Astor 10

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ASTATOR 10

Composition:

Active substance: montelukast;

1 tablet contains montelukast sodium equivalent to montelukast 10 mg;

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

Pharmaceutical form. Tablets.

Main physico-chemical characteristics: round, biconvex, light-brown tablets (orange specks may be present), with a break line on both sides of the tablet.

Pharmacotherapeutic group.

Preparations 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 (including airway smooth muscle cells and macrophages) and other pro-inflammatory cells (including eosinophils and certain myeloid progenitor cells). The presence of CysLT receptors is relevant to 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, CysLTs are released from nasal mucosa following allergen exposure during both early and late phases and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has demonstrated increased resistance of nasal airways and symptoms of nasal obstruction.

Montelukast, administered orally, 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 confirmed by its ability to inhibit LTD4-induced bronchoconstriction in asthmatic patients. Even a low dose of 5 mg results in significant inhibition of LTD4-stimulated bronchoconstriction. Montelukast induces bronchodilation within 2 hours after oral administration; this effect is additive to bronchodilation induced by β-agonists.

Treatment with montelukast suppresses both early- and late-phase bronchoconstriction, reducing the response to antigens. Compared to placebo, montelukast reduces the number of eosinophils in peripheral blood in both adult and pediatric patients. Studies have shown that montelukast significantly reduces eosinophil counts in the airways (measured in sputum) and in peripheral blood, improving clinical asthma control.

In clinical trials involving adults, montelukast 10 mg once daily compared to placebo demonstrated significant improvement 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 a significant reduction in overall use of β-agonists (change from baseline: –26.1% vs. –4.6%, respectively). Patient-reported daytime and nighttime asthma symptoms improved significantly more than with placebo.

Studies in adults demonstrated montelukast’s ability to complement the clinical effect of inhaled corticosteroids (change (% from baseline) for inhaled beclomethasone plus montelukast vs. beclomethasone alone: 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 the 12-week study period, beclomethasone produced a greater average therapeutic effect (% change from baseline for montelukast vs. beclomethasone: 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 on beclomethasone achieved an improvement in FEV1 of approximately 11% or more from baseline, compared to 42% of patients on montelukast achieving 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. This study demonstrated that montelukast tablets 10 mg once daily, compared to placebo, resulted in a statistically significant improvement 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, frequency of nocturnal awakenings). Patients and physicians reported significantly better overall assessment of allergic rhinitis treatment with montelukast 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 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 overall β-agonist use: –27.78% vs. +2.09%).

Pharmacokinetics.

Absorption

After oral administration, montelukast is rapidly and almost completely absorbed. In adults, following fasting administration of 10 mg tablets, maximum plasma concentration (Cmax) is reached within 3 hours (Tmax). Mean bioavailability is 64%. Administration with food does not affect plasma Cmax or bioavailability of the tablets. Safety and efficacy have been demonstrated in studies where 10 mg tablets were taken regardless of meals.

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

Distribution

Over 99% of montelukast is protein-bound in plasma. The mean steady-state volume of distribution is 8 to 11 L. In a study using radiolabeled montelukast, blood-brain barrier penetration was minimal. At 24 hours after dose administration, concentrations of radiolabeled drug in all other tissues 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, cytochromes CYP 3A4 and 2C9 play a minor role in its metabolism, although itraconazole (a CYP 3A4 inhibitor) did not alter the pharmacokinetic profile of montelukast in healthy volunteers receiving 10 mg daily.

In vitro studies using human liver microsomes have demonstrated that cytochromes P450 3A4, 2A6, and 2C9 are involved in montelukast metabolism. Based on further in vitro studies with human liver microsomes, montelukast at therapeutic concentrations does not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 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 an isotopically labeled oral dose, 86% of montelukast 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 patients with mild to moderate hepatic impairment. Studies in patients with renal impairment have not been conducted. However, since montelukast and its metabolites are eliminated via bile, dose adjustment in patients with renal impairment is not considered necessary. Pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9) are lacking.

Administration of high doses of montelukast (20 and 60 times the recommended adult dose) was associated with decreased plasma theophylline concentrations. 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 asthma of mild to moderate severity that is not adequately controlled by inhaled corticosteroids, as well as in cases of inadequate clinical control of asthma with short-acting β-agonists used on an as-needed basis. 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 montelukast use; therefore, montelukast should be used as a reserve medication in patients with inadequate response or intolerance to alternative therapies.

