Safety Alerts
Janus Kinase (JAK) inhibitors and risk of major adverse cardiovascular events, malignancy, thrombosis and death
13 December 2022
Audiences
Healthcare professional
Industry member
Product-type
Therapeutic Products
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HSA 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 (AEs) 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.
Locally approved JAK inhibitors
JAK inhibitors are immune modulating drugs used for the treatment of inflammatory conditions such as RA, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and atopic dermatitis. The JAK inhibitors approved in Singapore for the treatment of inflammatory conditions are Xeljanz®, Pfizer Private Limited (tofacitinib), Olumiant®, DKSH Singapore Pte. Ltd. (baricitinib), Rinvoq®, AbbVie Pte. Ltd. (upadacitinib) and Cibinqo®, Pfizer Private Limited (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.
Oral Rheumatoid Arthritis Trial (ORAL) Surveillance study1
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[a] in patients with active RA despite treatment with methotrexate (MTX). The population enrolled were at least 50 years of age and had at least one additional cardiovascular risk factor.[b] The co-primary endpoints of the study were adjudicated MACE[c] and malignancy (excluding nonmelanoma skin cancer [NMSC]). The noninferiority of tofacitinib would be shown if the upper limit of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor.
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). The demographic and clinical characteristics of patients at baseline were generally similar across trial groups. Most of the patients were female (78%) and Caucasian (76.9%), with a mean age of 61 years (median: 60 years; range: 50 to 88 years). In February 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 (excluding NMSC) (Table 1). 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.
[a] In the US, Puerto Rico and Canada, subjects randomised to receive a TNF inhibitor received adalimumab 40mg every two weeks by subcutaneous (SC) injection. In all other countries, subjects randomised to receive a TNF inhibitor received etanercept 50mg once weekly by SC injection.
[b] Current cigarette smoker, hypertension, high density lipoprotein (HDL) < 40mg/dL, diabetes mellitus, family history of premature coronary heart disease, extra-articular rheumatoid arthritis, history of coronary artery disease.
[c] MACE was defined as cardiovascular death (sudden cardiac death and death due to acute myocardial infarction, heart failure, stroke, cardiovascular procedures, cardiovascular haemorrhage, and other cardiovascular causes [e.g., peripheral artery disease], but not death due to pulmonary embolism), nonfatal myocardial infarction, and nonfatal stroke, including reversible focal neurologic defects with image evidence of a new cerebral lesion consistent with ischaemia or haemorrhage.
Table 1. Incidence of adverse events and hazard ratios
Table caption
Event Incidence, % (Hazard ratio, 95% CI) | Tofacitinib 5mg BD | Tofacitinib 10mg BD | Tofacitinib combined doses | TNF inhibitor (Reference) |
|---|---|---|---|---|
MACE | 3.2% (1.24, 0.80 – 1.90) | 3.5% (1.43, 0.94 – 2.18) | 3.4% (1.33, 0.91 – 1.94) | 2.5% |
Malignancy (excl. NMSC) | 4.3% (1.47, 0.99 – 2.18) | 4.1% (1.48, 0.99 – 2.19) | 4.2% (1.47, 1.04 – 2.09) | 2.9% |
VTE | 1.2% (1.66, 0.76 – 3.63) | 2.3% (3.52, 1.74 – 7.12) | NA | 0.7% |
Death from any cause | 1.8% (1.49, 0.81 – 2.74) | 2.7% (2.37, 1.34 – 4.18) | NA | 1.2% |
NA: Not available
International regulatory actions
International regulatory health authorities, namely the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and Health Canada have conducted safety reviews in light of the increased risks observed with tofacitinib in the ORAL Surveillance study. In addition to tofacitinib, their safety reviews were also extended to other JAK inhibitors used in the treatment of inflammatory conditions.2-7
1. Xeljanz® (Tofacitinib)
The reviews by these regulatory agencies concluded there was an increased risk of MACE, malignancy and thrombosis with tofacitinib compared to TNF inhibitors. As a result, all three agencies recommended for the tofacitinib package inserts (PI) to be updated with warnings on the increased risks observed in the ORAL Surveillance study. In addition, the US FDA and Health Canada also recommended changes to the approved indications of tofacitinib. The US FDA limited all approved uses of tofacitinib to patients who have had an inadequate response or intolerance to one or more TNF inhibitors, while Health Canada limited the use of tofacitinib for RA to patients who have had an inadequate response or intolerance to MTX and at least one other disease modifying anti-rheumatic drug (DMARD).
2. Other JAK inhibitors for inflammatory conditions
The US FDA, EMA and Health Canada concluded that other JAK inhibitors used in the treatment of inflammatory conditions (e.g., baricitinib and upadacitinib) may have similar risks as seen with tofacitinib in the ORAL Surveillance study. The US FDA extended its warnings and limitation on use for tofacitinib to other JAK inhibitors used for the treatment of inflammatory conditions, whereas Health Canada and EMA only recommended for updated warnings on the risks observed with tofacitinib in the ORAL Surveillance study, with no changes to the approved indications.
Local adverse event reports of MACE, malignancy, thrombosis or death associated with JAK inhibitors
To-date, HSA has received two AE 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 AE 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 AE reports of MACE, malignancy, thrombosis, or death with baricitinib and abrocitinib.
HSA’s benefit-risk assessment
HSA’s benefit-risk assessment took into consideration the findings from the ORAL Surveillance study, information provided by the pharmaceutical companies, local usage of JAK inhibitors, expert opinions of local clinicians (i.e., rheumatologists, gastroenterologists, dermatologists) and regulatory actions taken by the international health regulatory authorities.
Based on currently available information, HSA, in consultation with its PVAC, has assessed that the benefit-risk profile of JAK inhibitors remains positive for their approved indications, where the use of JAK inhibitors is already limited to second line or later therapy in Singapore. As the mechanism of occurrence of these AEs remains unknown, the risk of these AEs with other JAK inhibitors cannot be excluded, as they share a similar mechanism of action.
HSA’s advisory and actions
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, thromboembolic or malignancy risk factors.
HSA has issued a Dear Healthcare Professional Letter on 17 November 2022 to inform healthcare professionals of HSA’s advisory and actions following our benefit-risk assessment of JAK inhibitors.8 HSA is working with the product registrants to strengthen the PIs 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.
Healthcare professionals are encouraged to report any suspected serious AEs related to use of JAK inhibitors to the Vigilance and Compliance Branch of HSA.
References
The New England Journal of Medicine. 2022;386:316-26.