Astatore 4

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ASTATOR 4

Composition:

Active substance: montelukast;

1 tablet contains montelukast sodium equivalent to 4 mg of montelukast;

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

Pharmaceutical form. Chewable tablets.

Main physico-chemical properties: oval, biconvex, pink-colored tablets (pink specks may occur), with a score line on both sides.

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 important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) present in human airways and induce responses such as bronchoconstriction, mucus secretion, increased vascular permeability, and increased eosinophil recruitment. After oral administration, montelukast is an active compound that binds with high selectivity and affinity to CysLT1 receptors. According to clinical studies, montelukast inhibits LTD4-induced bronchoconstriction at a dose of 5 mg. Bronchodilation is observed within 2 hours after oral administration; this effect is additive to the bronchodilation caused by β-agonists. Montelukast treatment suppresses both early and late phases of bronchoconstriction induced by antigen stimulation. Compared with placebo, montelukast reduces peripheral blood eosinophil counts in adult and pediatric patients. In a separate study, montelukast intake significantly reduced eosinophil counts in the airways (measured in sputum). In adults and children aged 2 to 14 years, montelukast, compared with placebo, reduces peripheral blood eosinophil counts and improves clinical asthma control.

In studies involving adults, montelukast at a dose of 10 mg once daily demonstrated significant improvement compared with 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 a significant reduction in total β-agonist use (change from baseline: –26.1% vs. –4.6%, respectively). Patient-reported daytime and nighttime asthma symptoms were significantly improved compared with placebo.

Studies in adults have demonstrated montelukast's ability to complement the clinical effect of inhaled corticosteroids (change from baseline, %): for inhaled beclomethasone with montelukast vs. beclomethasone alone, FEV1: 5.43% vs. 1.04%; β-agonist use: –8.70% vs. 2.64%. Compared with inhaled beclomethasone (200 mcg twice daily, spacer device), montelukast showed a faster initial response, although over a 12-week study, beclomethasone produced a greater average therapeutic effect (change from baseline for montelukast vs. beclomethasone, respectively: 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 higher proportion of patients receiving montelukast compared with beclomethasone (50% of patients on beclomethasone vs. 42% on montelukast).

In a 12-week, placebo-controlled study in children aged 2 to 5 years, montelukast at a dose of 4 mg once daily improved asthma control compared with placebo, regardless of concomitant controller therapy (inhaled/nebulized corticosteroids, inhaled/nebulized sodium cromoglicate). Sixty percent of patients were not receiving other controller therapy. Montelukast improved daytime symptoms (including cough, wheezing, shortness of breath, and activity limitation) and nighttime symptoms compared with placebo. Montelukast also reduced the frequency of as-needed β-agonist use and emergency corticosteroid use during asthma exacerbations compared with placebo. Patients receiving montelukast had more days without asthma symptoms than those receiving placebo. Therapeutic effect was achieved after the first dose.

In a 12-month, placebo-controlled study in children aged 2 to 5 years with mild asthma and episodic exacerbations, montelukast at a dose of 4 mg once daily significantly (p ≤0.001) reduced the annual rate of asthma exacerbation episodes compared with placebo (1.60 vs. 2.34 exacerbation episodes, respectively) [exacerbation episodes defined as ≥3 consecutive days of daytime symptoms requiring β-agonist or corticosteroid (oral or inhaled) use, or hospitalization for asthma treatment]. The annual exacerbation rate was reduced by 31.9%, with a 95% CI of 16.9; 44.1.

In a placebo-controlled study in children aged 6 months to 5 years with intermittent (but not persistent) asthma, treatment with montelukast was administered either continuously for 12 months at 4 mg once daily or in 12-day courses initiated at the onset of each intermittent symptom episode. No significant difference was observed between patients receiving montelukast 4 mg and those receiving placebo in the number of asthma episodes progressing to asthma attacks (defined as an asthma episode requiring unscheduled physician visit, emergency department visit, or hospitalization; or treatment with oral, intravenous, or intramuscular corticosteroids).

In an 8-week study in children aged 6 to 14 years, montelukast at a dose of 5 mg once daily significantly improved respiratory function compared with placebo (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 β-agonist use (change from baseline: –11.7% vs. +8.2%).

In a 12-month study comparing the efficacy of montelukast and inhaled fluticasone for asthma control in children aged 6 to 14 years with mild persistent asthma, montelukast demonstrated non-inferiority to fluticasone in increasing (as a percentage) the number of days without use of rescue medication (primary endpoint). Over the 12-month treatment period, the percentage of days without rescue medication increased from 61.6% to 84.0% in the montelukast group and from 60.9% to 86.7% in the fluticasone group. The between-group difference in least squares (LS) mean increase in the number of days without rescue medication was statistically significant (–2.8 with 95% CI –4.7; –0.9), but within the pre-specified margin for clinical non-inferiority.

