FDA Limits Approved Uses of Tofacitinib (XELJANZ, XELJANZ XR) Because of Serious Adverse Effects

On Sept. 1, 2021, the Food and Drug Administration (FDA) issued an important alert for patients taking the oral drug tofacitinib (XELJANZ, XELJANZ XR), which is approved by the FDA to treat rheumatoid arthritis, psoriatic arthritis and ulcerative colitis in certain adult patients, as well as a type of arthritis called juvenile idiopathic arthritis in certain patients age 2 and older.[1]

In the alert, the FDA announced that it had completed its review of a large, randomized safety clinical trial of tofacitinib and concluded that the drug increased the risk of serious adverse cardiovascular events (such as heart attack and stroke), cancer, blood clots and death.[2] As a result, the agency decided to limit all approved uses of the drug to patients who have not responded to or cannot tolerate one or more of the other biologic disease-modifying antirheumatic drugs (DMARDs) known as tumor necrosis factor (TNF) blockers, which are commonly prescribed injectable drugs that are FDA-approved for treatment of rheumatoid arthritis and other inflammatory diseases.[3] In addition, the FDA required revisions to the black-box warning, the agency’s most prominent warning, in the product labeling for tofacitinib.

About tofacitinib

Tofacitinib is a potent immune-suppressing drug known as a Janus kinase (JAK) inhibitor.[4] It also is a member of the broader DMARD drug family. DMARDs are drugs that reduce signs and symptoms of rheumatoid arthritis and decrease progression of joint damage.

Several years ago, Public Citizen’s Health Research Group designated tofacitinib as Do Not Use for rheumatoid arthritis.[5] We have not evaluated the use of tofacitinib for treatment of other diseases.

Postmarket safety trial

When the FDA first approved tofacitinib for treatment of rheumatoid arthritis in 2012, the agency required the drug’s manufacturer, Pfizer, to conduct a large, randomized safety clinical trial among rheumatoid arthritis patients who were already taking the first-line oral DMARD methotrexate (TREXALL, XATMEP).[6]

The trial was designed to evaluate the risk of serious heart-related adverse events, cancer and infections in such subjects taking tofacitinib at a dosage of either 5 milligrams (mg) or 10 mg twice daily. The trial also included a comparison group of subjects who received an injectable TNF blocker (either adalimumab [ABRILADA, AMJEVITA, CYLTEZO, HADLIMA, HULIO, HUMIRA, HYRIMOZ] or etanercept [ENBREL, ERELZI, ETICOVO]) instead of oral tofacitinib.[7] To be eligible for the trial, subjects had to be at least 50 years old and have at least one risk factor for cardiovascular disease, such as high cholesterol levels or diabetes.

This safety trial, which enrolled nearly 4,400 subjects, began in 2014 and ended in July 2020.[8] In February 2021, the FDA initially had alerted the public that preliminary results from the safety clinical trial showed a higher rate of serious heart-related events and cancer in subjects treated with both dosages of tofacitinib compared with those treated with a TNF blocker.[9] At that time, the FDA noted that it was awaiting additional results from the trial to further assess the risk of these serious adverse effects of tofacitinib before making final conclusions and recommendations.

Of note, in February 2019, the FDA had warned that interim results from the same safety trial before it had been completed demonstrated an increased risk of blood clots in the lungs (also known as a pulmonary embolism) and death in rheumatoid arthritis patients taking only the higher tofacitinib dosage (10 mg twice daily).[10] Importantly, the highest FDA-approved dosage of Xeljanz for rheumatoid arthritis is 5 mg twice daily; for Xeljanz XR, the highest approved dosage for rheumatoid arthritis is 11 mg once daily.[11] The higher tofacitinib dosage of 10 mg twice daily is approved for certain patients with ulcerative colitis only.

However, the FDA’s final analysis of the safety trial data found higher rates of death and blood clots, as well as serious adverse cardiovascular events (such as heart attacks and stroke) and cancer, in subjects treated with both dosages of tofacitinib, not just the high dosage, compared with those treated with TNF blockers.[12] The data also showed that the risks of death, adverse cardiovascular events and blood clots were greater with the higher dosage of tofacitinib, whereas the increased risk of cancer was not dose-dependent. Higher rates of lung cancer and overall cancers were seen in patients treated with tofacitinib who were current or past smokers.

Other JAK inhibitors

Two other oral JAK inhibitors have been approved by the FDA for treatment of certain adult patients with rheumatoid arthritis: baricitinib (OLUMIANT),[13] which we designated as Do Not Use in 2018,[14] and upadacitinib (RINVOQ),[15] which we now designate as Do Not Use.

Although baricitinib and upadacitinib have not been studied in large safety clinical trials like the one conducted for tofacitinib, the FDA considers these drugs to have risks similar to those seen with tofacitinib because all JAK inhibitors work in the same way.[16] Therefore, the FDA has taken similar actions to limit the approved uses of these two drugs to patients who have not responded to or cannot tolerate one or more TNF blockers and to revise the black-box warnings in their product labeling.

