Tofacitinib (Xeljanz▼): new measures to minimise risk of major adverse cardiovascular events and malignancies

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.

From:
Medicines and Healthcare products Regulatory Agency
Published
6 October 2021
Therapeutic area:
GI, hepatology and pancreatic disorders, Rheumatology

Advice for healthcare professionals:

Information on cardiovascular events

  • a clinical safety trial in patients with rheumatoid arthritis aged 50 years or older with at least one cardiovascular risk factor (Study A3921133) found that the JAK inhibitor tofacitinib was associated with an increased risk of major adverse cardiovascular events compared with TNF-alpha inhibitors (etanercept or adalimumab)
  • the following predictive risk factors were identified: age older than 65 years, current or past smoking, history of diabetes, and history of coronary artery disease (including past myocardial infarction, coronary heart disease, stable angina pectoris, or coronary artery procedures)
  • only consider use of tofacitinib in patients with these cardiovascular risk factors, irrespective of indication, if no suitable treatment alternative is available

Information on malignancy

  • the same clinical safety trial in patients with at least one cardiovascular risk factor (some of which are also malignancy risk factors) found that tofacitinib was associated with an increased risk of malignancies (with the analysis excluding non-melanoma skin cancer [NMSC]), particularly lung cancer and lymphoma, compared with TNF-alpha inhibitors
  • the following predictive risk factors were identified: age older than 65 years and current or past smoking
  • only consider use of tofacitinib in patients with these and other malignancy risk factors (current or previous history of malignancy other than successfully treated NMSC), irrespective of indication, if no suitable alternative treatment is available

Advice for healthcare professionals to give to patients:

  • tofacitinib treatment has been associated with an increased risk of heart attacks and certain cancers compared with another type of treatment (TNF-alpha inhibitors) – the incidence of these events is low and they have been linked to existing risk factors for these conditions such as older age or smoking
  • patients who are already at increased risk of cardiovascular events or cancers should only be offered treatment with tofacitinib if their doctor feels there are no other suitable treatment options for their condition
  • do not stop taking tofacitinib without first talking to your doctor
  • always read the leaflet that accompanies your medicines and talk to your doctor, nurse, or pharmacist if you are concerned about any side effects

Safety review

Tofacitinib (Xeljanz▼) is a Janus kinase (JAK) inhibitor authorised for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis (see Background section).

Study ORAL Surveillance (A3921133) was a large, randomised, active-controlled, clinical safety trial to evaluate the safety of tofacitinib versus tumour necrosis factor (TNF)-alpha inhibitors. The study involved 4,362 patients with rheumatoid arthritis aged 50 years or older and with at least one additional cardiovascular risk factor. In 2018, secondary findings of this study led to new measures to minimise risks of venous thromboembolism and serious and fatal infections with tofacitinib.

The co-primary endpoints of study A3921133 were adjudicated major adverse cardiac events and adjudicated malignancies (with the analysis excluding non-melanoma skin cancer).

Doses of tofacitinib included in the study were 5mg twice-daily and 10mg twice-daily and endpoints in these groups were compared with those from patients randomised to TNF-alpha inhibitors (etanercept, 50mg once a week subcutaneously, or adalimumab, 40mg once every other week subcutaneously).

In 2021, final results from study A3921133 showed tofacitinib to be associated with an increased incidence of non-fatal myocardial infarction and malignancies, particularly lung cancer and lymphoma.

These results prompted a review into these risks of tofacitinib and how they should be minimised. Prescribers of tofacitinib were informed of the final trial results in a letter in March 2021 with a further letter with the final recommendations sent in July 2021. The product information and educational materials for healthcare professional and patients will also be updated with this information.

Cardiovascular risk

Study A3921133 showed an increase in non-fatal myocardial infarction in patients treated with tofacitinib (hazard ratio (HR) for combined tofacitinib doses versus TNF-alpha inhibitors 2.20 (95% CI 1.02 to 4.75)). These calculations were based on events occurring on-treatment or within 60 days of treatment discontinuation. See letter from July 2021 for further data, including incidence rates.

