Analysis of Spontaneous Postmarket Case Reports Submitted to the FDA Regarding Thromboembolic Adverse Events and JAK...

The Janus kinase (JAK) inhibitor baricitinib is approved in Europe and Japan for the treatment of rheumatoid arthritis. In April 2017, the US FDA expressed concern about thromboembolic events (deep venous thrombosis [DVT] and pulmonary embolism [PE]) observed in placebo-controlled clinical trials of baricitinib. The European and Japanese labels for baricitinib were recently updated to include a precaution related to potential thromboembolic events in patients at risk. Given that the FDA-approved drugs tofacitinib and ruxolitinib are in the same class, we conducted a safety review of the FDA's Adverse Event Reporting System (FAERS) to assess postmarketing reporting rates for related thromboembolic risks.

Adverse event (AE) data for tofacitinib, tofacitinib extended-release (XR), and ruxolitinib were obtained from the FAERS. Reporting odds ratios (RORs) and the R package 'PhViD' to estimate the empirical Bayesian geometric mean (EBGM) were used to detect AEs with higher-than-expected reporting rates within the FAERS.

We did not find evidence in the FAERS for elevated reporting rates for DVT and PE across the three JAK inhibitors we analyzed. However, multiple drug-AE combinations relating to thromboembolic events had both RORs and EBGM values above 1, indicating a trend toward higher-than-expected reporting rates. For pulmonary thrombosis, the ROR values for ruxolitinib, tofacitinib, and tofacitinib XR were 1.46 (95% confidence interval [CI] 0.76-2.80), 2.46 (1.55-3.91), and 2.48 (0.80-7.71), respectively, while the EBGM values were 1.25 (0.70), 2.46 (1.64), and 1.56 (0.57), respectively. Ruxolitinib had ROR values of 4.08 (2.25-7.38) and 1.22 (0.97-1.53) for portal vein thrombosis and thrombosis, respectively. The EBGM values for the same drug-AE combinations were 3.04 (1.79) and 1.16 (0.96).

Our safety review of postmarketing FAERS reports associated with three FDA-approved JAK inhibitors did not find elevated reporting rates for DVT and PE specifically. However, the FAERS data indicated that pulmonary thrombosis may potentially be a class-wide issue for JAK inhibitors. Portal vein thrombosis may also be a potential risk for ruxolitinib. While these FAERS data add to a growing body of evidence that JAK inhibitors may be contraindicated in patients at risk of thromboembolic events, the data need to be confirmed by future AE reporting trends, analysis of electronic health records, and/or future clinical trials.