Analysis of Spontaneous Postmarket Case Reports Submitted to the FDA Regarding Thromboembolic Adverse Events and JAK Inhibitors
- 1.1k Downloads
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.
Compliance with Ethical Standards
Conflict of interest
Abril Verden, Mo Dimbil, Robert Kyle, and Brian Overstreet are employees and equity owners (through stock and/or stock options) of Advera Health Analytics, Inc. Keith Hoffman is a member of the Scientific Advisory Board and an equity owner (through stock and/or stock options) of Advera Health Analytics. Data from Advera Health Analytics were used in the creation of this article and its findings.
No sources of funding were used to assist in the preparation of this study.
- 1.Eli Lilly and Company. Lilly and Incyte provide update on baricitinib. 2017. https://investor.lilly.com/releasedetail.cfm?releaseid=1034247. Accessed 25 Sep 2017.
- 2.European Medicines Agency. Committee for medicinal products for human use (CHMP). Draft agenda for the meeting on 17–20 July 2017. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/Agenda/2017/07/WC500231582.pdf. Accessed 25 Sep 2017.
- 6.Advera Health Analytics. Drug/AE analysis. 2017. https://info.adverahealth.com/drug-safety-reference-xeljanz-pulmonary-thrombosis. Accessed 25 Sep 2017.
- 7.Advera Health Analytics. Drug/AE analysis. 2017. https://info.adverahealth.com/drug-safety-reference-jakafi-pulmonary-thrombosis. Accessed 25 Sep 2017.
- 8.Advera Health Analytics. Drug/AE analysis. 2017. https://info.adverahealth.com/drug-safety-reference-jakafi-portal-vein-thrombosis. Accessed 25 Sep 2017.
- 10.FDA. Questions and answers: FDA recommends against the continued use of Meridia (sibutramine). 2010. https://www.fda.gov/Drugs/DrugSafety/ucm228747.htm. Accessed 5 Nov 2017.
- 11.FDA. FDA public health advisory: safety of Vioxx. 2004. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106274.htm. Accessed 5 Nov 2017.
- 12.FDA. FDA Adverse Events Reporting System (FAERS) public dashboard. 2017. https://fis.fda.gov/sense/app/777e9f4d-0cf8-448e-8068-f564c31baa25/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis. Accessed 5 Nov 2017.