On July 26, 2019, the FDA announced a new boxed warning for tofacitinib (Xeljanz) 10 mg twice daily, a dosing regimen currently approved for treatment of ulcerative colitis. This new warning draws attention to the increased risk of blood clots and death associated with higher doses of tofacitinib. Because of this, the FDA recommends that tofacitinib should be reserved for patients with ulcerative colitis who are not effectively treated or have experienced intolerable side effects with tumor necrosis factor (TNF) blockers (eg, infliximab, adalimumab, golimumab). This new boxed warning stems from the same data that sparked an FDA Alert in February 2019 related to the off-label use of tofacitinib 10 mg twice daily in rheumatoid arthritis. In a postmarketing safety clinical trial, patients with rheumatoid arthritis were randomized to high-dose tofacitinib (10 mg twice daily) or low-dose tofacitinib (5 mg twice daily) combined with methotrexate and were compared to TNF blocker monotherapy. An interim analysis of the safety trial data showed an increased incidence of blood clots and death for patients receiving the 10 mg twice daily dosing of tofacitinib. Researchers reported 19 cases of pulmonary embolism and 45 deaths from 3,884 patient-years in the tofacitinib 10 mg twice daily arm, compared to 3 cases of pulmonary embolism and 25 deaths in 3,982 patient-years with TNF blocker treatment. Rates of pulmonary embolism and death were not elevated in the tofacitinib 5mg twice daily group. The tofacitinib 10 mg twice daily arm was discontinued, though researchers are still collecting data for the low-dose and TNF blocker monotherapy arms.
At this time, tofacitinib 10 mg twice daily dosing is only approved for ulcerative colitis treatment and should not be used in patients with psoriatic arthritis or rheumatoid arthritis. Xeljanz XR, a once daily 11 mg dose, is approved for use in psoriatic and rheumatoid arthritis. The FDA has not provided any updated dosing recommendations for Xeljanz XR as this formulation was not included in the post-marketing safety trial and is not labeled for ulcerative colitis treatment.
Patients should inform health care providers of any history of blood clots or heart problems. Patients should also watch for signs of leg swelling and pain, sudden difficulty breathing, or chest pain, and should seek immediate medical care if any of these symptoms are present. Patients should not stop taking tofacitinib without first speaking with a health care provider.
Health care professionals should discontinue tofacitinib immediately if a patient develops a clot during treatment. Tofacitinib should be reserved for patients with ulcerative colitis who are not adequately treated with TNF blockers. Prior to starting tofacitinib, health care professionals should evaluate patients for clotting risks. If risk factors are present, consider an alternative agent. Following the initial 8 weeks of 10 mg twice daily for induction, the lowest effective dose of tofacitinib should be used to maintain response. If necessary, doses may be increased to 10 mg twice daily for short durations, but should be reduced as soon as clinically possible. Patients and professionals are also encouraged to report any additional side effects to FDA MedWatch: www.accessdata.fda.gov/scripts/medwatch/