Montelukast and fluticasone also improved asthma control on secondary endpoints assessed over the 12-month treatment period.

FEV1 increased from 1.83 L to 2.09 L in the montelukast group and from 1.85 L to 2.14 L in the fluticasone group. The between-group LS mean difference in FEV1 increase was –0.02 L (95% CI –0.06; 0.02). The mean percentage increase from baseline predicted FEV1 was 0.6% in the montelukast group and 2.7% in the fluticasone group. The LS mean difference from baseline predicted FEV1 was significant: –2.2% (95% CI –3.6; –0.7).

The percentage of days with β-agonist use decreased from 38.0% to 15.4% in the montelukast group and from 38.5% to 12.8% in the fluticasone group. The between-group LS mean difference in percentage of days with β-agonist use was significant: 2.7 (95% CI 0.9; 4.5).

The proportion of patients experiencing an asthma attack (defined as a period of worsening asthma requiring oral steroids, unscheduled physician visit, emergency care, or hospitalization) was 32.2% in the montelukast group and 25.6% in the fluticasone group; the risk ratio (95% CI) was significant: 1.38 (1.04; 1.84).

The proportion of patients using systemic (mainly oral) corticosteroids during the study period was 17.8% in the montelukast group and 10.5% in the fluticasone group. The between-group LS mean difference was significant: 7.3% (95% CI 2.9; 11.7).

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 dosing interval with once-daily administration.

In patients with aspirin sensitivity receiving ongoing therapy with inhaled and/or oral corticosteroids, montelukast treatment compared with 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. After administration of 10 mg film-coated tablets on an empty stomach to adults, the mean peak plasma concentration (Cmax) was reached at 3 hours (Tmax). The mean oral bioavailability is 64%. A normal meal does not affect bioavailability or Cmax after oral administration. Safety and efficacy have been confirmed in clinical studies with 10 mg film-coated tablets administered regardless of meal timing.

For 5 mg chewable tablets, the Cmax in adults is 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.

After administration of 4 mg chewable tablets on an empty stomach in children aged 2 to 5 years, Cmax is reached within 2 hours after dosing. The mean Cmax is 66% higher, and the mean Cmin is lower, compared with adults after administration of 10 mg tablets.

Distribution

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

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

Excretion

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 in patients with mild or 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. Data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score >9) are not available.

Decreased plasma theophylline concentrations were observed with high doses of montelukast (20 and 60 times the recommended adult dose). This effect is not observed with the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

As add-on therapy for bronchial asthma in patients aged 2 to 5 years with mild to moderate persistent asthma that is not adequately controlled by inhaled corticosteroids, and also in cases of inadequate clinical control of asthma with short-acting β-agonists used as needed.

As an alternative treatment instead of low-dose inhaled corticosteroids in patients aged 2 to 5 years with mild persistent asthma who have not experienced severe asthma attacks requiring oral corticosteroids in recent history, and who are unable to use inhaled corticosteroids (see section "Dosage and administration").

Prevention of asthma in which bronchospasm induced by physical exertion is the predominant component, in patients aged 2 years and older.

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 the medicinal product; therefore, it should be used as a reserve medication in patients with inadequate response to or intolerance of alternative therapies.

Contraindications.

Hypersensitivity to any component of the medicinal product. Age under 2 years.

Interaction with other medicinal products and other forms of interaction.

The medicinal product Astator 4 may be prescribed 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 significant clinical effect on the pharmacokinetics of the following medicinal products: 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 via 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 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 co-administered 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 are not expected with less potent 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 warned that Astator 4 for oral use is never to be used for the treatment of acute asthma attacks, and that they should always have a suitable rescue medication available. In the event of an acute attack, short-acting inhaled β-agonists should be used. Patients should seek immediate medical advice if they require more short-acting β-agonist than usual.

Sudden replacement of inhaled or oral corticosteroids with Astator 4 is not recommended.

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

Psychiatric and neurological reactions such as behavioral changes, depression, and suicidal ideation have been reported in patients of all age groups treated with montelukast (see section "Adverse reactions"). These manifestations may be serious and may persist if treatment is not discontinued. Therefore, montelukast should be discontinued if psychiatric or neurological symptoms occur. Patients and/or caregivers should be alert to psychiatric and neurological reactions and should inform their physician if behavioral changes occur.

