ADELPHI, MD. — A federal panel agreed that data on the oral anticoagulant rivaroxaban indicate that the drug's benefits in preventing venous thromboembolic events after hip and knee replacement surgery outweigh its potential risks of excess bleeding and potential risk of severe hepatotoxicity.
At a meeting of the Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Committee, the panel voted 15-2 that data from four clinical trials demonstrated that rivaroxaban has a favorable risk-benefit profile for the proposed indication—the prophylaxis of venous thromboembolism, in patients undergoing hip or knee replacement surgery. The recommended dosage is 10 mg once daily for 35 days (after hip surgery) or 14 days (after knee replacement).
Most of the panelists agreed that potential hepatoxicity should not preclude approval, although long-term data to assess hepatoxicity were critical. Panelists were concerned about off-label use of the drug and emphasized the importance of advising clinicians to avoid prescribing the drug for longer periods and for other uses, and of continuing to follow patients on rivaroxaban in clinical trials and clinical practice for hepatoxicity.
If approved, rivaroxaban, an oral, direct Factor Xa inhibitor manufactured by Johnson & Johnson Pharmaceutical Research & Development LLC, would be the first oral anticoagulant approved for these indications, as well as the first oral anticoagulant approved since warfarin.
The FDA usually follows the recommendations of its advisory panels.
The proposed regimen was compared with enoxaparin in four international studies of more than 12,000 patients (6,183 patients on rivaroxaban) after total hip or knee replacement surgery. Patients with significant liver disease were excluded. In the four studies, the composite end point of venographic evidence of deep-vein thrombosis (DVT), nonfatal pulmonary embolus (PE), or death was significantly lower among those treated with rivaroxaban, but patients on the drug had a higher rate of bleeding. In an analysis of pooled data from the four studies, the major bleeding rate was 0.4% among those on rivaroxaban, compared with 0.2% among those on enoxaparin. The one bleeding-related death in all four studies was in a patient on rivaroxaban.
There was also a greater number of serious ALT elevations (0.3% vs. 0.2%) among those on rivaroxaban, which was not a significant difference. A composite marker of liver injury—an ALT greater than three times the upper limit of normal with a total bilirubin greater than two times the upper limit of normal—was also more common among those on rivaroxaban (0.15% vs. 0.11%), but this was not a statistically significant difference.
The consumer representative on the panel was Dr. Sidney Wolfe, director of the Public Citizen Health Research Group. He voted no on the risk-benefit question and said he was concerned about the bleeding risk and was “very uncomfortable about the certainty of long-term use and the absence of long-term safety data on hepatoxicity.” Because there is no need for a regular blood test, as there is with warfarin, he expects it will be used “massively” for off-label indications for which there are no data.
If approved, Johnson & Johnson plans to market rivaroxaban as Xarelto.