Overview

Diclofenac is a non-steroidal compound with pronounced antirheumatic, anti-inflammatory, analgesic and antipyretic properties¹.

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) regarding the risk of anastomotic leakage and the risk of Kounis syndrome with the use of diclofenac (systemic formulations)². These two safety issues were picked up during the routine assessment of a Periodic Safety Update Report (PSUR) for diclofenac (systemic formulations) products in Europe, where EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) recommended that these risks should also be reflected in all combination products containing diclofenac for systemic use.

(i) Risk of anastomotic leakage

Anastomotic leakage is one of the serious complications after intestinal surgery, specifically after colorectal surgery. It is associated with a higher risk of mortality and significant morbidity, resulting in prolonged hospital stay³. In general, risk factors associated with anastomotic leakage include patient-related factors (e.g. male, above 60 years of age, smoking status and nutritional deficiencies) as well as procedure-related factors (e.g. open vs. laparoscopic approach, prolonged operation time and location of the anastomosis)⁴.

(ii) Risk of Kounis syndrome

Kounis syndrome is defined as acute coronary syndrome accompanying mast cell activation from allergic, hypersensitivity or anaphylactoid reactions⁵. It was first described by Kounis and Zavras in 1991 and has been referred to as “allergic angina” or “allergic myocardial infarction”. The mechanism of Kounis syndrome involves the release of inflammatory cytokines through mast cell activation, which leads to coronary artery vasospasm and/or atheromatous plaque erosion or rupture.

Local Scenario

In Malaysia, there are currently 65 registered products containing diclofenac (systemic use)⁶. The package insert (PI) of diclofenac innovator product has already been updated with the risk of Kounis syndrome and is in the process of a safety information update on the risk of anastomotic leakage.

Adverse Drug Reaction Reports

Since year 2000, the NPRA has received a total of 4,827 reports with 9,313 adverse events suspected to be related to diclofenac containing products. To date, no ADR related to anastomotic leakage and/or Kounis syndrome following the use of diclofenac has been reported to the NPRA. The most commonly reported adverse events were periorbital oedema (1,339), pruritus (1,223), orbital oedema (828), urticarial (594) and rash (532)⁷.

Advice for Healthcare Professionals

• Please be alert on the risk of anastomotic leakage and the risk of Kounis syndrome associated with the use of diclofenac (systemic use).
• It is recommended to maintain close medical surveillance and exercise caution when using diclofenac in patients after gastro-intestinal surgery.
• Consider the diagnosis of Kounis syndrome if patients develop hypersensitivity reaction and myocardial infarction simultaneously.
• Please report all adverse events related to diclofenac use to the NPRA, especially when anastomotic leakage and Kounis syndrome are suspected.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: (4) dlm. BPFK/PPP/07/25 Jld. 4] has been issued for registration holders of diclofenac-containing products to update the local package inserts and consumer medication information leaflet (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. Voltaren^® 50 mg Gastro-resistant tablets Malaysian package insert. [Last revision date: 5 February 2018]
2. EMA (2019). Report from the CMDh meeting held on 27-29 May 2019. EMA/CMDh/204499/2019.
3. Huang, S.R. Tang and C.J. Young (2017). Nonsteroidal anti-inflammatory drugs and anastomotic dehiscence after colorectal surgery: a meta-analysis. ANZ J Surg. doi: 10.111/ans.14322
4. Cata et. al (2017). Non-steroidal anti-inflammatory drugs in the oncological surgical population: beneficial or harmful? A systematic review of the literature. British Journal of Anaesthesia; 119(4):750-64(2017). doi: 10.1093/bja/aex225.
5. Sarfaraz et. al (2015) Allergic acute coronary syndrome (Kounis syndrome). Proc. (Bayl Univ Med Cent) 2015;28(3):358-362
6. The NPRA QUEST 3+ database [Accessed: July 2019]
7. The Malaysian Adverse Drug Reaction database, NPRA [Accessed: July 2019]

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.