Safety Alerts
Risk of venous thromboembolism with tofacitinib
17 September 2020
Audiences
Healthcare professional
Industry member
Product-type
Therapeutic Products
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HSA would like to bring to the attention of healthcare professionals the findings from a clinical study, which found a dose-dependent increased risk of serious venous thromboembolism (VTE) in patients with rheumatoid arthritis treated with tofacitinib.
Tofacitinib (Xeljanz, Pfizer Pte Ltd) is a Janus kinase (JAK) inhibitor that has been registered in Singapore since November 2014. It is approved for reducing the signs and symptoms of rheumatoid arthritis, in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate. The treatment consists of an oral dose of 5 mg administered twice daily.
Increased risk of venous thromboembolism with tofacitinib in study A3921133
Study A3921133 is an open-label clinical trial (n=4,362) evaluating the cardiovascular safety of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily, compared with a tumour necrosis factor (TNF) inhibitor therapy, in patients with rheumatoid arthritis. The patients in the study were 50 years of age or older, with at least one cardiovascular risk factor (e.g. current smoker, high blood pressure, high cholesterol levels, diabetes mellitus, history of heart attack, family history of coronary heart disease). In 2019, an interim analysis of the study results identified a signal of pulmonary embolism (PE) and mortality with the tofacitinib 10 mg twice daily treatment arm. This triggered an in-depth European review of the interim results, which found a dose-dependent increased risk of serious VTE, including cases of deep vein thrombosis (DVT) and PE, in patients taking tofacitinib.
Compared to treatment with a TNF inhibitor, tofacitinib 5 mg twice daily increased the risk of PE about 3-fold, while tofacitinib 10 mg twice daily increased the risk by approximately 6-fold (Table 1). In a sub-group analysis, the risk of PE was found to be further increased in patients with risk factors for VTE, with a hazard ratio of 9.14 (2.11 – 39.56) and 3.92 (0.83 – 18.48) for the tofacitinib 10 mg and 5 mg arms respectively, compared to TNF inhibitors.
Incidence rates for DVT and all-cause mortality (within 28 days of last treatment) were also increased for patients treated with tofacitinib compared with TNF inhibitors (Table 1). Mortality was mainly due to cardiovascular events, infections, and malignancies.
Table 1. Incidence rates and hazard ratios of VTE events and all-cause mortality in patients treated with tofacitinib 10 mg twice daily, tofacitinib 5 mg twice daily, versus TNF inhibitors
Table caption
Tofacitinib 10 mg twice daily | Tofacitinib 5 mg twice daily | TNF inhibitors (Reference) | |
|---|---|---|---|
Pulmonary embolism | |||
Incidence rate per 100 patient-years | 0.54 (0.32 – 0.87) * | 0.27 (0.12 – 0.52) * | 0.09 (0.02 – 0.26) * |
Hazard ratio | 5.96 (1.75 – 20.33) * | 2.99 (0.81 – 11.06) * | 1.0 |
Deep vein thrombosis | |||
Incidence rate per 100 patient-years | 0.38 (0.20 – 0.67) * | 0.30 (0.14 – 0.55) * | 0.18 (0.07 - 0.39) * |
Hazard ratio | 2.13 (0.80 – 5.69) * | 1.66 (0.60 – 4.57) * | 1.0 |
All-cause mortality | |||
Incidence rate per 100 patient-years | 0.89 (0.59 – 1.29)* | 0.57 (0.34 – 0.89) * | 0.27 (0.12 – 0.51) * |
Hazard ratio | 3.28 (1.55 – 6.95) * | 2.11 (0.96 – 4.67) * | 1.0 |
* Results are presented with 95% CI
European Medicines Agency’s (EMA) review
Following a review of the data from study A3921133, data from earlier studies, as well as consultation with experts, the EMA concluded that tofacitinib could increase the risk of VTE in patients who are already at high risk. Consequently, the EMA recommended that tofacitinib should be used with caution in all patients with known risk factors for VTE. This included patients who have had a heart attack or have heart failure, cancer, inherited blood clotting disorders or history of blood clots, patients taking combined hormonal contraceptives or hormone replacement therapy, and patients undergoing major surgery or are immobilised. Other risk factors to be considered when prescribing tofacitinib included age, obesity, smoking status, diabetes and hypertension. Additionally, the EMA recommended against the use of tofacitinib 10 mg twice daily for maintenance treatment in patients with ulcerative colitis who have known risk factors for VTE, unless there is no suitable alternative treatment available. For the treatment of rheumatoid arthritis and psoriatic arthritis, the current approved dose of 5 mg twice daily should not be exceeded.
Local situation and HSA’s advisory
In Singapore, tofacitinib has only been approved for the treatment of rheumatoid arthritis, at a dose of 5 mg twice daily. As of July 2020, HSA has not received any local adverse drug reaction reports of VTE associated with tofacitinib treatment. In light of the findings from study A3921133, HSA is working with Pfizer to update the Singapore package insert of Xeljanz with safety information regarding the increased risk of VTE events. Healthcare professionals are advised to use tofacitinib with caution in patients with risk factors for VTE. Healthcare professionals are also encouraged to report to HSA any suspected cases of VTE related to the use of tofacitinib.
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