EMA confirms that Xeljanz (tofacitinib) should be used with caution in patients at high risk of thrombosis

The EMA concluded that the medicinal product Xeljanz (tofacitinib) may increase the risk of blood clots in the lungs and deep veins in patients who already have a high risk of thrombosis.

As a result, the Agency recommends using Xeljanz with caution in all patients at high risk of thrombosis. In addition, maintenance doses of 10 mg 2 times/day should not be used in patients with ulcerative colitis who are at high risk of blood clots, unless there is no suitable alternative treatment. Furthermore, because of the increased risk of infections, the EMA recommends that patients older than 65 years be treated with Xeljanz only when there is no alternative treatment.

These recommendations are consistent with the results of the Agency's review of study A3921133, conducted in patients with rheumatoid arthritis and an increased risk of cardiovascular disease, as well as data from previous studies and consultations with experts in this field. All pooled data showed that the risk of blood clots in the deep veins and lungs was higher in patients taking Xeljanz, especially at a dose of 10 mg 2 times/day, and in those treated for a long period. The results also showed a further increase in the risk of serious infections and fatal infections in patients over 65 years of age.

These recommendations were provided by the PRAC and have now been endorsed by the CHMP. They will replace the measures that were taken at the start of the review in May 2019. The changes take effect when the European Commission issues its decision.

Information for patients

• Xeljanz may increase the risk of blood clots in patients who already have a high risk of thrombosis;
• if you are being treated with Xeljanz, your doctor will check the risk of blood clot formation and modify the treatment if necessary;
• you may be at high risk of blood clots in the lungs and deep veins if you have had a heart attack or heart failure, cancer, an inherited blood clotting disorder, or a history of blood clots;
• you are also at risk if you use combined hormonal contraceptives or hormone replacement therapy, are planning or have recently had major surgery, or are bedridden;
• to assess the risk, the doctor will also take into account age, obesity (body mass index above 30), diabetes, high blood pressure, or smoking;
• if you are prone to a high risk of thrombosis or your age is over 65 years, the doctor may change the medicinal product if alternative treatment is available;
• if you have been taking Xeljanz, you should not change the dose or stop taking the medicine without discussing it with your doctor;
• seek medical help immediately if you experience sudden shortness of breath or difficulty breathing, chest pain or pain in the upper back, swelling of a limb, pain or tenderness in the legs, redness or discoloration of the skin of the upper or lower limbs. These may be symptoms of a blood clot in the lungs or veins.
• if you have any concerns about your medicinal product, you should discuss them with a healthcare professional.

Information for healthcare professionals

• the EMA review found that, depending on the dose, Xeljanz increases the risk of serious venous thromboembolism, including pulmonary embolism (some cases were fatal) and deep vein thrombosis in patients taking tofacitinib;
• the review considered data from the ongoing open-label clinical study A3921133. The aim of the study is to evaluate the safety of tofacitinib at 5 mg 2 times/day and 10 mg 2 times/day compared with a tumor necrosis factor inhibitor in patients with rheumatoid arthritis. Patients in the study are aged 50 years and older, with at least one additional cardiovascular risk factor. After interim results became available, treatment with tofacitinib at a dose of 10 mg 2 times/day was discontinued, and patients were switched to a dose of 5 mg 2 times/day due to a signal of pulmonary embolism and all-cause mortality. The review also took into account additional data from previous studies;
• a review of study A3921133 showed that, compared with treatment with a tumor necrosis factor inhibitor, tofacitinib at a dose of 5 mg 2 times daily increased the risk of pulmonary embolism approximately 3-fold, while tofacitinib at a dose of 10 mg 2 times daily increased the risk approximately 6-fold;
• a total of 17 cases of pulmonary embolism were recorded over 3123 patient-years with tofacitinib at a dose of 2 times/day, and 9 cases over 3,317 patient-years with tofacitinib at a dose of 5 mg 2 times/day, compared with 3 cases over 3 319 patient-years with a tumor necrosis factor inhibitor. In addition, there were 28 deaths from all causes over 3140 patient-years in the tofacitinib 10 mg 2 times/day group and 19 deaths from all causes over 3,324 patient-years in the tofacitinib 5 mg 2 times/day group, compared with the group that used tumor necrosis factor inhibitors (9 cases over 3323 patient-years);
• as a result, tofacitinib should be used with caution in patients with known risk factors for venous thromboembolism, regardless of indication and dose. These include patients who have had a myocardial infarction or suffer from heart failure, cancer, inherited blood clotting disorders or a history of thrombosis, as well as patients using combined hormonal contraceptives or hormone replacement therapy, who have undergone major surgery or are immobilized;
• other risk factors to be considered when prescribing tofacitinib include age, diabetes, obesity (BMI> 30), smoking and hypertension.
• the use of tofacitinib at a dose of 10 mg 2 times/day for maintenance treatment is not recommended in patients with ulcerative colitis who have known risk factors for venous embolism, unless there is no suitable alternative treatment;
• for the treatment of rheumatoid arthritis and psoriatic arthritis, do not exceed the recommended dose of 5 mg 2 times/day;
• patients should be informed about the signs and symptoms of venous thromboembolism before the use of tofacitinib and warned of the need to seek urgent medical care if these symptoms occur during treatment;
• available data have also shown that the risk of serious and fatal infections was higher in patients over 65 years of age compared with younger patients. Therefore, the use of tofacitinib in these patients should be considered only if there is no suitable alternative treatment;
• a letter will be sent to all healthcare professionals planning to prescribe tofacitinib to inform them of the updated treatment recommendations. The Physician Guide and the Patient Alert Card will be updated with advice on minimizing the risk of thrombosis.

The review was carried out by the PRAC committee, which drew up a number of recommendations. The PRAC recommendations were sent to the CHMP committee, which adopted the Agency’s opinion. The CHMP opinion will now be sent to the European Commission, which will issue a final legally binding decision applicable in all EU member states.

Information on the medicinal product and on the procedure under which the review of Xeljanz was initiated is published on the official website of the State Expert Center of the MoH at the linkhttps://dec.gov.ua/materials/xeljanz-slid-zastosovuvati-z-oberezhnistyu-dlya-vsih-paczi%d1%94ntiv-z-visokim-rizikom-utvorennya-trombiv/?role=applicant

Link to the EMA press releasehttps://www.ema.europa.eu/en/documents/referral/xeljanz-article-20-procedure-ema-confirms-xeljanz-be-used-caution-patients-high-risk-blood-clots_en.pdf