Montelukast Sodium

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption and Bioavailability: Rapid absorption orally. Bioavailability of 64% for the 10 mg tablet. It is not affected in a clinically relevant way by concomitant food intake.
• Distribution: Very high binding to circulating plasma proteins (>99%). Small apparent volume of distribution (8-11 L). Minimally crosses the blood-brain barrier.
• Metabolism: Extensively metabolized in the liver by cytochrome CYP450 isoenzymes, mainly by CYP2C8, CYP3A4 and, to a lesser extent, by CYP2C9.
• Excretion: Almost exclusive elimination through bile and fecal routes (95%). Less than 0.2% of the dose is excreted renally.
• Half-life (t_1/2): Elimination half-life of 2.7 to 5.5 hours in healthy volunteers, allowing a single daily dosing (preferably nocturnal).

Indicators and dose

Clinical Indications and Off-Label Uses

• Allergic Rhinitis (Seasonal and Perennial): Adjuvant symptomatic treatment in patients who do not obtain optimal control with H1 antihistamines or intranasal corticosteroids, or who associate bronchial asthma.
• Aspirin Exacerbated Respiratory Disease (AERD - Samter's Triad) (off-label): Fundamental part of supportive treatment in patients with nasal polyposis, severe asthma and intolerance to NSAIDs.
• Chronic Eosinophilic Nasosinusal Polyposis: To reduce the recurrence of nasal polyps after endoscopic sinonasal surgery (FESS) in combination with intranasal corticosteroids.

Dosage and Clinical Adjustment

Daily Dosage Scheme (Night Taking):

• Adults and Adolescents (≥15 years): 10 mg orally once a day (coated tablet).
• Children (6 to 14 years): 5 mg orally once daily (chewable tablet).
• Children (2 to 5 years): 4 mg orally once a day (chewable tablet or oral granule sachets).

Adjustment in Renal or Hepatic Failure: No adjustment is required in renal failure or mild to moderate liver failure. No safety data are available in severe decompensated liver cirrhosis.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to montelukast sodium or the components of the tablet.

Relative Contraindications

• Personal history of severe psychiatric spectrum disorders or extreme emotional lability (due to risk of neuropsychiatric reactions).
• Concomitant use of potent enzyme inducers such as phenobarbital or rifampicin (accelerate the clearance of montelukast).

Adverse Effects (ADR) and Specific Toxicity

• Common (1%-10%): Headache, dyspepsia, abdominal pain, skin rashes, thirst, mild fever.
• Uncommon (0.1%-1%): Hypersensitivity reactions (hives, pruritus, anaphylaxis), sleep disorders (vivid nightmares, insomnia, sleepwalking), dry mouth, dizziness.
• Rare (0.01%-0.1%): Serious Neuropsychiatric Events, tendency to ecchymosis due to dysfunction of platelet hemostasis, palpitations.
• Very rare (<0.01%): Churg-Strauss syndrome (Granulomatosis with Eosinophilic Polyangiitis) in asthmatic patients after rapid withdrawal of systemic corticosteroids.

Safety Alert: Neuropsychiatric Events (FDA Black Box)

Montelukast has a Black Box Warning from the FDA due to its association with serious neuropsychiatric events. These include changes in behavior, psychomotor agitation, hostility, major depression, obsessive thoughts, severe sleep disturbances (repeated pathological nightmares), and suicidal ideation or behavior.

Onset of mood swings or nightmares Immediate discontinuation of Montelukast

The patient's family should be instructed to closely monitor the patient's behavior and immediately suspend taking the drug if any of these symptoms appear, notifying the specialist doctor.

Drug Interactions of Clinical Relevance

• CYP3A4 and CYP2C8 inducers (Rifampicin, Phenobarbital, Phenytoin): They reduce the area under the curve (AUC) of montelukast by approximately 40%. It is advisable to monitor clinical efficacy if co-administered.
• Gemfibrozil (Potent CYP2C8 inhibitor): May increase plasma levels of montelukast by up to 4-fold, increasing the risk of neuropsychiatric adverse effects.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Compatible. Observational studies and the global pregnancy registry have not shown an increase in congenital anomalies or spontaneous abortion after exposure to montelukast during pregnancy.
• Breastfeeding: Compatible. It is excreted in human milk in extremely low quantities, and is considered safe for full-term infants.