Montel

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONTÉL (MONTEL)

Composition:

Active substance: montelukast sodium;

1 tablet contains montelukast sodium 10.4 mg, equivalent to 10.0 mg of montelukast;

Excipients: microcrystalline cellulose, lactose monohydrate, low-substituted hydroxypropylcellulose, sodium croscarmellose, magnesium stearate;

film coating Opadry I yellow: hypromellose, hydroxypropylcellulose, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, from light yellow to yellow with a slight brownish tint, round-shaped, biconvex. The surface of the tablets bears the imprint «M9UT» and «10» on one side.

Pharmacotherapeutic group. Drugs for systemic use in obstructive respiratory tract diseases. Leukotriene receptor antagonists.

ATC code: R03DC03.

Pharmacological Properties

Pharmacodynamics

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released by various cells, including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) present in human airways (including smooth muscle cells and macrophages) and other pro-inflammatory cells (including eosinophils and certain myeloid progenitor cells). CysLTs are involved in the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil recruitment. In allergic rhinitis, following allergen exposure, CysLTs are released from the nasal mucosa during both early and late phases and contribute to the symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction.

Montelukast is an active compound that binds with high selectivity and affinity to CysLT1 receptors. Montelukast produces significant blockade of cysteinyl leukotriene receptors in the airways, as demonstrated by its ability to inhibit LTD4-induced bronchoconstriction in patients with asthma. Even a low dose of 5 mg results in substantial inhibition of LTD4-stimulated bronchoconstriction. Montelukast induces bronchodilation within 2 hours after oral administration; this effect is additive to the bronchodilation caused by β-agonists.

Treatment with montelukast suppresses both early- and late-phase bronchoconstriction, reducing the response to antigens. Montelukast reduces the number of eosinophils in peripheral blood in adult and pediatric patients, significantly decreases eosinophils in the airways (sputum analysis), and improves clinical asthma control.

Pharmacokinetics

Absorption. After administration, montelukast is rapidly and almost completely absorbed. In adults, following oral administration of 10 mg film-coated tablets under fasting conditions, peak plasma concentration (Cmax) is reached within 3 hours (Tmax). The average bioavailability is 64%. Co-administration with a standard meal does not affect the Cmax or bioavailability of film-coated tablets.

Distribution. Over 99% of montelukast is bound to plasma proteins. The steady-state volume of distribution averages between 8 and 11 liters. In studies using radiolabeled montelukast, penetration across the blood-brain barrier was minimal. In all other tissues, concentrations of radiolabeled material 24 hours after dose administration were also found to be minimal.

Metabolism. Montelukast is extensively metabolized. In studies using therapeutic doses, metabolite concentrations of montelukast in steady-state plasma levels in adults and pediatric patients were not detectable.

In vitro studies using human liver microsomes have shown that cytochrome P450 enzymes 3A4, 2A6, and 2C9 are involved in the metabolism of montelukast. Further in vitro studies with human liver microsomes demonstrated that at therapeutic concentrations, montelukast does not inhibit cytochrome P450 enzymes 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6. The contribution of metabolites to the therapeutic effect of montelukast is considered minimal.

Elimination. The plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After an oral dose of radiolabeled montelukast, 86% is excreted in feces within 5 days and less than 0.2% in urine. Combined with the oral bioavailability of montelukast, this indicates that its metabolites are almost exclusively eliminated via the biliary route.

Pharmacokinetics in Specific Patient Populations. Dose adjustment is not required for elderly patients or patients with mild to moderate hepatic impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score >9).

Studies in patients with renal impairment have not been conducted. However, since montelukast and its metabolites are primarily eliminated via bile, dose adjustment in patients with renal impairment is not considered necessary.

When high doses of montelukast (20 and 60 times the recommended adult dose) were administered, a decrease in plasma theophylline concentration was observed. This effect was not seen with the recommended dose of 10 mg once daily.

Clinical Characteristics.

Indications.

• Adjunctive treatment of mild to moderate persistent asthma that is not adequately controlled with inhaled corticosteroids, as well as in cases of inadequate clinical control of asthma with short-acting β-agonists used as needed.
• Symptomatic treatment of seasonal allergic rhinitis in patients with bronchial asthma.
• Prevention of bronchial asthma in which bronchospasm induced by physical exertion is the predominant component.
• Relief of symptoms of seasonal and perennial allergic rhinitis. The risk of developing neuropsychiatric symptoms in patients with allergic rhinitis may outweigh the benefit of montelukast use; therefore, montelukast should be used as a reserve medication in patients who have inadequate response or intolerance to alternative therapies.

