In its 2018 review of montelukast, the TGA said, “Current risk minimisation measures in Australia are comparable to other jurisdictions.” However, since then many other countries have increased their warnings about and restricted the use of montelukast. The TGA needs to consider the mass of medical research on montelukast’s side effects published since its last review and ensure Australian doctors and patients are adequately informed about them.
Taiwan Food and Drug Administration (2021)
FDA limits drugs containing montelukast
Taipei Times, 8 December 2021
“The Food and Drug Administration (FDA) has imposed restrictions on the prescription of drugs containing montelukast for people with allergic rhinitis, ruling that such medications should only be prescribed after other drugs have been used and failed to be effective. Drugs containing montelukast could affect a person’s mental health while they are taking the medication or after treatment has stopped, with side effects including changes in behavior, unusual movements or suicidal thoughts, the FDA said in a statement yesterday.
Hung Kuo-teng (洪國登), head of the FDA’s Medicinal Products Division, told reporters that there are 31 drug permit licenses that have been issued in Taiwan for medications containing montelukast, which is used to treat asthma and allergic rhinitis, a type of nasal inflammation that occurs when the immune system overreacts to allergens in the air. Citing National Health Insurance data, Hung said that each year, about 900,000 prescriptions of medication containing montelukast are given out.
Last year, the US Food and Drug Administration issued a warning against drugs containing montelukast, saying that their clinical effectiveness was not shown to be greater than the potential risk they posed to people’s mental health. It then determined that they should not be used until other medications for allergic rhinitis have been used and found to be ineffective, Hung said.
In light of the warning, Taiwan’s FDA re-evaluated the effectiveness and risk of such medications, and its drug safety assessment panel determined that while drugs containing montelukast are effective in treating allergic rhinitis, they might also cause people to develop mental health problems, Hung said. As a result, the agency has decided to list those medications as “rear-line” drugs, meaning that they can only be prescribed when other medications for nasal inflammation caused by allergies have failed to be effective, Hung said, adding that there are other drugs for treating asthma.
The ruling went into effect immediately. The companies that hold permit licenses for drugs containing montelukast have been told to change the content of their package inserts before July 31 so that they state that the drugs can only be used when other medications for allergic rhinitis have failed to be effective, Hung said. Companies that fail to make the change before the deadline would have their drug permit license revoked, Hung said.”
Sri Lankan National Medicines Regulatory Authority (2021)
8 October 2021
NMRA requires box warning and information for patient/care giver about serious mental health and side effects for asthma and allergy drug Montelukast to be included in the package insert (PIL) of the each and every commercial pack of Montelukast products -all oral dosage forms. And, Amended package insert/product information leaflet (PIL) need to be submitted to the NMRA within three months of this notice.
|RISK OF NEUROPSYCHIATRIC REACTIONS: Healthcare professionals are advised to be alert for neuropsychiatric reactions, including changes in behavior, speech impairment, depression and obsessive-compulsive symptoms, in adults, adolescents, and children taking montelukast. The risks and benefits of continuing treatment should be evaluated if these reactions occur. Patients should be advised to read the list of neuropsychiatric reactions in the product information leaflet and seek immediate medical attention if they occur.
US Food and Drug Adminstration (2020)
The FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis
“On March 4, 2020 FDA strengthened existing warnings about serious behavior and mood-related changes with montelukast (brand name Singulair), a prescription medicine for asthma and allergy. We are taking this action after a review of available information that led us to reevaluate the benefits and risks of montelukast use. Prescribing information already includes warnings about mental health side effects, including suicidal thoughts or actions; however, many health care professionals, patients and caregivers are not aware of the risk.
We decided a stronger warning is needed after conducting an extensive review of available information and convening a panel of outside experts. We are requiring a Boxed Warning, our most prominent warning, be added to the prescribing information to describe these serious mental health side effects. We are also requiring a new patient Medication Guide to educate patients about the medicine. We reviewed case reports submitted to FDA, conducted an observational study using data from the FDA’s Sentinel System, and reviewed observational and animal studies in the published literature. Given the available information, we also reevaluated the benefits and risks of use of montelukast and determined it should not be the first-choice treatment for mild allergic rhinitis.
