FDA Requires New Boxed Warning on Xeljanz, other JAK Inhibitors

The FDA is requiring an updated boxed warning on three top-selling Janus kinase (JAK) inhibitors used to treat rheumatoid arthritis and other inflammatory conditions.

The new boxed warning applies to Pfizer’s Xeljanz (tofacitinib), Eli Lilly’s Olumiant (baricitinib), and AbbVie’s Rinvoq (upadacitinib).

The FDA previously warned about an increased risk of heart problems and cancer with Xeljanz, and in September, updated and expanded its warning to other JAK inhibitors.

The agency’s Drug Safety Communication said that, after reviewing of a large, randomized safety clinical trial, “we have concluded there is an increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots, and death with the arthritis and ulcerative colitis medicines Xeljanz and Xeljanz XR.”

The trial’s final results also showed an increased risk of blood clots and death with the lower dose of Xeljanz. A prior Drug Safety Communication based upon earlier results from this trial reported an increased risk of blood clots and death only seen at the higher dose.

As a result, FDA required new and updated warnings on Olumiant and Rinvoq.

Because Olumiant and Rinvoq have not been studied in trials similar to the large safety clinical trial with Xeljanz, the risks have not been adequately evaluated, FDA said. “However, since they share mechanisms of action with Xeljanz, FDA considers that these medicines may have similar risks as seen in the Xeljanz safety trial.”

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The new boxed warning for major adverse cardiovascular events states that: “RA patients 50 years of age and older with at least one cardiovascular risk factor, treated with Xeljanz 5 mg twice daily or Xeljanz 10 mg twice daily, had a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction and stroke), compared with those treated with TNF blockers. Patients who are current or past smokers are at an increased risk. Discontinue Xeljanz Xeljanz XR/ Xeljanz Oral Solution in patients that have experienced a myocardial infarction or stroke,” Pfizer said in a news release.

The FDA’s updated boxed warning for malignancies states that: “Malignancies, including lymphomas and solid tumors, have occurred in patients treated with Xeljanz and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding nonmelanoma skin cancer [NMSC]) was observed in patients treated with Xeljanz 5 mg twice a day or Xeljanz 10 mg twice a day compared with TNF blockers.”

In addition, the updated boxed warning includes: “Lymphomas and lung cancers were observed at a higher rate in patients treated with Xeljanz 5 mg twice a day or Xeljanz 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with Xeljanz and concomitant immunosuppressive medications.”