FDA Flags Tofacitinib Safety Trial Data Showing Elevated Cardiac and Cancer Risk Across Both Doses

Preliminary results from an FDA-mandated post-market safety trial have placed tofacitinib (Xeljanz, Xeljanz XR) under renewed regulatory scrutiny, with initial data showing a higher occurrence of serious cardiovascular events and malignancies at both the 5 mg and 10 mg twice-daily doses compared to TNF inhibitors, a finding that extends risk signals beyond the higher dose already carrying a Boxed Warning.

The trial was required by FDA at the time of tofacitinib's 2012 approval under 21 CFR Part 314 post-marketing study commitments. Pfizer enrolled patients aged 50 and older with rheumatoid arthritis and at least one cardiovascular risk factor, comparing both approved and investigational doses against TNF inhibitor therapy. Interim results communicated in February and July 2019 had already prompted a Boxed Warning for blood clots and death at the 10 mg dose; the current release broadens that concern to the standard 5 mg RA dosage.

For regulatory affairs leads, the immediate compliance obligation is labeling. FDA has confirmed it is working with Pfizer to obtain further data and will issue final conclusions following full review, a sequence that typically triggers a labeling supplement under 21 CFR Part 314.70 and may require updates to the Risk Evaluation and Mitigation Strategy (REMS) framework or prescribing information across all approved indications, which include psoriatic arthritis (2017) and ulcerative colitis (2018).

The broader JAK inhibitor class is implicated. FDA's September 2021 Drug Safety Communication extended the safety review to other JAK inhibitors, signaling that post-market commitments and labeling revisions may not be limited to tofacitinib alone. Pharmacovigilance teams managing baricitinib, upadacitinib, or ruxolitinib portfolios should read the evolving tofacitinib dataset as a leading indicator for class-level regulatory action.

Final trial results, including data on pulmonary embolism and all-cause mortality, remain outstanding; FDA's conclusions and formal recommendations will follow completion of that review.

Source: U.S. Food and Drug Administration, Drug Safety and Availability, via FDA.gov, February 4, 2021; updated reference to September 1, 2021 Drug Safety Communication also noted.