In isolated cases, systemic eosinophilia, sometimes with clinical features of vasculitis (Churg-Strauss syndrome), has been observed in patients receiving anti-asthma medications, including montelukast. This condition is usually (but not always) associated with a reduction in or withdrawal of corticosteroid therapy. The possibility that leukotriene receptor antagonists may be linked to 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 presenting with such symptoms should be re-evaluated and their treatment regimen reconsidered.

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

Astator 4 contains aspartame, a source of phenylalanine. Patients with phenylketonuria should be informed that one 4 mg chewable tablet contains phenylalanine equivalent to 0.674 mg per dose.

The medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "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 the use of montelukast in pregnant women assessing major congenital malformations in offspring have not established a risk associated with the use of the medicinal product. However, the available studies have methodological limitations, including small sample sizes, in some cases retrospective data collection, and non-comparable control groups.

The drug 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.

Astator 4 may be used during breastfeeding only if considered absolutely necessary.

Ability to affect reaction speed when driving vehicles or operating machinery.

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

Dosage and Administration.

The medicinal product should be used by children under adult supervision. The tablets should be chewed before swallowing.

For patients with asthma and allergic rhinitis (seasonal and perennial), the recommended dose is 1 chewable tablet of 4 mg once daily. The timing of administration for relief of allergic rhinitis symptoms may be individually adjusted.

For asthma treatment, the dose for children aged 2 to 5 years is 1 chewable tablet (4 mg) daily, taken in the evening. Astator 4 should be taken 1 hour before or 2 hours after a meal. Dose adjustment is not required for this age group. The medicinal product Astator 4 in the form of chewable tablets (4 mg) is not recommended for children under 2 years of age.

General recommendations

The therapeutic effect of the medicinal product on asthma control parameters develops within 1 day. Patients should be advised to continue taking the medication even after achieving asthma control, as well as during asthma exacerbations.

Dose adjustment is not required for patients with renal impairment or mild to moderate hepatic impairment. There are no data available for patients with severe hepatic impairment. Dosage is the same for boys and girls.

As an alternative treatment instead of low-dose inhaled corticosteroids in mild persistent asthma

Montelukast is not recommended as monotherapy for patients with moderate persistent asthma. The use of montelukast as an alternative to low-dose inhaled corticosteroids in children aged 2 to 5 years with mild persistent asthma should be considered only for patients who have not had severe asthma attacks requiring oral corticosteroids in the recent past and who are unable to use inhaled corticosteroids (see section "Indications"). Mild persistent asthma is defined as asthma symptoms occurring more than once a week but less than once a day, nocturnal symptoms occurring more than twice a month but less than once a week, and normal lung function between episodes. If adequate asthma control is not achieved, the need for additional or alternative anti-inflammatory therapy should be assessed within the following period (usually within 1 month), based on a stepwise asthma management approach. Patients should be regularly evaluated for asthma control.

Prevention of asthma in patients aged 2 to 5 years whose primary component of asthma is exercise-induced bronchospasm

Astator 4 is recommended for children aged 2 to 5 years for the prevention of exercise-induced bronchospasm, which may be the primary manifestation of persistent asthma requiring inhaled corticosteroid therapy.

Patients should be evaluated after 2–4 weeks of montelukast treatment. If an adequate response is not achieved, additional or alternative therapy should be considered.

Use of the medicinal product Astator 4 in combination with other asthma treatments

When the medicinal product Astator 4 is used as add-on therapy to inhaled corticosteroids, inhaled corticosteroids should not be abruptly replaced by Astator 4 (see section "Special precautions").

Children

The product is intended for use in children aged 2 to 5 years.

Overdose

There is no specific information regarding the treatment of overdose with Astator 4. In clinical studies of chronic asthma, montelukast was administered at doses up to 200 mg daily to adult patients for 22 weeks, and in short-term studies up to 900 mg daily for approximately one week, without clinically significant adverse reactions.

During post-marketing use and clinical trials, cases of acute overdose with Astator 4 have been reported. These included 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 safety profile of the drug in adults and children. In most cases, no adverse reactions were reported. The most commonly observed adverse reactions 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 administered during clinical studies to patients with persistent asthma: 851 children aged 2 to 5 years received 4 mg chewable tablets.

Montelukast was evaluated in a clinical study in patients with intermittent asthma.

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

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 up to 12 months, the safety profile did not change.

A total of 502 children aged 2 to 5 years received montelukast treatment for at least 3 months, 338 for 6 months or longer, and 534 for 12 months or longer. With prolonged treatment, the safety profile in these patients remained unchanged.

Post-marketing period

Adverse reactions reported during the post-marketing period are listed by system organ class and using standardized terms in Table 2. The frequency is determined according to data from clinical trials.

Table 2

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 blisters in a 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.