Stay Informed: Montelukast and neuropsychiatric effects - GLP-1 agonists and pulmonary aspiration - Statins and ocular Myasthenia- (CAR-T) Therapies

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Montelukast

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Montelukast is a prescription medicine?used to prevent and treat chronic asthma in adults and children aged 2 years and older, and for symptomatic seasonal allergic rhinitis (hay fever).?

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Montelukast product safety information is being updated to strengthen warnings about serious neuropsychiatric side effects (published TGA review, July 2018), including behavioral changes, depression, and suicidal ideation and behavior.

The updated information will include:

1.?????? A new boxed warning.

2.?????? Additional guidance for prescribers and patients on managing these events.

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·???????? A December 18, 2024 searche of the Database of Adverse Event Notifications DAEN identified 356 reports of montelukast and psychiatric disorders.

·???????? Most common symptoms: aggression (100 cases), anxiety (87), suicidal ideation (72), depression (71), insomnia (52), nightmares (50).

·???????? 91 reports mentioned suicidal behaviors, 10 with fatal outcomes.

·???????? DAEN inclusion does not confirm the event or its link to montelukast.

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The following boxed warning will be included in the Australian PIs for montelukast products:

WARNING:

Serious neuropsychiatric events

Neuropsychiatric events such as behavioural changes, depression and suicidality have been reported in all age groups taking montelukast (see sections 4.4 and 4.8). Events are generally mild and may be coincidental. However, the symptoms may be serious and continue if the treatment is not withdrawn. Therefore, the treatment with montelukast should be discontinued if neuropsychiatric symptoms occur during treatment. Advise patients and/or caregivers to be alert for neuropsychiatric events and instruct them to notify their physician if these changes in behaviour occur.

Additional advice to prescribers will also be included in the existing information on neuropsychiatric events in?Section 4.4?Special warnings and precautions?of the PI, as follows:

Neuropsychiatric events

Prescribers should discuss the benefits and risks of montelukast use with patients and caregivers when prescribing montelukast. Patients and/or caregivers should be advised to be alert for changes in behaviour or for new neuropsychiatric symptoms when taking montelukast. If changes in behaviour are observed, or if new neuropsychiatric symptoms or suicidal thoughts and/or behaviour occur, patients should be advised to discontinue montelukast and contact a healthcare provider immediately. In many cases, symptoms resolved after stopping montelukast therapy; however, in some cases symptoms persisted after discontinuation of montelukast. Therefore, patients should be monitored and provided supportive care until symptoms resolve. Prescribers should carefully evaluate the risks and benefits of continuing treatment with montelukast if such events occur.

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GLP-1 and dual GIP/GLP-1 receptor agonists

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·???????? potential risk of pulmonary aspiration with patient who undergo surgery or procedures with general anesthesia or deep sedation.

·???????? GLP-1 and dual GIP/GLP-1 receptor agonists are known to cause delayed gastric emptying, which may increase the risk of residual gastric contents despite preoperative fasting.

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Pulmonary aspiration during general anesthesia or deep sedation has been reported in patients taking GLP-1 receptor agonists. These reports come from EudraVigilance, published literature, and data submitted by Marketing Authorisation Holders of these products. This adverse event is related to the increased risk of residual gastric content due to delayed gastric emptying associated with these medications.

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New warnings have been added to the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets. The new advice aims to raise awareness of the risk of pulmonary aspiration amongst healthcare professionals and patients. Anaesthetists are warned that residual gastric contents may remain despite routine recommended fasting in patients taking a GLP-1 or dual GIP/GLP-1 receptor agonists. This should be considered within the preoperative risk assessment, with subsequent management in preventing or minimising the risk.

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HMG-CoA Reductase Inhibitors (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin)

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HMG-CoA reductase inhibitors have been associated with reports of myasthenia gravis, including its ocular form (a neuromuscular disorder characterized by weakness of voluntary muscles, including those controlling the eyes and eyelids).

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·???????? Health Canada reviewed 31 cases of myasthenia gravis/ocular myasthenia in statin users (2 Canadian, 29 international).

·???????? 27 of the 31 cases (including 1 Canadian) were possibly linked to statin use.

·???????? 3 of the possibly linked cases had symptom recurrence with different statins, suggesting a class effect.

·???????? 4 studies, despite limitations, suggested a link between statins and worsening myasthenia gravis/ocular myasthenia.

·???????? Limited evidence linked statins to new onset myasthenia gravis/ocular myasthenia, though case reports suggest a possible association.

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Health Canada will work with the manufacturers to include the risk of myasthenia gravis, including ocular myasthenia, in the CPM for statin products that do not currently include this risk.

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Chimeric Antigen Receptor T-cell (CAR-T)

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Type of gene therapy for the treatment of various blood cancers, including certain types of leukemia, lymphoma, multiple myeloma in patients whose cancer has relapsed or is refractory. These treatments use a patient’s own T-cell to find and attack cancer cells throughout their body.

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Secondary T-cell malignancy (a new cancer, that forms in a type of white blood cells called T-cells, after starting CAR-T therapy to treat other forms of blood cancers)

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·???????? Health Canada reviewed 30 cases of secondary T-cell malignancy post-CAR-T therapy (1 Canadian, 29 international).

·???????? 6 cases were probably linked to CAR-T therapy, 9 were possibly linked, 9 were unlikely linked, and 6 (including 1 Canadian) were unassessable.

·???????? Secondary T-cell malignancy diagnosis ranged from 29 days to >3 years post-CAR-T.

