Overview

Azathioprine is an immunosuppressant antimetabolite that is indicated in combination with steroids and/or other immunosuppressive agents/procedures to improve the survival of organ transplants, including kidney, cardiac and liver transplants. Azathioprine, either alone or more commonly in combination with corticosteroid and/or other drugs and procedures, has also been indicated in the management of severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis, autoimmune chronic active hepatitis, pemphigus vulgaris, polyarteritis nodosa, autoimmune haemolytic anaemia, and chronic refractory idiopathic thrombocytopenic purpura.¹ 

In Malaysia, there are currently three (3) products containing azathioprine registered with the Drug Control Authority (DCA).²

Background of the Safety Issue

Erythema nodosum is an inflammation of the subcutaneous fat (septal panniculitis) presented by painful red nodules that are usually seen bilaterally and symmetrically on pretibial areas. Less common areas such as arms, thighs, trunk, buttocks, and face may also be affected. Some adults may encounter fever, malaise, and arthralgias. Erythema nodosum is caused by a hypersensitivity reaction triggered by numerous antigens including infection, medications, sarcoidosis, autoimmune disease, and various causes.³

After considering the evidence from literature, post-marketing reports, and safety data from product registration holders, the European Medicines Agency (EMA) concluded that a causal association between azathioprine and erythema nodosum cannot be ruled out as a new manifestation of azathioprine hypersensitivity reaction. The EMA has therefore requested a package insert and leaflet update for all azathioprine-containing products with the inclusion of erythema nodosum under immune system disorders.⁴

The exact mechanism of erythema nodosum is still unclear. However, it is postulated that the imidazole component of azathioprine might bind with certain proteins and cause hypersensitivity reactions.⁵ Erythema nodosum without complications usually has an excellent prognosis with spontaneous recovery in weeks without any sequelae.³ In published case reports and post-marketing reports, erythema nodosum developed within three (3) weeks following azathioprine initiation and resolved within three (3) weeks after azathioprine discontinuation. Positive rechallenges have been observed in some reports, in which erythema nodosum returned within hours to four (4) weeks following azathioprine reintroduction.⁶

Adverse Drug Reaction Reports⁷

The NPRA has received 214 reports with 418 adverse events suspected to be related to azathioprine-containing products. The most reported adverse events were pancytopenia (24), alanine aminotransferase increased (17), and vomiting (16). Thus far, no local cases of erythema nodosum have been reported to the NPRA but there were two (2) reports of erythema and one (1) report of erythema urticarial following the use of azathioprine.

Advice for Healthcare Professionals

• Be aware of the risk of hypersensitivity following the administration of azathioprine. The clinical manifestations may include erythema nodosum, myalgia, arthralgia, fever, dizziness, nausea, vomiting, and hypertension.
• Educate patients about the risk of hypersensitivity reaction while taking azathioprine, and remind them to notify healthcare professionals if any of the abovementioned signs and symptoms appear.   
• Report all suspected adverse events associated with azathioprine-containing products to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (7) Jld.1] has been issued for all registration holders of products containing azathioprine to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). IMURAN 50MG TABLET (azathioprine) [package insert]. 2021 Sep [cited 2022 Apr 4]. The Malaysian Product Registration Database (QUEST). Available from: http://www.npra.gov.my (access restricted).
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2022 [cited 2022 Apr 4]. Available from: https://www.npra.gov.my
3. Leung AKC, Leung KF, Lam JM. Erythema nodosum. World J Pediatr. 2018;14:548-554. Available from: https://doi.org/10.1007/s12519-018-0191-1
4. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC) Recommendations on signals. Adopted at the 6-9 April 2021 PRAC meeting. [Internet]. 2021 May 3 [cited 2022 Apr 4]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-6-9-april-2021-prac-meeting_en.pdf
5. Bidinger JJ, Sky K, Battafarano DF, Henning JS. The cutaneous and systemic manifestations of azathioprine hypersensitivity syndrome. J Am Acad Dermatol. 2011 Jul;65(1):184-91.Available from: https://pubmed.ncbi.nlm.nih.gov/21496951/#:~:text=Abstract,mimics%20infection%20or%20disease%20exacerbation.
6. Netherlands Pharmacovigilance Centre Lareb. Azathioprine and erythema nodosum [Internet]. 2020 Sep 30 [cited 2022 Apr 4]. Available from: https://databankws.lareb.nl/Downloads/Signals_2020_azathioprine_erythema_nodosum.pdf
7. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2022 [cited 2022 Apr 4]. 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.

Written by: Wang Khee Ing
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr Azuana Ramli