FDA Orders Black Box Warning for Xeljanz Blood Clots, Death

Published on July 29, 2019 by Sandy Liebhard

Federal regulators have ordered Pfizer, Inc. to add a new Black Box Warning to the Xeljanz label, after an ongoing clinical trial suggested a higher dose regimen could place patients at risk for pulmonary embolism (blood clots in the lungs) and death.

Xeljanz Black Box Warning: What You Need to Know.

The twice-daily 10mg dose of Xeljanz is only indicated to treat patients with ulcerative colitis.   While the clinical trial involved rheumatoid arthritis, the agency is concerned that the potential for Xeljanz blood clots and death could extend to those being treated for ulcerative colitis.

Along with the Black Box Warning, the FDA is restricting Xeljanz as a second-line treatment for ulcerative colitis patients “who are not treated effectively or who experience severe side effects with certain other medicines.”  According to a Drug Safety Communication published on July 26th, doctors should use the lowest effective dose when treating these patients and limit use of the 10mg twice-daily dose to the shortest duration possible. They should also avoid prescribing Xeljanz to those at risk for blood clots.

Patients taking Xeljanz need to tell their doctor if they have a history of blood clots. But they should not stop taking the drug without consulting a physician, as ending treatment could worsen their condition.  Xeljanz patients must also seek immediate medical help if they experience any unusual symptoms, especially those that could signify a blood clot:

• 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

FDA Xeljanz Review Launched in February

The FDA approved Xeljanz (5 mg twice daily) to treat rheumatoid arthritis in 2012. Four years later, the agency cleared Xeljanz XR, an 11 mg, once-daily, extended-release tablet. Both Xeljanz versions were approved to treat adults with psoriatic arthritis in 2017, while the 10 mg twice-daily Xeljanz regimen was approved to treat ulcerative colitis in 2018.

Upon Xeljanz’s approval, the FDA ordered Pfizer to conduct a post-market study to compare the rate of certain heart-related complications among rheumatoid arthritis patients receiving either the 5mg twice-daily dose, the 10-mg twice daily regimen, or another class of RA medications called TNF blockers.

The agency launched a Xeljanz safety review in February, after the study’s interim results suggested patients on the higher dose were more likely to experience a pulmonary embolism or die compared to those taking the lower dose or an alternative treatment. The findings prompted Pfizer to transition all study subjects on the 10mg twice-daily Xeljanz regimin to the 5mg twice-daily regimen.

According to an FDA Drug Safety Communication published last Friday, there were:

• 19 cases of pulmonary embolism out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 3 cases out of 3,982 patient-years in patients who received TNF blockers
• 45 cases of death from all causes out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 25 cases out of 3,982 patient-years in patients who received TNF blocker.

FDA Xeljanz Blood Clots Warning Lagged Behind Europe

Regulators in the European Union placed restrictions on the 10mg Xeljanz dose in May.  The FDA’s lack of action before last Friday had raised eyebrows in the United States, especially after former Commissioner Scott Gottleib accepted a position on Pfizer’s board of directors.

“It sounds like a reward for a job well done,” Carl Elliot, a physician and professor of bioethics at the University of Minnesota, told the Milwaukee Journal-Sentinel. “It sure does sound suspicious.”

Gottlieb and the FDA denied he had anything to do with the Xeljanz decision, insisting that only professional career staffers had the last word on the matter.  But those reassurances did little to quiet criticism of the FDA, which continued even after the agency announced the new Black Box Warning for  Xeljanz blood clots and death.

“This is another example of the FDA moving more slowly and less aggressively to protect public health relative to regulators in other countries,” Michael Carome, a physician with the watchdog group Public Citizen, told the Journal-Sentinel.