Klast

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLAST (SLAST)

Composition:

Active substance: montelukast;

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

Excipients: microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, hydroxypropylcellulose, magnesium stearate, coating Opadry Yellow OY-C 22902: hypromellose, titanium dioxide (E 171), ethylcellulose, quinoline yellow (E 104), yellow FCF (E 110), ponceau 4R (E 124).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, biconvex, film-coated tablets of yellow color.

Pharmacotherapeutic group. Agents for systemic use in obstructive diseases of the respiratory tract. 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 (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 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 asthmatic patients. 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 the bronchodilation produced by β-agonists.

Treatment with montelukast suppresses both early- and late-phase bronchoconstriction, reducing the response to antigens. Compared with placebo, montelukast reduces the number of eosinophils in peripheral blood in both adult and pediatric patients. In a separate study, montelukast treatment significantly reduced eosinophil counts in the airways (measured in sputum) and in peripheral blood, and improved clinical asthma control.

In clinical trials involving adults, montelukast at a dose of 10 mg once daily demonstrated significant improvement compared to placebo in morning forced expiratory volume in 1 second (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 significantly reduced 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.

Data from adult studies have shown that montelukast can complement the clinical effect of inhaled corticosteroids (change in % 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 with inhaled beclomethasone (200 mcg twice daily, via spacer), montelukast demonstrated a faster initial response, although over a 12-week study period, beclomethasone produced a greater 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 (i.e., approximately 50% of patients receiving beclomethasone achieved an improvement in FEV1 of about 11% or more from baseline, while 42% of patients receiving montelukast achieved a similar response).

A clinical study was conducted to evaluate montelukast as a symptomatic treatment for seasonal allergic rhinitis in patients aged 15 years and older who have asthma and concomitant seasonal allergic rhinitis. In this study, montelukast tablets at a dose of 10 mg once daily demonstrated statistically significant improvement compared to placebo in the average daily rhinitis symptom score. The average daily rhinitis symptom score is the mean of daytime nasal symptoms (nasal congestion, rhinorrhea, sneezing, nasal itching) and nighttime symptoms (nasal congestion upon awakening, difficulty falling asleep, and frequency of nighttime awakenings). Significantly better outcomes in overall patient and physician assessment of allergic rhinitis treatment were observed compared to placebo. Evaluation of efficacy for asthma treatment 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 need for rescue β-agonist use (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 minutes vs. 60.64 minutes). 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 minutes vs. 27.98 minutes). The effect in both studies was demonstrated at the end of the once-daily dosing interval.

In patients with aspirin sensitivity who were 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

After administration, montelukast is rapidly and almost completely absorbed. In adults, following oral administration of 10 mg coated tablets on an empty stomach, peak plasma concentration (Cmax) is achieved within 3 hours (Tmax). Mean bioavailability is 64%. A normal meal does not affect the Cmax or bioavailability of the coated tablets. Safety and efficacy have been demonstrated in clinical trials where 10 mg coated tablets were administered regardless of food intake.

Distribution

Over 99% of montelukast is protein-bound in plasma. The steady-state volume of distribution 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 undergoes extensive metabolism. In studies with therapeutic doses, metabolite concentrations in steady-state plasma 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. Based on further in vitro studies with human liver microsomes, montelukast at therapeutic concentrations 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 bile.

Pharmacokinetics in Specific Patient Populations

Dosage adjustment is not required for elderly patients or for 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, dosage adjustment in patients with renal impairment is not considered necessary. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score >9).

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

Clinical characteristics.

Indications.

Additional treatment of bronchial asthma in patients with persistent mild to moderate asthma not adequately controlled by 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 benefit of montelukast use; therefore, montelukast should be used as a reserve medication for patients with inadequate response to or intolerance of alternative therapies.

Contraindications.

Hypersensitivity to any component of the drug. Pediatric age under 15 years.

Interaction with other medicinal products and other forms of interaction.

The drug may be prescribed together with other medications used for prevention or long-term treatment of asthma. In drug interaction studies, the recommended clinical dose of montelukast had no significant clinical 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 required, especially in children, when prescribing montelukast 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, clinical drug interaction data involving montelukast and rosiglitazone (a marker substrate; a drug metabolized by CYP 2C8) demonstrate 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 (such as 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 clinical drug interaction studies 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, does not lead to a significant increase in systemic exposure to montelukast.

Special precautions for use.

Patients should be warned that the medication should not be used to relieve acute asthmatic attacks, and that they must always have with them an appropriate emergency rescue medication. In the case of an acute attack, short-acting inhaled β-agonists should be used. Patients should consult their doctor as soon as possible if they require a greater number of short-acting β-agonist inhalations 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 treated with montelukast (see section "Adverse reactions"). Patients and physicians should be alert to 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 rare cases, systemic eosinophilia, sometimes with clinical features of vasculitis (so-called Churg-Strauss syndrome), has been observed 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 reduction or withdrawal of corticosteroid therapy. The possibility that leukotriene receptor antagonists may be linked to the development of Churg-Strauss syndrome cannot be either ruled out or confirmed; therefore, 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 the aforementioned symptoms should undergo re-evaluation, and their treatment regimen should be revised.

Patients with aspirin-sensitive asthma being treated with montelukast should not use acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

The medication should not be administered to patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not demonstrated 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 medication. The available studies have methodological limitations, including small sample size, in some cases retrospective data collection, 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 into 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 affect reaction speed when driving or operating machinery.

Montelukast is not expected to affect the ability to drive a car or operate machinery. However, dizziness or somnolence may occur in individual patients.

Method of Administration and Dosage.

For the treatment of asthma or asthma associated with seasonal allergic rhinitis, adults and children aged 15 years and older should take 1 tablet of 10 mg once daily in the evening. For relief of allergic rhinitis symptoms, the time of administration should be individually adjusted.

General recommendations. The therapeutic effect of the medicinal product Klast 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 Klast even if asthma control is achieved, as well as during periods of asthma exacerbation. Klast should not be used simultaneously with medicinal products containing the active substance montelukast.

There is no need for dose adjustment in elderly patients, patients with renal impairment, or patients with mild to moderate hepatic impairment. Data regarding dose adjustment in patients with severe hepatic impairment are lacking. The dosage of the drug is the same for male and female patients.

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

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

Inhaled corticosteroids. The medicinal product Klast 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.

The medicinal product Klast should not abruptly replace 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 be given the drug in the form of chewable tablets.

Overdose.

There is no specific information on the treatment of overdose with this drug. In long-term studies involving 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, up to 900 mg/day for approximately one week, without clinically significant adverse reactions.

During post-marketing use and clinical trials, reports of acute overdose were received, including cases of ingestion by adults and children at doses exceeding 1000 mg (approximately 61 mg/kg, a 42-month-old child). The clinical and laboratory findings were consistent with the safety profile of the drug in adults and children.

In most cases, no adverse events were observed. The most commonly reported adverse effects were consistent with the drug'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.

Adverse reactions

Montelukast was evaluated in clinical studies:

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

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 for 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. Frequency is based on data from the relevant clinical studies.

Table 2

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

14 film-coated tablets in a blister. 2 or 6 blisters per cardboard pack.

Prescription category.

Prescription only.

Manufacturer.

NOBEL ILAC SANAI VE TICARET A.S.

Manufacturer's address and place of business.

Sankaklar Quarter, Eski Akcakoca Avenue, No. 299, 81100, Duzce, Turkey.