FDA WARNS TOFACITINIB (XELJANZ, XELJANZ XR) INCREASES RISK OF SERIOUS HEART-RELATED ADVERSE EFFECTS AND CANCER

March 1, 2021

Here’s an important alert for patients taking the oral drug tofacitinib (XELJANZ, XELJANZ XR), which is approved by the Food and Drug Administration (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]

Tofacitinib is a member of the disease-modifying antirheumatic drug (DMARD) family. DMARDs are drugs that reduce signs and symptoms of rheumatoid arthritis and decrease progression of joint damage. Public Citizen’s Health Research Group has designated tofacitinib as Do Not Use for rheumatoid arthritis.[2] We have not evaluated the use of the drug for treatment of other diseases.

On Feb. 4, 2021, the FDA issued a warning about preliminary results from a safety clinical trial that showed an increased risk of serious heart-related adverse effects and cancer in rheumatoid arthritis patients taking tofacitinib compared with those receiving one of two injectable biologic DMARDs known as tumor necrosis factor (TNF) inhibitors, which are commonly prescribed injectable drugs that are FDA-approved for treatment of rheumatoid arthritis and other diseases.[3]

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).[4] 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 inhibitor (either adalimumab [ABRILADA, AMJEVITA, CYLTEZO, HADLIMA, HULIO, HUMIRA, HYRIMOZ] or etanercept [ENBREL, ERELZI, ETICOVO]) instead of oral tofacitinib.[5] 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.[6] According to the FDA, initial results following trial completion 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 inhibitor. The FDA noted that it is awaiting additional results from the trial to further assess the risk of these serious adverse effects of tofacitinib.

Of note, in February 2019, the FDA warned that interim results from the same safety trial demonstrated an increased risk of blood clots in the lungs (also known as a pulmonary embolism) and death in rheumatoid arthritis patients taking tofacitinib 10 mg twice daily.[7] 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.[8] The higher tofacitinib dosage of 10 mg twice daily is approved for certain patients with ulcerative colitis only.

The FDA appropriately cautioned in its Feb. 4, 2021, warning that patients should not stop taking tofacitinib without first talking to their health care professionals because doing so could seriously worsen the disease being treated.

What You Can Do

If you have rheumatoid arthritis, you should avoid starting tofacitinib if you are not currently taking it. If you are already taking tofacitinib for rheumatoid arthritis, consult with your doctor about switching to another DMARD. DMARDs that we have designated as Limited Use for rheumatoid arthritis are adalimumab, etanercept, golimumab (SIMPONI, SIMPONI ARIA), infliximab (AVSOLA, INFLECTRA, IXIFI, REMICADE, RENFLEXIS), anakinra (KINERET), abatacept (ORENCIA) and rituximab (RIABNI, RITUXAN, RITUXAN HYCELA, RUXIENCE, TRUXIMA). Do not stop taking any drug before seeing your doctor.

If you are taking tofacitinib for any other disease, talk to your doctor about the risks and benefits of the drug compared with those of alternative treatments.

If you are taking tofacitinib for any reason, seek immediate medical evaluation if you experience any new symptoms suggestive of heart-related adverse effects or pulmonary embolism, including the following:

• Sudden shortness of breath or difficulty breathing
• Chest pain or pressure
• Back pain
• Coughing up blood
• Excessive sweating
• Clammy or bluish-colored skin

To see the FDA’s safety alert, visit the following link: https://www.fda.gov/media/145590/download.

References

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

[2] Tofacitinib (XELJANZ): The wrong choice for rheumatoid arthritis. October 2017. https://www.worstpills.org/newsletters/view/1155. Accessed February 11, 2021.

[3] 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 February 11, 2021.

[4] Ibid.

[5] ClinicalTrials.gov. Safety study of tofacitinib versus tumor necrosis factor (TNF) inhibitor in subjects with rheumatoid arthritis. https://clinicaltrials.gov/ct2/show/NCT02092467. Accessed February 11, 2021.

[6] Ibid.

[7] 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 February 11, 2021.

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