Systematic Review Finds Elevated Reporting for Thromboembolic Events With JAK Inhibitors

A systematic review of the FDA’s Adverse Event Reporting System (FAERS) found elevated reporting for both tofacitinib (Xeljanz) and ruxolitinib (Jakafi) for thromboembolic adverse events (AEs), suggesting the possibility of a class-wide issue with Janus kinase (JAK) inhibitors.

The review, published in Drug Safety, noted that the FDA has not issued warnings specific to thromboembolic safety signals for tofacitinib, a drug approved for the treatment of rheumatoid arthritis (RA), and ruxolitinib, which is approved for the treatment of myelofibrosis and polycythemia vera. However, the agency did issue a complete response letter for another proposed JAK inhibitor, baricitinib, in April 2017, citing safety concerns. In the European Union and Japan, where baricitinib is approved, the product label carries a precaution related to potential thromboembolic events in at-risk patients.

In order to investigate a potential safety risk with thromboembolic events and JAK inhibitors as a class, the researchers assessed spontaneous AE reports from FEARS for tofacitinib, ruxolitinib, and extended-release tofacitinib from their approval dates to March 31, 2017. Cases were included in the study if the drug was listed as the “primary suspect” for the AE by the person reporting the event.

The researchers found the following in the FAERS data (none of the below AEs were listed as potential safety risks on the drugs’ labels at the time of the analysis):

• Pulmonary thrombosis: 18 unique cases for tofacitinib (16 resulted in hospitalization), 9 for ruxolitinib (all resulted in hospitalization, and 2 deaths are suspected to be linked), 3 for extended-release tofacitinib (all resulted in hospitalization).
• Pulmonary embolism: 36 unique cases for tofacitinib (25 resulted in hospitalization, 4 in death, 5 in life-threatening events), 55 for ruxolitinib (36 resulted in hospitalization, 12 in death, 1 in disability, 5 in life-threatening events), and 3 for extended-release tofacitinib (all resulted in hospitalization).
• Portal vein thrombosis: 11 unique cases were reported for ruxolitinib (9 cases resulted in hospitalization and 2 in death).
• Deep vein thrombosis: 18 unique cases for tofacitinib (11 resulted in hospitalization, 3 in death, 1 in disability, and 1 in a life-threatening event), 40 for ruxolitinib (28 resulted in hospitalization, 10 in death, 1 in disability, and 3 in life-threatening events), and 1 for extended-release tofacitinib that did not have a specified outcome.
• Thrombosis: 43 unique cases for tofacitinib (19 resulted in hospitalization, 2 in death, and 1 in a life-threatening event), 75 for ruxolitinib (43 resulted in hospitalization, 11 in death, 1 in disability, and 2 in life-threatening events), and 5 for extended-release tofacitinib (4 resulted in hospitalization).

“A modest but growing body of evidence suggests that JAK inhibitors may not be suitable for patients at risk for thromboembolic event,” the authors concluded. “The risk for any thromboembolic event has not been added to the FDA-approved label of any of the compounds within this class to date. We look forward to examining future FAERS reports, clinical trial results, and other real-world data resources such as electronic health records regarding this class of medications to determine if these potential safety signals become more robust."