Janus kinase (JAK) inhibitors: new measures to reduce risks of major cardiovascular events, malignancy, venous thromboembolism, serious infections and increased mortality
We inform healthcare professionals of new risk minimisation measures for JAK inhibitors used to treat chronic inflammatory disorders, consistent with the measures introduced for tofacitinib (Xeljanz) in 2020 and 2021. This advice affects abrocitinib (Cibinqo▼), baricitinib (Olumiant), upadacitinib (Rinvoq▼), and filgotinib (Jyseleca▼) when used for chronic inflammatory disorders.
Advice for healthcare professionals:
- an increased incidence of malignancy, major adverse cardiovascular events (MACE), serious infections, venous thromboembolism (VTE) and mortality, when compared to those treated with tumour necrosis factor (TNF)-alpha inhibitors, has been observed in trials of patients with rheumatoid arthritis with certain risk factors when treated with some JAK inhibitors, particularly tofacitinib – see advice for tofacitinib from 2020 and 2021
- following a review, these risks are considered class effects across JAK inhibitors used for chronic inflammatory disorders and therefore it is advised to avoid prescribing these medicines unless there are no suitable alternatives in patients with the following risk factors:
- age 65 years or older
- current or past long-time smoking
- other risk factors for cardiovascular disease or malignancy
- use caution if prescribing in patients with risk factors for VTE other than those listed above (see below for more details)
- where applicable, use lower doses in patients with risk factors (see individual Summary of Product Characteristics of each medicine for further detail – abrocitinib (Cibinqo), baricitinib (Olumiant), upadacitinib (Rinvoq), and filgotinib (Jyseleca)
- the incidence of non-melanoma skin cancer in the study was also higher with tofacitinib than with a TNF inhibitor – therefore carry out periodic skin examinations in all patients on JAK inhibitor medicines to check for signs of skin malignancy
- inform patients of these risks and key signs and symptoms that could warrant urgent medical attention (see below)
- report suspected adverse drug reactions associated with JAK inhibitors on a Yellow Card
Advice for healthcare professionals to provide to patients and caregivers:
- JAK inhibitors are effective medicines for treating chronic inflammatory disorders such as severe arthritis, psoriatic arthritis, inflammatory bowel diseases, and atopic eczema (atopic dermatitis)
- however, these medicines can increase a patient’s risk of developing major cardiovascular problems (such as heart attack or stroke), cancer, blood clots in the lungs and in the deep veins of the body, serious infections, and death when compared with other treatments for these conditions called TNF-alpha inhibitors
- the risks are greater if you have risk factors, such as being age 65 years or older, have an already increased risk of major cardiovascular problems or cancer, or if you smoke or have smoked in the past for a long time
- if you have a risk factor, your doctor will consider alternative treatment options and only offer you treatment with a JAK inhibitor if nothing else is suitable for you
- your doctor may recommend a lower dose of the JAK inhibitor medicine, to minimise possible risks
- contact your doctor or seek urgent medical advice if, during treatment, you experience chest pain or tightness (which may spread to arms, jaw, neck and back), shortness of breath, cold sweats, light headedness, sudden dizziness, weakness in arms and legs or slurred speech – these are signs of a medical emergency
- examine your skin periodically and let your doctor or nurse know if you notice any new growths on your skin or changes to moles (including itching, shape and discharge, which may not be as obvious on darker skin tones); these could require investigation for possible skin cancer
- always read the leaflet that accompanies your medicines and talk to your doctor, nurse, or pharmacist if you are concerned about side effects
Janus kinase (JAK) inhibitors are a class of medicines that include Cibinqo (abrocitinib), Jyseleca (filgotinib), Olumiant (baricitinib), Rinvoq (upadacitinib), and Xeljanz (tofacitinib). They are used in the treatment of chronic inflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, ulcerative colitis, Crohn’s disease, atopic dermatitis, and alopecia areata. See specific product information for further detail – abrocitinib (Cibinqo), baricitinib (Olumiant), upadacitinib (Rinvoq), and filgotinib (Jyseleca).
This advice is not relevant for use of JAK inhibitors (ruxolitinib (Jakavi▼) and fedratinib (Inrebic▼) to treat myeloproliferative disorders, nor Olumiant used outside of the licence in the short-term treatment of COVID-19.
