European drug regulators have turned a temporary restriction on Pfizer’s Xeljanz into a formal one.
In a decision posted Friday, the European Medicines Agency said the immunology drug's 10-mg twice-daily maintenance dose should not be used in ulcerative colitis patients at high risk of blood clots unless there’s no alternative.
That represents a step back from the EMA safety committee’s previous, temporary restriction issued in May, which harshly stated that "doctors must not prescribe the 10 mg twice daily dose" in at-risk patients. It's also slightly less restrictive than the FDA’s “boxed warning” issued in July, which advised against the 10-mg dose across the board, either as a starting dose for the first eight weeks or as a maintenance dose.
But in its final version, the EMA warning goes further in asking that Xeljanz—at any dose—be used with caution “in all patients at high risk of blood clots,” and that it not be used in patients older than 65 years of age “due to an increased risk of infections” if there’s an available alternative.
The drug’s initial FDA label already includes a “boxed warning” of serious infections.
The warning was endorsed by EMA’s drug review body, the Committee for Medicinal Products for Human Use (CHMP), and will become official once the European Commission signs off on it.
Both the EMA’s and the FDA’s decisions were triggered by alarming cardiovascular signals in an ongoing postmarketing study in patients with rheumatoid arthritis.
In February, Pfizer had to take patients in that study off the 10-mg twice-daily schedule after it found increased risk of blood clots in leg veins and lungs with the high-dose regimen. Patients in that study are at least 50 years old with at least one prior CV risk factor.
According to the EMA, its review of that study showed even Xeljanz 5-mg twice daily increased the risk of pulmonary embolism about threefold compared with a TNF inhibitor, while 10-mg twice-daily hiked the risk roughly sixfold.
“As a result, [Xeljanz] should be used with caution in patients with known risk factors for [venous thromboembolism], regardless of indication and dosage,” the agency said (PDF). This includes those who have had a heart attack, heart failure, a history of blood clots, among other disorders.
The 10-mg twice-daily strength in question is approved by both the EMA and FDA in ulcerative colitis, and the 5-mg twice-daily dose is approved in rheumatoid arthritis, colitis and psoriatic arthritis.
Despite the FDA's boxed warning and the EMA's preliminary restriction, the JAK inhibitor still managed a 40% sales jump in the third quarter, primarily driven by the 34% growth from the U.S.