Pharma Times, 17 March 2009

FDA staff fears over bleeding risk of Bayer/J&J’s rivaroxaban

The chances of Bayer and Johnson & Johnson getting approval for their oral anticoagulant Xarelto look grimmer today after US regulatory staff declared their doubts about the safety of the drug.

Ahead of a US Food and Drug Administration's Cardiovascular and Renal Advisory Committee meeting tomorrow (March 19), agency staff have posted documents expressing concern about the risks of bleeding linked to Xarelto (rivaroxaban). Bayer and US partner J&J are trying to get the drug approved to prevent deep vein thrombosis and pulmonary embolism in patients undergoing hip replacement or knee replacement surgery.

In a memo published on the FDA website, the agency reviewers said Xarelto “could lead to bleeding events in significantly more patients” than the gold-standard drug, Sanofi-Aventis’ injectable Lovenox (enoxaparin). This evidence “amplifies this safety concern for rivaroxaban”, the FDA staff note.

The memo goes on to state that “all categories of bleeding were numerically higher for patients receiving rivaroxaban in the RECORD studies (the basis of the filing), compared to enoxaparin”. It also notes that in the integrated analyses of the RECORD studies, "any major bleeding" event occurred in 0.39% of the Xarelto group and 0.21% of the Lovenox group.

The FDA staffers said that “the risks for liver injury/hepatotoxicity and other toxicities are less clear” with Xarelto. However, J&J, which will sell the drug in the USA if approved, believes the benefits of Xarelto outweighed its risks, noting that once-a-day rivaroxaban showed a more than 50% reduction in clotting or deaths when compared with twice-a-day Lovenox across four studies.

The agency staff also noted that a risk evaluation and mitigation strategy (REMS) has not been proposed by the companies for use with rivaroxaban, but J&J says it would take the necessary measures to monitor potential problems after approval. The FDA has requested a lower-dose Xarelto tablet for high-risk patients, though “to date, the sponsor has regarded this modification as unnecessary,” the review states.

Xarelto has already been approved in Canada for hip and knee surgery, a relatively small indication, but Bayer and J&J are investigating rivaroxaban in the more lucrative areas of stroke and acute coronary syndrome. Still the less-than-ringing endorsement from the FDA staffers has alarmed investors somewhat, especially in Germany where Bayer’s shares closed at 32.69 euros, down 10.3%.

By Kevin Grogan