Health Sciences Authority (HSA) announces that it has completed its assessment on the risk of major adverse cardiovascular events (MACE), malignancy, thrombosis and death associated with Janus Kinase (JAK) inhibitors for the treatment of inflammatory conditions. The assessment was conducted in response to findings from a post-authorisation safety study (ORAL Surveillance), which found an increased risk of these adverse events with tofacitinib compared to tumour necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA) patients who were 50 years of age or older, and with at least one additional cardiovascular risk factor.
Based on currently available information, HSA, in consultation with its Product Vigilance Advisory Committee (PVAC), has concluded that the benefit-risk profile of JAK inhibitors for the treatment of inflammatory conditions remains positive for their approved indications, where the use of JAK inhibitors is already limited to second line or later therapy in Singapore. As other JAK inhibitors used in the treatment of inflammatory conditions may have similar risks as observed with tofacitinib in the ORAL Surveillance study, healthcare professionals are advised to consider the benefits and risks of JAK inhibitors before prescribing these drugs, and to monitor their patients for these potential risks during treatment, particularly the elderly, current or past smokers, or with other cardiovascular, malignancy or thromboembolic risk factors.
The JAK inhibitors approved in Singapore for the treatment of inflammatory conditions are Xeljanz® (tofacitinib), Olumiant® (baricitinib), Rinvoq® (upadacitinib) and Cibinqo® (abrocitinib). Other JAK inhibitors that are not indicated for the treatment of inflammatory conditions (e.g., ruxolitinib) were not included in the scope of HSA’s benefit-risk assessment.
The ORAL Surveillance study was a randomised, open-label, noninferiority trial evaluating the safety of tofacitinib at two doses (5mg and 10mg twice daily) compared with a TNF inhibitor in patients with active RA despite treatment with methotrexate. A total of 4,362 subjects were randomised to receive treatment with at least one dose of tofacitinib 5mg twice daily (n=1,455), tofacitinib 10mg twice daily (n=1,456), or a TNF inhibitor (n=1,451). In Feb 2019, patients who were treated with tofacitinib 10mg twice daily were transitioned to the lower dose of 5mg twice daily, after an interim analysis of the ongoing study noted a higher incidence of pulmonary embolism and mortality among patients receiving tofacitinib 10mg twice daily than among those receiving tofacitinib 5mg twice daily or a TNF inhibitor. The median on-study follow-up time was four years and patients were analysed in their originally assigned group, including those who were switched from tofacitinib 10mg to 5mg twice daily.
In the final analysis, noninferiority was not shown for the combined doses of tofacitinib as compared with a TNF inhibitor for the co-primary endpoints of MACE and malignancy. The incidences of MACE and malignancy were higher with the combined tofacitinib doses than with a TNF inhibitor (Hazard ratio 1.33 [95% CI 0.91 – 1.94] and 1.47 [95% CI 1.04 – 2.09], respectively). The signal of malignancy was mainly driven by higher incidences of lung cancer and lymphoma. Adjudicated venous thromboembolism (VTE) and death from any cause were more frequent with both tofacitinib doses than with a TNF inhibitor. A dose-dependent increased risk for MACE, VTE and death was observed for both tofacitinib doses compared with the TNF inhibitor. In subgroup analyses stratified by age, the incidence rates of MACE and malignancy across trial groups were higher in patients 65 years of age or older than those younger than 65 years of age. Among patients aged 65 years and older, both tofacitinib doses were associated with a higher risk of MACE and malignancy than with a TNF inhibitor.
To date, HSA has received two adverse event reports of breast cancer and death associated with the use of tofacitinib. The event of breast cancer was assessed by the reporting company to be an intercurrent medical condition unrelated to tofacitinib treatment, while confounding factors (e.g., concomitant use of other chemotherapeutic agents) were present for the case with a fatal outcome following infections. HSA has also received one adverse event report of stroke associated with upadacitinib use. However, the event of stroke was assessed to be unlikely related to upadacitinib treatment and the patient was subsequently restarted on the same JAK inhibitor for treatment of RA with no reported issues. There have been no local adverse event reports of MACE, malignancy, thrombosis, or death with baricitinib and abrocitinib.
HSA has issued a Dear Healthcare Professional Letter on 17 Nov 2022 to inform healthcare professionals of HSA’s advisory and actions following its benefit-risk assessment of JAK inhibitors. HSA is working with the product registrants to strengthen the package inserts of JAK inhibitors approved for the treatment of inflammatory conditions to include warnings on the increased risks of MACE, malignancy, thrombosis and death observed with tofacitinib in the ORAL Surveillance study. HSA will continue to closely monitor the international and local developments of this issue and update healthcare professionals of any new significant findings.
Please refer to the following website in HSA for details:
http://www.hsa.gov.sg/announcements/safety-alert/janus-kinase-(jak)-inhibitors-and-risk-of-major-adverse-cardiovascular-events-malignancy-thrombosis-and-death
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.
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 and 3 cases were related to deep vein thrombosis), baricitinib (3 cases; of which one case was related to deep vein thrombosis) and upadacitinib (6 cases).
Related news on the risk of blood clots, serious heart-related problems and cancer 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 18 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/Wednesday, Dec 14, 2022
Issued at HKT 16:00
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