Contraindications.

• Hypersensitivity to montelukast or to any other component of the medicinal product.
• Children under 15 years of age (for the 10 mg dose).

Interaction with other medicinal products and other forms of interaction.

Montelukast may be administered together with other medications used for the prevention or long-term management of bronchial asthma. The recommended clinical dose of montelukast has no significant clinical effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients who concurrently took phenobarbital, the area under the concentration–time curve (AUC) for montelukast decreased by approximately 40%. Since montelukast is metabolized by CYP 3A4, 2C8, and 2C9, caution is advised, especially in children, when montelukast is co-administered with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital, and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. Drug interaction studies involving montelukast and rosiglitazone (a marker substrate; a drug metabolized by CYP 2C8) demonstrated that montelukast is not an inhibitor of CYP 2C8 in vivo. Therefore, montelukast does not significantly affect the metabolism of drugs metabolized by CYP 2C8 (e.g., paclitaxel, rosiglitazone, and repaglinide).

In vitro studies have established that montelukast is a substrate of CYP 2C8 and, to a lesser extent, of CYP 2C9 and 3A4. In a clinical drug interaction study of montelukast and gemfibrozil (an inhibitor of CYP 2C8 and 2C9), gemfibrozil increased systemic exposure to montelukast by 4.4-fold. When montelukast is used concomitantly with gemfibrozil or other potent inhibitors of CYP 2C8, dose adjustment of montelukast is not required; however, physicians should be aware of the increased risk of adverse reactions.

Based on in vitro data, clinically significant interactions are not expected with less potent inhibitors of CYP 2C8 (e.g., trimethoprim).

Concomitant administration of montelukast with itraconazole (a potent inhibitor of CYP 3A4) did not result in a significant increase in systemic exposure to montelukast.

Special precautions for use.

Patients should be warned that Montel should not be used to treat acute asthmatic attacks, and that they must always have a suitable rescue medication available. In the event of an acute attack, short-acting inhaled β-agonists should be used. Patients should seek medical advice as soon as possible if they find they need more short-acting β-agonist inhalations than usual.

Montelukast should not be used to abruptly replace inhaled or oral corticosteroids. The drug should not be taken together with medicinal products that also contain montelukast.

There are no data demonstrating that doses of oral corticosteroids can be reduced when montelukast is administered concomitantly.

Cases of neuropsychiatric events have been reported in adults, adolescents, and children taking montelukast (see section "Adverse reactions"). Patients and physicians should be alert to the possibility of such neuropsychiatric events occurring. Patients and/or their caregivers should be instructed to inform their physician if any neuropsychiatric changes occur. Physicians should carefully evaluate the risks and benefits of continuing montelukast therapy if such events occur.

In isolated cases, patients receiving anti-asthma medications, including montelukast, may develop systemic eosinophilia, sometimes manifesting clinically as vasculitis, known as Churg-Strauss syndrome (allergic granulomatous angiitis), which is treated with systemic corticosteroids. Such cases have usually been associated with a reduction in dose or discontinuation of oral corticosteroids. A causal relationship between leukotriene receptor antagonists and the development of Churg-Strauss syndrome cannot be definitively ruled out or confirmed. Therefore, physicians should remain aware of the possibility of eosinophilia, vasculitic skin rashes, worsening pulmonary symptoms, cardiovascular complications, and/or neuropathy in patients. Patients who develop the aforementioned symptoms should undergo re-evaluation, and their treatment regimen should be reviewed.

Treatment with montelukast does not eliminate the need for patients with aspirin-induced bronchial asthma to avoid the use of aspirin or other nonsteroidal anti-inflammatory drugs.

The medicinal product Montel, film-coated tablets, should not be used in patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Animal studies have not shown any harmful effects on pregnancy or embryonal/fetal development.

Data from prospective and retrospective cohort studies on the use of montelukast in pregnant women, assessing major congenital malformations in offspring, have not established a risk associated with the use of the medicinal product. However, these studies have methodological limitations, including small sample size, retrospective data collection in some cases, and inadequate control groups.

Montel may be used during pregnancy only if it is considered absolutely necessary.

Animal studies have shown that montelukast passes into breast milk. It is unknown whether montelukast passes into human breast milk. Montel may be used during breastfeeding only if it is considered absolutely necessary.

Ability to influence reaction speed when driving or operating machinery.

Montelukast is not expected to affect a patient's ability to drive or operate machinery. However, dizziness or drowsiness may occur in isolated cases.

Method of Administration and Dosage

The medicinal product should be administered orally, independent of food intake.

