High doses of tofacitinib (Xeljanz) were tied to in a postmarketing safety study, the FDA said late Monday.
When the agency approved tofacitinib in 2012, it mandated that the manufacturer Pfizer undertake a clinical trial for patients with RA specifically to look for increased risks of cardiac events, malignancy, and opportunistic infections. Risks were analyzed for patients given tofacitinib in dosages of 5 mg or 10 mg twice daily, in combination with methotrexate, or a tumor necrosis factor (TNF) inhibitor.
A review by the data safety monitoring board detected a signal among patients taking 10 mg twice daily for pulmonary embolism and overall mortality, and the trial's sponsor has already moved patients in the 10-mg group to 5 mg, which is the approved dose for RA. The higher dose is only approved for the treatment of ulcerative colitis.
"The FDA is actively examining the data from the trial and working directly with Pfizer to better understand the safety signal, its impact on patients, and how tofacitinib should be used," said Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research.
Patients in the safety monitoring study were required to be age 50 years or older and to have one or more cardiovascular risk factors.
In a safety communication, the FDA stated that healthcare professionals should follow the recommendations given in tofacitinib's prescribing information for the specific condition being treated, and that patients should be monitored for symptoms of pulmonary embolism. These include:
- Shortness of breath
- Pain in the chest or back
- Hemoptysis
- Bluish skin or excessive perspiration
Tofacitinib is an oral janus kinase (JAK) inhibitor approved for the treatment of moderate to severe RA, active psoriatic arthritis, and moderate to severe ulcerative colitis. Patients taking the drug have an increased risk for serious infections including pneumonia, cellulitis, urinary tract infections, and herpes zoster.
Just 2 months ago, researchers from Harvard Medical School and Brigham and Women's Hospital in Boston published an analysis in Arthritis & Rheumatology that found no increased risk for venous thromboembolism (VTE) among patients with RA being treated with tofacitinib compared with those given a TNF inhibitor. That analysis was based on data from claims in Medicare and Truven MarketScan.
Concerns about VTE had been raised during the premarketing trials of another JAK inhibitor, baricitinib (Olumiant), and that drug had been approved only for use in a low dose. The Harvard researchers observed, "It remains unknown whether the risk for VTE is attributable to JAK inhibition and extends to tofacitinib."