·???????? 10 deaths were reported (5 in the probably/possibly linked groups), but cause of death and CAR-T relation were unclear.

·???????? Underlying disease and prior therapies are T-cell malignancy risk factors, but a CAR-T contribution cannot be excluded.

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Manufacturers will be required to update their product’s educational materials to include information about this risk and a recommendation for life-long monitoring of patients for secondary T-cell malignancies. They will also be required to update testing procedures for patients with secondary T-cell malignancies.

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Glatiramer Acetate (Copaxone, Glatopa)

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• FDA-approved injectable medication for relapsing forms of multiple sclerosis (MS).
• Modulates the immune system's attack on the central nervous system, reducing MS relapses.
• Available in daily or three-times-weekly dosages.

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• Risk of anaphylaxis, a severe and potentially life-threatening allergic reaction.
• Can occur at any time during treatment, even after months or years of use.
• Most commonly occurs within one hour of injection.
• Distinct from and more severe than the common immediate post-injection reaction.

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• 82 cases of anaphylaxis identified from global post-marketing data (December 1996 - May 2024).
• Rare compared to overall usage (over 3 million patient-years of exposure).
• Serious adverse events, often requiring emergency care and hospitalization.
• Six of the 82 cases resulted in death.
• Most reactions occurred within one hour of injection.
• Some occurred after longer periods of treatment (19 cases after more than one year).
• Anaphylaxis symptoms may initially mimic the less severe immediate post-injection reaction.
• Anaphylaxis symptoms typically worsen and require prompt medical intervention.

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• Boxed Warning added to prescribing information and patient Medication Guide.
• Patients should be educated about anaphylaxis signs and symptoms.
• Patients should seek immediate medical attention for more than mild reactions, worsening symptoms, or non-resolving symptoms.
• Healthcare providers should be aware of the risk and prepared to manage anaphylaxis.

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Veoza (fezolinetant)

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• Serious liver injury, including elevations in ALT and AST, with some cases showing concurrent bilirubin and/or alkaline phosphatase elevations, has been observed.
• Post-marketing reports include cases with ALT/AST >10x ULN and associated symptoms suggestive of liver injury (fatigue, pruritus, jaundice, dark urine, decreased appetite, abdominal pain).
• While ALT/AST elevations were noted in clinical trials, these serious post-marketing cases, in otherwise healthy women using the drug for menopausal symptoms, raise concerns about the benefit-risk balance.

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• The EU-wide review by the EMA considered adverse drug reaction reports and published literature.
• Elevated LFTs and suggestive symptoms were generally reversible upon discontinuation.
• The risk of serious liver injury necessitates careful patient selection and monitoring.

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• Treatment should not be initiated if ALT or AST are ≥2x ULN or bilirubin is ≥2x ULN.
• LFTs must be checked before starting treatment, monthly for the first three months, then as clinically indicated, and immediately if liver injury symptoms appear.
• Treatment must be stopped if: Transaminases are ≥3x ULN with bilirubin >2x ULN OR if liver injury symptoms develop. Transaminases are >5x ULN.
• LFT monitoring should continue until levels normalize.
• The product information will be updated to reflect these new risk information and recommendations, including DILI as an adverse reaction ("frequency not known").

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Metamizole-containing medicines

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Metamizole is a pyrazolone derivative classified as a non-opioid analgesic. It has potent analgesic, antipyretic, and spasmolytic properties.

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Agranulocytosis, a serious and potentially fatal adverse reaction, is associated with metamizole. It leads to a significant decrease in granulocytes, increasing the risk of severe infections. The frequency of this reaction is rare to very rare, and it can occur at any time during treatment, even in patients who previously tolerated the drug without complications.

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• Patients should be informed of early symptoms of agranulocytosis, such as fever, chills, sore throat, and mucosal pain, and should seek immediate medical attention if symptoms appear.
• Agranulocytosis symptoms may be masked in patients taking metamizole for fever or those on antibiotics.
• If agranulocytosis is suspected, immediate blood testing (including differential count) is required, and treatment should be discontinued. If confirmed, metamizole must not be reintroduced.
• Routine blood count monitoring is no longer recommended, as it does not provide effective early detection.
• Metamizole is contraindicated in patients with a history of metamizole-induced agranulocytosis, bone marrow impairment, or hematopoietic disorders.

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Following an EDA review, contraindications, warnings, and precautions for metamizole-containing medicines will be updated to enhance patient safety. The revised product information will emphasize the importance of recognizing agranulocytosis symptoms early and discontinuing treatment immediately if suspected.

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N-acetyl-cysteine (NAC)-containing medicines (IV and inhalation preparations)

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N-acetyl-cysteine (NAC) is a cysteine derivative with antioxidant and mucolytic properties. It is used intravenously as an antidote for acetaminophen overdose and via inhalation as an adjuvant therapy for respiratory conditions with excessive mucus production.

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• Inhalation preparations are contraindicated in children under 2 years old.
• Some IV formulations contain benzyl alcohol, which is contraindicated in neonates under 4 weeks due to the risk of gasping syndrome. These formulations are also contraindicated in pregnant and nursing women.
• Strict adherence to the approved dosage and administration method for both IV and inhalation forms is essential to ensure safety and efficacy.

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• Healthcare professionals should strictly follow the approved indications, dosage, and administration guidelines for NAC-containing medicines. Inhalation use is contraindicated in children under 2 years, and IV preparations containing benzyl alcohol should not be used in neonates, pregnant, or lactating women.

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