Medicines and Healthcare products Regulatory Agency (MHRA) announces new risk minimisation measures for Janus kinase (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.
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) 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, venous thromboembolism (VTE), and serious and fatal infections, compared with tumour necrosis factor (TNF)-alpha inhibitors (etanercept or adalimumab). The tofacitinib product information and educational materials were updated at this time. Given the findings, MHRA 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.
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 United Kingdom and sought independent advice from the Pharmacovigilance Expert Advisory Group of the United Kingdom’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.
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.
Advice for healthcare professionals:
- An increased incidence of malignancy, MACE, serious infections, VTE and mortality, when compared to those treated with 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.
- 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.
- Where applicable, use lower doses in patients with risk factors.
- 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.
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/janus-kinase-jak-inhibitors-new-measures-to-reduce-risks-of-major-cardiovascular-events-malignancy-venous-thromboembolism-serious-infections-and-increased-mortality
In Hong Kong, there are 3 registered pharmaceutical products containing tofacitinib, namely Xeljanz Tablets 5mg (HK-63303), Xeljanz XR Extended Release Tablets 11mg (HK-66141) and Xeljanz Tablets 10mg (HK-66833) which are registered by Pfizer Corporation Hong Kong Limited; 2 products containing baricitinib, namely Olumiant Tablets 2mg (HK-65663) and Olumiant Tablets 4mg (HK-65664) which are registered by Eli Lilly Asia, Inc.; 2 products containing upadacitinib, namely Rinvoq Prolonged-Release Tablets 15mg (HK-66872) and Rinvoq Prolonged-Release Tablets 30mg (HK-67512) which are registered by Abbvie Limited; and 3 products containing abrocitinib, namely Cibinqo Tablets 100mg (HK-67658), Cibinqo Tablets 200mg (HK-67659) and Cibinqo Tablets 50mg (HK-67660) which are registered by Pfizer Corporation Hong Kong Limited. All products are prescription-only medicines. There is no registered pharmaceutical product containing filgotinib.
So far, the Department of Health (DH) has received adverse drug reaction related to tofacitinib (9 cases; of which 2 cases were related to cancer, 3 cases were related to deep vein thrombosis, one case was related to disseminated tuberculosis, one case was related to cellulitis, one case was related to pneumonia and one case was related to herpes zoster disseminated), baricitinib (3 cases; of which one case was related to deep vein thrombosis and one case was related to pneumocystis jirovecii pneumonia) and upadacitinib (6 cases; of which 4 cases were related to herpes zoster, one case was related to cytomegalovirus colitis). The DH has not received any case of adverse drug reaction related to abrocitinib.
Related news on the risk of blood clots, serious heart-related problems, cancer and serious infections of JAK inhibitors 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 25 Apr 2023. Letters to inform local healthcare professionals were issued by the DH on 29 Jul 2019, 19 Jun 2020, 15 Jun 2021, 2 Sep 2021 and 31 Oct 2022.
In Dec 2019, the Registration Committee of the Pharmacy and Poisons Board (the Committee) discussed the matter on the risk of blood clots and death associated with the use of tofacitinib, and decided that the sales pack or package insert of tofacitinib products should include safety information about increased risk of blood clots and death with higher dose (10 mg twice daily).
In Dec 2021, the Committee discussed the matter on the risk of venous thromboembolic events (including deep vein thrombosis and pulmonary embolism) associated with the use of JAK inhibitors (tofacitinib, baricitinib and ruxolitinib), and decided that the sales pack or package insert of these products should include the relevant safety information.
As previously reported, the matter will be further discussed by the Committee.
Ends/Thursday, Apr 27, 2023
Issued at HKT 18:00
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