What You Can Do

Do not stop taking tofacitinib, baricitinib or upadacitinib before seeing your doctor because doing so could seriously worsen the disease being treated.

If you have rheumatoid arthritis, you should avoid starting tofacitinib, baricitinib or upadacitinib if you are not currently taking them. If you are already taking any of these drugs for rheumatoid arthritis, consult with your doctor about switching to another DMARD. DMARDs that we have designated as Limited Use for rheumatoid arthritis include the TNF blockers adalimumab, etanercept, golimumab (SIMPONI, SIMPONI ARIA) and infliximab (AVSOLA, INFLECTRA, IXIFI, REMICADE, RENFLEXIS); the interleukin inhibitor anakinra (KINERET); the T-cell inhibitor abatacept (ORENCIA); and the B-cell inhibitor rituximab (RIABNI, RITUXAN, RITUXAN HYCELA, RUXIENCE, TRUXIMA).[17]

If you are currently taking or considering taking tofacitinib for psoriatic arthritis, ulcerative colitis or juvenile idiopathic arthritis, talk to your doctor about the risks and benefits of the drug compared with those of alternative treatments. Also, tell your doctor if you are a current or past smoker or have had a heart attack, other heart problems, stroke or blood clots in the past as these may put you at higher risk for serious problems with tofacitinib. If you are taking tofacitinib and have not previously been shown to be unresponsive to or intolerant of one or more TNF blockers, talk to your doctor about switching to a TNF blocker.

Seek immediate medical help if you experience any new symptoms suggestive of a heart attack, stroke or blood clots, including the following:

• Discomfort in the center of your chest that lasts for more than a few minutes or that goes away and comes back
• Severe tightness, pain, pressure or heaviness in your chest, throat, neck or jaw
• Pain or discomfort in your arms, back, neck, jaw or stomach
• Shortness of breath, with or without chest discomfort
• Breaking out in a cold sweat
• Nausea or vomiting
• Feeling lightheaded
• Weakness in one part or on one side of your body
• Slurred speech
• Drooping on one side of your mouth
• Swelling of a leg or arm
• Leg pain or tenderness, or red or discolored skin in the painful or swollen leg or arm

Also contact your doctor if you experience any of the following signs or symptoms:

• Swelling of lymph nodes in your neck, armpits or groin
• Constantly feeling tired
• Fever
• Night sweats
• Persistent or worsening cough
• Hoarseness or wheezing
• Unexplained weight loss.

References

[1] Pfizer. Label: tofacitinib (XELJANZ). September 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203214s026lbl.pdf. Accessed September 14, 2021.

[2] Food and Drug Administration. FDA drug safety communication: 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. September 1, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death. Accessed September 16, 2021.

[3] Ibid.

[4] Food and Drug Administration. FDA drug safety communication: 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. September 1, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death. Accessed September 16, 2021.

[5] Tofacitinib (XELJANZ): The wrong choice for rheumatoid arthritis. Worst Pills, Best Pills News. October 2017. http://www.worstpills.org/member/newsletter.cfm?n_id=1155. Accessed September 14, 2021.

[6] Ibid.

[7] ClinicalTrials.gov. Safety study of tofacitinib versus tumor necrosis factor (TNF) inhibitor in subjects with rheumatoid arthritis. https://clinicaltrials.gov/ct2/show/NCT02092467. Accessed September 14, 2021.

[8] Ibid.

[9] Food and Drug Administration. FDA drug safety communication: Initial safety trial results find increased risk of serious heart-related problems and cancer with arthritis and ulcerative colitis medicine Xeljanz, Xeljanz XR (tofacitinib). FDA will evaluate the trial results. February 4, 2021. https://www.fda.gov/media/145590/download. Accessed September 14, 2021.

[10] Food and Drug Administration. FDA drug safety communication: Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. February 25, 2019. https://www.fda.gov/media/120485/download. Accessed September 14, 2021.

[11] Pfizer. Label: tofacitinib (XELJANZ). September 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203214s026lbl.pdf. Accessed September 14, 2021.

[12] Food and Drug Administration. FDA drug safety communication: 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. September 1, 2021. https://www.fda.gov/media/151936/download. Accessed September 14, 2021.

[13] Eli Lilly and Company. Label: baricitinib (OLUMIANT). July 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207924s002lbl.pdf. Accessed September 14, 2021.

[14] Baricitinib (OLUMIANT): The wrong choice for rheumatoid arthritis. Worst Pills, Best Pills News. December 2018. https://www.worstpills.org/newsletters/view/1236. Accessed September 14, 2021.

[15] AbbVie Inc. Label: upadacitinib (RINVOQ). July 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211675s001lbl.pdf. Accessed September 14, 2021.

[16] Food and Drug Administration. FDA drug safety communication: 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. September 1, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death. Accessed September 16, 2021.

[17] New biologic drugs for rheumatoid arthritis: Which are safe? Worst Pills, Best Pills News. March 2016. https://www.worstpills.org/newsletters/view/1024. Accessed September 14, 2021.