Overview

Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor (ARNi), which is a combination of a neprilysin inhibitor (sacubitril) and an angiotensin II receptor blocker (ARB) (valsartan).¹ In Malaysia, sacubitril/valsartan is indicated in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction.² It is also used in combination with other heart failure therapies (e.g. beta-blockers, diuretics, and mineralocorticoid antagonists) as appropriate, in place of an angiotensin-converting enzyme (ACE) inhibitor or ARB.

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) on the risk of psychiatric disorders associated with the use of sacubitril/valsartan.³ 

It has been observed that the use of sacubitril/valsartan has been linked to psychiatric events such as hallucination, paranoia and sleep disorders, in context of psychotic events.⁴ Based on the cases reported in the literature, it was found that psychiatric events occurred after sacubitril/valsartan treatment initiation or when the dose of the combination drug was increased.⁵ The time to onset was reported to be between two (2) to seven (7) days after starting treatment or after dose escalation.^1,5 The exact mechanism on how sacubitril/valsartan causes these psychiatric events are not known. However, it was postulated that neprilysin blockade may contribute to the inhibition of beta-amyloid degradation, a protein that is involved in the pathogenesis of neurodegenerative diseases.

Considering all available data obtained from literature, spontaneous reports including multiple cases with a close temporal relationship, a positive de-challenge and/or re-challenge and plausible mechanism of action, EMA concluded that there is a reasonable possibility of a causal association between sacubitril/valsartan and psychiatric events.³

 Adverse Drug Reaction (ADR) Reports

To date, NPRA has received 170 reports with 434 adverse events suspected to be related to sacubitril/valsartan.⁶ The most frequently reported adverse events for sacubitril/valsartan were dyspnoea (40), dizziness (23), fatigue (19) and cough (13). There were four (4) reports with seven (7) psychiatric events, which were restlessness (2), agitation (1), mental disorder (1), hallucination (1), difficulty sleeping (1) and insomnia (1).

Advice for Healthcare Professionals:

• Consider stopping sacubitril/valsartan treatment if the patient develops any psychiatric events.
• Please report all suspected adverse events associated with sacubitril/valsartan-containing products to the NPRA.

References:

1. Wooster J, Cook E, Shipman D. Psychiatric Manifestations with Sacubitril/Valsartan: A Case Report. Journal of Pharmacy Practice [Internet]. 2019 [Cited 2021 July 14]; 33(4):553-557. Available from https://journals.sagepub.com/doi/abs/10.1177/0897190019842700
2. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). Entresto 50mg Film-coated Tablets [Internet]. Revision date: Dec 2017 [Cited 2021 July 14]. Available from https://www.npra.gov.my
3. European Medicines Agency. Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s) [Internet]... 2021 [Cited 2021 July 14]. EMEA/H/C/PSUSA/00010438/202007. Available from: https://www.ema.europa.eu/en/documents/scientific-conclusion/entresto-epar-emea/h/c/psusa/00010438/202007-scientific-conclusions-grounds-variation-terms-marketing-authorisation-s_en.pdf
4. European Medicines Agency. Annex I Summary of Product Characteristics: Entresto [Internet]. 2021 [Cited 2021 July 14]. Available from: https://www.ema.europa.eu/en/documents/product-information/entresto-epar-product-information_en.pdf
5. Pérez-Roselló V, Batalla-Monedero M, Sánchez-Lázaro I, López-Vilella R, Sierra-San Miguel P, Almenar-Bonet L. Three cases of psychosis after use of sacubitril/valsartan. Revista Espanola de Cardiologia (English ed.). 2020 Jul 29 [Cited 2021 July 14]. Available from https://europepmc.org/article/med/32739142National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2021 [Cited 2021 June 10]. Available from https://www.npra.gov.my
6. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2021 [Cited 2021 Aug 5]. 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, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.