FDA Slaps Restrictions on JAK Inhibitors Over Serious Safety Risks

The FDA has finished its review of a large postmarketing safety study of tofacitinib (Xeljanz, Xeljanz XR), and its conclusions do not bode well for the popular drug and the larger class of JAK inhibitors.

Data from the trial revealed increased risks for serious heart-related events -- including myocardial infarction (MI) and stroke -- as well as a higher risk for cancer, blood clots, and death. Even the lower 5-mg dose of tofacitinib turned up an increased risk of blood clots and death in the final analysis, the agency noted.

FDA is requiring new and updated warnings for tofacitinib, as well as two other arthritis medicines in the JAK inhibitor class -- baricitinib (Olumiant) and upadacitinib (Rinvoq). All three JAK inhibitors are approved for rheumatoid arthritis (alone or in combination), while tofacitinib is also approved in psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis.

"Since they share mechanisms of action with Xeljanz, FDA considers that these medicines may have similar risks," the agency said.

In the safety trial, tofacitinib was compared to tumor necrosis factor (TNF) blockers in rheumatoid arthritis patients also on methotrexate. Treatment with the JAK inhibitor was associated with an increased risk for major adverse cardiac events (MACE), including MI, cardiovascular death, and stroke (HR 1.33, 95% CI 0.91-1.94), which missed criteria for non-inferiority, as well as a higher risk for cancer (HR 1.48, 95% CI 1.04-2.09).

"To ensure the benefits of these three medicines outweigh the risks in patients who receive them, we are limiting all approved uses to certain patients who have not responded or cannot tolerate one or more TNF blockers," FDA said. "This is particularly the case in patients who are current or past smokers, those with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy other than a successfully treated nonmelanoma skin cancer."

Notably, the restrictions will not apply to two JAK inhibitors used for certain blood disorders -- ruxolitinib (Jakafi) and fedratinib (Inrebic) -- as these are not indicated for arthritis and other inflammatory conditions.

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