Montelukast-intelі

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONTLEUKAST-INTELI

Composition:

Active substance: montelukast;

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

Excipients:

Core: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, magnesium stearate;

Film coating: hypromellose, macrogol 6000, titanium dioxide (E 171), talc, yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex cream-colored tablets imprinted with "M10" on one side and smooth on the other.

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

ATC code R03DC03.

Pharmacological Properties

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). 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 the nasal mucosa following allergen exposure during both early- and late-phase reactions, and this is accompanied by symptoms of allergic rhinitis. Studies have shown that intranasal administration of CysLT leads to increased nasal airway resistance and symptoms of nasal obstruction.

Montelukast, when administered orally, is an active compound that binds with high selectivity and affinity to CysLT1 receptors. According to clinical studies, montelukast inhibits bronchoconstriction following inhalation of LTD4 at a dose of 5 mg. Bronchodilation is observed within 2 hours after oral administration, and this effect is additive to the bronchodilation caused by β-agonists. Treatment with montelukast suppresses both the early and late phases of bronchoconstriction induced by antigen stimulation. Montelukast, compared to placebo, reduces the number of eosinophils in peripheral blood in adult and pediatric patients. In a separate study, montelukast intake 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, spacer device), montelukast demonstrated a faster initial response, although over a 12-week study, beclomethasone resulted in a more pronounced 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 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 mean daily rhinitis symptom score compared to placebo. The mean daily rhinitis symptom score is the average value obtained from assessing nasal symptoms during the day (nasal congestion, rhinorrhea, sneezing, nasal itching) and at night (nasal congestion upon awakening, difficulty falling asleep, frequency of nighttime awakenings). Significantly better results were obtained for overall assessment of allergic rhinitis treatment by both patients and physicians compared to placebo. Evaluation of the efficacy of this treatment for asthma was not the 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, compared to placebo, significantly improved respiratory function (change from baseline in FEV1: 8.71% vs. 4.16%; change in PEFR: 27.9 L/min vs. 17.8 L/min) and reduced the frequency of as-needed use of β-agonists (change from baseline: –11.7% vs. +8.2%).

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 observed throughout the 12-week study period. Reduction in EIB was also demonstrated in a short-term study involving 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 dosing interval with once-daily administration.

In patients with aspirin sensitivity receiving ongoing therapy with inhaled and/or oral corticosteroids, treatment with montelukast, compared to placebo, led to significant improvement in asthma control (change from baseline in FEV1: 8.55% vs. –1.74%; change from baseline in reduction of 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 on an empty stomach in adults, 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 montelukast after oral administration. Safety and efficacy were confirmed in clinical studies when the drug was administered regardless of meal timing.

For 5 mg chewable tablets, the Cmax in adults was achieved within 2 hours after administration on an empty stomach. 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 volume of distribution at steady state averages between 8 and 11 liters. In studies in rats using radiolabeled montelukast, passage across the blood-brain barrier was minimal. Furthermore, 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, plasma concentrations of montelukast metabolites at steady state in adults and pediatric patients are not detectable.

Cytochrome P450 2C8 is the primary enzyme involved in the metabolism of montelukast. Additionally, cytochromes CYP 3A4 and 2C9 play a minor role 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 cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Elimination

The 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 bile.

Pharmacokinetics in Specific Patient Populations

Dose adjustment is not required for patients with mild to moderate hepatic impairment. Studies in patients with renal impairment have not been conducted. Since montelukast and its metabolites are eliminated via bile, dose adjustment in patients with renal impairment is not considered necessary. Data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score >9) are not available.

At high doses of montelukast (20 and 60 times the recommended adult dose), a decrease in plasma theophylline concentration was observed. 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 cases of inadequate clinical control of asthma with short-acting β-adrenergic agonists used as needed. In patients with asthma taking montelukast, this medication 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.

The risk of developing neuropsychiatric symptoms in patients with allergic rhinitis may outweigh the benefit of montelukast use; therefore, the medicinal product should be used as a reserve treatment in patients with inadequate response to or intolerance of alternative therapies.

Contraindications.

Hypersensitivity to any component of the drug. Children under 15 years of age (for the 10 mg dose).

