Thromboembolic events in Janus kinase inhibitors: A pharmacovigilance study from 2012 to 2021 based on the Food and Drug Administration's Adverse Event Reporting System

Abstract

Aims As a new type of drug developed rapidly in recent years, Janus kinase inhibitors (JAKinibs) have caused controversy due to possible adverse reactions of thromboembolism. The aim of this study was to analyse and evaluate the association between thromboembolic events and the use of JAKinibs, on the base of the latest data in the Food and Drug Administration's Adverse Event Reporting System. Methods A disproportionality analysis was conducted, utilizing data from 1 January 2012 to 30 September 2021 in the FAERS. For each drug‐adverse event pair, reporting odds ratio (ROR) and information components (IC) were calculated. Results A total of 15 positive safety signals were detected within the FAERS: ruxolitinib was significantly associated with portal vein thrombosis (ROR025 = 3.49, IC025 = 1.50); tofacitinib immediate release with pulmonary embolism (ROR025 = 2.09, IC025 = 1.02) and thrombosis (ROR025 = 1.15, IC025 = 0.18); tofacitinib extended release with pulmonary embolism (ROR025 = 1.27, IC025 = 0.26) and thrombosis (ROR025 = 1.29, IC025 = 0.33); baricitinib with deep vein thrombosis (ROR025 = 8.27, IC025 = 3.00), portal vein thrombosis (ROR025 = 1.97, IC025 = 0.63), pulmonary embolism (ROR025 = 7.90, IC025 = 2.94), thrombosis (ROR025 = 2.04, IC025 = 0.93) and venous thrombosis (ROR025 = 2.15, IC025 = 0.81); upadacitinib with pulmonary embolism (ROR025 = 1.25, IC025 = 0.25), pulmonary thrombosis (ROR025 = 5.32, IC025 = 2.33) and thrombosis (ROR025 = 2.72, IC025 = 1.39); and filgotinib with pulmonary embolism (ROR025 = 4.83, IC025 = 2.10). In the analysis of the time to onset of thromboembolic events, no obviously recognizable pattern was found. Several safety signals with embolic and thrombotic events (Standardised MedDRA Query) were found in the study. Conclusion This pharmacovigilance study covered 8 types of JAKinib that are already on the market, and provided new safety signals based on past safety information. Some of these signals still need more medical evidence.

Clinical experience and safety of Janus kinase inhibitors in giant cell arteritis: a retrospective case series from Sweden

“…Obviously, causality between JAKi and pulmonary embolism in this patient cannot be excluded. Increased incidence of venous thrombosis and pulmonary embolism has indeed been reported in patients with rheumatoid arthritis (RA) treated with JAKi, both by the Food and Drug Administration’s adverse event reporting system and the Swedish Rheumatology Quality registers ( 26 , 27 ). With regard to other adverse events and despite careful follow-up, we observed surprisingly few side effects considering that most of our patients were monitored for more than 1 year.…”

Adverse events in patients treated with Jak‐inhibitors for alopecia areata: A systematic review

“…Several studies have reported safety warnings about thromboembolism with JAK‐I, with the highest rates seen in baricitinib, followed by ruxolitinib and tofacitinib in patients with previous cardiovascular risk factors 13,21 . Interestingly, in our review focussing on AA, no thromboembolic events were identified.…”

“…Several studies have reported safety warnings about thromboembolism with JAK-I, with the highest rates seen in baricitinib, followed by ruxolitinib and tofacitinib in patients with previous cardiovascular risk factors. 13,21 Interestingly, in our review focussing on AA, no thromboembolic events were identified. Long-term safety analyses of baricinitib and tofacitinib for the treatment of rheumatoid arthritis showed incidence rates (IR) of major adverse cardiovascular events of 0.5 and 0.4 per 100 patient-years at risk, respectively.…”

Risk of Major Adverse Cardiovascular Events and Venous Thromboembolism with JAK Inhibitors versus TNF Inhibitors in Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis

“… 47 Additionally, a ten-year pharmacovigilance study, based on FDA reporting system for adverse events, highlighted the high risk for thromboembolic events with JAK inhibitors. 48 …”