Risks previously identified for Xeljanz (tofacitinib)
In 2020, the results of a clinical safety trial in patients with rheumatoid arthritis aged 50 years or older with at least one cardiovascular risk factor (Study A3921133; the phase 3B/4 randomised safety endpoint trial)[footnote 1] found that tofacitinib was associated with an increased risk of major adverse cardiovascular events (MACE, defined as death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke), malignancies, VTE, and serious and fatal infections, compared with TNF-alpha inhibitors (etanercept or adalimumab).
Prescribers of tofacitinib were informed of the trial findings and the recommended risk minimisation measures in a letter and Drug Safety Update in 2020 and a further letter and Drug Safety Update in 2021. The tofacitinib product information and educational materials were updated at this time.
Further information on the incidence rates and hazard ratios for these events in the tofacitinib groups compared with the TNF-alpha inhibitor group can be found in the letters for healthcare professionals relating to venous thromboembolism and serious and fatal infections (2020) and major adverse cardiovascular events and malignancies (2021).
Given the findings, we advised that 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.
Review of the risks across the class of JAK inhibitors
Following the findings for tofacitinib, a broader review was conducted by the European Medicines Agency in 2022, looking at all JAK inhibitors indicated for inflammatory diseases.
As well as the results of study A3921133 for tofacitinib, the review considered the preliminary findings of a multi-database observational cohort study of baricitinib (Olumiant) treatment (study B023), which also suggested an increased risk of major cardiovascular events (incidence rate ratio (IRR) 1.92; 95% CI 1.27 to 2.91) and VTE (IRR 1.34; 95% CI 0.84 to 2.14) in patients with rheumatoid arthritis treated with Olumiant compared with those treated with TNF-alpha inhibitors.
The latest review looked at the available mechanistic and safety data for each of the 5 JAK inhibitors approved as treatments for inflammatory conditions. The review concluded that the effects could be considered a class effect, while acknowledging that the extent to which the findings of study A3921133 applied to all JAK inhibitors was dependent on the similarities of each treated population in terms of the presence of risk factors.
The MHRA reviewed the recommendations together with information relevant to the use of these medicines in the UK and sought independent advice from the Pharmacovigilance Expert Advisory Group of the UK’s Commission on Human Medicines. Following this review, changes are being made to the product information for all JAK inhibitor medicines authorised for inflammatory diseases to note the updated risk characterisation and expanded risk minimisation measures. A letter has also been sent to UK healthcare professionals to advise of these changes.
Information on updated risk factors
Based on the data assessed, some updates to the existing warnings for tofacitinib were recommended and these will be implemented for all JAK inhibitors included in the review.
The advice across the class of medicines on the need for caution in use in patients with risk factors for VTE was updated to include VTE risk factors, which are distinct from the cardiovascular and malignancy risk factors mentioned elsewhere. VTE risk factors other than cardiovascular or malignancy risk factors include previous VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, and inherited coagulation disorders.
In the previous update to the tofacitinib product information, it was advised that tofacitinib should only be used in current or past smokers if no suitable treatment alternatives are available, as current or past smoking were identified as predictive factors for development of MACE and malignancies. Further analysis of this risk factor in participants of study A3921133 found that more than 90% of tofacitinib-treated patients who were current or past smokers had a smoking duration of more than 10 years and a median of 35.0 and 39.0 smoking years, respectively. The warnings on MACE and malignancy for all JAK inhibitors have therefore been updated from past smoking to specify long-time past smoking as a risk factor, in addition to current smoking.
Post-hoc analyses of study A3921133 showed that a history of atherosclerotic cardiovascular disease (a composite of coronary artery disease, cerebrovascular disease, or peripheral artery disease) is a risk factor for MACE. Therefore, the warning on MACE for all JAK inhibitors is being updated to include history of atherosclerotic cardiovascular disease as a risk factor.
Increased all-cause mortality is being added as a risk for patients 65 years of age and older.
Where possible, lower doses are recommended for patients with risk factors for these serious side effects (see individual product information for specific advice).
Report suspected reactions on a Yellow Card
Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:
- the Yellow Card website
- the Yellow Card app; download from the Apple App Store or Google Play Store
- some clinical IT systems for healthcare professionals (EMIS, SystmOne, Vision, MiDatabank, and Ulysses)
When reporting suspected adverse drug reactions, please provide as much information as possible, including information about medical history, any concomitant medication, onset timing, and treatment dates. When reporting for a biological medicine or vaccine, please ensure that you provide the brand name (or product licence number and manufacturer), and the specific batch number.
Article citation: Drug Safety Update volume 16, issue 9: April 2023: 2.
Ytterberg SR and others. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. New England Journal of Medicine 2022. Issue 386; pages 316 to 326. ↩