More data needed on Xeljanz, venous thromboembolism risk in ulcerative colitis
SAN ANTONIO — A post hoc analysis evaluating the safety of Xeljanz in ulcerative colitis revealed comparable incidence rates of pulmonary embolism and deep vein thrombosis in patients who did and did not receive the agent. However, researchers at the American College of Gastroenterology Annual Meeting stressed the need for more data to better understand the link between the agent and venous thromboembolic events after previous safety signals led to a change in prescribing guidelines in the United States.
“On one level, these data are somewhat reassuring,” William J. Sandborn, MD, director of the inflammatory bowel disease center at University of California, San Diego Health, said during a presentation. “On the other hand, we still have a relatively small sample size. We should not overinterpret these findings.”
Xeljanz (tofacitinib, Pfizer) — an oral, small molecule Janus kinase inhibitor — was approved in May 2018 for the treatment of moderate-to-severe ulcerative colitis. Its safety profile was assessed during an 8-week, phase 2 induction study; two identical 8-week, phase 3 induction studies (OCTAVE 1 and OCTAVE 2); a 52-week, placebo-controlled maintenance trial (OCTAVE Sustain); and an ongoing, open-label extension study (OCTAVE Open), according to Sandborn.
Tofacitinib is also available as treatment for rheumatoid arthritis. Earlier this year, the data safety monitoring board of a postmarketing study identified an increase in pulmonary embolisms among patients aged older than 50 years with rheumatoid arthritis and at least one cardiovascular risk factor who received 10 mg twice daily of tofacitinib vs. patients who received 5 mg tofacitinib twice daily or TNF blockers.
“Subsequently, updates to the U.S. prescribing information have been made of the risk for thrombosis as a boxed warning,” Sandborn said. “Tofacitinib for ulcerative colitis is approved in a 10 mg [twice daily] dose for 8 to 16 weeks of induction therapy, and then either 5 mg or 10 mg [twice daily] for maintenance. Now it is required that we attempt to go down to 5 mg for maintenance because of the risk.”
To further investigate the risk for venous thromboembolic events with tofacitinib in ulcerative colitis, Sanborn and colleagues examined data from patients who were enrolled in the 8-week, phase 2 induction study of tofacitinib and the OCTAVE trials. The patients were categorized into three cohorts: an induction cohort, which included 938 patients who received 10 mg tofacitinib twice daily and 282 patients who received placebo; a maintenance cohort, which included 198 patients who received 5 mg tofacitinib twice daily, 196 patients who received 10 mg tofacitinib twice daily, and 198 patients who received placebo; and an overall cohort, which included 1,157 patients who received either dose of tofacitinib.
Overall, there were 2,404 patient-years of tofacitinib exposure. In the induction cohort, one case of deep vein thrombosis (DVT) and one case of pulmonary embolism (PE) were reported among patients who received placebo. Similarly, in the maintenance cohort, one case each of DVT and PE were reported among patients who received placebo. There were no cases of DVT or PE among patients who received tofacitinib in either the induction or maintenance cohorts.
In the overall cohort, four cases of PE and one case of DVT were reported. All five cases occurred among patients in the higher tofacitinib-dose group who had comorbidities or other potential risk factors for venous thromboembolic events in addition to ulcerative colitis, according to Sandborn. The incidence rate among patients who received 10 mg tofacitinib twice daily was 0.05 for DVT and 0.21 for PE, which is “about half or less” than the incidence rates observed among patients who received tofacitinib in the rheumatoid arthritis postmarketing study, Sandborn said.
“The incidence rates for DVT and PE were comparable with those that you would see in ulcerative colitis among people who do not take tofacitinib, but we really need more data about this,” he concluded. “I refer all of you to the revised prescribing information that requires you to make an attempt to move patients from 10 mg to 5 mg during the maintenance period ... in order to optimize the risk-benefit of this drug.” – by Stephanie Viguers
Sandborn WJ, et al. Abstract 59. Presented at: American College of Gastroenterology Annual Meeting; Oct. 25-30, 2019; San Antonio.
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