Bristol-Myers Squibb's and Pfizer's Eliquis

Eliquis (apixaban) tablets are approved to reduce the risk of stroke and systemic embolism in adults with nonvalvular atrial fibrillation.

The FDA approved Bristol-Myers Squibb’s and Pfizer’s Eliquis (apixaban) tablets to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation. The December 2012 approval excludes atrial fibrillation as a result of a heart valve defect, as these patients were not studied in clinical trials. Atrial fibrillation is a serious heart rhythm disorder that has traditionally been treated with warfarin, an older-generation anticoagulant with a narrow therapeutic index, monitoring requirements, and many drug and food interactions. Eliquis is the third addition to a new generation of anticoagulant drugs inciting market competition with Pradaxa (dabigatran), a direct thrombin inhibitor, and Xarelto (rivaroxaban), another factor Xa inhibitor.^1,3

Pharmacology and Pharmacokinetics

Apixaban is a reversible and selective inhibitor of free and clot-bound factor Xa, which decreases thrombus development and indirectly inhibits thrombin-induced platelet aggregation. Apixaban’s prolonged absorption yields a 12-hour half-life, allowing twice-daily dosing to provide adequate anticoagulation. Apixaban is 50% bioavailable and maximum concentrations are achieved 3 to 4 hours after administration. Apixaban is metabolized mainly through CYP3A4 pathways with no active metabolites and is also a substrate of P-glycoprotein. Co-administration with strong CYP3A4 inhibitors may require dosage adjustment, and use with strong inducers is not recommended.¹

Dosage and Administration

Eliquis is available in 2.5-mg and 5-mg tablets. The recommended dose for most patients is 5-mg orally twice daily with or without food. The recommended dose is 2.5 mg twice daily for patients concomitantly taking CYP3A4 or P-gp inhibitors or for patients with 2 of the following characteristics: age >80 years, body weight <60 kg, or serum creatinine >1.5 mg/dL. The tablets should be swallowed whole with a glass of water and not crushed, chewed, or dissolved. Use in hepatically impaired patients has not been studied and Eliquis should be avoided in severe impairment.¹

Clinical Trials

The ARISTOTLE study, a double-blind randomized controlled trial with more than 18,000 patients, compared efficacy of Eliquis 5 mg or 2.5 mg twice daily to warfarin dosed to target INR of 2.0-3.0. Outcomes included incidence of hemorrhagic stroke or systemic embolism as well as major bleeds. After an average duration of 1.8 years, the study determined that fewer patients experienced stroke while taking Eliquis, 1.27% per year, versus warfarin, 1.6% per year. Also, fewer patients in the Eliquis group were observed with major bleeds, 2.13% per year, compared with warfarin, 3.09% per year.^1,2

The ARISTOTLE study concluded that Eliquis is non-inferior to warfarin for stroke and embolism prevention as well as better tolerated with less therapeutic monitoring, fewer drug and food interactions, and a wider therapeutic index. The other new anticoagulants, dabigatran and rivaroxaban, showed similar results with respect to stroke prevention; however, Eliquis also decreased risk of major bleeds, including intracranial hemorrhage.²

Contraindications, Warnings, and Precautions

Eliquis is contraindicated in patients with active bleeding or severe hypersensitivity. The most prominent adverse effect of Eliquis is the increased bleeding potential. Inform patients on identifying signs of bleeding such as blood in the vomit or stool, unexpected pain, or unexpected bleeds that may last a long time. Other medications used for treatment or prevention of blood clots may enhance the bleeding risk. There is no known agent to reverse the anticoagulant effects of Eliquis, which may persist for up to 24 hours after the last dose; however, activated charcoal may be useful in an overdose or accidental ingestion.^1,2

Other adverse effects observed in clinical trials include hypersensitivity reactions involving skin rash, syncope, and anaphylaxis in <1% of patients.¹ It is important to inform patients that abruptly stopping treatment with Eliquis can increase their chance of having a stroke. Eliquis holds a pregnancy category B, although no well-controlled studies have been conducted in pregnant women. Women should not breast-feed while taking Eliquis because it is unknown whether the drug passes into breast milk. Eliquis has not been studied in pediatric patients and is not approved for this population.¹

Jeff Prescott, PharmD, RPh, is Senior Vice President of Clinical and Scientific Affairs at Intellisphere, LLC. Nicole Braccio is a PharmD Candidate at the Ernest Mario School of Pharmacy at Rutgers University.

References:

• Eliquis [package insert]. Bristol-Myers Squibb Company, Princeton, NJ; December 2012. http://packageinserts.bms.com/pi/pi_eliquis.pdf. Accessed February 7, 2013.
• Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.
• Walsh S. FDA approves Eliquis to reduce the risk of stroke, blood clots in patients with non-valvular atrial fibrillation [press release]. US Food and Drug Administration website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333634.htm. Accessed February 7, 2013.