On Monday, September 1, the U.S. Food and Drug Administration (FDA) announced that Xeljanz (tofacitinib), Xeljanz XR, Oluminant (baricitinib), and Rinvoq (upadacitinib) will be required have new and updated warnings about an increased risk of heart-related events such as heart attack or stroke, cancer, blood clots, and death.
All three medications are JAK inhibitors and are approved for rheumatoid arthritis (RA) alone or in combination; Xeljanz and Xeljanz XR are also approved for psoriatic arthritis (PsA) and ulcerative colitis, and an oral solution of Xeljanz is approved to treat polyarticular juvenile idiopathic arthritis (JIA).
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Xeljanz, Xeljanz XR, Oluminant, and Rinvoq already had a box warning, but the FDA will now require those to be revised to include information about the risks of serious cardiovascular-related events, malignancy, thrombosis, and death. Additionally, the FDA is limiting all approved uses of these drugs to patients who had an inadequate response or can’t tolerate one or more TNF blockers.
How JAK Inhibitors Treat Disease
These medicines decrease the activity of the immune system by blocking certain enzymes that cause inflammation. In addition to the risk of major adverse events, common side effects of these JAK inhibitors include upper respiratory tract infections such as the common cold and sinus infections, bronchitis, headache, cough, high blood pressure, rash, nausea, and shingles.
Don’t Stop Taking JAK Inhibitor Medication Without Talking to Your Doctor
If you are on tofacitinib (Xeljanz, Xeljanz XR), baricitinib (Oluminant), or upadacitinib (Rinvoq) medications, it is very important that you not stop them without consulting your provider first, says Jonathan Greer, MD, a rheumatologist at Arthritis & Rheumatology Associates of Palm Beach in Florida and a medical adviser to the arthritis advocacy organization CreakyJoints.
“In my opinion, these are excellent medications that have helped us manage our patients with rheumatoid arthritis (RA) and put people into remission where this was otherwise not possible,” says Dr. Greer.
New Warnings Are Based on Further Review of Safety Study
The FDA decision was based on a review of a large randomized clinical safety trial that compared Xeljanz with tumor necrosis factor (TNF) blockers, such as Humira (adalimumab) or Enbrel (etanercept), in people with rheumatoid arthritis who were also taking methotrexate.
This warning is an update to a previous alert issued by the FDA that was based on earlier interim results; those found an increased risk of blood clots only at the higher 10 milligram (mg) twice daily dose of tofacitinib, but the trial’s final results showed an increased risk at the lower dose as well.
There are a few things to keep in mind when considering these results, which are continuing to be reviewed, says Greer. “This review is a look back over 10 years; it wasn’t a controlled study, and it only included one subgroup of patients, men over the age of 50 who had at least one cardiovascular risk factor. These findings may not be generalizable to other populations, such as women or people without these risk factors,” he says.
It’s also important to note there was no placebo control in this review, and so it doesn’t show us what would happen to these people if they weren’t on any type of medication to control their RA, says Greer. “We know from previous studies that patients who are not treated for RA have the same mortality as people who have three vessel coronary artery disease. They die sooner without treatment for RA because the disease itself increases the risk of heart attack and stroke,” he says.
The idea that rheumatoid arthritis might not be treated out of fear of possible side effects is a terrible thing to consider, he adds.
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The American College of Rheumatology Weighs In On the New Safety Warning
The American College of Rheumatology (ACR), the professional association for rheumatology, released a statement on September 9, 2021, in response to the additional warning on the three JAK inhibitors.
According to the ACR's president, David Karp, MD, PhD, the organization is currently reviewing the available data that spurred the charge in order to “more clearly identify risks to patients and are engaging in conversations with the FDA.” At this time, the ACR is not making any specific recommendations or changes in their guidelines, which were updated and published in Arthritis Care & Research in July 2021.
The ACR echoed Greer’s assertions that the JAK inhibitors can make a “dramatic improvement” in disease activity, and that there are serious health risks associated with not treating RA. Doctors and patients should discuss the best option for the patient moving forward, said Dr. Karp.
Other JAK Inhibitors Are Included in the New Warning
Because of the mechanism of action (the way the drug works in the body) is the same for Oluminant and Rinvoq, the FDA considers these medications to have similar risks to those seen with Xeljanz, and they will also carry the additional warning, according to the announcement.
Greer finds the decision to include these medications questionable. “Even though these drugs are in the same class, they are very different molecules, and they have somewhat different targets to control the immune system,” he says.
The results found for Xeljanz may not be generalizable to these other medications, says Greer. “I think we need to be careful about overinterpreting these findings as a class effect of all the drugs,” he says.
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Jakafi (ruxolitinib) and Inrebic (fedratinib), also JAK inhibitors, aren’t required to make the same safety updates because these drugs are not indicated for the treatment of arthritis and other inflammatory conditions, according to the agency.
What Does the Black Box Warning Mean?
The warning is intended to alert physicians so that they may carefully weigh the benefits of the drugs versus any potential serious adverse event. It also serves to warn doctors to use special caution when prescribing the drug to people with certain risk factors, or to put restrictions on when and how the drug can be used.
What Does the New Warning Mean for People Who Are on These Drugs?
Before prescribing or continuing patients on these medications, a doctor will weigh the risk of heart events, cancer, blood clots, and death with any potential benefits. Physicians should especially consider the risks of the medications in people who are current or past smokers, have cardiovascular risk factors, develop a malignancy, have a known malignancy (other than a successfully treated nonmelanoma skin cancer), as these people may be at a higher risk of one of the adverse events.
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Finally, Xeljanz, Xeljanz XR, Oluminant, and Rinvoq should be prescribed only to people who have had an inadequate response to or intolerance of one or more TNF blockers.
Talk With Your Doctor if You Take One of the JAK Inhibitors Included in the Warning
According to an article published in American Family Physician, doctors are required to provide patients with information about the relevant risks of a box warning drug before prescribing.
Greer plans on discussing the risks and benefits of these medications with patients, as with any drug he prescribes. “I am planning on continuing to use these medications for patients with rheumatoid arthritis who are in remission, doing well, and haven’t found other drugs that have helped them,” says Greer.
If you and your doctor decide that one of these medications is the right choice for your treatment, you will also discuss the importance of seeking emergency medical attention if you have any signs and symptoms of a heart attack, stroke, or blood clot.