Montemac 10

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONTMAK 10

Composition:

Active substance: montelukast;

One film-coated tablet contains montelukast sodium equivalent to montelukast 10 mg;

Excipients: microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, hydroxypropylcellulose, disodium edetate, magnesium stearate; coating Instacoat Aqua Brown ICG-A-10310: hypromellose, hydroxypropylcellulose, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: beige, square-shaped, biconvex film-coated tablets with rounded edges, engraved with "CL 26" on one side and smooth on the other.

Pharmacotherapeutic group.

Agents for systemic use in obstructive airway 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). The CysLT type 1 receptor (CysLT1) is 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 secretion, vascular permeability, and eosinophilia. In allergic rhinitis, CysLT protein is released from nasal mucosa following allergen exposure during both early- and late-phase reactions, and this is associated with symptoms of allergic rhinitis. According to studies, intranasal administration of CysLT leads to increased nasal airway resistance and enhanced symptoms of nasal congestion.

Montelukast, following oral administration, is an active compound that binds with high selectivity and affinity to CysLT1 receptors. Clinical studies have shown that montelukast at a dose of 5 mg inhibits bronchospasm induced by inhaled LTD4. Bronchodilation is observed within 2 hours after oral administration; this effect is additive to bronchodilation caused by β-agonists.

Treatment with montelukast suppresses bronchoconstriction caused by antigenic stimulation at both early and late stages. Montelukast, compared to placebo, reduces the number of eosinophils in peripheral blood in adult and pediatric patients. In a separate study, montelukast significantly reduced the number of eosinophils in the airways (measured in sputum) and in peripheral blood and improved clinical asthma control.

In studies involving adults, montelukast at a dose of 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 overall use of β-agonists (change from baseline: –26.1% vs. –4.6%, respectively). Improvement in patient-reported daytime and nighttime asthma symptoms was significantly better than with placebo.

Studies in adults have demonstrated montelukast's ability to complement the clinical effect of inhaled corticosteroids (change (%) from 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, via spacer device), montelukast showed a faster initial response, although over a 12-week study period, beclomethasone resulted in a more pronounced average 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 greater proportion of patients receiving montelukast achieved a similar clinical response compared to beclomethasone (i.e., 50% of patients receiving beclomethasone achieved an improvement in FEV1 of approximately 11% or more from baseline, while 42% of patients receiving montelukast achieved the same response).

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. In this study, montelukast tablets administered at a dose of 10 mg once daily demonstrated statistically significant improvement in the average daily rhinitis symptom score compared to placebo. The average daily rhinitis symptom score is a mean value derived from assessment of nasal symptoms during the day (average nasal congestion, rhinorrhea, sneezing, nasal itching) and at night (average nasal congestion upon awakening, difficulty falling asleep, and frequency of nocturnal awakenings). Significantly better outcomes were observed for overall patient and physician assessment of allergic rhinitis treatment compared to placebo. Evaluation of efficacy for asthma was not a primary objective of this study.

In an 8-week study involving children aged 6 to 14 years, montelukast at a dose of 5 mg once daily significantly improved respiratory function compared to placebo (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 during 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 overall β-agonist use: –27.78% vs. 2.09%).

Pharmacokinetics.

Absorption

Montelukast is rapidly absorbed following oral administration. In adults, after fasting administration of 10 mg film-coated tablets, maximum plasma concentration (Cmax) is achieved within 3 hours (Tmax). The average oral bioavailability is 64%. A standard meal does not affect Cmax or oral bioavailability. Safety and efficacy have been demonstrated in clinical trials where 10 mg film-coated tablets were taken regardless of food intake.

For 5 mg chewable tablets, Cmax in adults is achieved within 2 hours after fasting administration. The average oral bioavailability is 73%, decreasing to 63% when taken with a standard meal.

Distribution

Over 99% of montelukast is bound to plasma proteins. The volume of distribution at steady state averages between 8 and 11 liters. In rat 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 with therapeutic doses, metabolite concentrations of montelukast in steady-state plasma in adults and pediatric patients were not detectable.

Cytochrome P450 2C8 is the primary enzyme involved in montelukast metabolism. Additionally, cytochromes CYP 3A4 and 2C9 play minor roles in its metabolism, although itraconazole (a CYP3A4 inhibitor) did not alter the pharmacokinetic parameters of montelukast in healthy volunteers receiving 10 mg montelukast daily. According to in vitro studies using human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Elimination

Plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After oral administration of radiolabeled montelukast, 86% of the dose is excreted in feces within 5 days and less than 0.2% in urine. In addition to oral bioavailability, this confirms that metabolites are almost entirely excreted via bile.

