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FDA Approves Boxed Warning About Increased Risk of Blood Clots and Death with Higher Dose of Tofacitinib (Xeljanz, Xeljanz XR)

Audience: Consumer, Health Professional, Pharmacy

July 26, 2019 -- The U.S. Food and Drug Administration has approved new warnings about an increased risk of blood clots and of death with the 10 mg twice daily dose of tofacitinib (XeljanzXeljanz XR), which is used in patients with ulcerative colitis. In addition, the approved use of tofacitinib for ulcerative colitis will be limited to certain patients who are not treated effectively or who experience severe side effects with certain other medicines. We approved these changes, including adding our most prominent Boxed Warning, after reviewing interim data from an ongoing safety clinical trial of tofacitinib in patients with rheumatoid arthritis (RA) that examined a lower and this higher dose of the medicine.

The 10 mg twice daily dose of tofacitinib is not approved for RA or psoriatic arthritis (PsA). This dose is only approved for ulcerative colitis for initial treatment and for long-term use in limited situations. While the increased risks of blood clots and of death were seen in patients taking this dose for RA, these risks may also apply to those taking tofacitinib for ulcerative colitis.

Tofacitinib works by decreasing the activity of the immune system; an overactive immune system contributes to RA, PsA, and ulcerative colitis. Tofacitinib was first approved in 2012 to treat adult patients with RA who did not respond well to the medicine methotrexate. In RA, the body attacks its own joints, causing pain, swelling, and loss of function. In 2017, we approved the medicine to treat patients with a second condition that causes joint pain and swelling, PsA, who did not respond well to methotrexate or other similar medicines. In 2018, we approved tofacitinib to treat ulcerative colitis, which is a chronic, inflammatory disease affecting the colon.

Patients should tell your health care professionals if you have a history of blood clots or heart problems, and talk to them about any questions or concerns. Stop taking tofacitinib and seek emergency medical attention right away if you experience any unusual symptoms, including those that may signal a blood clot such as:

  • 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

Do not stop taking tofacitinib without first talking to your health care professional, as doing so can worsen your condition.

Health care professionals should discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis. Counsel patients about the risks and advise them to seek medical attention immediately if they experience any unusual symptoms, including those of thrombosis listed above. Reserve tofacitinib to treat ulcerative colitis for patients who have failed or do not tolerate tumor necrosis factor (TNF) blockers. Avoid tofacitinib in patients who may have a higher risk of thrombosis. When treating ulcerative colitis, use tofacitinib at the lowest effective dose and limit the use of the 10 mg twice daily dosage to the shortest duration needed (See Additional Information for Health Care Professionals for more recommendations).

When FDA first approved tofacitinib in 2012, we required a postmarketing clinical trial in patients with RA on background methotrexate, to evaluate the risk of heart-related events, cancer, and infections. The trial is studying two different doses of tofacitinib (5 mg twice daily, which is the currently approved dose for RA, and a higher, 10 mg twice daily dosage) in comparison to a TNF blocker. An interim analysis of the trial’s results found an increased occurrence of blood clots and of death in patients treated with tofacitinib 10 mg twice daily compared to patients treated with tofacitinib 5 mg twice daily or a TNF blocker. Based on these results, the 10 mg twice daily treatment was stopped and patients were allowed to continue treatment on 5 mg twice daily.

This safety trial is ongoing. Patients in the 5 mg twice daily group and the TNF blocker group continue to be followed. FDA will reassess these safety issues when the trial has completed and final, verified data are available. We will update the public when additional information is available.

The interim results of the trial, as of January 2019, have identified the following:

  • 19 cases of blood clots in the lung 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 blockers
  • To help FDA track safety issues with medicines, we urge patients and health care professionals to report side effects involving tofacitinib or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.

    Facts about tofacitinib (Xeljanz, Xeljanz XR)

    • Tofacitinib is approved to treat rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.
    • Tofacitinib works by decreasing the activity of the immune system.
    • Tofacitinib is available as 5 and 10 mg immediate-release tablets, as well as an 11 mg extended-release tablet that releases the medicine into the body over time.
    • Tofacitinib 5 mg immediate-release tablet is approved for the treatment of rheumatoid arthritis and for maintenance treatment of ulcerative colitis. Tofacitinib 10 mg immediate-release tablet is approved for the induction treatment in patients with ulcerative colitis.
    • Common side effects of tofacitinib include nasal congestion, sore throat, runny nose, headache, increased cholesterol levels, high blood pressure, upper respiratory tract infections, increased muscle enzyme levels, rash, diarrhea, and shingles.

    Additional Information for Patients

    • FDA has approved new warnings about an increased risk of blood clots and death with the 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR).
    • Tofacitinib 10 mg twice daily is currently only approved for ulcerative colitis. This dose is not approved or recommended for rheumatoid arthritis or psoriatic arthritis.
    • The approved use of tofacitinib for ulcerative colitis will be limited to certain patients who are not treated effectively or experience severe side effects with other medicines called tumor necrosis factor (TNF) blockers. Examples of TNF blockers include adalimumab, golimumab, and infliximab.
    • Inform your health care professional if you have a history of blood clots or heart problems.
    • Stop taking tofacitinib and seek emergency medical attention right away if you experience any unusual symptoms, including those that may signal a blood clot such as:
      • Sudden shortness of breath
      • Chest pain that worsens with breathing
      • Swelling of leg or arm
      • Leg pain or tenderness, or red or discolored skin in the painful or swollen leg or arm
    • Blood clots can form in, or travel to the blood vessels in the brain, heart, kidneys, lungs, and limbs. This can lead to heart attack, stroke, damage to the body's organs, or even death.
    • Do not stop taking tofacitinib without first talking to your health care professional, as doing so can worsen your condition.
    • Read the patient Medication Guide every time you receive a prescription for tofacitinib. The Medication Guide will be updated with this new or other important information about your medicine. It explains the important things that you need to know. These include the side effects, what the medicine is used for, how to take and store it properly, and other things to watch out for when you are taking the medicine.
    • Talk to your health care professional if you have any questions or concerns about tofacitinib.
    • To help FDA track safety issues with medicines, report side effects from tofacitinib or other medicines to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of this page.

    Additional Information for Health Care Professionals

    • FDA has approved new warnings about an increased risk of thrombosis and death in patients treated with the 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR).
    • Tofacitinib 10 mg twice daily is not approved or recommended for the treatment of rheumatoid arthritis or psoriatic arthritis.
    • For the treatment of ulcerative colitis, reserve tofacitinib as second-line therapy for use in patients who have failed or cannot tolerate TNF blockers.
    • For ulcerative colitis, use tofacitinib at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.
      • The induction dose is 10 mg twice daily for 8 weeks. Evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed, continue 10 mg twice daily for an additional 8 weeks or a maximum of 16 weeks. Discontinue 10 mg twice daily after 16 weeks if adequate therapeutic response is not achieved.
      • The maintenance dose is 5 mg twice daily. Use of 10 mg twice daily beyond induction should be limited to those with loss of response and used for the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response.
    • Discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis.
    • Avoid tofacitinib in patients who may be at increased risk of thrombosis.
    • Counsel patients to seek medical attention immediately if they experience unusual symptoms, including those of thrombosis.
    • Encourage patients to read the Medication Guide they receive with each tofacitinib prescription, which explains the safety risks and provides other important information.
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