Overview

Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb) indicated for the treatment of advanced melanoma as monotherapy in adults, or treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC).¹ While nivolumab facilitates the patient’s immune system to fight the tumour cells, it may also direct the immune system against other ‘healthy’ tissues and cause severe immune-related adverse events such as immune-related colitis.²

Background

The National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) on reports of cytomegalovirus (CMV) infection or reactivation associated with the use of nivolumab.³ In a European review of spontaneous and clinical trial reports of nivolumab, there was a total of 20 serious cases of CMV infection or reactivation. From this total, there were two (2) cases of colitis associated with CMV infection or reactivation, one of which was fatal.⁴

Based on the assessment made, EMA concluded that the benefit-risk balance of nivolumab remains favourable. However, the product registration holder of nivolumab is required to revise the existing warning on immune-related colitis to include CMV infection or reactivation in the product information.

Adverse Drug Reaction Reports

NPRA has received two (2) reports with three (3) adverse events suspected to be related to nivolumab use. No adverse event regarding CMV infection or reactivation has been reported locally.⁴

Advice for Healthcare Professionals

• Advise patients to inform their doctor immediately at the onset of symptoms suggestive of colitis, such as diarrhoea, blood in stools or abdominal pain.⁴
• In patients presenting with diarrhoea or colitis following nivolumab therapy, investigate possible causes by performing a stool infection work-up and CMV screening.
• In patients diagnosed with corticosteroid-refractory immune-related colitis, the use of an additional immunosuppressive agent should only be considered after other causes including CMV infection or reactivation are excluded.
• Report all suspected adverse events associated with nivolumab-containing products to the NPRA.

References:

1. Nivolumab Malaysian Local Product Information [Last revision date: July 2019]
2. Franklin et al. (2017). Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis. European Journal of Cancer 86:248-256.
3. European Medicine Agency (2019). PRAC: minutes of the meeting. EMA/PRAC/692665/2019. Retrieved from https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-8-11-july-2019_en.pdf
4. Medicines and Healthcare products Regulatory Agency (2019). Drug Safety Update. Nivolumab (Opdivo): Reports of Cytomegalovirus (CMV) Gastrointestinal Infection or Reactivation. Retrieved from: https://www.gov.uk/drug-safety-update/nivolumab-opdivo-reports-of-cytomegalovirus-cmv-gastrointestinal-infection-or-reactivation
5. The Malaysian Adverse Drug Reaction database, NPRA [Accessed: January 2020]

 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.