FDA Strengthens Warnings for Xeljanz, Olumiant and Rinvoq

By Jill Tyrer | Sept. 3, 2021

The Food and Drug Administration has issued warnings about the use of tofacitinib (Xeljanz and Xeljanz XR) as well as baricitinib (Olumiant) and upadacitinib (Rinvoq). All three belong to a medication class called Janus kinase (JAK) inhibitors and are used to treat arthritis and other inflammatory conditions.

A large, randomized safety clinical trial compared the use of tofacitinib for rheumatoid arthritis (RA) with a different type of drug, called tumor necrosis factor (TNF) inhibitors. Results showed a higher risk of heart-related problems, including heart attack, stroke, as well as cancer, blood clots and death with tofacitinib than with anti-TNFs, according to the FDA’s announcement. As a result, the FDA will require a “boxed warning” on the package, its most serious warning.

But if you take one of these medications, don’t stop, doctors say. Not enough data is available to understand exactly how to interpret the announcement and who might be affected.

“There’s nothing in this that says there’s an urgent need to stop the drug, and people should absolutely not stop on their own without discussing with their rheumatologist,” says Eric Ruderman, MD, rheumatologist and professor of medicine at Northwestern University Feinberg School of Medicine.

Tofacitinib is approved to treat polyarticular juvenile idiopathic arthritis, psoriatic arthritis and rheumatoid arthritis, as well as ulcerative colitis. It is used off-label in certain cases for psoriasis and for hospitalized COVID-19 patients. Baricitinib and upadacitinib are each approved to treat RA.

Safety Trial

When it approved tofacitinib, the FDA required drugmaker Pfizer to conduct the safety trial in RA patients who were taking methotrexate to find out its risks for heart issues, cancer and infections. Trial participants were over 50 years old with at least one risk factor for heart disease. Researchers looked at two doses of tofacitinib — 5 mg twice a day, which is approved for RA treatment, and 10 mg twice a day.

The FDA earlier this year warned about an increased risk of blood clots and death only with a higher dose of tofacitinib. But with the conclusion of the trial, results show the risks are also increased with the lower dose. The FDA now will limit the use of these JAK inhibitors for use only in patients who have not responded adequately to TNF inhibitors.

The trial was designed as a “non-inferiority study,” trying to show that the risk of using tofacitinib was no higher than with TNF inhibitors. “Essentially, they didn’t meet that non-inferiority, so they weren’t able to say with certainty that Xeljanz was no worse than TNF [inhibitors] for some of these safety events,” Dr. Ruderman says.

Questions Remain

Rheumatologist Jasvinder Singh, MD, MPH, professor of Medicine and Epidemiology at University of Alabama, Birmingham, and director of rheumatology research at Birmingham VA Medical Center, is waiting for more information before drawing any conclusions about who should be concerned and to what extent. The study itself was not yet available.

“I’m an epidemiologist so I like looking at the numbers. That usually helps me in understanding what the true risk is. That’s why I’m a little skeptical about making any definitive conclusions,” he says. For example, a 52-year-old woman with hypertension and a 62-year-old man who smokes, has high cholesterol and diabetes, both fit the profile of those in the study. “But those are two very different profiles,” he explains. “So when we say cardiovascular risk factors, which ones, how many, how does that differ by age and sex?”

Plus, Dr. Ruderman adds, “having RA itself is a risk factor for cardiovascular events and blood clots and cancers. Is everybody high risk? We don’t know.”

Drs. Singh and Ruderman also want to learn more about the warnings for baricitinib and upadacitinib. Safety trials have not directly compared either of those to anti-TNFs, but because they work in the same way in the body that tofacitinib does, the FDA expects the same outcomes and extended the warnings to them.

“What [the FDA] said is they don’t have any data for Rinvoq or Olumiant, but since they’re kind of the same class with a similar mechanism, they don’t know that those don’t have the same issues, so they’re going to include the same kind of language in those labels as well,” Dr. Ruderman says.

Drug Options

Tofacitinib, approved in 2012, was the first JAK inhibitor approved to treat arthritis. Baracitinib followed in 2018, and upadacitinib the following year. They are seen as an alternative to biologics and are preferred by many patients because they are in pill form rather than injection or infusion.

Still, JAK inhibitors are not as widely prescribed for arthritis as other medications, including biologics, which have been around longer and have a more robust track record. Dr. Singh estimates about 10% of eligible patients use JAK inhibitors.

Several options are available if you and your doctor decide it’s a good idea to switch. But Drs. Ruderman and Singh are unlikely to advise their patients to make any changes until they have more information, they say.

“Until I see the final recommendations from the FDA and the data from the study on which they’re based, I don’t really know what to tell them, so I’m not going to change anybody’s medicine until I have more information,” Dr. Ruderman says.

What Should You Do?

If you take one of these medications, don’t stop taking it, but be aware of the warning, and reach out to your rheumatologist for guidance.

“All medicines have side effects even when used correctly as prescribed, but in general the benefits of taking a medicine outweigh these risks,” the FDA says in the statement. “However, if you are a current or past smoker, or have had a heart attack, other heart problems, stroke or blood clots in the past, you should tell your health care professional as these may put you at higher risk for serious problems with these medicines.”

The FDA recommends that you seek emergency care if you experience any of the following, which could be a sign of a heart attack, stroke or blood clot:

    • 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

And tell your doctor if you experience any of these symptoms:

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

Updated Sept. 5 with comments from Drs. Singh and Ruderman

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