Overview

Mirtazapine is an antidepressant agent that is indicated for the treatment of major depression.¹ In Malaysia, there are currently six (6) registered oral products containing mirtazapine.

Background of the safety issue

The National Pharmaceutical Regulatory Agency (NPRA) has received information from the European Medicines Agency (EMA) regarding the risk of amnesia and the risk of drug reaction with eosinophilia and systemic symptoms (DRESS), both of which have been associated with mirtazapine use. Based on all available evidence, EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) concluded that there is a causal association between the risk of amnesia and the risk of DRESS with the use of mirtazapine, and that the product information of all mirtazapine-containing products needs to be updated to incorporate information on these two risks.²

(i) Amnesia

In pre-clinical studies, the postulated mechanisms for amnesia were thought to be related to mirtazapine’s antagonistic effect on H1 receptors, as well as through the stimulation of serotonergic and noradrenergic neurotransmission.³ Based on a safety review, most of the patients recovered following mirtazapine discontinuation.

(ii) DRESS

DRESS is a rare, severe idiosyncratic, potentially fatal hypersensitivity reaction to a drug.^3,4 An early diagnosis of DRESS and immediate discontinuation of the suspected drug are crucial for its treatment.

Adverse Drug Reaction (ADR) Reports

NPRA has received a total of 96 ADR reports with 169 adverse events suspected to be related to mirtazapine-containing products.⁵ To date, no ADR related to amnesia or DRESS has been reported to the NPRA.

Advice for Healthcare Professionals:

• Be alert on the risk of amnesia and the risk of DRESS associated with the use of mirtazapine-containing products.
• Counsel patients on the signs and symptoms of DRESS, such as widespread rash accompanied by high body temperature and enlarged lymph nodes. Advise patients to stop taking mirtazapine and immediately seek medical attention if they develop any signs and symptoms of DRESS.
• If the patient has developed DRESS reactions with the use of mirtazapine, treatment must not be restarted in this patient at any time.
• Please report all suspected adverse events associated with mirtazapine-containing products to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (22)] has been issued for registration holders of mirtazapine-containing products to update the local package inserts and consumer medication information leaflet (Risalah Maklumat Ubat untuk Pengguna) with this new safety information.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). Malaysian Product Registration Database (Quest 3+). Remeron local package insert [Internet]. Last revision date: 2020 July [Cited 2021 March 5]. Available from http://www.npra.gov.my.
2. European Medicines Agency (EMA). PRAC recommendations on signals. 2020 June 22 [Cited on 2021 March 5]. EMA/PRAC/257435/2020. 
3. National Authority of Medicines and Health Products (INFARMED). Mirtazapine and possible occurrence of amnesia DRESS. Boletim de Farmacovigilância [Internet]. 2020 July [Cited 2021 March 5]; 24(7): 1-2. Available from: https://www.infarmed.pt/documents/15786/3591914/Boletim+de+Farmacovigil%C3%A2ncia%2C+Volume+24%2C+n%C2%BA7%2C+julho+de+2020/b71abf01-d347-bad3-fcf8-08108e2cba54.
4. New Zealand Medicines and Medical Devices Safety Authority (MEDSAFE). DRESS: A pleat for help [Internet]. 2017 June 1 [Cited 2021 March 5]. Available from: https://medsafe.govt.nz/profs/PUArticles/June2017/DRESS.htm.
5. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2021 [Cited 2021 March 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.