FDA Adds Boxed Warning on Risk for PE, Death With Higher Dose Tofacitinib (Xeljanz)

Megan Brooks


July 26, 2019

The US Food and Drug Administration (FDA) has added a boxed warning to tofacitinib (Xeljanz, Xeljanz XR; Pfizer) noting an increased risk for pulmonary embolism (PE) and death with the 10-mg twice-daily dose of the drug, which is used in patients with ulcerative colitis.

In addition, the agency has limited the use of tofacitinib for ulcerative colitis to patients who are not treated adequately or who experience severe adverse effects with other drugs.

The changes follow a review of interim data from a postmarketing safety study of tofacitinib in patients with rheumatoid arthritis (RA) that examined a lower dose as well as this higher dose of the medicine, the FDA said in a safety communication posted today on its website.

The safety study found an increased occurrence of blood clots and death in patients treated with tofacitinib 10 mg twice daily compared with patients treated with tofacitinib 5 mg twice daily or a tumor necrosis factor (TNF) blocker.

The 10-mg twice-daily dose of tofacitinib is not approved for RA or psoriatic arthritis. It's 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," the FDA warns. 

The FDA first warned about these risks in February 2019, as reported by Medscape Medical News

At the time, interim study results identified 19 cases of PE and 45 deaths out of 3884 patient-years of follow-up in those taking tofacitinib 10 mg twice daily, compared with three cases of PE and 25 deaths out of 3982 patient-years in those taking TNF blockers. The safety study is ongoing.

In May, the European Medicines Agency's (EMA's) Pharmacovigilance Risk Assessment Committee (PRAC) advised physicians not to prescribe the 10-mg twice-daily dose of tofacitinib to patients at high risk for PE, as reported by Medscape Medical News.

Recommended Actions for Clinicians

In today's safety communication, the FDA recommends that clinicians take the following actions:

  • For ulcerative colitis, reserve tofacitinib as second-line therapy in patients who fail or do not tolerate TNF blockers; use the lowest effective dose and limit the use of the 10-mg twice-daily dose to the shortest duration needed.

  • The induction dose for ulcerative colitis 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.

  • Counsel patients about the risks and advise them to seek medical attention immediately if they experience any unusual symptoms, including those of thrombosis. These include 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.

  • Avoid the drug in patients who may have a higher risk for thrombosis.

  • Encourage patients to read the Medication Guide they receive with each tofacitinib prescription, which explains the safety risks and provides other important information.

The FDA encourages healthcare professionals and patients to report adverse events or side effects that occur while using tofacitinib to the FDA's MedWatch Safety Information and Adverse Event Reporting Program. A report can be made by completing an online form or by calling 1-800-332-1088.

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