Drug Update · Gastroenterology

FDA Requires Boxed Warning for Upadacitinib (Rinvoq): Heart Events, Cancer, Clots, Death

August 17, 2026

FDA safety action

FDA requires revisions to the Boxed Warning for Xeljanz/Xeljanz XR, Olumiant, and Rinvoq to include risks of serious heart-related events, cancer, blood clots, and death [4].

RINVOQ label effective date

2026-06-30 [6].

RINVOQ indications (IBD)

Adults with moderately to severely active ulcerative colitis and adults with moderately to severely active Crohn’s disease with prior inadequate response or intolerance to one or more TNF blockers [6].

Clinical Perspective

This update affects gastroenterologists, other clinicians prescribing JAK inhibitors, and patients with inflammatory bowel disease who are receiving or being considered for JAK inhibitor therapy, as identified in the FDA communication and label materials ^[1]^[3]. The FDA-required Boxed Warning revisions support explicit counseling about the FDA-identified risks and consideration of alternative therapies when those risks are a concern, and they highlight the need to review product labeling for indication-specific guidance ^[1]^[3]. What additional comparative safety data are needed to define relative risk across JAK inhibitors and between JAK inhibitors and non-JAK biologics in IBD populations?

Dr. Sanjay Iyer, MBBS, MD (General Medicine), DM (Gastroenterology) · Gastroenterology

The FDA is requiring revisions to the Boxed Warning for Janus kinase (JAK) inhibitors to include information about increased risks of serious heart-related events, cancer, blood clots, and death, and has specified these updates apply to Xeljanz/Xeljanz XR (tofacitinib), Olumiant (baricitinib), and Rinvoq (upadacitinib) ^[1]. Rinvoq (upadacitinib) is approved for multiple inflammatory conditions including ulcerative colitis and Crohn’s disease; its most recent label revision is effective 2026-06-30 ^[3]. Recent reviews note that upadacitinib, mirikizumab, and risankizumab have entered the evolving therapeutic landscape for inflammatory bowel disease (IBD) ^[2].

Clinical Context

Janus kinase (JAK) inhibitors are an oral small-molecule class that modulates intracellular cytokine signaling via inhibition of JAK enzymes; upadacitinib (RINVOQ) modulates JAK activity and prevents phosphorylation and activation of STAT proteins, with greater inhibitory potency at JAK1 and JAK2 relative to JAK3 and TYK2 reported in cellular assays ^[3]. The FDA safety communication applies to multiple agents in this class and lists audiences that include gastroenterology clinicians, reflecting the use of these agents in inflammatory bowel disease as well as rheumatologic indications ^[1]. A recent review characterizing the changing IBD treatment landscape cites recent approvals of etrasimod, upadacitinib, mirikizumab, and risankizumab as part of that evolution ^[2]. Clinicians prescribing JAK inhibitors in IBD should note the updated regulatory safety emphasis and consult product labeling for approved indications and dosing ^[1]^[3]^[2].

Key Findings

The FDA has required revisions to the Boxed Warning for Xeljanz/Xeljanz XR (tofacitinib), Olumiant (baricitinib), and Rinvoq (upadacitinib) to include risks of serious heart-related events, cancer, blood clots, and death, based on review of a large randomized safety clinical trial with Xeljanz and mechanistic considerations for related agents ^[1].
The FDA Safety Communication explicitly states that Olumiant and Rinvoq have not been studied in trials similar to the large Xeljanz safety trial; however, because they share mechanisms of action with Xeljanz, FDA considers that these medicines may have similar risks as seen in the Xeljanz safety trial ^[1].
RINVOQ prescribing information lists approvals and indications across specialties and shows label effective date 2026-06-30 and original approval date 2024-04-26; for inflammatory bowel disease indications, RINVOQ is indicated for adults with moderately to severely active ulcerative colitis and adults with moderately to severely active Crohn’s disease who have had an inadequate response or intolerance to one or more TNF blockers ^[3].
A 2025 review paper notes recent approvals of etrasimod, upadacitinib, mirikizumab, and risankizumab in the evolving IBD treatment landscape, positioning these agents as recently introduced therapeutic options within the literature summarized there ^[2].

Safety & Tolerability

Serious heart-related events (such as heart attack or stroke) ^[1]
Cancer ^[1]
Blood clots ^[1]
Death ^[1]

Study Design

This article summarizes regulatory and label information rather than a single clinical trial. RINVOQ (upadacitinib) prescribing information documents that the original FDA approval date was 2024-04-26 and that the most recent label revision is effective 2026-06-30; RINVOQ is indicated for adults with moderately to severely active ulcerative colitis and adults with moderately to severely active Crohn’s disease with prior inadequate response or intolerance to one or more TNF blockers ^[3]. The FDA Safety Communication that instituted the Boxed Warning revisions arose from a review that included a large randomized safety clinical trial with tofacitinib; details of that trial and comparable trials for Olumiant and Rinvoq were not fully reported in the provided source excerpts ^[1].

FAQ

What is upadacitinib (Rinvoq) approved for?

RINVOQ (upadacitinib) is indicated for multiple inflammatory conditions; specifically for inflammatory bowel disease the prescribing information lists indications for adults with moderately to severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers, and for adults with moderately to severely active Crohn’s disease who have had an inadequate response or intolerance to one or more TNF blockers.

How does upadacitinib (Rinvoq) work?

Upadacitinib is a Janus kinase (JAK) inhibitor that modulates intracellular signaling by inhibiting JAK enzymes, preventing phosphorylation and activation of signal transducers and activators of transcription (STATs); in cell assays upadacitinib showed greater inhibitory potency at JAK1 and JAK2 relative to JAK3 and TYK2.

What is the dose of upadacitinib for IBD?

For ulcerative colitis the prescribing information gives a recommended induction dosage of 45 mg once daily for 8 weeks followed by a maintenance dosage of 15 mg once daily, with a maintenance dosage of 30 mg once daily considered for refractory or severe disease; for Crohn’s disease the recommended induction dosage is 45 mg once daily for 12 weeks followed by a maintenance dosage of 15 mg once daily, with a maintenance dosage of 30 mg once daily considered for refractory or severe disease.

What are the side effects clinicians should counsel patients about?

The FDA safety communication requires Boxed Warning revisions to include increased risks of serious heart-related events (such as heart attack or stroke), cancer, blood clots, and death for Xeljanz/Xeljanz XR, Olumiant, and Rinvoq; the communication notes these risks on the basis of a large randomized safety trial with tofacitinib and mechanistic considerations for related agents.

Clinicians should consult current prescribing information for complete dosing guidance.

FDA Requires Boxed Warning for Upadacitinib (Rinvoq): Heart Events, Cancer, Clots, Death

Direct Clinical Takeaway & Evidence Summary

FDA Requires Boxed Warning for Upadacitinib (Rinvoq): Heart Events, Cancer, Clots, Death

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

Get weekly clinical updates for Gastroenterology in your inbox.

Related Clinical Updates

FDA Approves Linerixibat for PBC Pruritus: -0.72 WI-NRS in GLISTEN

Verified HCP Portal