Rheumatoid arthritis

FDA issues warning about increased risk of serious cardiovascular events, malignancy, thrombosis, and death with tofacitinib and other JAK inhibitors

The US Food and Drug Administration (FDA) has issued a warning about an increased risk of serious cardiovascular events, malignancy, thrombosis, and death with tofacitinib and two other Janus kinase (JAK) inhibitors (baricitinib and upadacitinib).[46]Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Sep 2021 [internet publication]. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death

This follows final results from a large randomized safety clinical trial comparing tofacitinib with tumor necrosis factor (TNF)-alpha inhibitors in patients with rheumatoid arthritis. The study found an increased risk of blood clots and death with the lower dose of tofacitinib (5 mg twice daily); this serious event had previously been reported only with the higher dose (10 mg twice daily) in the preliminary analysis.[47]ClinicalTrials.gov. Safety study of tofacitinib versus tumor necrosis factor (TNF) inhibitor in subjects with rheumatoid arthritis (A3921133). NCT02092467. Aug 2021 [internet publication]. https://clinicaltrials.gov/ct2/show/NCT02092467

The FDA advises clinicians to:[46]Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Sep 2021 [internet publication]. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death

• Reserve tofacitinib, baricitinib, and upadacitinib for patients who have had an inadequate response or are intolerant to one or more TNF-alpha inhibitors

• Consider the patient's individual benefit-risk profile when deciding to prescribe or continue treatment with these medications, particularly in patients who are current or past smokers, patients with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy (other than a successfully treated nonmelanoma skin cancer).

Two other JAK inhibitors, ruxolitinib and fedratinib, are not indicated for the treatment of arthritis and other inflammatory conditions and so are not affected by this warning.

A similar safety alert was issued by the European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) for tofacitinib, based on results from the same study. The EMA advice relates to patients ages >65 years, those who are current or past smokers, patients with other cardiovascular risk factors, and patients with other malignancy risk factors. In these patient groups, tofacitinib should only be used to treat moderate or severe ulcerative colitis, if no suitable treatment alternative is available.[47]ClinicalTrials.gov. Safety study of tofacitinib versus tumor necrosis factor (TNF) inhibitor in subjects with rheumatoid arthritis (A3921133). NCT02092467. Aug 2021 [internet publication]. https://clinicaltrials.gov/ct2/show/NCT02092467 [48]European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 7-10 June 2021. Jun 2021 [internet publication]. https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-7-10-june-2021 [49]Medicines and Healthcare products Regulatory Agency. Tofacitinib (Xeljanz): new measures to minimise risk of major adverse cardiovascular events and malignancies. Oct 2021 [internet publication]. https://www.gov.uk/drug-safety-update/tofacitinib-xeljanzv-new-measures-to-minimise-risk-of-major-adverse-cardiovascular-events-and-malignancies

See Management: approach

See Management: treatment algorithm

Original source of update