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

Astartor 10 may be prescribed together with other medications for the 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 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, clinical drug interaction 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. 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 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; however, physicians should be aware of the increased risk of adverse reactions.

Based on in vitro data, 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 lead to a significant increase in systemic exposure to montelukast.

Special precautions for use.

Patients should be advised that Astator 10 for oral use must not be used to relieve acute asthmatic attacks. Treatment with conventional appropriate medications for relieving attacks should be continued. In the case of an acute attack, short-acting inhaled β-agonists should be used. Patients should consult their physician as soon as possible if they require a greater than usual number of inhalations of short-acting β-agonists.

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

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

Cases of neuropsychiatric reactions such as behavioral changes, depression, and suicidal ideation have been reported in patients of all age groups receiving montelukast (see section "Adverse reactions"). These manifestations may be serious and may persist if treatment is not discontinued. Therefore, montelukast therapy should be discontinued if neuropsychiatric symptoms occur.

Patients and/or caregivers should remain alert for neuropsychiatric reactions and should inform their physician of any behavioral changes.

In rare cases, systemic eosinophilia, sometimes accompanied by clinical signs of vasculitis, such as Churg-Strauss syndrome (allergic granulomatous angiitis), has been observed in patients receiving anti-asthmatic agents, including montelukast. This condition is treated with systemic corticosteroid therapy. These cases were usually (but not always) associated with the reduction or discontinuation 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. Therefore, physicians should be alerted to the potential development of 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 re-assessed.

Treatment with montelukast does not allow patients with aspirin-induced asthma to use aspirin or other nonsteroidal anti-inflammatory drugs.

Astator 10 contains aspartame, which is a source of phenylalanine. Patients with phenylketonuria should be informed that one 10 mg tablet contains phenylalanine equivalent to 1.685 mg of phenylalanine.

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 significant congenital malformations in children, have not established a risk associated with the use of the medicinal product. However, existing studies have methodological limitations, including small sample size, retrospective data collection in some cases, and non-comparable control groups.

Astator 10 should be used during pregnancy only if clearly needed.

Breastfeeding. Studies in rats have demonstrated that montelukast passes into milk. It is unknown whether montelukast passes into human breast milk.

Astator 10 may be used during breastfeeding only if considered absolutely necessary.

Ability to influence the speed of reactions when driving vehicles or operating machinery.

Montelukast is not expected to affect the ability to drive vehicles or operate machinery. However, dizziness or somnolence has been reported very rarely.

Dosage and Administration

The medication is intended for use in adults and children aged 15 years and older. For patients with asthma or with asthma and concomitant seasonal allergic rhinitis, the recommended dose is 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 medication regarding control of asthmatic symptoms lasts throughout the day. The medication can be taken without regard to food intake. Patients should be advised to continue taking the medication even when asthma is well-controlled, as well as during asthma exacerbations. The medication should not be taken together with other medicinal products containing montelukast.

Dosage adjustment is not required for elderly patients or for patients with mild to moderate hepatic impairment or renal impairment. Data regarding dosage adjustment in patients with severe hepatic impairment are lacking. The dosage of the medication is the same for male and female patients.

Use of Astator 10 in relation to other asthma treatments. The medication may be added to the patient's existing treatment regimen.

Inhaled Corticosteroids

Astator 10 may be used as add-on therapy in patients whose disease is not adequately controlled with inhaled corticosteroids together with as-needed short-acting β-agonists.

Inhaled corticosteroids should not be abruptly replaced by Astator 10 (see section "Special Warnings and Precautions for Use").

Children

The medication is indicated for use in children aged 15 years and older. Children under 15 years of age should receive the medication in the form of chewable tablets.

Overdose

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

In long-term studies in patients with chronic asthma, montelukast was administered at doses up to 200 mg/day in 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, cases of acute overdose have been reported, including ingestion by adults and children at doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). The observed clinical and laboratory findings were consistent with the known safety profile of the medication in adults and children. In most cases, no adverse events were reported. The most commonly observed adverse effects were consistent with the medication's safety profile and included abdominal pain, drowsiness, 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:

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

During clinical studies, the adverse reactions listed below were reported commonly (from ≥ 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 system organ classes and using standard terms in Table 2. The frequency is based on data from relevant clinical studies.

Table 2

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister; 3 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Torrent Pharmaceuticals Ltd.

Manufacturer's address and place of business.

Indrad Plant, Vill. Indrad, Taluka Kadi, Dist. Mehsana Gujarat 382721, India.