Overview

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which the overactive immune system attacks the healthy joint tissues, causing pain, swelling, stiffness, and result in loss of joint function.¹ Tofacitinib, baricitinib and upadacitinib are drugs classified as Janus kinase (JAK) inhibitors, which are approved in Malaysia for the treatment of rheumatoid arthritis and certain chronic inflammatory conditions.^2-4 These medicines work by suppressing the JAK enzymes that transmit cytokine or growth factor signals involved in inflammatory responses and immune functions, thus decreasing the activity of the overactive immune system.^2-5

In Malaysia, the Drug Control Authority (DCA) had registered one (1) product containing tofacitinib, two (2) products containing baricitinib, and one (1) product containing upadacitinib.^2-4

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from the United States Food and Drug Administration (US FDA) on the risk of major adverse cardiovascular events (MACE) and malignancies [excluding non-melanoma skin cancer (NMSC)] related to Janus kinase (JAK) inhibitors used in RA patients.⁵ 

The safety concern was highlighted by a large randomised post-authorisation safety study (PASS) in RA patients who were aged ≥50 years with at least one additional cardiovascular risk factor, comparing tofacitinib with tumour necrosis factor (TNF) blockers (etanercept or adalimumab). The co-primary endpoints were MACE (defined as cardiovascular deaths, myocardial infarction, and stroke) and malignancies (excluding NMSC).⁶ NMSC was excluded from the review because it has been previously reported and sufficiently documented in the package insert (PI), where periodic skin examination is recommended for patients at increased risk of skin cancer.²

For MACE, the estimated HR and 95% CI relative to TNF blockers were 1.33 (0.91, 1.94). For malignancies (excluding NMSC), the HR and 95% CI were 1.48 (1.04, 2.09). In particular, an increase in non-fatal myocardial infarction, lung cancer and lymphoma, has been observed in patients treated with tofacitinib versus TNF blockers.^6-8

Baricitinib and upadacitinib are both JAK inhibitors that are also used for the treatment of rheumatoid arthritis. Despite they have not been studied in similar large safety clinical trials, US FDA has imposed a PI update requiring the most prominent Boxed Warnings on both baricitinib and upadacitinib considering their similar mechanism of actions with tofacitinib.⁵ On the other hand, the European Medicines Agency (EMA)⁸, the Swiss Agency for Therapeutic Products (Swissmedic)⁹, the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (UK MHRA)¹⁰, and the Japan's Pharmaceuticals and Medical Devices Agency (PMDA)¹¹ have all only taken action on tofacitinib thus far.

Adverse Drug Reaction (ADR) Reports

To date, NPRA has received 64 reports totalling 93 adverse events following the administration of tofacitinib and baricitinib, while no report has been received for upadacitinib. Out of these reports, chest pain (1) has been reported with tofacitinib therapy. However, no adverse events related to MACE and malignancies (excluding NMSC) have been reported in association with JAK inhibitors.¹²

NPRA is currently evaluating the need to update the local PI of baricitinib and upadacitinib with this safety information.

Advice for Healthcare Professionals

• Consider the benefits and risks before prescribing or continuing therapy with JAK inhibitors including tofacitinib, baricitinib and upadacitinib.
• Try to reserve the usage of tofacitinib for patients who have not responded or cannot tolerate one or more TNF blockers.
• Only use tofacitinib if no suitable treatment alternatives are available in patients over 65 years of age, current or past smokers, and those with other cardiovascular or malignancy risk factors.
• Inform patients on the emerging cardiovascular and malignancy risks related to JAK inhibitors. Advise patients to monitor on the signs and symptoms and to seek medical attention if they occur.
• Please report all suspected adverse events associated with JAK inhibitors to the NPRA.

References:

1. United States National Institute of Arthritis and Musculoskeletal and Skin Diseases. Rheumatoid arthritis [Internet]. 2019 Sep [cited 2021 Dec 24]. Available from: https://www.niams.nih.gov/health-topics/rheumatoid-arthritis/advanced
2. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST): XELJANZ (tofacitinib) package insert [Internet]. 2020 Jun 20 [cited 2021 Dec 24]. Available from: http://www.npra.gov.my (access restricted).
3. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST): OLUMIANT (baricitinib) package insert [Internet]. 2021 Sep 30 [cited 2021 Dec 24]. Available from: http://www.npra.gov.my (access restricted).
4. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST): RINVOQ (upadacitinib) package insert [Internet]. 2021 Aug 2 [cited 2021 Dec 24]. Available from: http://www.npra.gov.my (access restricted).
5. United States Food and Drug Administration (U.S. FDA). FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions [Internet]. FDA Drug Safety Communication. 2021 Sep 1 [cited 2021 Sep 7]. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death
6. United States National Library of Medicine. Safety study of tofacitinib versus tumor necrosis factor (TNF) inhibitor in subjects with rheumatoid arthritis [Internet]. ClinicalTrials.gov. 2021 Aug 17 [cited 2021 Oct 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT02092467
7. United States Food and Drug Administration (U.S. FDA).  Drugs@FDA: XELJANZ (tofacitinib) package insert [Internet]. 2021 Dec [cited 2021 Dec 24]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/
8. European Medicines Agency (EMA). PRAC recommendations on signals: Adopted at the 7-10 June 2021 PRAC meeting [Internet]. 2021 Jul 5 [cited 2021 Jul 14]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-7-10-june-2021-prac-meeting_en.pdf
9. Swissmedic: Healthcare Professional Communications. DHPC - XELJANZ® (tofacitinib): Increased risk of serious adverse cardiovascular events and malignancies when using tofacitinib compared to TNF-alpha inhibitors [Internet]. 2021 Sep 15 [cited 2021 Sep 21]. Available from: https://www.swissmedic.ch/swissmedic/en/home/humanarzneimittel/market-surveillance/health-professional-communication--hpc-/dhpc-xeljanz-tofacitinib0.html
10. Medicines and Healthcare Products Regulatory Agency (MHRA). Tofacitinib (Xeljanz): new measures to minimise risk of major adverse cardiovascular events and malignancies [Internet]. Drug Safety Update. 2021 Oct 6 [cited 2021 Oct 25]. Available from: https://www.gov.uk/drug-safety-update/tofacitinib-xeljanzv-new-measures-to-minimise-risk-of-major-adverse-cardiovascular-events-and-malignancies
11. Pharmaceuticals and Medical Devices Agency (PMDA). Summary of investigation results: Tofacitinib citrate [Internet]. 2021 Oct 21 [cited 2021 Oct 25]. Available from: https://www.pmda.go.jp/files/000243235.pdf
12. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2021 [cited 2021 Oct 27]. Available from: https://www.npra.gov.my (access restricted).

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.