Pharmacokinetics in Specific Patient Populations

Dose 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. Since montelukast and its metabolites are excreted via bile, dose adjustment in patients with renal impairment is not considered necessary. There are no data on the pharmacokinetic profile of montelukast in patients with severe hepatic impairment (Child-Pugh score >9).

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 is not observed with the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

Adjunctive treatment of bronchial asthma in patients with persistent mild to moderate 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 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 benefits of the drug; therefore, Montemac 10 should be used as a reserve medication in patients with inadequate response to or intolerance of alternative therapies.

Contraindications.

Hypersensitivity to the components of the drug. Children under 15 years of age.

Interaction with other medicinal products and other forms of interactions.

Montemac 10 may be prescribed concomitantly with other medications used for prevention or long-term treatment of asthma and treatment of allergic rhinitis. In drug interaction studies, the recommended clinical dose of montelukast had 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 taking phenobarbital concomitantly, the area under the concentration-time curve (AUC) of montelukast decreased by approximately 40%. Since montelukast is metabolized by CYP 3A4, 2C8, and 2C9, caution is advised—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. However, 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 this enzyme (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 using montelukast and gemfibrozil (an inhibitor of CYP 2C8 and 2C9), gemfibrozil increased systemic exposure to montelukast by 4.4 times. 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 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 Montemac 10 for oral use should not be used for the treatment of acute asthma attacks, and that they must always have a suitable emergency 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 require more frequent use of a short-acting β-agonist than usual.

Inhaled or oral corticosteroid therapy should not be abruptly replaced with montelukast.

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

Psychoneuropsychiatric reactions have been reported in adults, adolescents, and children taking montelukast (see section "Side effects"). Patients and physicians should be vigilant for psychoneuropsychiatric reactions. Patients and/or caregivers should be instructed to inform their physician if such reactions occur. Physicians should carefully evaluate the risks and benefits of continuing montelukast therapy if such reactions occur.

In isolated cases, systemic eosinophilia, sometimes accompanied by 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 treated with systemic corticosteroid therapy. These cases have usually (but not always) been associated with a reduction in dose or discontinuation of corticosteroid therapy. It is not possible to either rule out or confirm a causal relationship between leukotriene receptor antagonists and the occurrence of Churg-Strauss syndrome. Physicians should be aware of the possibility of eosinophilia, vasculitic rash, worsening of pulmonary symptoms, or cardiac and/or neurological complications in patients. Patients who develop such symptoms should be re-evaluated and their treatment regimen reconsidered.

Montelukast therapy does not allow patients with aspirin-induced asthma to take aspirin or other nonsteroidal anti-inflammatory drugs.

Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

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 the use of montelukast in pregnant women assessing major congenital malformations in children have not established a risk associated with the use of the drug. The existing studies have methodological limitations, including small sample size, retrospective data collection in some cases, and non-comparable control groups.

The drug should be used during pregnancy only if clearly needed.

Breastfeeding. Studies in rats have shown that montelukast passes into milk. It is unknown whether montelukast passes into human breast milk. Montemac 10 may be used during breastfeeding only if considered absolutely necessary.

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration.

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

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

No dose adjustment is necessary for elderly patients, patients with renal impairment, or patients with mild to moderate hepatic impairment. There are no data available regarding patients with severe hepatic impairment. Dosage is the same for men and women.

Use of the medicinal product in relation to other asthma treatments.

The medicinal product may be added to an existing asthma treatment regimen.

Inhaled corticosteroids. The medicinal product may 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.

The medicinal product should not abruptly replace inhaled corticosteroids (see section "Special precautions for use").

Children.

The product is indicated for use in patients aged 15 years and older. Children under 15 years of age should be administered the product in the form of chewable tablets.

Overdose.

There is no specific information regarding treatment of overdose with this product.

In long-term studies in patients with chronic asthma, montelukast was administered at doses up to 200 mg/day to adult patients for 22 weeks, and in short-term studies at doses up to 900 mg/day for approximately 1 week, without clinically significant adverse reactions.

Cases of acute overdose have been reported. Specifically, administration of the product in doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child) has been reported in adults and children. The observed clinical and laboratory findings were consistent with the safety profile of the product in adults and children.

In most reports of overdose, no adverse events were observed. The most commonly reported adverse effects were consistent with the product's safety profile and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

It is unknown whether montelukast is eliminated by peritoneal dialysis or hemodialysis. Treatment is symptomatic.

Adverse reactions

Montelukast was evaluated in clinical trials:

• 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 trials, the adverse reactions listed below were reported commonly (≥ 1/100 to < 1/10) in patients receiving montelukast treatment and more frequently than in patients receiving placebo.

Table 1

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

Post-marketing period

Adverse reactions reported during the post-marketing period are listed below by system organ classes and using standardized terms in Table 2. Frequencies are based on data from the relevant clinical studies.

Table 2

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and place of business.

Village Thedda, P.O. Lodhymaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.