FDA Issues Safety Alert: High-Dose Xeljanz (Tofacitinib) Linked to Increased Risk of Pulmonary Thrombosis and Death

Recently, the U.S. Food and Drug Administration (FDA) issued a boxed warning for Pfizer’s immunotherapy drug tofacitinib (Xeljanz, and its extended-release formulation Xeljanz XR). This action was taken because study data indicated a potential link between treatment with high-dose tofacitinib (10 mg) and an increased risk of pulmonary thrombosis and even death.

In a safety warning, the FDA pointed out that post-marketing safety studies were required when Xeljanz was approved for the treatment of rheumatoid arthritis (RA) in 2012. However, early data recently released from this trial indicate that patients taking higher doses are more prone to pulmonary embolism, which refers to blood clots in the lungs and can have fatal consequences or lead to death. Pfizer decided last week to adjust the dosage of Xeljanz from 10 mg daily to 5 mg twice daily for patients in the trial, but the study will continue.

Safety Study A3921133 was conducted in 4,400 patients aged 50 years or older with rheumatoid arthritis (RA) who were receiving stable doses of the immunosuppressant methotrexate and had at least one cardiovascular risk factor. The study aimed to assess the risks of cardiovascular events, malignancies, and certain infections in RA patients following treatment. Participants were divided into three groups: Treatment Group 1 received Xeljanz 5 mg twice daily; Treatment Group 2 received Xeljanz 10 mg twice daily; and the control group received tumor necrosis factor (TNF) inhibitor therapy. The Data and Safety Monitoring Board reported that, compared with patients treated with TNF inhibitors, those receiving Xeljanz 10 mg exhibited a statistically and clinically significant increase in the incidence of pulmonary embolism, whereas the risk–benefit profile for Xeljanz 5 mg twice daily was relatively balanced.

Xeljanz is a JAK inhibitor that selectively inhibits JAK kinases and blocks the JAK/STAT pathway, a cytokine-stimulated signal transduction pathway discovered in recent years that participates in many important biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation.

Xeljanz was first approved in 2012 for the treatment of adult patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate. In these patients, the autoimmune system attacks the body itself, leading to pain, joint swelling, and loss of function. Xeljanz works by reducing the activity of the immune system. In 2017, the FDA approved a second indication for the drug: patients with psoriatic arthritis who had an inadequate response to methotrexate or other similar agents [known as non-biologic disease-modifying antirheumatic drugs (DMARDs)]. Psoriatic arthritis is also a condition that causes joint pain and swelling. In 2018, the drug was approved for the treatment of ulcerative colitis, a chronic inflammatory bowel disease affecting the colon. The drug’s sales in 2018 amounted to $1.774 billion.

The FDA notified healthcare professionals to adhere to the approved prescribing information for Xeljanz, clarifying that the 10 mg dose is not approved for patients with rheumatoid arthritis; however, this dose may be used in patients with ulcerative colitis. Meanwhile, the FDA warned that patients should not stop or change their Xeljanz dosage without first consulting their healthcare professionals, as doing so may worsen their condition. Patients taking Xeljanz who experience symptoms of pulmonary embolism or other unusual symptoms, such as sudden shortness of breath or difficulty breathing, back pain or chest pain, coughing up blood, excessive sweating, cold clammy skin, or cyanosis, should seek immediate medical attention. In a statement, Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research, said, “The latest safety alert underscores the importance of monitoring and addressing post-marketing safety issues. Given the seriousness of the current safety concerns with Xeljanz, we are now communicating with relevant stakeholders to ensure that patients understand that the benefits of Xeljanz for its approved indications still outweigh the safety risks.”

It is important to note that Pfizer’s Xeljanz is not the only JAK inhibitor in its class to encounter dose-related safety issues. Following study data indicating a risk of serious thrombosis, the FDA approved only the low-dose labeling for Eli Lilly’s Olumiant and required a boxed warning in the package insert to clearly inform patients of the potential risks associated with the medication. The rationale for rejecting the higher dose was the need for additional data to clarify the safety profile of the drug.

Concerns raised by the Safety Monitoring Committee regarding high-dose Xeljanz have also sparked public scrutiny over the potential safety risks of other JAK inhibitors. The FDA is currently reviewing multiple JAK inhibitors, including AbbVie’s upadacitinib and Gilead’s filgotinib. Phase 3 clinical data for upadacitinib indicated that treatment with this drug could lead to fatal hemorrhagic stroke and pulmonary embolism; however, AbbVie attributed these events to patients’ pre-existing cardiovascular risk factors. The FDA will prioritize its review of the New Drug Application (NDA) for upadacitinib in adult patients with moderate-to-severe rheumatoid arthritis, with a regulatory decision expected in the third quarter of 2019. Analysts suggest that Gilead, in collaboration with Galapagos, may hold an advantage in terms of drug safety, as filgotinib has not demonstrated serious thrombotic risks in its trials to date.(SinaPharmaceuticals(Compiled by Fan Dongdong, Edited by Kerr)

Source:

1、Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate

2、FDA issues red alert on Pfizer's Xeljanz after trial tags higher dose with blood clots, death

3、FDA: Clot Risk Up for Xeljanz in RA

4、FDA Alerts on Increased Risks Linked to Pfizer’s Xeljanz

Source: Sina Medical News