminished response seen with the co-administration of Plavix and CYP2C19-inhibiting agents is a cause for concern in all patients or only for those who have certain CYP2C19 mutations. This too will need to be studied further in clinical trials.
For the time being, in the absence of more specific clinical data, FDA advises doctors to discuss the OTC drugs their patients take. "Be aware that patients may be taking non-prescription forms of omeprazole and cimetidine," the FDA told doctors.
Sanofi-Aventis' partner Bristol-Myers Squibb markets Plavix in the US. The recent labeling update includes data from a new study conducted by Sanofi-Aventis at the request of the FDA.
The cross-over clinical study submitted by Sanofi-Aventis involved 72 subjects who received Plavix alone and then with Prilosec for five days. According to the study's results, simultaneous exposure to Plavix and Prilosec worsens a patient's ability to metabolize Plavix.
"The exposure to the active metabolite of clopidogrel was decreased by 46 percent (Day 1) and 42 percent (Day 5) when Plavix and omeprazole were administered together," the new label informs. "Mean inhibition of platelet aggregation was diminished by 47 percent (24 hours) and 30 percent (Day 5) when Plavix and omeprazole were administered together." These reductions in response were seen whether the drugs were given at the same time or 12 hours apart, the labeling notes.
Sanofi-Aventis is conducting additional studies looking at the genetic and clinical factors underlying Plavix metabolism.
In its note to healthcare providers and the public, the FDA said it is in the midst of reviewing results from additional studies that might provide additional information about the clinical outcomes associated with these drug interactions, including the Clopidogrel and Optimization of Gastrointestinal Events (COGENT) study.
However, in its initial review of the COGENT trial, the agency is not enthusiastic about the results, as the study did not involve enough patients and did not look at cardiac events as a main endpoint, Ross Southworth noted.
"Although the FDA has not fully reviewed the study results, the applicability of these data is limited because of the study design and follow-up," the agency noted. "Therefore, based on the current scientific information, the clopidogrel label has been updated with new warnings on omeprazole and other drugs that inhibit the CYP2C19 enzyme that could interact with clopidogrel in the same way."
Medco is looking into the relationship between Plavix response and proton pump inhibitors. Last year, Medco conducted an outcomes study involving Plavix, which found that concomitant administration of proton pump inhibitors, such as heartburn drugs, can diminish the anti-clotting effects of clopidogrel. At the time, Medco said in a statement that "since PPIs mimic the effect of a variant gene, which also renders clopidogrel ineffective, this study further suggests a potential role for genetic testing."
Under its Genetics for Generics program, the pharmacy benefit manager is planning to offer genetic testing to its customers to encourage more efficient administration of Plavix [see PGx Reporter 10-7-2009].
Meanwhile, Quest Diagnostics last month began offering genetic testing for Plavix in a Scripps Health hospital in California [see PGx Reporter 10-28-2009]. The move raised questions from researchers as to whether CYP2C19 testing should be broadly marketed without results from randomized controlled trials providing additional information on patient outcomes associated with testing, genomically guided Plavix dosing, and alternative treatments for CYP2C19 poor metabolizers.
Absent data from ongoing studies, the FDA noted that it will continue to investigate other drug interactions with clopidogrel. The agency will also present this topic at the next meeting of its Drug Safety Oversight Board later this month. "The Agency will communicate any further recommendations or conclusions once additional information is available," the FDA said in its note to healthcare providers and the public.