ISSUE: FDA has approved new warnings about an increased risk of blood clots and of death with the 10-mg, twice-daily dose of Xeljanz, Xeljanz XR (tofacitinib), which is used in patients with ulcerative colitis. In addition, the approved use of tofacitinib for ulcerative colitis will be limited to certain patients who are not treated effectively or who experience severe side effects with certain other medicines. We approved these changes, including adding our most prominent Boxed Warning, after reviewing interim data from an ongoing safety clinical trial of tofacitinib in patients with rheumatoid arthritis (RA) that examined a lower and this higher dose of the medicine.

BACKGROUND: Tofacitinib works by decreasing the activity of the immune system; an overactive immune system contributes to RA, psoriatic arthritis (PsA), and ulcerative colitis. Tofacitinib was first approved in 2012 to treat adult patients with RA who did not respond well to the medicine methotrexate. When FDA first approved tofacitinib in 2012, FDA required a post-marketing clinical trial in patients with RA on background methotrexate to evaluate the risk of heart-related events, cancer, and infections. The trial is studying two different doses of tofacitinib (5 mg twice daily, which is the currently approved dose for RA, and a higher, 10-mg, twice-daily dosage) in comparison to a TNF blocker. In RA, the body attacks its own joints, causing pain, swelling, and loss of function. An interim analysis of the trial’s results found an increased occurrence of blood clots and of death in patients treated with tofacitinib 10 mg twice daily compared to patients treated with tofacitinib 5 mg twice daily or a TNF blocker. In 2017, we approved the medicine to treat patients with a second condition that causes joint pain and swelling, PsA, who did not respond well to methotrexate or other similar medicines. In 2018, we approved tofacitinib to treat ulcerative colitis, which is a chronic, inflammatory disease affecting the colon.

RECOMMENDATION: Patients should tell their healthcare professionals if they have a history of blood clots or heart problems, and talk to them about any questions or concerns. Stop taking tofacitinib and seek emergency medical attention right away if you experience any unusual symptoms, including those that may signal a blood clot such as:

• Sudden shortness of breath
• Chest pain that worsens with breathing
• Swelling of a leg or arm
• Leg pain or tenderness, or red or discolored skin in the painful or swollen leg or arm

Do not stop taking tofacitinib without first talking to your healthcare professional, as doing so can worsen your condition.

Healthcare professionals should discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis. Counsel patients about the risks and advise them to seek medical attention immediately if they experience any unusual symptoms, including those of thrombosis listed above. Reserve tofacitinib to treat ulcerative colitis for patients who have failed or do not tolerate tumor necrosis factor (TNF) blockers. Avoid tofacitinib in patients who may have a higher risk of thrombosis. When treating ulcerative colitis, use tofacitinib at the lowest effective dose and limit the use of the 10-mg, twice daily dosage to the shortest duration needed (See Additional Information for Health Care Professionals for more recommendations).

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the form, or submit by fax to 1-800-FDA-0178