Overview

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated in the combination treatment of human immunodeficiency virus (HIV-1).¹

Currently, there are 11 products containing efavirenz (including combination products) registered in Malaysia, all of which are in oral formulations.

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) has received information from the registration holder of efavirenz products regarding the risk of late onset neurotoxicity associated with efavirenz use.

Efavirenz is mainly metabolised by the cytochrome P450 system (e.g. isozymes CYP2B6) in the liver.^1-3 Efavirenz toxicities occur more commonly in patients with CYP2B6 slow metaboliser genotypes, such as black African genetic ancestry which are associated with increased efavirenz levels.^2,3

Based on all available evidence reviewed from signal detection from adverse event reports and literature studies, Swissmedic has requested the registration holders of efavirenz products to update package insert with this safety information.

Adverse Drug Reaction (ADR) Reports

The NPRA has received a total of 502 ADR reports with 925 adverse events suspected to be related to efavirenz containing products.⁴ To date, no ADR related to ataxia or encephalopathy following the use of efavirenz products has been reported to the NPRA.

Advice for Healthcare Professionals

• Be alert on the risk of late onset neurotoxicity including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), which may occur months to years after the use of efavirenz containing products.
• Patients with signs and symptoms of serious neurologic adverse events should be evaluated promptly to assess the possibility of relatedness to efavirenz and whether or not discontinuation of efavirenz is warranted.
• Report all suspected adverse events associated with efavirenz containing products to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (14)] has been issued for registration holders of efavirenz containing products to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

References:

1. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). Efavirenz local package insert [Internet]. Last revision date: 2020 May [Cited 2020 November 30]. Available from: https://www.npra.gov.my
2. Variava E, Sigauke FR, Norman J, Rakgokong M, Muchichwa P, Mochan A, Maartens G, Martinson NA. Late efavirenz-induced ataxia and encephalopathy: a case series. Journal of acquired immune deficiency syndromes (1999). 2017 Aug 15 [Cited on 2020 Novmeber 30];75(5):577. Available from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532735/
3. Cross HM, Chetty S, Asukile MT, Hussey HS, Pan EL, Tucker LM. A proposed management algorithm for late-onset efavirenz neurotoxicity. South African Medical Journal. 2018 May 8 [Cited on 2020 November 30];108(4):271-4. Available from https://www.ajol.info/index.php/samj/article/view/170663
4. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2021 [Cited 2020 November 30]. 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.