Montel

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

Composition:

Active substance: montelukast sodium;

1 tablet contains montelukast sodium 5.2 mg, equivalent to 5.0 mg of montelukast;

Excipients: mannitol (E 421), microcrystalline cellulose, low-substituted hydroxypropylcellulose, sodium croscarmellose, aspartame (E 951), cherry flavor, magnesium stearate, iron oxide red (E 172).

Pharmaceutical form. Chewable tablets.

Main physicochemical properties: round, biconvex tablets of pink color*. The surface of the tablets bears the imprint «M9UT» and «5» on one side.

* Speckles may be present, which are due to the manufacturing process.

Pharmacotherapeutic group. Agents for systemic use in obstructive respiratory 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 key pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) present in human airways and induce responses such as bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil recruitment.

Montelukast is an active compound that selectively and with high affinity binds 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 blockade of LTD4-stimulated bronchoconstriction. Montelukast induces bronchodilation within 2 hours after oral administration; this effect is additive to bronchodilation caused by β-agonists.

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

Pharmacokinetics

Absorption. After administration, montelukast is rapidly and almost completely absorbed. Following a 5 mg chewable tablet taken on an empty stomach, Cmax is reached within 2 hours. The mean oral bioavailability is 73% and decreases to 63% when taken with food.

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

Metabolism. Montelukast is extensively metabolized. In studies using therapeutic doses, plasma concentrations of montelukast metabolites at steady state were not detectable in adults or pediatric patients.

In vitro studies using human liver microsomes have shown that cytochrome P450 enzymes 3A4, 2A6, and 2C9 are involved in the metabolism of montelukast. At therapeutic concentrations, montelukast does not inhibit these cytochrome enzymes. 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 bile.

Pharmacokinetics in Specific Patient Populations. Dose adjustment is not required in elderly patients or in 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 montelukast was administered at doses 20 and 60 times higher than the recommended adult dose, a decrease in plasma theophylline concentrations was observed. This effect was not seen at the recommended dose of 10 mg once daily.

Pharmacokinetic studies have shown that the concentration profiles of 5 mg chewable tablets in children aged 6 to 14 years are similar to those of 10 mg coated tablets in adults.

Clinical characteristics.

Indications.

For children aged 6 to 14 years:

• As add-on therapy for mild to moderate persistent asthma that is not adequately controlled with inhaled corticosteroids, as well as in cases of inadequate clinical control of asthma symptoms with short-acting β-agonists used as needed;
• As an alternative to low-dose inhaled corticosteroids in patients with mild persistent asthma who have not recently experienced severe asthma attacks requiring oral corticosteroids, and in patients who cannot use inhaled corticosteroids;
• Prevention of asthma where bronchospasm induced by physical exercise 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; therefore, montelukast should be used as a reserve medication in patients with inadequate response or intolerance to alternative therapies.

Contraindications.

Hypersensitivity to montelukast or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Montelukast may be administered concomitantly with other medications used for the prevention or long-term treatment of 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 receiving phenobarbital concomitantly, the area under the plasma concentration-time curve (AUC) for montelukast decreased by approximately 40%. Since montelukast is metabolized by CYP 3A4, 2C8, and 2C9, caution should be exercised, especially in children, when montelukast is administered concomitantly 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 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 shown 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 with 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 consider the increased risk of adverse reactions.

Based on in vitro studies, 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 relieve 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 introduced abruptly to replace inhaled or oral corticosteroids. The drug should not be taken together with medicinal products that also contain montelukast.

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

Psychoneurological events have been reported in adult patients, adolescents, and children taking montelukast (see section "Adverse reactions"). Patients and physicians should remain vigilant for possible psychoneurological events. Patients and/or caregivers should be instructed to inform their physician if any psychoneurological changes occur. Physicians should carefully evaluate the risks and benefits of continuing montelukast therapy if such events occur.

In rare cases, systemic eosinophilia, sometimes with clinical features of vasculitis, such as Churg-Strauss syndrome (allergic granulomatous angiitis), has been observed in patients receiving anti-asthma medications, including montelukast. This condition is usually treated with systemic corticosteroids. Such cases have typically 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 either ruled out or confirmed. Therefore, physicians should be aware of the possibility of eosinophilia, vasculitic rash, worsening of 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 reassessed.

