The Medicines and Healthcare products Regulatory Agency (MHRA) announces new measures to minimise risk of venous thromboembolism and of serious and fatal infections of tofacitinib.
In 2019, interim results from the ongoing study A3921133 prompted a European review into the benefits and risks of tofacitinib. Study A3921133 included patients aged 50 years or older with rheumatoid arthritis and an increased risk of cardiovascular disease. While the review was ongoing, the MHRA advised healthcare professionals of the potential risk of venous thromboembolism and temporary contraindications for the 10mg twice-daily dose of tofacitinib in patients with risk factors for pulmonary embolism.
Following the conclusion of the review, the interim contraindications communicated in May 2019 have been replaced with the measures outlined below. Venous thromboembolism is an uncommon reaction with tofacitinib treatment (up to 1 in 100 patents). Study A3921133 showed an increased risk of pulmonary embolism in this population with tofacitinib 5mg twice daily compared with TNF inhibitors and an even greater risk with 10mg twice-daily. Incidence rates for deep vein thrombosis were also increased with tofacitinib. Risks of pulmonary embolism were further increased in patients with risk factors for venous thromboembolism.
In an ongoing extension trial to assess use of tofacitinib in ulcerative colitis, cases of pulmonary embolism and deep vein thrombosis were also observed in patients using tofacitinib 10mg twice-daily who had underlying venous thromboembolism risk factors.
New recommendations include:
- For any dose and in any indication, exercise caution when considering tofacitinib in patients who have known risk factors for venous thromboembolism, in addition to their underlying disease.
- Maintenance treatment for ulcerative colitis at the 10mg twice-daily dose is not recommended in patients with known risk factors for venous thromboembolism, unless there is no suitable alternative treatment.
Risk factors for venous thromboembolism include previous venous thromboembolism, patients undergoing major surgery, immobilisation, myocardial infarction (within previous 3 months), heart failure, use of combined hormonal contraceptives or hormone replacement therapy, inherited coagulation disorder, malignancy. Other venous thromboembolism risk factors that should be considered include age, obesity (body-mass index ≥30 kg/m2), diabetes, hypertension, and smoking status.
Tofacitinib is known to increase the risk of serious and fatal infections such as pneumonia, cellulitis, herpes zoster, and urinary tract infections. Existing advice contraindicates use of tofacitinib in patients with active infections, and advises healthcare professionals to consider the benefits and risks in patients with recurrent infections, a history of serious or opportunistic infection, or travel to areas of endemic mycoses, and in those who have underlying conditions that may predispose them to infection.
Study A3921133 showed incidence of non-fatal serious infections to be higher in patients with rheumatoid arthritis receiving tofacitinib than in those receiving a TNF inhibitor. The risk of serious infections and fatal infections was further increased in older patients aged 65 years or older, as compared to younger patients (aged 50–64 years).
Healthcare professionals are advised only to use tofacitinib in patients older than age 65 years if there is no alternative treatment.
Healthcare professionals are advised:
Venous thromboembolism risk
- Tofacitinib is associated with a dose-dependent increased risk of serious venous thromboembolism.
- Use caution in any patients with known risk factors for venous thromboembolism in addition to the underlying disease.
- In patients with ulcerative colitis who have known risk factors for venous thromboembolism in addition to the underlying disease, use of 10mg twice-daily tofacitinib for maintenance treatment is not recommended unless no suitable alternative treatment is available.
- Do not exceed the recommended dose of 5mg twice-daily (or 11mg prolonged-release once-daily) for rheumatoid arthritis or 5mg twice-daily for psoriatic arthritis in any patients.
- Vigilance for events and actions if they occur: inform patients of the signs and symptoms of venous thromboembolism before they start tofacitinib and advise them to seek prompt medical help if they develop signs such as a painful swollen leg, chest pain, or shortness of breath.
- Discontinue tofacitinib treatment permanently if signs of venous thromboembolism occur.
Infection risk
- Tofacitinib increases the risk of serious and fatal infections, with rates of infections greater in older patients.
- Only consider use of tofacitinib in patients older than 65 years if no suitable alternative treatment is available.
In the interim analysis of study A3921133 in patients with rheumatoid arthritis, mortality within 28 days of last treatment was increased in patients treated with tofacitinib compared with those treated with TNF inhibitors. Mortality was mainly due to cardiovascular events, infections, and malignancies.
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/tofacitinib-xeljanz-new-measures-to-minimise-risk-of-venous-thromboembolism-and-of-serious-and-fatal-infections
In Hong Kong, Xeljanz Tablets 5mg (HK-63303) and Xeljanz XR Extended Release Tablets 11mg (HK-66141) are registered pharmaceutical products containing tofacitinib. Both products are registered by Pfizer Corporation Hong Kong Limited, and are prescription-only medicines. So far, the Department of Health (DH) has received 5 cases of adverse drug reaction related to tofacitinib, of which one case is related to deep vein thrombosis and 3 cases are related to infections (pneumonia, cellulitis and disseminated tuberculosis).
Related news on the risk of blood clots of tofacitinib 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 3 Dec 2019. Letters to inform local healthcare professionals were issued by the DH on 29 Jul 2019. In Dec 2019, the Registration Committee of the Pharmacy and Poisons Board discussed the matter, and decided that the sales pack or package insert of tofacitinib should include the relevant safety information. The current local package insert of the tofacitinib products also include caution on serious infections in the elderly population. The DH will remain vigilant on safety update of the drug issued by other overseas drug regulatory authorities.
Ends/Thursday, Mar 19, 2020
Issued at HKT 17:30
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