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On Feb. 4, 2021, the Food and Drug Administration (FDA) issued a warning about preliminary results from a safety clinical trial that showed increased risks of serious heart-related adverse effects and cancer in rheumatoid arthritis patients taking the oral drug tofacitinib (XELJANZ, XELJANZ XR) compared with those receiving one of two commonly prescribed injectable drugs known as tumor necrosis factor (TNF) inhibitors, which are FDA-approved for treatment of rheumatoid arthritis and other...
On Feb. 4, 2021, the Food and Drug Administration (FDA) issued a warning about preliminary results from a safety clinical trial that showed increased risks of serious heart-related adverse effects and cancer in rheumatoid arthritis patients taking the oral drug tofacitinib (XELJANZ, XELJANZ XR) compared with those receiving one of two commonly prescribed injectable drugs known as tumor necrosis factor (TNF) inhibitors, which are FDA-approved for treatment of rheumatoid arthritis and other diseases.[1]
Tofacitinib, like the TNF inhibitors, is a member of the disease-modifying antirheumatic drug (DMARD) family. It 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.[2]
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.[3] We have not evaluated the use of the drug for treatment of other diseases.
Our prior assessment
In 2017, we recommended against using tofacitinib for treatment of rheumatoid arthritis because the drug can cause serious adverse effects including fatal infections and cancer, and it has not been shown to be as effective as the TNF inhibitor adalimumab (ABRILADA, AMJEVITA, CYLTEZO, HADLIMA, HULIO, HUMIRA, HYRIMOZ), an older biologic DMARD originally marketed under the well-recognized brand name Humira. In addition, the long-term cardiovascular safety of tofacitinib was not known.
Data from one trial used to support the approval of tofacitinib showed that it was no more effective than adalimumab in relieving rheumatoid arthritis symptoms. In contrast to tofacitinib, however, adalimumab has been proven effective in reducing disease progression and preventing joint damage in rheumatoid arthritis patients.
FDA’s new warning
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 subjects taking tofacitinib at a dosage of either 5 milligrams (mg) or 10 mg twice daily.[7] The trial also included a comparison group of subjects who received an injectable TNF inhibitor (either adalimumab 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 than in 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. 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 consulting your doctor.
If you are taking tofacitinib for any other condition, 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.
References
[1] 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 April 16, 2021.
[2] Pfizer. Label: tofacitinib (XELJANZ). September 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203214s026lbl.pdf. Accessed April 16, 2021.
[3] Tofacitinib (XELJANZ): The wrong choice for rheumatoid arthritis. October 2017. https://www.worstpills.org/member/newsletter.cfm?n_id=1155. Accessed April 16, 2021.
[4] 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 April 16, 2021.
[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 April 16, 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 April 16, 2021.
[8] Pfizer. Label: tofacitinib (XELJANZ). September 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203214s026lbl.pdf. Accessed April 16, 2021.
