European Medicines Agency review of Xeljanz (Article 20 Referral)

The European Medicines Agency's safety committee (PRAC) has concluded a review of Xeljanz (tofacitinib) and recommended updates to product information and new risk minimisation measures.

Further to correspondence from Eadaoin O'Mahony (see attached) earlier this year, the European Medicines Agency has recommended new risk minimisation measures for the use of Xeljanz (authorised in Ireland for rheumatoid arthritis, psoriatic arthritis and ulcerative colitis). Therefore the HPRA would appreciate if the following information and attachment above could be disseminated to your members so prescribers are made aware of the recommendations.

We would be happy to discuss this further if necessary and would appreciate if you could acknowledge receipt of this email. We will be in contact with further information as it becomes available.

'Dear Doctor,

This email is sent, further to our correspondence in May of this year, to update you that the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) has now finalised its review of Xeljanz (tofacitinib). The PRAC has recommended a number of risk minimisation measures, having concluded that Xeljanz (tofacitinib) could increase the risk of blood clots in the lungs and in deep veins in patients who are already at high risk.

Indications for tofacitinib:

• Tofacitinib in combination with methotrexate (MTX), or as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate, is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs, at a dose of 5mg twice daily.
• Tofacitinib in combination with MTX is also indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior disease-modifying antirheumatic drug (DMARD) therapy, also at a dose of 5mg twice daily.
• Tofacitinib is also indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent. The recommended dose is 10 mg given orally twice daily for induction for 8 weeks and 5 mg given twice daily for maintenance. For some patients, such as those who have failed prior tumour necrosis factor (TNF) antagonist therapy or those who experience a decrease in response on tofacitinib, the maintenance dose can be increased to 10mg twice daily.

The PRAC commenced a review of Xeljanz (tofacitinib) following observation of an increased risk of pulmonary embolism (PE) and overall mortality in patients with rheumatoid arthritis taking tofacitinib 10 mg twice daily in an ongoing clinical trial (Study A3921133). Study A3921133 is an ongoing open-label clinical trial evaluating the safety of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily compared with a tumour necrosis factor (TNF) inhibitor in patients with rheumatoid arthritis. The study included patients >50 years of age with at least one additional cardiovascular risk factor.

The PRAC assessed data from Study A3921133 and also re-assessed additional data from earlier studies. All data combined showed that the risk of blood clots was higher in patients taking Xeljanz, especially with the 10 mg twice daily dose and in those being treated for an extended period. Results also showed a further increased risk of serious and fatal infections in patients older than 65 years of age.

As a result, the PRAC has recommended that:

• Xeljanz should be used with caution in patients at high risk of blood clots.
• Maintenance doses of 10 mg twice daily should not be used in patients with ulcerative colitis who are at high risk of blood clots unless there is no suitable alternative treatment. 
• Patients older than 65 years of age should be treated with Xeljanz only when there is no alternative treatment.

Patients at high risk of blood clots include those who have had a heart attack or have heart failure, cancer, inherited blood clotting disorders or a history of blood clots, as well as patients who take combined hormonal contraceptives, are receiving hormone replacement therapy, are undergoing major surgery or are immobile. Doctors should also consider other factors that may increase the risk of blood clots including age, obesity, diabetes, hypertension or smoking.

PRAC recommended that the product information for Xeljanz should be updated with new warnings and recommendations based on data from the study and that it should list blood clots as an uncommon side effect occurring in between 1 in 1,000 and 1 in 100 patients.

The new PRAC recommendations replace the temporary measures put in place at the start of the review in May 2019 when the PRAC contraindicated use of the 10 mg twice daily dose of Xeljanz in patients with risk factors for VTE while it reviewed data from study A3921133.

The PRAC's recommendation will be sent to the EMA's human medicines committee (CHMP), which will adopt the Agency's final opinion, before passing to the European Commission for final decision. Therefore, recommended updates to the product information and educational materials will be implemented once the European Commission decision is issued. A direct healthcare professional communication (DHPC) will be disseminated after the European Commission decision to inform prescribers of the outcome.

The EMA public health communication on the PRAC conclusion is attached to this email and further information on the review can be found here.