A large post-marketing rheumatoid arthritis safety study of the JAK inhibitor tofacitinib (Oral Surveillance Study) found an increased risk of major cardiovascular problems, such as heart attack and stroke, cancer, blood clots, serious infections and death, as compared with tumour necrosis factor (TNF) inhibitors.
Based on the results of this study, a class-wide boxed warning and strengthened precautions about these risks have been added to the Australian Product Information documents for JAK inhibitors used to treat chronic inflammatory conditions – baricitinib, tofacitinib and upadacitinib.
To minimise the risk of these side effects, JAK inhibitors should not be prescribed for chronic inflammatory conditions in people:
- with a history of cardiovascular disease (eg. heart attack or stroke)
- at increased risk of cardiovascular problems (eg. current or past long-time smokers)
- at increased risk of cancer
- aged 65 years and over
unless there are no suitable alternative treatments.
What’s new in this article
These new warnings for baricitinib, tofacitinib and upadacitinib follow a TGA review of a randomised safety trial called the ORAL Surveillance Study (Ytterberg SR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med 2022; 386:316-326. DOI: 10.1056/NEJMoa2109927). This trial compared the safety of tofacitinib at two doses – 5 mg twice daily and 10 mg twice daily – to TNF inhibitors in around 4,300 patients with rheumatoid arthritis. Patients were followed for an average of four years. To be enrolled, they had to be aged 50 years or older and have at least one cardiovascular risk factor.
The final results of the study found a higher incidence of major adverse cardiovascular events, malignancies (particularly lung cancer, lymphoma and non-melanoma skin cancer), thromboembolic events, serious infections and death due to any cause with tofacitinib compared to TNF inhibitors.
The TGA considers the findings of this study relevant to the other JAK inhibitors baricitinib and upadacitinib as they share similar mechanisms of action to tofacitinib. As such a class-wide update has been made to the Product Information and the Consumer Medicines Information across all approved chronic inflammatory indications.
What should health professionals do
If you are treating patients taking JAK inhibitors for chronic inflammatory conditions, please be aware of these risks and discuss them with your patients. Consider the benefits and risks for each individual before initiating or continuing therapy.
Periodic skin examination is recommended for patients taking these medicines, particularly those with risk factors for skin cancer. Patients should also be regularly re-evaluated to assess for changes in their venous thromboembolism (VTE) risk.
The TGA has also published a safety advisory on this topic for the general public.
JAK inhibitors are disease-modifying anti-rheumatic oral drugs (DMARDs) that block the activity of enzymes called Janus kinases.
Three JAK inhibitors are currently available in Australia for chronic inflammatory conditions:
- baricitinib (OLUMIANT)
- tofacitinib (XELJANZ and XELJANZ XR)
- upadacitinib (RINVOQ)
They are used to treat at least one of the following conditions (refer to each Product Information for the approved indications):
- rheumatoid arthritis
- psoriatic arthritis
- juvenile idiopathic arthritis
- axial spondyloarthritis
- ulcerative colitis
- atopic dermatitis
In October 2019, the TGA published a safety alert regarding increased risks of blood clots and of death for certain patients on tofacitinib at the higher dose of 10 mg twice daily, based on the preliminary results of the ORAL Surveillance Study. This followed a Product Information (PI) update by the sponsor of tofacitinib (Pfizer) with a warning about the use of the 10 mg dose.
The current PI safety updates for baricitinib (Olumiant), tofacitinib (Xeljanz) and upadacitinib (Rinvoq) include a new boxed warning with the information below (consult full PI of individual products for exact wording):
[Name of JAK inhibitor] should only be used if no suitable treatment alternatives are available in patients:
- with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (such as current or past long-time smokers).
- with malignancy risk factors (e.g. current malignancy or history of malignancy).
- who are 65 years of age and older.
See section 4.4 Special warnings and precautions for use: Mortality, Major adverse cardiovascular events, Thrombosis, Malignancy, Infections and Use in the elderly.
