FDA adds black box warning to JAK inhibitors; cites heart-related issues, cancer, death
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The FDA has called for additional warning labels on janus kinase inhibitors after a safety review found this class of medications was associated with an excess risk for serious heart-related events, cancer, blood clots and death.
An alert was previously issued by the FDA in February about the risk for serious health-related problems and cancer linked to tofacitinib (Xeljanz, Pfizer) compared with TNF inhibitors among older patients. However, given new safety data, the FDA has also issued new and updated warnings for two additional JAK inhibitors: baricitinib (Olumiant, Eli Lilly & Co.) and upadacitinib (Rinvoq, AbbVie).
“We are requiring revisions to the Boxed Warning, FDA’s most prominent warning, for Xeljanz/Xeljanz XR, Olumiant, and Rinvoq to include information about the risks of serious heart-related events, cancer, blood clots and death,” the FDA said in a statement.
“Other JAK inhibitors have not been studied in similar large safety clinical trials, so the risk with these medicines has not been evaluated. However, since they share mechanisms of action with Xeljanz, FDA considers that these medicines may have similar risks as seen in the safety trial with Xeljanz.”
The FDA based its warning on results from ORAL Surveillance, a post-marketing safety clinical trial required by the FDA to demonstrate non-inferiority of Xeljanz compared to TNF inhibitors among patients with rheumatoid arthritis with regard to risk for cardiovascular events and malignancies. This trial also investigated other potential risks, including blood clots in the lungs and death.
“Our review of the final trial results showed a higher rate of serious heart-related events such as heart attack and stroke, cancer, blood clots, and death in patients treated with both doses of Xeljanz compared to those treated with TNF blockers,” the FDA noted. “Importantly, a higher rate of blood clots and death was seen with both doses of Xeljanz compared to TNF blockers, whereas previous interim results showed the risk only with the higher dose. For cancers, a higher rate of lymphomas was observed in patients treated with Xeljanz compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with Xeljanz compared to those treated with TNF blockers.”
The new and updated warning labels on all JAK inhibitors will address the increased risk of major adverse cardiovascular events, malignancy, thrombosis and mortality. Additionally, the FDA recommends that health care professionals consider the benefits and risks for individual patients before initiating or continuing treatment with JAK inhibitors, particularly among 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.
Perspective
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I have reviewed the FDA warnings about increased risk for serious heart-related events, cancer, blood clots and death for JAK inhibitors and have mixed feelings on the process and the results. Clearly, safety is our number one consideration when prescribing any medication, especially biologic/targeted synthetic DMARDs, and the results of the recent ORAL Surveillance trial with regards to cardiovascular events and malignancies with tofacitinib is both disturbing and difficult to explain.
This study, which was performed in high-risk patients aged 50 and older, raises concern about a drug that has also clearly been associated with increased risks at this 10 mg twice daily dose not approved for rheumatic conditions. Despite this study, other long-term real-life safety data on tofacitinib is formidable and reassuring.
A recent post-approval study from the U.S.-based Corrona registry by Kremer and colleagues comparing the safety of tofacitinib and other biologics found no differences in MACE, serious infection events, malignancy or death and represents the longest term real-life safety study in the field. Collectively, I agree that the results from Oral Surveillance cannot be ignored and, while the increased risks are numerically small, caution must be exercised in patients at high risk, especially for cardiovascular disease with tofacitinib.
With regards to modifications of labeling to other JAK inhibitors in rheumatic diseases, upadacitinib and baricitinib, I am not in accord with the requirement for updated warnings based on inference not data. Thus far, the safety signals for these agents have not raised alarms beyond their current label. I believe such warnings are not only premature but will be challenging for many of our patients to interpret, which places practitioners on the spot to defend their recommended use.
The FDA, in my opinion, has been overly harsh on this class of drugs as evidenced by the agency’s limitation in dosing and indication for baricitinib as well as the rejection of the promising agent, filgotinib. The European Medicines Agency, by contrast, has viewed these risks differently and has issued a more liberal dosing and indication labeling for baricitinib and, more recently, fully approved filgotinib in doses of 100 mg and 200 mg daily for rheumatoid arthritis.
The basis for these differences of approvals is complex but the mere rift between two respected agencies suggests that the data are far from clear regarding this exciting class of therapeutics. Finally, I am personally not at ease with these impending label changes as they stand in contrast to my own personal experience with this class as a whole and, in my opinion, will only serve to fuel third-party payers to further limit access to highly valued therapeutics.
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Stanley Cohen, MD
The new FDA communication about Xeljanz will impact treatment of patients significantly. The agency has clearly come out with a statement that they are limiting use of JAK inhibitors to patients who have failed TNF inhibitors.
This stance certainly differs from the EMA, which recommended that considering the increased risk of serious infections, myocardial infarction and malignancies linked to Xeljanz in patients over 65 years of age, the drug should only be used in these patients if no suitable treatment alternatives are available. The EMA also recommended against the use of Xeljanz in smokers, in patients with previous history of diabetes, malignancy or coronary artery disease or significant risk factors for venous thromboembolism.
The FDA also included Rinvoq and Olumiant in their recommendation due to similar mechanism of action, which was not the case with the EMA. I favor the EMA approach as clearly the differential in malignancy, MACE and VTE with a JAK inhibitor compared with TNF inhibitors seems to have been driven by older patients with increased risk for these events and those with comorbidities associated with these events.
I think a young healthy rheumatoid or psoriatic arthritis patient would be at low risk for these complications and, if they preferred oral therapy over injectable or IV therapy, that should still be an option with proper discussion of the benefits and risk. However, if I read the FDA communication correctly, that option no longer exists. The totality of the clinical trial program did not demonstrate a signal for these events and the all-comer population, which included a number of younger people without comorbidities; that is why I would favor a more targeted approach.
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Andrew J. Laster, MD, FACR
Rheumatologists’ overall sense of wellness likely took another hit this week with the FDA announcement of a new Boxed Warning for Olumiant, Rinvoq and Xeljanz.
Although the open-label Oral Surveillance safety clinical trial compared tofacitinib with etanercept or adalimumab in patients 50 years of age and older with moderate to severe rheumatoid arthritis on methotrexate with at least one cardiovascular risk factor, the Boxed Warning appears to apply to all patients prescribed any one of these JAK inhibitors, whether or not they have rheumatoid arthritis, psoriatic arthritis or ulcerative colitis. This decision may also impact pending approvals of JAK inhibitors for treatment of SLE, ankylosing spondylitis and atopic dermatitis.
Bracing for the deluge of phone calls from appropriately concerned patients currently taking JAK inhibitors, rheumatologists are already feeling the strain of the shortage of tocilizumab for non-COVID-related disease and the need to reassign patients to alternate biologics. Anxious about the potential lack of immunogenicity of COVID-19 vaccines for our patients on rituximab, abatacept and mycophenolate, the rheumatologist’s options for alternative choices to JAK inhibitors suddenly become vanishingly small.
Rheumatologists already face mounting challenges of caring for immunocompromised patients during the COVID-19 pandemic with the delta variant now inundating local schools where children are often not vaccinated and unmasked. In addition to this, we are dealing with patient concerns about COVID vaccines and debates in the scientific community regarding correlates of protection, as well as advisability and timing of the third dose/booster vaccine. I believe it’s time to brush up on your mindfulness/meditation and go for a run or jump in the pool.
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