Tofacitinib (Xeljanz▼): restriction of 10 mg twice-daily dose in patients at high risk of pulmonary embolism while safety review is ongoing

Following observation in a clinical study of an increased risk of pulmonary embolism and overall mortality with tofacitinib 10 mg twice-daily in rheumatoid arthritis, a safety review has started and new contraindications introduced. The 10 mg twice-daily dose of tofacitinib (authorised for ulcerative colitis) must not be used in patients at high risk of pulmonary embolism.

Post-publication note

The European safety review of tofacitinib has now concluded and new recommendations were issued in a March 2020 Drug Safety Update.

Post-publication note: October 2021

Following final results from the clinical study ORAL Surveillance (A3921133), new measures have been been recommended to minimise the risks of cardiovascular events and malignancies for tofactinib treatment. Tofacitinib should not be used in patients older than 65 years of age, people who are current or past smokers, or individuals with other cardiovascular (such as diabetes or coronary artery disease) or malignancy risk factors unless there are no suitable treatment alternatives. See Drug Safety Update October 2021 for more information

A European safety review of tofacitinib (Xeljanz▼) has begun following results from an ongoing study (study A3921133) in patients with rheumatoid arthritis aged 50 years and older with at least one cardiovascular risk factor. The findings show an increased risk of pulmonary embolism and overall mortality, compared with a TNF inhibitor, when patients were treated with 10 mg of tofacitinib twice-daily (twice the recommended dose for rheumatoid arthritis of 5 mg twice-daily).

Since the 10 mg twice-daily dose is recommended for the initial treatment (for up to 16 weeks) in ulcerative colitis, until the review has concluded, patients with ulcerative colitis at high risk of pulmonary embolism should not start treatment with tofacitinib. Patients who are already being treated with the 10 mg twice-daily dose of tofacitinib who are at high risk of pulmonary embolism should be switched to alternative treatments. For more information on the measures, see EMA press release.

While an in-depth review of these risks is ongoing, the 10 mg twice-daily dose of tofacitinib must not be prescribed in patients with one or more of the following risk factors for pulmonary embolism:

  • Use of combined hormonal contraceptives or hormone replacement therapy
  • Heart failure
  • Previous venous thromboembolism, either deep venous thrombosis or pulmonary embolism
  • Inherited coagulation disorder
  • Malignancy
  • Patients undergoing major surgery

Additionally, other risk factors for pulmonary embolism to be considered when prescribing tofacitinib 10 mg twice-daily are age, obesity (BMI>30 kg/m2), smoking, and immobilisation.


The start of this safety review follows interim advice in March 2019 for prescribers to adhere to the authorised dose of 5 mg twice-daily for the treatment of rheumatoid arthritis and psoriatic arthritis (letter to healthcare professionals).

Patients receiving tofacitinib, irrespective of indication, should be monitored for the signs and symptoms of pulmonary embolism, and be advised to seek medical attention immediately if they experience them.

For information for patients, see EMA website.

We will communicate more information on these measures and further advice as it arises. A letter is being sent to healthcare professionals to inform of the temporary recommendations.

Article citation: Drug Safety Update volume 12, issue 10: May 2019: 2.

Published 17 May 2019