Section 4.4 ‘Special warnings and precautions for use’ has been updated to the following (consult full PI of individual products for exact wording):
In a large, randomised, post-marketing safety study in rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor comparing tofacitinib to tumour necrosis factor (TNF) inhibitors, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with tofacitinib compared to TNF inhibitors. Mortality was mainly due to cardiovascular events, infections and malignancies. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with [JAK inhibitor].
Major adverse cardiovascular events (MACE)
In a large randomised post-marketing safety study of tofacitinib in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to TNF inhibitors. MACE, including events of myocardial infarction, were more common in older patients and in patients who were current or past smokers.
Therefore, in patients 65 years of age and older, patients who are current or past long-time smokers, and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, [JAK inhibitor] should only be used if no suitable treatment alternatives are available.
Serious and sometimes fatal events of thrombosis, including deep vein thrombosis (DVT), arterial thrombosis and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors. In a large randomised post-marketing safety study of tofacitinib in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dose dependent increased risk for these thrombotic events was observed with tofacitinib compared to TNF inhibitors.
In patients with cardiovascular or malignancy risk factors, [JAK inhibitor] should only be used if no suitable treatment alternatives are available.
Avoid [JAK inhibitor] in patients with an increased risk of thrombosis or in whom risk factors are identified. VTE risk factors include patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, and inherited coagulation disorder.
Patients should be re-evaluated periodically during [JAK inhibitor] treatment to assess for changes in VTE risk.
Promptly evaluate patients with signs and symptoms of VTE and discontinue [JAK inhibitor] in patients with suspected VTE, regardless of dose or indication.
In a large randomised post-marketing safety study of tofacitinib in rheumatoid arthritis patients 50 years and older with at least one cardiovascular risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) was observed with tofacitinib compared to TNF inhibitors.
In patients 65 years of age and older, patients who are current or past long-time smokers, or with other malignancy risk factors (e.g. current malignancy or history of malignancy), [JAK inhibitor] should only be used if no suitable treatment alternatives are available.
Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Use in the elderly
Considering the increased risk of MACE, malignancies, serious infections and all-cause mortality in patients 65 years and older, as observed in a large randomised post-marketing study of tofacitinib, [JAK inhibitor] should only be used in these patients if no suitable treatment alternatives are available.
What to report? You don't need to be certain, just suspicious!
The TGA encourages the reporting of all suspected adverse reactions to medicines, including vaccines, over-the-counter medicines, herbal, traditional or alternative remedies.
We particularly request reports of:
- all suspected reactions to new medicines (look for the Black Triangle in PI and CMI documents - this symbol identifies medicines that are new or being used differently)
- all suspected medicines interactions
- suspected reactions causing death, admission to hospital or prolongation of hospitalisation, increased investigations or treatment, or birth defects.
Reports may be submitted:
- online at www.tga.gov.au
- by fax to 02 6232 8392
- by email to ADR.Reports@tga.gov.au
For more information about reporting, visit www.tga.gov.au or contact the TGA's Pharmacovigilance and Special Access Branch ADR.Reports@tga.gov.au.
Medicines Safety Update is aimed at health professionals. It is intended to provide practical information to health professionals on medicine safety, including emerging safety issues. The information in Medicines Safety Update is necessarily general and is not intended to be a substitute for a health professional's judgment in each case, taking into account the individual circumstances of their patients. Reasonable care has been taken to ensure that the information is accurate and complete at the time of publication. The Australian Government gives no warranty that the information in this document is accurate or complete, and shall not be liable for any loss whatsoever due to negligence or otherwise arising from the use of or reliance on this document.
© Commonwealth of Australia 2021
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For correspondence or further information about Medicines Safety Update, contact the TGA's Pharmacovigilance and Special Access Branch at ADR.Reports@tga.gov.au.
Medicines Safety Update is written by staff from the Pharmacovigilance and Special Access Branch.
Acting Editor: Tahli Fenner
Deputy Editor: Fiona Mackinnon
Contributors: Jovi van der Kallen, Emma Knott and Angela Gowland
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