Overview

Vascular endothelial growth factor (VEGF) inhibitors are indicated for the treatment of various types of cancers, including renal cell carcinoma, hepatocellular carcinoma, thyroid and soft tissue cancers (for full prescribing information, please see package inserts).¹ Currently, there are 21 registered products containing VEGF inhibitors for systemic use (except application on eyes).

Artery dissection refers to the tear along the inside wall of an artery.² It is usually presented with sudden, severe abdominal, chest, or back pain.³ Artery aneurysm is a balloon-like bulge in an artery. This bulge can rupture, causing internal bleeding and possibly lead to death, if not treated urgently.

The mechanism of VEGF inhibitors for systemic use (except application on eyes) causing artery dissections and aneurysms remain unclear but is thought to be due to the weakening of vascular wall integrity.³ Risk factors include hypertension or aggravation of pre-existing hypertension, a previous history of aneurysm, smoking, diabetes mellitus, coronary, cerebrovascular or peripheral arterial disease.^2,3 Hypertension is also a well-known adverse effect of VEGF inhibitors.¹

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) on the risk of artery dissections and aneurysm associated with the use of VEGF inhibitors.⁴ Following a safety assessment, EMA concluded that product registration holders of VEGF inhibitors for systemic use (except application on eyes) are required to update the package insert with the risk of artery dissections and aneurysms.

Adverse Drug Reaction (ADR) Reports

NPRA has received a total of 922 reports with 1,767 adverse events suspected to be related to products containing VEGF inhibitors for systemic use (except application on eyes).⁵ To date, there are two (2) reports of aneurysms associated with bevacizumab use.

Advice for Healthcare Professionals

• Be alert on the risk of artery dissections and aneurysms following the use of VEGF inhibitors.
• Before prescribing VEGF inhibitors for systemic use (except application on eyes), carefully consider the risk of artery dissections and aneurysms in patients with risk factors.
• In patients receiving a systemic VEGF inhibitor, reduce as far as possible any modifiable risk factors such as smoking and hypertension.
• Please report all suspected adverse events associated with products containing VEGF inhibitors to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9 (20)] has been issued for all registration holders of products containing VEGF inhibitors for systemic use (except application on eyes) to update the local package inserts to reflect this safety information.

References:

1. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). VEGF inhibitors local package insert [Internet]. Cited on 2021 March 18. Available from https://www.npra.gov.my
2. Health Canada. Summary Safety Review: Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors [Internet]. 2018 December 3 [Cited on 2021 March 18]. Available from https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00213
3. United Kingdom Medicines and Healthcare Products Regulatory Agency (UK MHRA). Drug Safety Update. Systemically Administered VEGF Pathway Inhibitors: Risk of Aneurysm and Artery Dissection [Intenet]. 2020 July 31 [Cited on 2021 March 18]. Available from https://www.gov.uk/drug-safety-update/systemically-administered-vegf-pathway-inhibitors-risk-of-aneurysm-and-artery-dissection
4. European Medicines Agency (EMA). PRAC Recommendations on Signals Adopted at the 8-11 July 2019 PRAC Meeting. 2019 August 6 [Cited on 2021 March 18]. EMA/PRAC/347675/2019.
5. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database [Internet]. 2021 [Cited on 2021 February 2]. 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.