Overview

The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has reviewed the safety of five JAK inhibitors (abrocitinib [▼Cibinqo], baricitinib [Olumiant], filgotinib [▼Jyseleca], tofacitinib [Xeljanz] and upadacitinib [▼Rinvoq].1 2 Along with safety data, PRAC reviewed the results from a clinical trial of tofacitinib and preliminary findings from an observational study involving baricitinib. PRAC also received advice from a group of rheumatologists, dermatologists, gastroenterologists and patient representatives.

The results of an open-label non-inferiority postauthorisation safety study that assessed cardiovascular events and cancers in patients with rheumatoid arthritis receiving tofacitinib or a tumour necrosis factor (TNF) alpha inhibitor were published in 2022.3 Trial participants were aged ≥50 years and had at least one additional cardiovascular risk factor. During a median follow-up of 4 years, there were higher incidences of cardiovascular events and cancer with tofacitinib (3.4% and 4.2%, respectively) than with a TNF alpha inhibitor (2.5% and 2.9%, respectively). PRAC’s review confirmed that tofacitinib increases the risk of major cardiovascular problems, cancer, venous thromboembolism, serious infections and death due to any cause when compared with TNF alpha inhibitors.1 PRAC concluded that these findings apply to all approved uses of JAK inhibitors in chronic inflammatory disorders (rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis and alopecia areata).

PRAC recommends that these medicines should be used only if no suitable treatment alternatives are available for the following groups: those aged ≥65 years, those at increased risk of major cardiovascular problems, those who smoke or have done so for a long time in the past, and those at increased risk of cancer.1 2 The drugs should be used in caution in patients with risk factors for pulmonary or venous thromboembolism, and lower doses should be used in some patient groups. The product information for JAK inhibitors used in the EU to treat chronic inflammatory disorders will be updated with the new recommendations. Educational material for patients and healthcare professionals will also be updated.

The JAK inhibitors, ruxolitinib (Jakavi) and fedratinib (▼Inrebic), which are used to treat myeloproliferative disorders, were not included in the EMA’s review.1

Context

In the UK, the JAK inhibitors included in the review have a range of licensed indications and should be initiated by specialists.4 Abrocitinib is licensed for moderate to severe atopic eczema; baricitinib is licensed for moderate to severe active rheumatoid arthritis (RA) and moderate to severe atopic eczema; filgotinib is licensed for RA and ulcerative colitis (UC); tofacitinib is licensed for moderate to severe RA, psoriatic arthritis, moderate to severe UC and ankylosing spondylitis; and upadacitinib is licensed for severe RA, psoriatic arthritis, ankylosing spondylitis and atopic eczema.

In 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) highlighted concerns over cardiovascular events and malignancies with tofacitinib based on the results of the safety study that were initially released in 2021.3 5 The MHRA advised that patients who are already at increased risk of cardiovascular events or cancers should only be offered treatment with tofacitinib if there are no other suitable treatment options. In light of the EMA’s recommendations, the MHRA is considering additional safety measures for other JAK inhibitors used in the UK.6