Health care professionals should consider the risks and benefits of montelukast when deciding to prescribe or continue patients on the medicine. Counsel all patients about mental health side effects and advise them to stop the medicine and contact a health care professional immediately if they develop any symptoms. Only prescribe montelukast for allergic rhinitis in patients who have an inadequate response or intolerance to alternative therapies and for patients with asthma, we recommend that health care professionals consider the benefits, and risks of mental health side effects, before prescribing montelukast.
We continue to receive reports of mental health side effects with montelukast use. A wide variety of mental health side effects have been reported, including completed suicides. Some occurred during montelukast treatment and resolved after stopping the medicine. Other reports indicated that mental health side effects developed or continued after stopping montelukast.”
Health Canada (2020)
Key messages for healthcare professionals:
- Serious neuropsychiatric (NP) events have been reported in patients with and without a previous history of psychiatric disorder during Singulair treatment and after its discontinuation. The mechanisms underlying NP events associated with Singulair use are currently not well understood.
- Highly variable NP event types were reported with the use of Singulair including, but not limited to, agitation, aggression, depression, sleep disturbances, suicidal thoughts and behaviour (including suicide).
- The benefits of Singulair may not outweigh the risks in some patients due to the risk of serious NP events, particularly when the symptoms of the disease may be mild and adequately treated with alternative therapies.
- The use of Singular should be reserved for patients with allergic rhinitis who have an inadequate response or intolerance to alternative therapies. In patients with asthma or exercise-induced bronchoconstriction, healthcare professionals should consider the benefits and risks before prescribing Singulair.
- Although in many cases NP symptoms resolved after stopping Singulair therapy, in some cases symptoms persisted after discontinuation of Singulair. Patients should be monitored and provided supportive care until NP symptoms resolve.
- Healthcare professionals are reminded to advise patients and/or caregivers to:
- be alert for changes in behaviour or new NP symptoms when taking Singulair;
- discontinue Singulair and contact a healthcare professional immediately if changes in behaviour are observed, or if new NP symptoms or suicidal thoughts and/or behaviour occur.
Health Sciences Authority Singapore (2020)
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)1 to 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.
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.
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.
Drug Regulatory Authority of Pakistan (2020)
Advice for Healthcare Professionals:
Health care professionals should consider the risks and benefits of montelukast when deciding to prescribe or continue patients on the medicine.
Only prescribe montelukast for allergic rhinitis in patients who have an inadequate response or intolerance to alternative therapies.
Consider the risks and benefits of montelukast when deciding to prescribe or continue patients on the medicine.
Advise all patients of the risk of neuropsychiatric events when prescribing montelukast.
Advise patients and parents/caregivers that the patient should stop taking montelukast and contact a health care professional immediately if changes in behavior or new neuropsychiatric symptoms, suicidal thoughts or behavior occur.
Monitor all patients treated with montelukast for neuropsychiatric symptoms. Events have occurred in patients with and without pre-existing psychiatric disease.
Report neuropsychiatric or any other suspected adverse drug reaction to Pakistan National Pharmacovigilance Centre, DRAP.
Advice for Patients/Caregivers and Relatives:
Serious mental health side effects have occurred in patients with and without a history of mental illness.
Stop taking montelukast and notify a health care professional right away if you or your child experience behavior or mood-related changes while taking the medicine. These may include: agitation, including aggressive behavior or hostility, attention problems, bad or vivid dreams, depression, disorientation or confusion, feeling anxious, hallucinations (seeing or hearing things that are not really there), irritability, memory problem, obsessive-compulsive symptom, restlessness, sleepwalking, stuttering, suicidal thoughts and actions, tremor or shakiness, trouble sleeping, uncontrolled muscle movements.
Talk to your health care professional about any history of mental illness before starting treatment.
You should take montelukast for allergic rhinitis or hay fever only if you cannot tolerate other medicines or they do not work for you. Many other safe and effective allergy medicines are widely available, talk to your healthcare professionals in case you intend to change montelukast for allergic rhinitis.
Italian Medicines Agency (2020)
ANSM France (2020)
Saudi Food and Drug Authority (2019)
SAFETY COMMUNICATION, 10 October 2019
Montelukast: reminder of the risk of neuropsychiatric reactions
The Saudi Food and Drug Authority (SFDA) would like to inform healthcare professionals about the occurrence of neuropsychiatric reactions in patients using montelukast.
