Safety Warnings for Higher Dose Tofacitinib Save

Pfizer has issued a press release regarding the safety of tofacitinib, citing higher rates of pulmonary embolism and death associated with the use of higher dose tofacitinib 10mg bid in rheumatoid arthritis (RA) patients treated in a long-term safety trial.  

The open-label study in question enrolled RA patients over 50 years, on methotrexate, who had cardiovascular risk factors and were randomized to receive either tofacitinib (either 5 mg bid or 10 mg bid) or a tumor  necrosis factor inhibitor (TNFi). 

The Data Safety Monitoring Board (DSMB) from this study has issued a critical safety warning regarding the tofacitinib 10 mg twice daily treatment arm.  Specifically, they observed that patients treated with tofacitinib 10 mg twice daily had a statistically and clinically important difference in the occurrence of pulmonary embolism (PE) events compared to those treated with a TNFi.

In addition, the DSMB also noted an increase in overall mortality in the 10 mg twice daily treatment group compared to the tofacitinib 5 mg twice daily and TNFi treatment arms.

The DSMB stated it firmly believes that the risk-benefit profile of tofacitinib 5 mg twice daily in comparison to the TNFi group remains appropriately balanced in this study.

Patients in this study have been instructed to no longer take tofacitinib 10 mg bid. Such patients have the option of either lowering the dose (to 5mg bid) or stopping the study, after discussing this with the managing physician. Others on the TNFi are not affected. 

Pfizer notes that the study is fully enrolled and will continue through to completion and that other, ongoing studies of tofacitinib in RA, juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis should continue unchanged.

Similar new cases of venous thromboembolic (VTE) disease VTE, PE and DVT events have not been noted in excess in prior tofacitinib studies and the current product label bears no mention of a risk or warning for VTE. 

This warning is primarily directed at those patients enrolled in this research protocol, with the investigators and patients having been notified first.

Other RA and PsA patients, treated with tofacitinib (in practice) should continue their current dosing at 5 mg bid or 11 mg once daily - as these are the approved doses. Those taking higher, unapproved doses, should immediately cease high dose therapy and discuss further dosing or use with their prescribing physician. 

The issue of VTE and JAK inhibition has been rigorously reviewed at the FDA advisory hearing on baricitinib in 2018 and with new research presented at the 2018 ACR Annual meeting.  What is clear is that RA is a significant risk factor for the development of VTE.  The evidence that newer therapies (JAK inhibitors, TNF inhibitors, MTX) will further increase this risk is inconsistent a this point.