Interaction with other medicinal products and other types of interactions.

MONTELUCAST-INTELI can be administered together with other medicinal products commonly used for prevention or long-term treatment of asthma. In drug interaction studies, the recommended clinical dose of montelukast 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 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. However, clinical drug interaction study data involving montelukast and rosiglitazone (a marker substrate; a drug metabolized by CYP 2C8) indicate that montelukast is not an inhibitor of CYP 2C8 in vivo. Thus, 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-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 consider the increased risk of adverse reactions.

Based on in vitro studies, clinically significant interactions are not expected with weaker inhibitors of CYP 2C8 (e.g., trimethoprim). 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 MONTELUCAST-INTELI for oral use is never to be used for the treatment of acute asthma attacks, and that they should always have an appropriate rescue medication available. In acute attacks, short-acting inhaled β-agonists should be used. Patients should seek medical advice as soon as possible if they require more short-acting β-agonist than usual.

Montelukast should not be used to abruptly displace inhaled or oral corticosteroid therapy.

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

Psychoneuropsychiatric events have been reported in patients taking montelukast (see section "Adverse reactions"). As other factors may influence these events, it is unknown whether they are related to the use of MONTELUCAST-INTELI. Physicians should discuss these adverse events with their patients and/or caregivers. Patients and/or caregivers should be instructed to report any such changes to their physician.

In rare cases, systemic eosinophilia, sometimes manifesting with clinical features of vasculitis, such as Churg-Strauss syndrome, may occur in patients receiving anti-asthma medications, 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 discontinuation of corticosteroid therapy. The possibility that leukotriene receptor antagonists may be associated with the occurrence 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.

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

The medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, 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.

Limited data from the pregnancy registry do not indicate a causal relationship between the use of MONTELUCAST-INTELI and the occurrence of malformations (such as limb defects) that have been rarely reported during worldwide post-marketing experience.

Montelukast may be used during pregnancy only if clearly needed.

Lactation. Studies in rats have shown that montelukast passes into milk. It is unknown whether montelukast is excreted in human breast milk.

Montelukast may be used during breastfeeding only if clearly needed.

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 asthma with concomitant seasonal allergic rhinitis is 10 mg (1 tablet) once daily in the evening. For relief of allergic rhinitis symptoms, the timing of administration may be adjusted individually.

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

No dosage adjustment is necessary for 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.

Treatment with MONTÉLUCAST-INTEL in relation to other asthma therapies.

MONTÉLUCAST-INTEL may be added to a patient's existing treatment regimen.

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

MONTÉLUCAST-INTEL should not be abruptly substituted for inhaled corticosteroids (see section "Special precautions").

Children.

For use in children aged 15 years and older. Montelukast should be administered in another pharmaceutical form for children under 15 years of age.

Overdose.

Detailed information on the treatment of montelukast overdose is lacking. In clinical trials of chronic bronchial asthma, patients 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 one week, without any clinically significant adverse reactions observed in any patient.

In post-marketing experience and during clinical trials of montelukast, reports of acute overdose have been received. These included reports of adults and children who had taken doses up to 1000 mg (approximately 61 mg/kg for a 2-year-old child). Clinical and laboratory findings were consistent with the safety profile observed in adults and children. In most cases of overdose, patients did not experience any adverse reactions. The most commonly reported adverse reactions were consistent with the known safety profile of montelukast and included abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity.

Treatment

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

Adverse reactions

Montelukast was evaluated in clinical studies:

film-coated tablets, 10 mg – in approximately 4000 patients with asthma aged 15 years and older;

film-coated tablets, 10 mg – in approximately 400 patients with asthma and seasonal allergic rhinitis aged 15 years and older;

chewable tablets, 5 mg – in approximately 1750 patients with asthma 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 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 according to organ system classes and preferred terms, as shown in Table 2. Frequencies were determined based on data from the relevant clinical studies.

Table 2

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 30 ºC in the original packaging. Keep out of reach of children.

Packaging.

7 tablets per blister pack. 4 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LABORATORIOS NORMON, S.A.

Manufacturer's address and place of business.

Ronda de Valdecarrizo, 6, Tres Cantos 28760 (Madrid), Spain.