FDA: New Warnings and Limitations Set for Certain JAK Inhibitors

The revisions are based on a completed review of a large randomized safety clinical trial, which included 4362 patients with rheumatoid arthritis.

The Food and Drug Administration (FDA) is requiring revisions to the Boxed Warning for Xeljanz (tofacitinib), Xeljanz XR (tofacitinib extended-release), Olumiant (baricitinib), and Rinvoq (upadacitinib) to include information about the risks of serious cardiovascular-related events, malignancy, thrombosis, and death.

The revisions are based on a completed review of a large randomized safety clinical trial (ClinicalTrials.gov Identifier: NCT02092467), which included 4362 patients with rheumatoid arthritis who were taking methotrexate without adequate control of symptoms. Patients were randomly assigned 1:1:1 to receive Xeljanz 5mg or 10mg orally twice daily or tumor necrosis factor inhibitor (TNF blockers) (adalimumab or etanercept). The coprimary endpoints were major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke; and malignancy, excluding nonmelanoma skin cancer (NMSC).

According to the FDA’s review, final trial results showed an increased risk of MACE, death, malignancies, and thrombosis among patients treated with both regimens of Xeljanz compared with those who received TNF blockers. While early data showed the risk for blood clots and death was higher with the 10mg twice daily dose, the final analysis demonstrated that both regimens were associated with a higher risk. Additionally, there was an increased risk for malignancy, particularly lymphomas and lung cancers, with both doses of Xeljanz compared with TNF blockers. Higher rates of lung cancer and overall cancer were also observed in current or past smokers treated with Xeljanz. 

While the trial only evaluated Xeljanz, the FDA has included Olumiant and Rinvoq to the Boxed Warning revisions because these agents are Janus kinase inhibitors indicated for rheumatoid arthritis. The FDA did not include other Janus kinase inhibitors, such as Jakafi (ruxolitinib) and Inrebic (fedratinib), in the update because these drugs are not indicated to treat arthritis or other inflammatory conditions. 

Prior to initiating or continuing treatment with Xeljanz/Xeljanz XR, Olumiant, or Rinvoq, the FDA is recommending health care professionals consider the benefits and risks for the patient, particularly in 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. Moreover, the FDA is limiting all approved uses of these medications to patients who have had an inadequate response or intolerance to 1 or more TNF blockers.


FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. News release. US Food and Drug Administration. Accessed September 1, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death