Montelukast therapy does not eliminate the need for patients with aspirin-induced bronchial asthma to avoid aspirin or other nonsteroidal anti-inflammatory drugs.

Montel chewable tablets contain aspartame, a source of phenylalanine. Patients with phenylketonuria should be advised that each 5 mg tablet contains aspartame equivalent to 0.842 mg of phenylalanine.

Use during pregnancy or breastfeeding.

Animal studies have not demonstrated any harmful effects on pregnancy or embryonic/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 drug. 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 clearly necessary.

Studies in rats have shown that montelukast is excreted into breast milk. It is unknown whether montelukast is excreted into human breast milk. Montel may be used during breastfeeding only if clearly necessary.

Ability to influence the reaction rate when driving or operating machinery.

Montelukast is not expected to affect a patient's ability to drive or operate machinery. However, very rare cases of somnolence or dizziness have been reported.

Dosage and Administration.

The medicinal product should be administered to children under adult supervision.

For patients with asthma and allergic rhinitis (seasonal and perennial), the recommended dose is 1 chewable tablet of 5 mg once daily. The time of administration should be individually adjusted to alleviate symptoms of allergic rhinitis.

For the treatment of asthma, the dosage for children aged 6 to 14 years is 1 chewable tablet (5 mg) once daily in the evening, taken 1 hour before or 2 hours after a meal. Dose adjustment is not required for this age group.

Adults and adolescents aged 15 years and older should take montelukast 10 mg tablets.

General Recommendations.

Therapeutic effect of the medicinal product on asthma control parameters develops within 1 day. Patients should be advised to continue taking the medication even after achieving asthma control, as well as during asthma exacerbations.

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

Dosage of the drug is the same for male and female patients.

Alternative to low-dose inhaled corticosteroids in mild persistent asthma.

Montelukast is not recommended as monotherapy for patients with moderate persistent asthma. The decision to use montelukast as an alternative to low-dose inhaled corticosteroids in children with mild persistent asthma may be considered only for patients who have not experienced severe asthma attacks requiring oral corticosteroids in the recent past, and for those who have demonstrated inability to use inhaled corticosteroids.

Mild persistent asthma is defined as asthma symptoms occurring more than once a week but less than once a day, nocturnal symptoms more than twice a month but less than once a week, and normal lung function between episodes.

If satisfactory asthma control is not achieved within 1 month of montelukast therapy, the need for additional or alternative anti-inflammatory treatment should be evaluated based on a stepwise asthma management approach. Patients should be periodically assessed to monitor asthma control.

Prophylactic use prior to physical exertion to prevent asthma attacks.

Exercise-induced bronchospasm may be the primary manifestation of persistent asthma requiring treatment with inhaled corticosteroids. The patient's condition should be evaluated 2–4 weeks after initiating montelukast therapy. If satisfactory treatment response is not observed, a decision on additional or alternative therapy should be made.

Montelukast therapy in combination with other asthma treatments.

When montelukast is used as add-on therapy to inhaled corticosteroids, inhaled corticosteroids should not be abruptly replaced by montelukast.

Children.

For use in children aged 6 to 14 years. For children aged 15 years and older, montelukast 10 mg tablets should be used.

Overdose.

In long-term studies of chronic 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.

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). Observed clinical and laboratory findings were within the safety profile of montelukast in adult and pediatric patients. Most cases of overdose were not associated with reported adverse reactions. The most commonly observed adverse reactions were consistent with the safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

Treatment. There is no specific information on the treatment of montelukast overdose. Management is symptomatic. No antidote is available. It is unknown whether montelukast is effectively removed by peritoneal dialysis or hemodialysis.

Adverse reactions

Long-term treatment across various age groups during clinical studies has demonstrated a consistent safety profile.

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 (≥ 1/10000, < 1/1000), very rare (< 1/10000).

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 disturbances, 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, paraesthesia/hypoaesthesia, convulsions.

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, 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 – angioneurotic edema, very rare – erythema nodosum, 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/increased fatigue, malaise, edema.

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

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

§This adverse reaction was observed with a frequency of "rare".

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 status. Prescription only.

Manufacturer.

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

Manufacturer's address.

17 Myru Street, Kyiv, 03134, Ukraine.