Overview

Mycophenolic acid (MPA) is an immunosuppressant that is potent, selective, non-competitive and is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), which is involved in the de novo pathway of guanosine nucleotide synthesis.¹ It is indicated with corticosteroids and ciclosporin for the prophylaxis of acute transplant rejection in adult patients receiving renal transplants.²

Mycophenolate mofetil (MMF), the 2-morpholinoethyl ester of mycophenolic acid (MPA), is indicated for the prophylaxis of acute organ rejection in patients receiving organ transplants such as kidney, heart and liver.¹ It is also indicated with corticosteroids for treatment of lupus nephritis (for full prescribing details, please refer to product package insert).

Both MMF and MPA exert immunosuppressive effects which are mainly based on the inhibition of the de novo purine biosynthesis required for proliferation of T- and B-lymphocytes.^1-3

De novo purine synthesis inhibitor-associated acute inflammatory syndrome is an extremely rare paradoxical reaction which is characterised by pyrexia, arthritis, arthralgia, myalgia and elevated levels of inflammatory markers.^3-5

In Malaysia, there are currently eight (8) MMF products and four (4) MPA products registered with the Drug Control Authority (DCA). Adverse events such as arthralgia, myalgia and pyrexia have been documented as common manifestations of acute inflammatory syndrome in MMF and MPA package inserts.^1,2

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) has received information from European Medicines Agency (EMA) on de novo purine synthesis inhibitors-associated acute inflammatory syndrome.⁴ The signal was identified from the assessment of Periodic Safety Update Report (PSUR) for MMF and MPA-containing products. Based on reports from literature and post-marketing reports with close temporal relationship, positive dechallenge and rechallenge and plausible mechanism of action, the Pharmacovigilance Risk Assessment Committee (PRAC) of EMA considers a causal relationship between MMF, MPA and de novo purine synthesis inhibitors-associated acute inflammatory syndrome. EMA has requested the product registration holders of the products involved to update package insert with the risk of de novo purine synthesis inhibitors-associated acute inflammatory syndrome.⁶

Adverse Drug Reaction (ADR) Reports

NPRA has received 34 ADR reports with 59 adverse events suspected to be related to mycophenolic acid (MPA) and 134 ADR reports with 256 adverse events suspected to be related to mycophenolate mofetil (MMF).⁷ The most frequently reported adverse events for MPA were diarrhoea (7), white blood count decreased (4) and kidney transplant rejection (4), while for MMF were diarrhoea (55), vomiting (11), nausea (11) and abdominal discomfort (9). To date, no ADR report of acute inflammatory syndrome related to MPA and MMF has been received by NPRA.

Advice for Healthcare Professionals

• Be alert on the risk of acute inflammatory syndrome following the use of MPA and MMF.
• Carefully consider this risk when patients are showing the signs and symptoms of pyrexia, arthritis, arthralgia, myalgia and elevated inflammatory markers.
• Consider discontinuation of MMF or MPA containing products as literature case reports showed rapid improvement and resolution of symptoms.
• Please report all suspected adverse events associated with MMF and MPA containing products to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (29)] has been issued for registration holders of mycophenolate-containing products (mycophenolate mofetil dan mycophenolic acid) to update the local package inserts with this new safety information.

References:

1. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). Mycophenolate mofetil local package insert [Internet]. Last revision date: 2018 May [Cited 2021 March 18]. Available from https://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). Mycophenolic acid local package insert [Internet]. Last revision date: 2016 August [Cited 2021 March 18]. Available from https://www.npra.gov.my
3. Maruyama, T. Sadahira, Y. Mitsui, K. Wada et al. Acute inflammatory syndrome paradoxically induced by de novo purine inhibitors synthesis before renal transplantation: A case report and review of the literature. Article in press [Internet]. 2017. [Cited 17 March 2021]; 0041-1345/18. Available from https://pubmed.ncbi.nlm.nih.gov/29571743/
4. European Commision. Annex I Scientific Conclusions and Grounds for the Variation of the Terms of the Marketing Authorisation(s). EMEA/H/C/PSUSA/00010550/202005. 2021 February 19 [Cited 2021 March 24]. Available from https://ec.europa.eu/health/documents/community-register/html/ho27343.htm
5. Konon, Mary E. Cronin and Lawrence M. Ryan. Acute Inflammatory Syndrome Following Introduction of Mycophenolate Mofetil in a Patient with Systemic Lupus Erythematosus. Arthritis & Rheumatism (Arthritis Care & Research) [Internet]. 2008 [Cited 17 March 2021]. Vol.59, No.5, pp 754-756. Available from https://onlinelibrary.wiley.com/doi/full/10.1002/art.23574
6. Pharmacovigilance Risk Assessment Committee (PRAC). Minutes of PRAC meeting on 23-26 November 2020: European Medicines Agency (EMA) [Internet]. 28 January 2021 [Cited 2021 March 15]. Available from https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-23-26-november-2020_en.pdf
7. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2021 [Cited 2021 May 5]. Available from https://www.npra.gov.my

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.