FDA’s New Warning Includes Xeljanz and other JAK Inhibitors

The FDA previously warned about an increased risk of heart problems and cancer with Pfizer’s Xeljanz (tofacitinib), but now that warning has been updated and expanded to other Janus kinase (JAK) inhibitors.

The agency’s new Drug Safety Communication said that, after reviewing of a large, randomized safety clinical trial, “we have concluded there is an increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots, and death with the arthritis and ulcerative colitis medicines Xeljanz and Xeljanz XR.”

The trial’s final results also showed an increased risk of blood clots and death with the lower dose of Xeljanz. A prior Drug Safety Communication based upon earlier results from this trial reported an increased risk of blood clots and death only seen at the higher dose.

FDA is also requiring new and updated warnings for two other arthritis medicines: Eli Lilly’s Olumiant (baricitinib) and AbbVie’s Rinvoq (upadacitinib).

Because Olumiant and Rinvoq have not been studied in trials similar to the large safety clinical trial with Xeljanz, the risks have not been adequately evaluated, FDA said. “However, since they share mechanisms of action with Xeljanz, FDA considers that these medicines may have similar risks as seen in the Xeljanz safety trial.”

Geoffrey Porges

Pharmaceutical industry analyst Geoffrey Porges, senior analyst with SVB Leerlink, criticized the FDA’s inclusion of Olumiant and Rinvoq in the new warning.

"It is hard to recall a situation where the agency has applied such a blanket approach to molecules in a class with clear and potentially significant pharmacological differences. We wonder how far the agency will extend this over-reach to drugs in other related classes, such as TYK2 (tyrosine kinase 2) inhibitors…” Porges wrote in a research note.

The FDA has “effectively invented indication statements for major medicines Rinvoq and Olumiant…based on read-throughs from one trial with another quite different medicine in the class (Xeljanz),” Porges wrote. “It is hard to understand how the FDA justified restricting the use of these medicines to settings (second line only) and indications where in some cases these medicines have not even been fully studied (exclusively post-tumor necrosis factor patients) and in diseases where many patients have risk factors and pre-existing conditions that preclude them from being candidates for tumor necrosis factors.”

“TNF’s themselves have significant liabilities, and the agency seems to now be endorsing them as preferred first-line agents, regardless of those liabilities,” Porges added.

Meanwhile, FDA said that two other JAK inhibitors, Incyte’s Jakafi (ruxolitinib) and Celgene’s Inrebic (fedratinib), will not require the warnings because they are not indicated for the treatment of arthritis and other inflammatory conditions.

“Jakafi and Inrebic are used to treat blood disorders and require different updates to their prescribing information. If FDA becomes aware of any additional safety information or data that warrants updates to the prescribing information for these medicines, we may take further action and will alert the public,” the agency said.