High Dose Tofacitinib Increases Mortality Risk in RA Patients

Rheumatoid arthritis (RA) patients taking a 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR) may have an increased risk for blood clots in the lungs and death, according to a safety alert from the U.S. Food and Drug Administration (FDA).

Tofacitinib is FDA approved for the treatment of RA—but only in a 5 mg twice daily dose; the 10 mg twice daily dose is only approved for the treatment of ulcerative colitis.

The FDA required a trial be conducted to compare the risks for heart-related events, cancer, and infections associated with two tofacitinib doses (10 mg twice daily and 5 mg twice daily) in combination with methotrexate, as well as a tumor necrosis factor (TNF) inhibitor. Inclusion criteria included age 50 years and older, moderate to severe RA, uncontrolled symptoms while taking methotrexate, and at least one cardiovascular risk factor. Patients with current or recent infection, with clinically significant laboratory abnormalities, or who were pregnant were not included in the trial.

Trial Finds Increase in Adverse Events, Mortality for High Dose of Tofacitinib

According to a press release from Pfizer, who sponsored the trial, “Based on the most recent analysis of the ongoing A3921133 study, the (Rheumatology Data Safety Monitoring Board [DSMB]) observed that patients treated with tofacitinib 10 mg twice daily had a statistically and clinically important difference in the occurrence of pulmonary embolism, compared with patients in this study who were treated with a TNFi. The DSMB also noted an increase in overall mortality in the 10 mg twice daily treatment group compared to the tofacitinib 5 mg twice daily and TNFi treatment arms.”

The trial began in March 2014 and is estimated to end in March 2020. Pfizer noted that the trial is anticipated to continue through the end, but the patients in the 10 mg twice daily arm will be transitioned to 5 mg twice daily.

The FDA said in its statement that patients should not change their current dose without first speaking with their provider, as this could worsen their disease. Further, patients should seek immediate medical attention if they experience signs of a blood clot in the lungs or any of the following symptoms:

  • Sudden shortness of breath or difficulty breathing
  • Chest pain or pain in your back
  • Coughing up blood
  • Excessive sweating
  • Clammy or blush colored skin

In addition to RA and ulcerative colitis, tofacitinib is also indicated for psoriatic arthritis (PsA), with the same dose recommendations for PsA as RA.