Predictive factors for development of myocardial infarction (fatal and non-fatal) were identified using a multivariate Cox model with backward selection. These factors were age older than 65 years, male sex, current or past smoking, history of diabetes, and history of coronary artery disease (which includes past myocardial infarction, coronary heart disease, stable angina pectoris, or past coronary artery procedures).

Results suggest that these risks are associated with both the 5mg twice-daily dose and the 10mg twice-daily dose (which is approved only in ulcerative colitis).

Risk of malignancy

Study A3921133 showed an increase in malignancies (with the analysis excluding non-melanoma skin cancer), particularly lung cancer and lymphoma, in patients treated with tofacitinib compared with TNF-alpha inhibitors (HR for combined tofacitinib doses 1.48 (95% CI 1.04 to 2.09)). These calculations were based on events occurring on treatment or after treatment discontinuation up to the end of the study. See letter from July 2021 for further data, including incidence rates.

Predictive factors for development of malignancies (excluding non-melanoma skin cancer) were identified using a multivariate Cox model with backward selection. These were age older than 65 years and current or past smoking.

Lung cancers and lymphoma in patients treated with tofacitinib have also been observed in other clinical studies and in the post-marketing setting.[footnote 1][footnote 2][footnote 3][footnote 4]

Results suggest that these risks are associated with both the 5mg twice-daily dose and the 10mg twice-daily dose (which is approved only in ulcerative colitis).

Non-melanoma skin cancer has been previously reported in patients treated with tofacitinib and was listed in the product information before this review. The risk may be higher in patients treated with tofacitinib 10 mg twice daily than in patients treated with 5 mg twice daily. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Background, including full indications for tofacitinib

Tofacitinib (Xeljanz▼) is a JAK inhibitor which was first authorised in the EU in March 2017. It is authorised for the treatment of:

  • moderate to severe active rheumatoid arthritis in combination with methotrexate (unless not tolerated or inappropriate) in adults who have responded inadequately to, or who are intolerant to, one or more disease-modifying anti-rheumatic drugs (DMARD)
  • active psoriatic arthritis in combination with methotrexate, in adults who have responded inadequately to, or who are intolerant of, one or more DMARD
  • moderately to severely active ulcerative colitis in adults who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biological agent

Tofacitinib is also indicated for the treatment of active polyarticular juvenile idiopathic arthritis (rheumatoid factor positive [RF+] or negative [RF-] polyarthritis and extended oligoarthritis), and juvenile psoriatic arthritis (PsA), in combination with methotrexate (unless not tolerated or inappropriate), in patients 2 years of age and older, who have responded inadequately to previous therapy with DMARDs.

Approved formulations of tofacitinib are 5mg film-coated tablets, 10mg film-coated tablets and 11mg prolonged-release tablets. Tofacitinib 11 mg prolonged-release product once daily has demonstrated pharmacokinetic equivalence to tofacitinib 5 mg film-coated tablets twice-daily.

Based on previous findings from study A3921133, tofacitinib should be used with caution in patients with known risk factors for venous thromboembolism, regardless of indication and dosage. See March 2020, Drug Safety Update. In the same article, we also advised that patients older than 65 years of age are at an increased risk of serious infections and should be treated with tofacitinib only if there is no alternative treatment.

Reporting 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.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines or medical device and diagnostic adverse incidents used in coronavirus (COVID-19) using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app.

Article citation: Drug Safety Update volume 15, issue 3: October 2021: 1.

  1. Cohen SB and others. Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme. RMD Open 2020: volume 6, number e001395. ↩

  2. van Vollenhoven RF and others. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. New England Journal of Medicine 2012: volume 367, pages 508 to 519. ↩

  3. van der Heijde D and others. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: Twelve-month data from a twenty-four–month phase III randomized radiographic study. Arthritis & Rheumatism 2013: volume 65, pages 559 to 570. ↩

  4. Fleischmann R and others. Safety and maintenance of response for tofacitinib monotherapy and combination therapy in rheumatoid arthritis: an analysis of pooled data from open-label long-term extension studies. RMD Open 2017; volume 3, article e000491 ↩

Updates to this page

Published 6 October 2021
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