Rheumatoid arthritis

FDA requires new safety warnings for all doses of JAK inhibitors


The US Food and Drug Administration (FDA) is imposing new restrictions and warnings on JAK inhibitors in the treatment of rheumatic inflammatory disorders after a tofacitinib safety trial showed an increased risk of major adverse cardiovascular events, malignancy, thrombosis, and mortality.

The measures will apply to tofacitinib, baricitinib, and upadacitinib, based on results from a postmarketing safety trial of Pfizer’s tofacitinib, from which interim findings in 2019 showed increased thrombosis risks with the higher dose of 10mg.

According to the FDA, the completed analysis has now shown a higher rate of serious cardiovascular events such as heart attack and stroke, cancer, thrombosis, and death in patients treated with both 5mg and 10mg doses of tofacitinib compared to those treated with TNF blockers.

For cancers, a higher rate of lymphomas was observed in patients treated with tofacitinib compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with tofacitinib compared to those treated with TNF blockers.

In response the FDA said it would limiting approved uses of JAK inhibitors to certain patients who have not responded or cannot tolerate one or more TNF blockers. It would also require updates to the Boxed Warning to include information about the risks of serious heart-related events, cancer, blood clots, and death.

As well as tofacitinib, the updates will also apply to two other JAK inhibitors, baricitinib and upadacitinib, even though they had not been studied in trials similar to the safety clinical trial with tofacitinib. The FDA said it considered the safety signals to be a class effect of JAK inhibitors  and since these two other drugs shared the same mechanisms of action with tofacitinib it considered these medicines may have similar risks as seen in the tofacitinib safety trial.

In its advice to healthcare professionals, the FDA advised that the JAK inhibitors be reserved  for patients who have had an inadequate response or intolerance to one or more TNF blockers.

“Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Xeljanz/Xeljanz XR [tofacitinib], Olumiant [baricitinib], or Rinvoq upadacitinib, particularly in patients who are current or past smokers, those with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy other than a successfully treated nonmelanoma skin cancer,” it advised.

“Counsel patients about the benefits and risks of these medicines and advise them to seek emergency medical attention if they experience signs and symptoms of a heart attack, stroke, or blood clot,” it added.

The FDA noted that two other JAK inhibitors, ruxolitinib and fedratinib were not indicated for the treatment of arthritis and other inflammatory conditions and so were not a part of the updated warnings.

In the safety trial, adverse outcomes were assessed for tofactinib 5 mg twice daily (n=1455), 10 mg twice daily (n=1456) in comparison to treatment with a TNF blocker (n=1451) in patients with RA over the age of 50 with at least one cardiovascular risk factor who were taking methotrexate.

After a mean follow up of four years there was an increased risk of death, major adverse cardiovascular events (MACE), malignancies, and thrombosis associated with both regimens of tofacitinib.

According to the FDA, the data showed evidence of a dose-dependent increased risk for MACE, all-cause mortality, and thrombosis at both doses when compared to treatment with TNF blockers.

There was also evidence of a non-dose-dependent increased risk for malignancy excluding non-melanoma skin cancer at both doses when compared to TNF blockers.

“Lymphomas and lung cancers were observed at a higher rate in patients treated at both doses of tofacitinib compared to those treated with TNF blockers. In particular, a higher rate of lung cancers was observed in current or past smokers treated with Xeljanz. Current or past smokers had an additional increased risk of overall cancers,” the FDA advisory stated.

A spokesperson for the TGA said the regulator has been evaluating the issue of tofacitinib and major cardiovascular events and malignancies, including the findings of post-market safety studies. “We are currently working with the Sponsor on changes to the Product Information document to address these risks,” they told the limbic.

“The TGA is also in the process of reviewing the FDA regulatory action for upadacitinib and baracitinib, in addition to the issue of blood clots with lower doses of tofacitinib. Any updates to the Product Information documents will be published on the TGA website and in the form of a Medicines Safety Update.”

Pfizer has been contacted for comment.

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