> Be alert for neuropsychiatric reactions in patients using montelukast; events have been reported in adults, adolescents, and children
> Advise patients and their caregivers to read carefully the list of neuropsychiatric reactions in the patient information leaflet and seek medical advice immediately should they occur
> Evaluate carefully the risks and benefits of continuing treatment if neuropsychiatric reactions occur
> Be aware of newly recognised neuropsychiatric reactions of speech impairment (stuttering) and obsessive–compulsive symptoms
Neuropsychiatric reactions may occur in association with montelukast treatment, and these reactions are listed as possible side effects in the product information. A recent review confirmed the known risks of neuropsychiatric reactions and found that the magnitude of risk was unchanged. However, the review identified some cases in which there had been a delay in neuropsychiatric reactions being recognised as a possible adverse drug reaction. Therefore, we remind healthcare professionals about the possible risks with montelukast and the need to consider the benefits and risks of continuing treatment if they occur.
Health Products Regualtory Authority Ireland (2019)
Montelukast – Reminder of risk of neuropsychiatric reactions and product information update, August 2019
Therapeutic Goods Administration Australia (2018)
Montelukast Safety review, 12 July 2018
“The TGA is undertaking additional risk mitigation activities following a new safety review of montelukast. The review evaluated literature published since 2013 (when the issue was last reviewed) and included consultation with international regulators and obtaining expert advice from the Advisory Committee on Medicines (ACM). This approach has the support of the Royal Australian College of General Practitioners (RACGP) and the Australian Medical Association….
There is a known association between montelukast and neuropsychiatric events (such as agitation, sleep disturbance and depression) including, in rare cases, suicidal thinking and behaviour. The Product Information (PI) for montelukast contains a precaution about this risk. The Government requested the latest safety review following reports in the media of serious neuropsychiatric events occurring in association with montelukast in children and adolescents.
Expert advice and TGA actions
The ACM reviewed the issue on 5 April 2018 and offered the following advice (see meeting statement):
- In current clinical practice, montelukast is a useful first-line treatment for mild to moderate asthma in a small but well-defined population.
- It would be helpful if the TGA liaised with various authoring bodies of guidance documents used by prescribers and asthma nurse educators to insert advice similar to that in the Asthma Australia fact sheet, which provides one page of consumer-friendly advice on this issue. They also recommended
- liaison with relevant parties who provide templates for asthma management plans to include a prompt in these plans regarding counselling on potential neuropsychiatric events
- inclusion of the Consumer Medicine lnformation (CMI) in the packaging and encouraged active provision of the CMl to the parent/carer, with counselling, at the point of dispensing.
- Liaison with the Australian Paediatric Surveillance Unit may be useful to provide additional Australian data on the association between montelukast and neuropsychiatric events.
- Consideration could be given to developing a more general consumer educational activity using montelukast as an example.
In response to the ACM’s advice and the findings of its safety review, the TGA has:
- written to State and Territory health departments, NPS MedicineWise, Health Direct and Therapeutic Guidelines to formally request inclusion of advice regarding montelukast and neuropsychiatric events in relevant clinical guidelines and educational activities.
- written to all sponsors of montelukast to request inclusion of the CMI in the packaging with information regarding potential neuropsychiatric events
- contacted the Australian Paediatric Surveillance Unit about potentially including montelukast and neuropsychiatric events in their monthly survey of clinicians.
Information for consumers
If you or someone you provide care for takes montelukast, please be aware of the potential for neuropsychiatric events (such as agitation, sleep disturbance and depression) associated with this medicine. If you notice a change in behaviour, seek medical attention. If the patient is a child or adolescent, or the symptoms are severe (such as suicidal thinking or behaviour), seek urgent medical attention. If you have any questions or concerns about this issue, talk to your health professional.
Information for health professionals
You are reminded of the known association between montelukast and neuropsychiatric events, particularly when initiating therapy or increasing the dose. This is especially important if your patient is a child. Prescribers should consult the PI for further information on potential neuropsychiatric adverse events and carefully evaluate the risks and benefits of continuing treatment with montelukast if such events occur. When treating children with montelukast, the TGA recommends that you also educate caregivers about these potential adverse effects and consider providing them the CMI. Advise them to seek medical advice if they have any concerns.”