The TGA follows the FDA and EMA in requiring boxed warnings for all JAK inhibitors.
The TGA has followed in the footsteps of the FDA, and more recently the European regulatory authority, requiring a boxed warning for a class effect on all Janus kinase (JAK) inhibitors used for treating chronic inflammatory conditions.
JAK inhibitors approved in Australia for such conditions are tofacitinib (Xeljanz, Pfizer), baricitinib (Olumiant, Lilly) and upadacitinib (Rinvoq, AbbVie), with indications including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, juvenile idiopathic arthritis, atopic dermatitis and ulcerative colitis.
The boxed warnings for Xeljanz, Olumiant and Rinvoq state that the drugs should only be used if no suitable treatment alternatives are available in patients:
- with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (such as current or past long-time smokers)
- with malignancy risk factors (such as current malignancy or history of malignancy)
- who are 65 years of age and older.
Section 4.4 Special Warnings and Precautions for Use includes information on major cardiovascular events (MACE), malignancies, thrombosis, use in the elderly, serious infections and mortality.
ORAL Surveillance, the FDA-mandated post-authorisation safety study of tofacitinib, found there was an increased risk, when compared with a TNF inhibitor, of major adverse cardiovascular events (MACE) and malignancies when used in a cohort of rheumatoid arthritis (RA) patients aged ≥50 with one additional cardiovascular risk factor.
These findings led to an FDA boxed warning on all JAK inhibitors used for arthritis and other inflammatory conditions in September 2021.
The European regulator conducted its own review of JAK inhibitors in the treatment of inflammatory disorders and made its recommendations late last year (updated this year).
In addition to the ORAL Surveillance data, it also considered an observational multi-database study of patients with rheumatoid arthritis taking baricitinib compared with those taking a TNFi.
The study found an increased risk of venous thromboembolism (VTE) in patients taking baricitinib, with numerically greater risk observed for MACE and serious infections.
Along similar lines to the boxed warnings above, the EMA recommends that JAK inhibitors only be used when there is no suitable alternative in patients who are 65 and older, at increased risk of MACE, present or long-time former smokers, or at increased risk of cancer. It also added cautions for patients at risk of VTE.
When it comes to replicating these adverse outcomes, various studies in RA patients, including real-world studies, have had mixed results.
Study populations selected with risk factors designed to replicate those in the ORAL Surveillance cohort have shown some support for the findings, but study cohorts from the broader patient population suggest similar risks for tofacitinib and TNF inhibitors.
