Overview

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that exhibits virological suppression, reducing the amount of virus in the body. Efavirenz is commonly used along with other medications for the treatment of human immunodeficiency virus (HIV) infection.

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received safety information from the Pharmaceuticals and Medical Devices Agency (PMDA), Japan, regarding the risk of rate corrected QT(QTc) interval prolongation following the use of efavirenz. QTc interval prolongation together with the elevation of efavirenz blood concentration were observed in a clinical study. Based on the expert opinions, evidence from the literature, and international reports of QTc interval prolongation in patients taking this medication, PMDA concluded that the product information of efavirenz must be revised to include “prolonged QT” in the adverse reactions section¹.

Efavirenz is metabolised by the CYP2B6 enzyme, which is part of the cytochrome P450 (CYP) group of enzymes. Studies have shown that patients with genetic polymorphism on the CYP2B6 enzyme (CYP2B6*6/*6 carriers) are prone to develop QTc interval prolongation. This is due to the decreased clearance of the drug from the body, causing increased concentration of efavirenz in the blood. Despite that, the propensity for efavirenz to provoke torsade de pointes (TdP) is not known².

A study conducted to explore the genetic polymorphism of CYP2B6 among the major ethnic groups in Malaysia has shown that CYP2B6 polymorphism in Malaysia is variable among the Malays, Chinese and Indians. From the study, CYP2B6*6 has shown to be more prevalent among the Malays as compared to Indians and Chinese. Although the difference was very small and may not have an impact at population level, this study provided some insights on the genetic variability of CY2B6 enzyme among Malaysians³.

Adverse Drug Reaction Reports

Since year 2010, NPRA has received 333 reports with680 adverse events suspected to be linked to efavirenz. The most commonly reported reactions were maculopapular rash, pruritus and dizziness. None of the reports was on QTcprolongation⁴.

 Advice for Healthcare Professionals

• Monitor the electrocardiogram (ECG) profile of patients taking antiretroviral drugs, especially efavirenz or any other drug that has the risk to induce QTc interval prolongation.
• Consider alternative treatment for patients who are prescribed concomitantly a drug with a known risk of TdP, as well as patients at increased risk for TdP.
• Please report any adverse drug reactions suspected to be associated to the use of efavirenz to NPRA.

A directive [Ruj. Kami: (18) dlm. BPFK/PPP/07/25 Jld. 2] has been issued by NPRA for updates to the local product packaging insert and consumer medication information leaflet (Risalah Maklumat Ubat untuk Pengguna) related to this safety issue. Please refer to the directive for more information.

References:

1. Pharmaceutical and Medical Devices Agency (PMDA)Japan (2018). Summary of Investigation Results – Efavirenz.
2. Abdelhady A.M et al. (2016). Efavirenz inhibits the human ether-a-go-go related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele carriers. J Cardiovasc Electrophysiol 27(10):1206–1213.
3. N. Musa et al (2012). Haplotypes frequencies of CYP2B6 in Malaysia. J Postgrad Med. 58 (4) 235-241.
4. The Malaysian Adverse Drug Reaction database, NPRA [Accessed: 12 March 2018]

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.