Therapeutic Goods Administration (TGA) announces that a large post-marketing rheumatoid arthritis safety study of the Janus kinase (JAK) inhibitor tofacitinib 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.
These new warnings for baricitinib, tofacitinib and upadacitinib follow a TGA review of a randomised safety trial called the ORAL Surveillance Study. 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.
If health professionals are treating patients taking JAK inhibitors for chronic inflammatory conditions, please be aware of these risks and discuss them with their 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 risk.
The current Product Information safety updates for baricitinib (Olumiant), tofacitinib (Xeljanz) and upadacitinib (Rinvoq) include a new boxed warning with the information below:
The product 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 in Mortality, Major adverse cardiovascular events, Thrombosis, Malignancy and Use in the elderly.
Please refer to the following website in TGA for details:
http://www.tga.gov.au/news/safety-updates/important-safety-information-janus-kinase-jak-inhibitors
In Hong Kong, there are 3 registered pharmaceutical products containing tofacitinib, namely Xeljanz Tablets 5mg (HK-63303), Xeljanz XR Extended Release Tablets 11mg (HK-66141) and Xeljanz Tablets 10mg (HK-66833) which are registered by Pfizer Corporation Hong Kong Limited; 2 products containing baricitinib, namely Olumiant Tablets 2mg (HK-65663) and Olumiant Tablets 4mg (HK-65664) which are registered by Eli Lilly Asia, Inc.; and 2 products containing upadacitinib, namely Rinvoq Prolonged-Release Tablets 15mg (HK-66872) and Rinvoq Prolonged-Release Tablets 30mg (HK-67512) which are registered by Abbvie Limited. All products are prescription-only medicines.
So far, the Department of Health (DH) has received adverse drug reaction related to tofacitinib (9 cases; of which 2 cases were related to cancer, 3 cases were related to deep vein thrombosis, one case was related to disseminated tuberculosis, one case was related to cellulitis, one case was related to pneumonia and one case was related to herpes zoster disseminated), baricitinib (3 cases; of which one case was related to deep vein thrombosis and one case was related to pneumocystis jirovecii pneumonia) and upadacitinib (6 cases; of which 4 cases were related to herpes zoster and one case was related to cytomegalovirus colitis).
Related news on the risk of blood clots, serious heart-related problems, cancer and serious infections of JAK inhibitors was previously issued by various overseas drug regulatory authorities, and was posted on the Drug Office website since 26 Feb 2019, with the latest update posted on 27 Apr 2023. Letters to inform local healthcare professionals were issued by the DH on 29 Jul 2019, 19 Jun 2020, 15 Jun 2021, 2 Sep 2021 and 31 Oct 2022.
In Dec 2019, the Registration Committee of the Pharmacy and Poisons Board (the Committee) discussed the matter on the risk of blood clots and death associated with the use of tofacitinib, and decided that the sales pack or package insert of tofacitinib products should include safety information about increased risk of blood clots and death with higher dose (10 mg twice daily).
In Dec 2021, the Committee discussed the matter on the risk of venous thromboembolic events (including deep vein thrombosis and pulmonary embolism) associated with the use of JAK inhibitors (tofacitinib, baricitinib and ruxolitinib), and decided that the sales pack or package insert of these products should include the relevant safety information.
As previously reported, the matter will be further discussed by the Committee.
Ends/Thursday, May 11, 2023
Issued at HKT 15:00
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