Astatore 5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ASTATOR 5

Composition:

Active substance: montelukast;

1 tablet contains montelukast sodium equivalent to 5 mg of montelukast;

Excipients: mannite (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: round pink tablets (slight speckling in dark pink may occur), with a break line on both sides.

Pharmacotherapeutic group.

Agents 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 important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) present in human airways and cause responses such as bronchoconstriction, mucus secretion, increased vascular permeability, and recruitment of eosinophils.

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

Treatment with montelukast suppresses both early and late phases of bronchoconstriction caused by antigen challenge. Montelukast, compared to placebo, reduces the number of peripheral blood eosinophils in adult and pediatric patients. In a separate study, montelukast significantly reduced eosinophil counts in the airways (measured in sputum). In adults and children aged 2 to 14 years, montelukast, compared to placebo, reduces peripheral blood eosinophil counts and improves 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 demonstrated montelukast's ability to complement the clinical effect of inhaled corticosteroids (change from baseline, %): for inhaled beclomethasone with montelukast vs. beclomethasone alone, respectively, for FEV1: 5.43% vs. 1.04%; for β-agonist use: –8.70% vs. 2.64%. Compared to inhaled beclomethasone (200 μg twice daily, spacer device), montelukast showed a faster initial response, although over the 12-week study period, beclomethasone produced a greater mean therapeutic effect (change from baseline for montelukast vs. beclomethasone, respectively, for FEV1: 7.49% vs. 13.3%; β-agonist use: –28.28% vs. –43.89%). However, a higher 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, whereas 42% of patients receiving montelukast achieved the same response).

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 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-inferior efficacy 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 use 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 use 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 with respect to 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 proportion 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 the percentage of days with β-agonist use was significant: 2.7 (95% CI 0.9; 4.5).

The proportion of patients experiencing an asthma exacerbation (defined as a period of worsening asthma requiring treatment with oral steroids, unscheduled physician visits, 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 who used systemic (primarily 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, treatment with montelukast, compared to placebo, led to significant improvement in asthma control (change from baseline 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 after oral administration. Following administration of 10 mg film-coated tablets on an empty stomach to adults, the mean peak plasma concentration (Cmax) is achieved within 3 hours (Tmax). The mean oral bioavailability is 64%. A normal meal does not affect bioavailability or Cmax following 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.

Distribution

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

Cytochrome P450 2C8 is the primary enzyme involved in montelukast metabolism. Additionally, CYP 3A4 and 2C9 play minor roles 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.

In vitro studies using human liver microsomes indicate that therapeutic plasma concentrations of montelukast do not inhibit cytochrome P450 enzymes 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Excretion

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 the biliary route.

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. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score >9).

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

Clinical characteristics.

Indications.

As an add-on treatment 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-adrenoceptor agonists used as needed.

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

Prevention of asthma in which exercise-induced bronchospasm is the predominant component.

Relief of symptoms of seasonal and perennial allergic rhinitis. The risk of 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 or intolerance to alternative therapies.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

The medicinal product Astator 5 may be prescribed concomitantly with other medicinal products commonly used for the 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 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 was reduced by approximately 40%. Since montelukast is metabolized via CYP 3A4, 2C8, and 2C9, caution is required, 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) 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 shown 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 co-administered with gemfibrozil or other potent inhibitors of CYP 2C8, dosage adjustment of montelukast is not required; however, physicians should be aware of 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 5 for oral use is never to be used for the treatment of acute asthma attacks, and that they should always have access to an appropriate rescue medication. 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 find they need to use a short-acting β-agonist more frequently than usual.

Sudden replacement of inhaled or oral corticosteroids with Astator 5 is not recommended.

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 taking montelukast (see section "Adverse reactions"). These manifestations may be severe and may persist if treatment is not discontinued. Therefore, montelukast therapy should be discontinued if neuropsychiatric symptoms occur.

Patients and/or caregivers should be alert to neuropsychiatric reactions and should inform their physician if behavioral changes 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 a reduction in or discontinuation of corticosteroid therapy. A causal relationship between leukotriene receptor antagonists and the occurrence of Churg-Strauss syndrome cannot be ruled out or confirmed. Physicians should be aware of the possibility of 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-sensitive asthma to take acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

Astator 5 contains aspartame, which is a source of phenylalanine. Patients with phenylketonuria should be advised that one 5 mg chewable tablet contains phenylalanine equivalent to 0.842 mg of phenylalanine.

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 demonstrated any harmful effects on pregnancy or embryonic/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 medicinal product. However, the available studies have methodological limitations, including small sample size, retrospective data collection in some cases, and non-comparable control groups.

The medicinal product should be used during pregnancy only if clearly needed.

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

Astator 5 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, very rare cases of somnolence or dizziness have been reported.

Dosage and Administration

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 5 mg once daily. The time of administration for relief of allergic rhinitis symptoms may be individualized.

For the treatment of asthma, the dose for children aged 6 to 14 years is 1 chewable tablet (5 mg) daily, taken in the evening. Astator 5 should be taken 1 hour before or 2 hours after a meal. Dose adjustment is not required for this age group.

General Recommendations

The therapeutic effect of the medicinal product on asthma control parameters begins within 1 day. Patients should be advised to continue taking the medicinal product even if asthma control is achieved, as well as during asthma exacerbations.

Dose adjustment is not required for patients with renal impairment or mild to moderate hepatic impairment. There is 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 with mild persistent asthma should be considered only for patients who have not experienced 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 treatment approach. Patients should be regularly evaluated for asthma control.

Use of Astator 5 in relation to other asthma treatments

When Astator 5 is used as add-on therapy to inhaled corticosteroids, inhaled corticosteroids should not be abruptly replaced by Astator 5 (see section "Special precautions").

Children

The product is indicated for use in children aged 6 to 14 years.

Overdose

There is no specific information on the treatment of overdose with Astator 5. In clinical studies of chronic asthma, montelukast was administered to adult patients at doses up to 200 mg daily for 22 weeks and up to 900 mg daily for approximately one week in short-term studies, without clinically significant adverse reactions.

During post-marketing use and clinical trials, cases of acute overdose of Astator 5 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 in adult and pediatric patients. In most cases, no adverse reactions were reported. The most commonly observed adverse reactions were consistent with the safety profile of Astator 5 and included abdominal pain, somnolence, 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: approximately 1750 children aged 6 to 14 years received the 5 mg chewable tablets.

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

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 terminology in Table 2. Frequency is based on data from 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.

Prescription status. Prescription only.

Packaging.

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

Manufacturer.

Torrent Pharmaceuticals Ltd.

Manufacturer's address and location of business activity.

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