FDA Warns of Life-Threatening Blood Clots with Use of High-Dose Tofacitinib

On Feb. 25, 2019, the Food and Drug Administration (FDA) issued an important safety alert about the oral drug tofacitinib (XELJANZ, XELJANZ XR), which was initially approved by the FDA in 2012 for the treatment of moderate-to-severe rheumatoid arthritis in adults who have had an inadequate response to methotrexate (OTREXUP, RASUVO, TREXALL, XATMEP).[1] The drug subsequently was approved by the agency to treat psoriatic arthritis and ulcerative colitis in certain adult patients.[2]

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.[3] The drug works by inhibiting an enzyme that plays a key role in causing joint inflammation and damage. Public Citizen’s Health Research Group has designated tofacitinib as Do Not Use for rheumatoid arthritis because it can cause serious adverse effects, including fatal infections and cancer, but has not been shown to be as effective as adalimumab (AMJEVITA, CYLTEZO, HUMIRA), an older injectable biologic DMARD known as a tumor necrosis factor (TNF) inhibitor. We also were concerned that the long-term cardiovascular safety of the drug was unknown.[4]

In its February alert, the FDA warned about an increased risk of blood clots in the lungs (also known as a pulmonary embolism) and death in rheumatoid arthritis patients taking tofacitinib 10 milligrams (mg) twice daily.[5] 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.[6] The higher dosage of 10 mg twice daily is approved only for certain patients with ulcerative colitis.

When the FDA first approved tofacitinib in 2012, the agency required the drug's manufacturer to conduct a large post-approval randomized clinical trial among rheumatoid arthritis patients to evaluate the risk of heart-related adverse events, cancer and serious infections when the drug is taken at two dosages (10 mg or 5 mg, each twice daily) in combination with the firstline oral DMARD methotrexate.[7] The trial also was required to include a comparison group of subjects who instead receive an injectable TNF inhibitor (either adalimumab or etanercept [ENBREL, ERELZI]).[8] For the trial, subjects must be at least 50 years old and have at least one risk factor for cardiovascular disease, such as high cholesterol levels or diabetes.

The trial began in 2014 and is expected to enroll approximately 4,400 subjects and be completed in 2020. A preliminary analysis of data collected so far found a higher occurrence of blood clots in the lungs and death in rheumatoid arthritis subjects taking 10 mg of tofacitinib twice daily than in those receiving either 5 mg of tofacitinib twice daily or a TNF inhibitor.

The FDA therefore recommended that patients taking tofacitinib seek immediate medical attention if they experience symptoms of a blood clot in the lung. Such symptoms include the following:

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

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 your doctor about switching to another DMARD. DMARDs that we have designated as Limited Use are adalimumab, etanercept, golimumab (SIMPONI), infliximab, anakinra (KINERET), abatacept (ORENCIA) and rituximab (RITUXAN). Do not stop taking any prescription medication without consulting your doctor.

Regardless of the rheumatoid arthritis treatment chosen by you and your doctor, you should consider engaging in an exercise program and physical therapy designed within the limits of pain. This will help to strengthen muscles and maintain or improve range of motion in the joints.

If you are taking tofacitinib for any reason, seek immediate medical evaluation if you experience any of the symptoms listed above.
 

References

[1] Food and Drug Administration. Letter to Pfizer approving NDA 203214/Original 1. November 6, 2012.

[2] Pfizer. Label: tofacitinib (XELJANZ). October 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203214s020,208246s006lbl.pdf. Accessed March 14, 2019.

[3] Tofacitinib (Xeljanz) for rheumatoid arthritis. Med Lett Drugs Ther. 2013 Jan 7;55(1407):1-3.

[4] Tofacitinib (XELJANZ): The wrong choice for rheumatoid arthritis. October 2017. /newsletters/view/1155. Accessed March 14, 2019.

[5] Food and Drug Administration. Xeljanz, Xeljanz XR (tofacitinib): Safety communication - safety trial finds increased risk of blood clots in the lungs and death with higher dose in rheumatoid arthritis patients. February 25, 2019. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm632016.htm. Accessed March 14, 2019.

[6] Pfizer. Label: tofacitinib (XELJANZ). October 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203214s020,208246s006lbl.pdf. Accessed March 14, 2019.

[7] Food and Drug Administration. Xeljanz, Xeljanz XR (tofacitinib): Safety communication - safety trial finds increased risk of blood clots in the lungs and death with higher dose in rheumatoid arthritis patients. February 25, 2019. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm632016.htm. Accessed March 14, 2019.

[8] ClinicalTrials.gov. Safety study of tofacitinib versus tumor necrosis factor (TNF) inhibitor in subjects with rheumatoid arthritis. https://clinicaltrials.gov/ct2/show/NCT02092467. Accessed March 14, 2019.