Safety Alerts

Advisory on restriction on the use of montelukast and neuropsychiatric effects

10 December 2020

Audiences

Healthcare professional

Industry member

Product-type

Therapeutic Products

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HSA has completed a benefit-risk assessment of montelukast which concluded that the benefit-risk profile of montelukast remains favourable for its approved indication, if additional precautionary measures are put in place to mitigate the known but rare risk of neuropsychiatric events. These measures include restricting the use of montelukast in the treatment of allergic rhinitis to patients who have inadequate response or are intolerant to alternative therapies, and the strengthening of existing warnings on neuropsychiatric risks in the package inserts (PIs) of montelukast-containing products. Healthcare professionals are advised to consider the benefits of treatment and risks of neuropsychiatric effects before prescribing montelukast.

Background

Montelukast is a selective leukotriene receptor antagonist (LTRA) that has been registered in Singapore since 1998 for the prophylaxis and chronic treatment of asthma and the relief of symptoms of allergic rhinitis. Neuropsychiatric event is a rare but known adverse effect of montelukast and there are existing warnings on this risk in the PIs of locally registered montelukast products.

In March 2020, HSA initiated a safety review on montelukast in response to the regulatory actions taken by the US Food and Drug Administration (FDA)¹to include a Boxed Warning on serious behaviour and mood-related changes with montelukast and to restrict the use of montelukast in the treatment of allergic rhinitis in patients with inadequate response or intolerance to alternative therapies. FDA’s review did not identify new evidence regarding the known neuropsychiatric safety concern but highlighted a lack of awareness of healthcare professionals to this safety issue despite earlier communications by the agency.

Internationally, several regulatory agencies had also incorporated restrictions to the use of montelukast in allergic rhinitis. In July 2020, Health Canada adopted similar measures as the US FDA.² In the United Kingdom, montelukast is only indicated for symptomatic relief of seasonal allergic rhinitis in patients with asthma.

International clinical practice guidelines on the use of montelukast

International clinical practice guidelines^3,4,5 on the treatment of allergic rhinitis recommend the use of intranasal steroid (e.g. mometasone, fluticasone) and/or oral antihistamines (e.g. cetirizine, loratadine) as primary therapies for allergic rhinitis. In particular, the American Academy of Otolaryngology- Head and Neck Surgery Foundation recommended against the use of LTRAs, including montelukast, as primary treatment therapy for allergic rhinitis, except in asthmatic patients. The British Society of Allergy and Clinical Immunology also recommended that LTRAs may have a place in therapy for asthmatic patients with seasonal allergic rhinitis. The Global Initiative for Asthma (GINA) guideline lists montelukast as an option for initial controller therapy in asthma.

Local reports of neuropsychiatric adverse events (AEs) associated with montelukast

HSA has received a small number of reports of neuropsychiatric events associated with the use of montelukast since its registration in Singapore in 1998. The events include aggressive behaviour, agitation, depression, tremor, hallucinations, hyperactivity, and sleep disturbances such as somnolence, insomnia and nightmares. There were no reports received for suicidal behaviour. The use of concomitant medicines and/or presence of comorbidities were not reported for most cases, limiting firm causality assessment.

HSA’s benefit-risk assessment

HSA’s benefit-risk assessment took into consideration the local safety data, current international clinical practice guidelines on the treatment of allergic rhinitis and asthma, the availability of alternative treatments for allergic rhinitis, inputs from local clinicians (including respiratory specialists, general practitioners and psychiatrists) and international regulatory actions.

Based on currently available information, HSA, in consultation with its Product Vigilance Advisory Committee, has concluded that the benefit-risk profile of montelukast remains favourable for its approved indications, if additional precautionary measures are taken to mitigate the risk of neuropsychiatric events. These additional measures include restricting the use in allergic rhinitis to patients who are inadequately treated or intolerant to alternative therapies and the strengthening of warnings on neuropsychiatric events in the PIs of products containing montelukast.

HSA’s advisory and actions

Healthcare professionals are advised of the following, when considering the use of montelukast:

To consider the benefits of treatment with montelukast and its risks of neuropsychiatric effects before prescribing montelukast
To discuss with their patients and/or caregivers on the benefits and risks of treatment when prescribing montelukast. Healthcare professionals may make use of the patient educational material available for montelukast (e.g. article on MOH Health Hub⁶) for patient counselling
To advise their patients and/or caregivers to be alert to changes in behaviour or new neuropsychiatric symptoms when taking montelukast and to seek medical attention if neuropsychiatric symptoms occur

HSA has issued a Dear Healthcare Professional Letter on 30 October 2020 to inform healthcare professionals of the advisory on the new restriction on montelukast use and neuropsychiatric events.⁷ HSA is working with the product registrants of montelukast-containing products to update the local PIs with the new recommendations on the indicated use of montelukast in allergic rhinitis and additional safety information on the risk of neuropsychiatric AEs.

Healthcare professionals are encouraged to report any suspected serious AEs related to montelukast to the Vigilance and Compliance Branch of HSA.