Adults and children aged 15 years and older: For treatment of asthma or asthma associated with seasonal allergic rhinitis, one tablet (10 mg) should be taken once daily in the evening.

General recommendations

The therapeutic effect of the drug in controlling bronchial asthma occurs within 1 day. Patients should be advised to continue taking the drug even after achieving control of bronchial asthma, as well as during asthma exacerbations. The drug should not be taken concomitantly with medicinal products that also contain montelukast.

Dosage adjustment is not required in elderly patients, patients with renal impairment, or patients with mild to moderate hepatic impairment. There is no data available for patients with severe hepatic impairment.

The dosage of the drug is the same for both male and female patients.

Treatment with montelukast in relation to other methods of bronchial asthma management

Montelukast may be prescribed as an additional treatment alongside the patient's current therapy regimen.

Inhaled corticosteroids

Montelukast can be used as add-on therapy when inhaled corticosteroids in combination with short-acting β-agonists as rescue medication do not provide adequate clinical control of the disease.

Inhaled corticosteroids must not be abruptly replaced by montelukast.

Children

For use in children aged 15 years and older. Children under the age of 15 should be administered the drug in the form of chewable tablets.

Overdose

During long-term studies of chronic bronchial asthma, montelukast was administered at doses up to 200 mg/day in adult patients, and in short-term studies at doses up to 900 mg/day for approximately one week, without clinically significant adverse reactions occurring.

Symptoms
Acute montelukast overdose has been reported. These cases involved adults and children who ingested doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). Clinical and laboratory findings were within the safety profile observed in adults and children. In most cases, no adverse reactions were reported. The most commonly observed adverse reactions were consistent with the known safety profile of montelukast and included abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity.

Treatment
There is no specific information available regarding treatment of montelukast overdose. Treatment is symptomatic. No antidote is available. It is unknown whether montelukast is eliminated by peritoneal dialysis or hemodialysis.

Adverse Reactions

The adverse reactions listed below were observed during clinical trials and in the post-marketing period. Adverse reactions are classified by frequency: common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000).

Blood and lymphatic system disorders: rare – tendency to increased bleeding, very rare – thrombocytopenia.

Immune system disorders: uncommon – hypersensitivity reactions, including anaphylaxis, very rare – hepatic eosinophilic infiltration.

Psychiatric disorders: uncommon – sleep disorders, including nightmares, insomnia, somnambulism, anxiety, agitation (including aggressive behavior or hostility), psychomotor hyperactivity (including irritability, restlessness, tremor§), depression; rare – attention disturbances, worsening/loss of memory, tic; very rare – dysphemia, hallucinations, disorientation, suicidal ideation and behavior (suicide attempts), obsessive-compulsive disorders.

Nervous system disorders: common – headache, uncommon – lethargy, dizziness, somnolence, paresthesia/hypoesthesia, seizures.

Cardiac disorders: rare – palpitations.

Respiratory system disorders: uncommon – epistaxis, very rare – pulmonary eosinophilia. Isolated cases of Churg-Strauss syndrome have been reported in patients with bronchial asthma.

Gastrointestinal disorders: common – abdominal pain, diarrhea**, nausea**, vomiting**, uncommon – dyspepsia, dry mouth, sensation of thirst.

Hepatobiliary disorders: common – increased serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]), very rare – hepatitis (including cholestatic, hepatocellular, mixed-type liver injury).

Skin and subcutaneous tissue disorders: common – rash**, uncommon – bruising, urticaria, pruritus, rare – angioedema, very rare – nodular erythema, erythema multiforme.

Renal and urinary disorders: uncommon – enuresis in children.

Musculoskeletal and connective tissue disorders: uncommon – arthralgia, myalgia, including muscle spasms.

Infections and infestations: very common – upper respiratory tract infections*.

General disorders: common – pyrexia**, uncommon – asthenia/fatigue, discomfort (malaise), edema.

*This adverse reaction was observed at a "very common" frequency in patients receiving montelukast as well as in patients receiving placebo during clinical trials.

**This adverse reaction was observed at a "common" frequency in patients receiving montelukast as well as in patients receiving placebo during clinical trials.

§This adverse reaction was observed at a "rare" frequency.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

7 tablets in a blister, 4 blisters in a carton.

Prescription category. Prescription only.

Manufacturer. Public Joint-Stock Company "Scientific and Production Center "Boryspil Chemical and Pharmaceutical Plant".

Address of manufacturer and location of business activity.

17 Myru Street, Boryspil, Kyiv region, 03134, Ukraine.