European Medicines Agency (EMA) announces that the Committee for Medicinal Products for Human Use (CHMP) has endorsed the measures recommended by the Pharmacovigilance Risk Assessment Committee (PRAC) to minimise the risk of serious side effects with Janus kinase (JAK) inhibitors used to treat several chronic inflammatory disorders. These side effects include cardiovascular conditions, blood clots, cancer and serious infections.
These medicines should be used in the following patients only if no suitable treatment alternatives are available: those aged 65 years or above, those at increased risk of major cardiovascular problems (such as heart attack or stroke), those who smoke or have done so for a long time in the past and those at increased risk of cancer.
JAK inhibitors should be used with caution in patients with risk factors for blood clots in the lungs and in deep veins (venous thromboembolism, VTE) other than those listed above. Further, the doses should be reduced in patient groups who are at risk of VTE, cancer or major cardiovascular problems, where possible.
The recommendations follow a review of available data, including the final results from a clinical trial of the JAK inhibitor Xeljanz (tofacitinib) and preliminary findings from an observational study involving Olumiant (baricitinib). The review also included advice from an expert group of rheumatologists, dermatologists, gastroenterologists and patient representatives.
The review confirmed Xeljanz increases the risk of major cardiovascular problems, cancer, VTE, serious infections and death due to any cause when compared with medicines belonging to the class of TNF-alpha inhibitors. EMA has now concluded that these safety findings apply to all approved uses of JAK inhibitors in chronic inflammatory disorders (rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis and alopecia areata).
The product information for JAK inhibitors used to treat chronic inflammatory disorders will be updated with the new recommendations and warnings. In addition, the educational material for patients and healthcare professionals will be revised accordingly.
Information for healthcare professionals:
- An EMA review has found that, compared with TNF-alpha inhibitors, JAK inhibitors used to treat chronic inflammatory disorders (rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis and alopecia areata) are linked to a higher risk of major adverse cardiovascular events (MACE), VTE, malignancy, serious infections and all-cause mortality.
- The review included the final results from an open-label clinical trial (ORAL Surveillance study) of the JAK inhibitor Xeljanz (tofacitinib) in patients with rheumatoid arthritis and cardiovascular risk factors which found a higher risk of these events with Xeljanz than with TNF-alpha inhibitors.
- Preliminary findings from an observational study (B023) involving another JAK inhibitor, Olumiant (baricitinib), also suggest an increased risk of MACE and VTE in patients with rheumatoid arthritis treated with Olumiant compared with those treated with TNF-alpha inhibitors.
- EMA concluded that the identified risks apply to all JAK inhibitors approved for the treatment of chronic inflammatory disorders.
- These medicines (Xeljanz, Cibinqo, Olumaint, Rinvoq and Jyseleca) should only be used in the following patients if no suitable treatment alternatives are available: those aged 65 years or above, those who are current or past long-time smokers, those with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, or those with other malignancy risk factors. Cautious use is also recommended in patients with known risk factors for VTE other than those listed above.
- If JAK inhibitors are needed in patients with these risk factors, a lower dose may be recommended, depending on the medicine, the indication and the specific risk factor.
- Healthcare professionals should discuss the risks associated with JAK inhibitors with their patients.
- It is recommended that healthcare professionals carry out periodic examinations of their patients’ skin to check for skin cancer, particularly for patients at risk for skin cancer.
Please refer to the following website in EMA for details:
http://www.ema.europa.eu/en/news/ema-confirms-measures-minimise-risk-serious-side-effects-janus-kinase-inhibitors-chronic
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. There is no registered pharmaceutical product containing abrocitinib or filgotinib.
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, one case was related to pneumocystis jirovecii pneumonia and one case was related to hypotension) 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 2 Nov 2022. 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/Saturday, Nov 12, 2022
Issued at HKT 12:00
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