Overview

Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor, which is indicated for the treatment of breast cancer in postmenopausal women.¹

Depression is a mental disorder that causes a constant feeling of sadness and loss of interest in previously rewarding or enjoyable activities. People with depression often feel tired and have problems with sleep, appetite & concentration.²

Background of Safety Issue

In February 2021, the National Pharmaceutical Regulatory Agency (NPRA) had learned from the European Medicines Agency (EMA) on the risk of depression associated with anastrozole. Based on the available evidence from a variety of sources, including the European (EudraVigilance) and the Netherlands (Lareb) pharmacovigilance databases, literature, cumulative review of clinical trial data, and the biological plausibility, EMA concluded there is a drug-risk association of anastrozole with depression that warranted product information update for all anastrozole-containing products.³

In postmenopausal women, oestrogen is primarily synthesised in the peripheral tissues through the conversion of adrenal androgens to oestrone and oestradiol by the aromatase enzyme. As an aromatase inhibitor, anastrozole inhibits this conversion which consequently leads to the reduction of serum oestradiol concentrations. This mechanism of effect is postulated to cause mood disturbances.^4,5 The time-to-onset of depression reported in the safety review ranges from one (1) day to one (1) year after anastrozole is taken.⁴ Depression has been documented in the product information of other aromatase inhibitors registered in Malaysia, namely letrozole and exemestane^6,7, suggesting a class effect.⁴

Adverse Drug Reaction (ADR) Reports

To date, NPRA has received a total of 13 reports with 25 adverse events suspected to be related to anastrozole. The most frequently reported adverse events were from System Organ Class (SOC) of musculoskeletal and connective tissue disorders such as arthralgia (2), bone pain (1), arthritis (1) and musculoskeletal pain (1). No report of depression related to anastrozole has been received by NPRA thus far.⁸

Advice for Healthcare Professionals

• Be aware of the risk of depression when prescribing anastrozole to patients, especially in women with a past history of mood disorders.
• Advise patients and their caregivers to inform healthcare professionals if they have low mood or depression after being started on anastrozole.
• Report all suspected adverse events associated with anastrozole to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (31)] has been issued for all registration holders of products containing anastrozole 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+). ARIMIDEX local package insert [Internet]. Last revision date: 2013 Sep [Cited 2021 Oct 13]. Available from https://www.npra.gov.my (access restricted).
2. World Health Organization (WHO). Depression [Internet]. 2021 [Cited 2021 Oct 13]. Available from: https://www.who.int/health-topics/depression#tab=tab_1.
3. European Medicines Agency (EMA). PRAC recommendations on signals adopted at the 11-14 Jan 2021 PRAC meeting [Internet]. 8 Feb 2021 [Cited 2021 Oct 13]. Available from: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-11-14-january-2021-prac-meeting_en.pdf.
4. Netherlands Pharmacovigilance Centre Lareb. Anastrozole and depressed mood disorders [Internet]. 29 July 2020 [Cited 2021 Oct 13]. Available from: https://databankws.lareb.nl/Downloads/Signals_2020_Anastrozole%20and%20depressed%20mood%20disorders.pdf.
5. Goodwin GM. Aromatase inhibitors and bipolar mood disorder: a case report. Bipolar Disord. 2006 Oct;8(5 Pt 1):516–8.
6. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). FEMARA local package insert [Internet]. Last revision date: 2016 Dec [Cited 2021 Oct 13]. Available from https://www.npra.gov.my (access restricted).
7. National Pharmaceutical Regulatory Agency. Malaysian Product Registration Database (Quest 3+). AROMASIN local package insert [Internet]. Last revision date: 2018 Aug [Cited 2021 Oct 13]. Available from https://www.npra.gov.my (access restricted).
8. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. [Cited 2021 Oct 13]. Available from https://www.npra.gov.my (access restricted).

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.