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.

Overview

Azacitidine is an antineoplastic agent approved in Malaysia for the treatment of myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), and acute myeloid leukaemia (AML), where haematopoietic stem cell transplantation is not eligible.¹ Azacitidine exerts its antineoplastic effects through various mechanisms, including cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of DNA. There are currently 10 products containing azacitidine products registered with the Drug Control Authority (DCA), 8 of which are in injectable forms.²

Cutaneous vasculitis is an inflammation of small or medium-sized blood vessels in the skin.^3-4 It can be caused by infections, medications, autoimmune diseases, malignancies, or blood disorders. These stimuli can trigger the body’s immune system to target and damage blood vessels, causing blood and fluid leakage into nearby tissues, which leads to rash and swelling.³ Cutaneous vasculitis encompasses a broad spectrum of disease states, ranging from single-organ vasculitis of the skin to a component of the systemic vasculitis.^4-5 The severity can range from mild and self-limiting to potentially life-threatening.

Leukocytoclastic vasculitis is a form of cutaneous vasculitis that affects the small vessels.⁶ It is clinically characterised by palpable purpura and histopathologically by: (1) inflammatory infiltrate composed of neutrophils with signs of leukocytoclasia (disintegration of nuclei into fragments or nuclear dust); (2) fibrinoid necrosis; and (3) signs of damage of the vessel wall and surrounding tissue (e.g., extravasated red blood cells).

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA), through its global safety signal monitoring, became aware that the European Medicines Agency (EMA) had requested the product registration holders of azacitidine-containing medicinal products (injectable formulation only) to update their package insert with cutaneous vasculitis-related information.⁷ The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has considered that there is at least a reasonable possible causal relationship between azacitidine injectable formulations and cutaneous vasculitis based on available data in EuraVigilance and the literature. At the moment, no similar action is required for oral azacitidine, but the risk will continue to be monitored through routine pharmacovigilance activities.  

In the literature, a case report described biopsy-proven azacitidine-induced leucocytoclastic vasculitis in a 59-year-old Indian female with MDS.⁸ The patient developed painful, burning erythematous plaques of varying sizes over the trunk and extremities two days after receiving subcutaneous azacitidine injections. The condition resolved following the discontinuation of azacitidine (positive dechallenge) and treatment with oral prednisolone. No recurrence of skin lesions was reported after switching to decitabine. The mechanisms by which azacitidine contributes to cutaneous vasculitis have not been described. However, underlying haematological malignancies may also act as a potential confounder.^4,6

Adverse Drug Reaction Reports⁹

NPRA has received 17 reports with 31 adverse events suspected to be related to azacitidine. While not all reports specified the formulation used, all were received before the oral products were registered in March 2024. The most frequently reported adverse events were injection site erythema (2 reports), death (2), and dermatitis contact (1). No local reports of cutaneous vasculitis related to azacitidine have been received till date.

Advice for Healthcare Professionals

• Be alert to the potential risk of cutaneous vasculitis following the use of azacitidine, especially with the injectable form.
• Educate patients about to seek immediate medical attention if they experience any unusual or worsening skin symptoms after receiving azacitidine, such as rashes or bruises-like marks that do not fade when pressed, which may be accompanied by pain or burning sensations, particularly on the lower extremities.
• If cutaneous vasculitis is suspected, consider referring the patient to dermatologists for diagnosis confirmation and further management. Carefully weigh the risks and benefits of discontinuing azacitidine after ruling out other potential triggers, and consider alternative treatment options.
• Report all suspected adverse events associated with all forms of azacitidine-containing products to the NPRA.

Regulatory Actions

The NPRA has completed a review of this safety issue, and a directive [Ruj. Kami: NPRA.600-1/9/13 (44) Jld.1] has been issued for all registration holders of products containing azacitidine (injectable formulations only) to update the local package inserts to reflect this safety information.

While there is currently insufficient evidence to warrant similar updates to the local package inserts for oral azacitidine products, the NPRA will continue to monitor the safety profiles of all azacitidine products.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). Vidaza Powder for Suspension for Injection 100mg/vial local package insert [Internet]. 2023 Dec [cited 2024 Apr 09]. Available from: http://www.npra.gov.my.
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Apr 09]. Available from: https://www.npra.gov.my
3. British Association of Dermatologists. Patient information leaflet – cutaneous vasculitis [Internet]. 2023 Jul [cited 2024 Apr 09]. Available from: https://cdn.bad.org.uk/uploads/2021/11/19174046/Cutaneous-vasculitis-PIL-July-2023.pdf
4. Alpsoy E. Cutaneous vasculitis; An algorithmic approach to diagnosis. Front Med (Lausanne). 2022 Sep 21;9:1012554. doi: 10.3389/fmed.2022.1012554. Available from: https://doi.org/10.3389/fmed.2022.1012554
5. Micheletti RG. Treatment of cutaneous vasculitis. Front Med (Lausanne). 2022 Nov 18;9:1059612. doi: 10.3389/fmed.2022.1059612. Available from: https://doi.org/10.3389%2Ffmed.2022.1059612
6. Fraticelli P, Benfaremo D, Gabrielli A. Diagnosis and management of leukocytoclastic vasculitis. Intern Emerg Med. 2021 Jun;16(4):831-841. Available from: https://doi.org/10.1007/s11739-021-02688-x
7. European Medicines Agency (EMA). PRAC recommendations on signals. Adopted at the 25-28 September 2023 PRAC meeting. Azacitidine – Cutaneous vasculitis [Internet]. 2023 Oct 23 [cited 2024 Apr 09]. Available from: https://www.ema.europa.eu/en/documents/committee-report/prac-recommendations-signals-adopted-25-28-september-2023-prac_en.pdf
8. Lunge, S & Bhise, R. Azacitidine-induced Leukocytoclastic Vasculitis. Indian Journal of Drugs in Dermatology [Internet]. 2016 Jul–Dec [cited 2024 Apr 09];2(2):p 112-114. Available from: https://journals.lww.com/iodd/fulltext/2016/02020/azacitidine_induced_leukocytoclastic_vasculitis.14.aspx
9. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Apr 09]. Available from: https://www.npra.gov.my (access restricted).

Written by: Wang Khee Ing

Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali