Montular

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONTULAR® (MONTULAR®)

Composition:

Active substance: montelukast sodium;

One tablet contains montelukast sodium equivalent to 10 mg of montelukast;

Excipients: microcrystalline cellulose, sodium croscarmellose, sodium lauryl sulfate, magnesium stearate, Opadry 20A520035 yellow coating: hydroxypropylcellulose, hypromellose, titanium dioxide (E 171), carnauba wax, yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: beige-colored, round, biconvex, smooth on both sides, film-coated tablets.

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 important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT). CysLT type 1 receptors (CysLT1) are located in human airways (including airway smooth muscle cells and airway macrophages), as well as on other pro-inflammatory cells (including eosinophils and certain myeloid progenitor cells). The presence of CysLT receptors correlates with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucus hypersecretion, increased vascular permeability, and increased eosinophil counts. In allergic rhinitis, CysLT protein is released from nasal mucosa following allergen exposure during both early- and late-phase reactions, accompanied by symptoms of allergic rhinitis. Intranasal administration of CysLT leads to increased nasal airway resistance and enhanced symptoms of nasal congestion.

Orally administered montelukast is an active compound that binds selectively and with high affinity to CysLT1 receptors. Clinical studies have shown that montelukast inhibits LTD4-induced bronchoconstriction at a dose of 5 mg. Bronchodilation is observed within 2 hours after oral administration, and this effect is additive to bronchodilation induced by β-agonists. Treatment with montelukast suppresses both early and late phases of antigen-induced bronchoconstriction. Compared to placebo, montelukast reduces peripheral blood eosinophil counts in adult and pediatric patients. Clinical data indicate that montelukast treatment significantly reduces eosinophil counts in peripheral blood and airways (measured in sputum), improving clinical asthma control.

In studies involving adults, montelukast 10 mg once daily, compared to placebo, demonstrated significant improvement in morning FEV1 (change from baseline: 10.4% vs. 2.7%, respectively), morning peak expiratory flow rate (PEFR) (change from baseline: 24.5 L/min vs. 3.3 L/min, respectively), and a significant reduction in total β-agonist use (change from baseline: –26.1% vs. –4.6%, respectively). Patient-reported improvements in daytime and nighttime asthma symptoms were significantly better than with placebo.

Studies in adults demonstrated montelukast’s ability to complement the clinical effect of inhaled corticosteroids (change (% baseline) for inhaled beclomethasone plus montelukast vs. beclomethasone alone: for FEV1: 5.43% vs. 1.04%; β-agonist use: –8.70% vs. 2.64%). Compared to inhaled beclomethasone (200 mcg twice daily, spacer device), montelukast showed a faster initial response, although over the 12-week study period, beclomethasone produced a greater mean therapeutic effect (% change from baseline for montelukast vs. beclomethasone: for FEV1: 7.49% vs. 13.3%; β-agonist use: –28.28% vs. –43.89%). However, a similar clinical response (i.e., improvement in FEV1 of approximately 11% or more from baseline) was achieved in a greater proportion of patients receiving montelukast compared to beclomethasone (50% of patients on beclomethasone vs. 42% on montelukast).

A clinical study was conducted to evaluate montelukast as a symptomatic treatment for seasonal allergic rhinitis in patients aged 15 years and older with asthma and concomitant seasonal allergic rhinitis. This study demonstrated that montelukast tablets 10 mg once daily, compared to placebo, significantly improved the average daily rhinitis symptom score. The average daily rhinitis symptom score is a mean value derived from assessments of daytime nasal symptoms (nasal congestion, rhinorrhea, sneezing, nasal itching) and nighttime symptoms (nasal congestion upon awakening, difficulty falling asleep, and frequency of nocturnal awakenings). Patient and physician global evaluations of allergic rhinitis treatment were significantly better with montelukast compared to placebo. Assessment of efficacy for asthma was not the primary objective of this study.

In an 8-week study involving children aged 6 to 14 years, montelukast 5 mg once daily, compared to placebo, significantly improved respiratory function (change from baseline in FEV1: 8.71% vs. 4.16%; change in morning PEFR: 27.9 L/min vs. 17.8 L/min) and reduced the frequency of as-needed β-agonist use (change from baseline: –11.7% vs. +8.2%).

A significant reduction in exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximum decrease in FEV1: 22.33% for montelukast vs. 32.40% for placebo; time to recovery within 5% of baseline FEV1: 44.22 min vs. 60.64 min). This effect was maintained throughout the 12-week study period. Reduction in EIB was also demonstrated in a short-term study in children aged 6 to 14 years (maximum decrease in FEV1: 18.27% vs. 26.11%; time to recovery within 5% of baseline FEV1: 17.76 min vs. 27.98 min). The effect in both studies was demonstrated at the end of the once-daily dosing interval.

In patients with aspirin sensitivity receiving ongoing therapy with inhaled and/or oral corticosteroids, treatment with montelukast, compared to placebo, resulted in significant improvement in asthma control (change from baseline in FEV1: 8.55% vs. –1.74%; change from baseline in total β-agonist use: –27.78% vs. +2.09%).

Pharmacokinetics.

Absorption

Montelukast is rapidly absorbed after oral administration. Following administration of 10 mg film-coated tablets to adults under fasting conditions, the mean peak plasma concentration (Cmax) was achieved within 3 hours (Tmax). The mean oral bioavailability is 64%. A normal meal does not affect the bioavailability or Cmax of orally administered montelukast. Safety and efficacy have been confirmed in clinical trials with 10 mg film-coated tablets administered regardless of meal timing.

For 5 mg chewable tablets, the Cmax in adults was achieved within 2 hours after administration under fasting conditions. The mean oral bioavailability is 73% and decreases to 63% when taken with a standard meal.

Distribution

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

Metabolism

Montelukast is extensively metabolized. In studies using therapeutic doses, metabolite concentrations of montelukast in steady-state plasma in adults and pediatric patients are undetectable.

Cytochrome P450 2C8 is the primary enzyme involved in montelukast metabolism. Additionally, CYP 3A4 and 2C9 play minor roles in its metabolism, although itraconazole (a CYP 3A4 inhibitor) did not alter the pharmacokinetic parameters of montelukast in healthy volunteers receiving 10 mg montelukast daily. In vitro studies using human liver microsomes indicate that therapeutic plasma concentrations of montelukast do not inhibit cytochrome P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Excretion

Plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After oral administration 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 montelukast and its metabolites are almost entirely eliminated via the biliary route.

Pharmacokinetics in Specific Patient Populations

Dosage adjustment is not required for elderly patients or patients with mild to moderate hepatic impairment. Studies in patients with renal impairment have not been conducted. However, since montelukast and its metabolites are excreted via bile, dosage adjustment in patients with renal impairment is not considered necessary. Pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9) are not available.

Administration of high doses of montelukast (20- and 60-fold higher than the recommended adult dose) was associated with decreased plasma theophylline concentrations. This effect is not observed at the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

As add-on therapy for bronchial asthma in patients with mild to moderate persistent asthma that is not adequately controlled with inhaled corticosteroids, and in patients with inadequate clinical control of asthma using short-acting β-adrenoceptor agonists as needed. In patients with asthma who are taking Montelukast®, this medicinal product also relieves symptoms of seasonal allergic rhinitis.

Prevention of asthma in which bronchospasm induced by physical exertion is the predominant component.

Relief of symptoms of seasonal and perennial allergic rhinitis. Since the benefit of montelukast in patients with allergic rhinitis may not outweigh the risk of developing neuropsychiatric symptoms (see section "Special precautions for use"), Montelukast® should be used as a second-line agent in patients with inadequate response or intolerance to alternative therapies.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Age under 15 years (for the 10 mg dose).

Interaction with other medicinal products and other forms of interaction.

Montelukast may be administered together with other medicinal products commonly used for the prevention or long-term treatment of asthma. In drug interaction studies, montelukast at the recommended clinical dose had no clinically significant effect on the pharmacokinetics of the following agents: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients concurrently taking phenobarbital, the area under the plasma concentration-time curve (AUC) for montelukast decreased by approximately 40%. Since montelukast is metabolized via CYP 3A4, 2C8, and 2C9, caution should be exercised, 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. However, clinical drug interaction data involving montelukast and rosiglitazone (a marker substrate; a drug metabolized by CYP 2C8) have demonstrated that montelukast is not an inhibitor of CYP 2C8 in vivo. Therefore, montelukast does not significantly affect the metabolism of medicinal products metabolized by this enzyme (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 using 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, but physicians should be aware of the increased risk of adverse reactions.

Based on in vitro data, clinically significant interactions with weaker inhibitors of CYP 2C8 (e.g., trimethoprim) are not expected. Concomitant administration of montelukast with itraconazole, a strong inhibitor of CYP 3A4, did not result in a significant increase in systemic exposure to montelukast.

Special precautions for use

Patients should be advised that Montular® is never used to treat acute asthma attacks, and that they should always have with them an appropriate emergency medication. In the event of an acute attack, short-acting inhaled β-agonists should be used. Patients should seek immediate medical advice if they require a greater amount of short-acting β-agonist than usual.

Montelukast should not be used to abruptly replace therapy with inhaled or oral corticosteroids.

There are no data confirming that the dose of oral corticosteroids can be reduced when montelukast is used concomitantly.

In isolated cases, systemic eosinophilia, sometimes with clinical features of vasculitis, such as Churg-Strauss syndrome, has been observed in patients receiving anti-asthmatic agents, including montelukast. This condition is treated with systemic corticosteroid therapy. Such cases have usually (but not always) been associated with a reduction in dose or withdrawal of corticosteroid therapy. The possibility that leukotriene receptor antagonists may be linked to the development of Churg-Strauss syndrome cannot be definitively ruled out or confirmed. Physicians should be aware of the potential for eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy in patients. Patients who develop such symptoms should be re-evaluated and their treatment regimen reviewed.

Treatment with montelukast does not permit patients with aspirin-sensitive asthma to take acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

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

Available data from published prospective and retrospective cohort studies on montelukast use in pregnant women assessing major congenital malformations in children have not established a risk associated with the use of the medicinal product. The available studies have methodological limitations, including small sample size, retrospective data collection in some cases, and non-comparable control groups.

Montelukast should be used during pregnancy only if clearly needed.

Breastfeeding period. Studies in rats have shown that montelukast is excreted in breast milk. It is unknown whether montelukast is excreted in human breast milk.

Montelukast may be used during breastfeeding only if considered absolutely necessary.

Ability to influence the speed of reactions 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.

Method of Administration and Dosage.

The dose for patients (aged 15 years and older) with asthma or asthma with concomitant seasonal allergic rhinitis is 10 mg (1 tablet) once daily in the evening. For relief of allergic rhinitis symptoms, the time of administration may be individually adjusted.

General recommendations. The therapeutic effect of montelukast on asthma control parameters develops within 1 day. The medicinal product can be taken regardless of food intake. Patients should be advised to continue taking the medicinal product Montular®, even when asthma is under control, as well as during asthma exacerbations. Montular® should not be used concomitantly with medicinal products containing montelukast as the active ingredient.

There is no need to adjust the dose in elderly patients, patients with renal impairment, or patients with mild to moderate hepatic impairment. There are no data available for patients with severe hepatic impairment. Dosage is the same for men and women.

Use of the medicinal product Montular® in relation to other asthma treatments

Montular® may be added to a patient's existing asthma treatment regimen.

Inhaled corticosteroids. Montular® can be used as add-on therapy in patients in whom inhaled corticosteroids together with short-acting β-agonists used as needed do not provide adequate clinical control of the disease.

Montular® should not be used as a substitute for inhaled corticosteroids (see section "Special precautions for use").

Children.

For use in children aged 15 years and older.

Children under 15 years of age should receive montelukast in the form of chewable tablets.

Overdose.

There is no specific information on the treatment of montelukast overdose. In clinical studies, adult patients with chronic asthma received montelukast at doses up to 200 mg per day for 22 weeks and, in short-term studies, up to 900 mg per day for approximately 1 week, without clinically significant adverse reactions.

Cases of acute overdose have been reported during post-marketing surveillance and clinical trials of montelukast. These cases occurred following administration of doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). Clinical and laboratory findings were consistent with the safety profile of montelukast in adults and children. Most cases of overdose were not associated with adverse reactions. The most commonly reported adverse reactions were consistent with the known safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

It is unknown whether montelukast is removed by peritoneal dialysis or hemodialysis.

Adverse reactions

Montelukast was evaluated in clinical studies:

• 10 mg film-coated tablets – in approximately 4000 asthma patients aged 15 years and older;
• 10 mg film-coated tablets – in approximately 400 asthma patients with seasonal allergic rhinitis aged 15 years and older;
• 5 mg chewable tablets – in approximately 1750 asthma patients aged 6 to 14 years.

During clinical studies, the adverse reactions listed below were reported commonly (≥ 1/100 to < 1/10) in patients receiving montelukast treatment and at a higher frequency than in patients receiving placebo.

Table 1

During clinical studies with prolonged treatment of a small number of adult patients for up to 2 years and children aged 6 to 14 years for 12 months, the safety profile did not change.

Post-marketing period

Adverse reactions reported during the post-marketing period are listed according to system organ classes and using standard terminology in Table 2. The frequencies are based on data from the relevant clinical studies.

Table 2

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals should report all suspected adverse reactions to the State Expert Centre of the Ministry of Health of Ukraine and to the Marketing Authorization Holder via the feedback form on the website: https://kusum.ua/pharmacovigilance/.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 3 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and address of its business location.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.