Post-publication note: October 2021
Following final results from the clinical study ORAL Surveillance (A3921133), new measures have been been recommended to minimise the risks of cardiovascular events and malignancies for tofactinib treatment. Tofacitinib should not be used in patients older than 65 years of age, people who are current or past smokers, or individuals with other cardiovascular (such as diabetes or coronary artery disease) or malignancy risk factors unless there are no suitable treatment alternatives. See Drug Safety Update October 2021 for more information
Advice for healthcare professionals:
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
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
Safety review and interim restrictions
Tofacitinib is authorised for treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis (see Background). 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, we advised healthcare professionals of the potential risk of venous thromboembolism (see Drug Safety Update, May 2019) and temporary contraindications for the 10mg twice-daily dose of tofacitinib in patients with risk factors for pulmonary embolism.
Risk of venous thromboembolism
Following the conclusion of the review, the interim contraindications communicated in May 2019 have been replaced with the measures outlined in this article. A letter has been sent to prescribers and dispensers. 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 (see letter for detailed data). 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 (see letter for detailed data).
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.
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
- myocardial infarction (within previous 3 months)
- heart failure
- use of combined hormonal contraceptives or hormone replacement therapy
- inherited coagulation disorder
Other venous thromboembolism risk factors that should be considered include age, obesity (body-mass index ≥30 kg/m2), diabetes, hypertension, and smoking status.
An increased risk of venous thromboembolism has also been reported with other JAK inhibitors used to treat inflammatory conditions, including baricitinib and upadacitinib. See Drug Safety Update, March 2020.
Risk of serious and fatal infections
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 (see letter for study data). 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) – see letter for data.
Healthcare professionals are advised only to use tofacitinib in patients older than age 65 years if there is no alternative treatment.
Mortality in rheumatoid arthritis
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 (see letter for data). Mortality was mainly due to cardiovascular events, infections, and malignancies.
Tofacitinib (Xeljanz▼) was first authorised in the EU in March 2017. It is authorised for the treatment of:
adults with moderate to severe rheumatoid arthritis or active psoriatic arthritis in patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs
adults with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent
Report any suspected adverse drug reactions
Tofacitinib (Xeljanz▼) is a black triangle medicine and any suspected adverse drug reactions (ADRs) should be reported to the Yellow Card Scheme. Reporting suspected ADRs, even those known to occur, adds to knowledge about the frequency and severity of these reactions and can be used to identify patients who are most at risk. Your report helps the safer use of medicines.
Article citation: Drug Safety Update volume 13, issue 8: March 2020: 2.