M-cast

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT M-KAST (M-KAST)

Composition:

Active substance: montelukast;

One chewable tablet contains montelukast sodium 5.19 mg (equivalent to montelukast 5 mg);

Excipients: mannite (E 421), microcrystalline cellulose, hydroxypropylcellulose, sodium croscarmellose, iron oxide (E 172), purified water, aspartame (E 951), artificial cherry flavor, magnesium stearate.

Pharmaceutical form. Chewable tablets.

Main physicochemical characteristics: pink, mottled, round, biconvex uncoated tablets, with "X" embossed on one side and "53" on the other.

Pharmacotherapeutic group. Systemic preparations for 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 induce responses such as bronchoconstriction, mucus secretion, increased vascular permeability, and recruitment of eosinophils.

Oral montelukast is an active compound that binds selectively and with high affinity to CysLT1 receptors.

Clinical studies have shown that montelukast at a dose of 5 mg inhibits LTD4-induced bronchoconstriction following inhalation. Bronchodilation is observed within 2 hours after oral administration, and this effect is additive to that produced by β-agonists.

Treatment with montelukast suppresses both early and late phases of bronchoconstriction induced by antigen challenge. Compared to placebo, montelukast reduces the number of eosinophils in peripheral blood in both 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 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 total use of β-agonists (change from baseline: –26.1% vs. –4.6%, respectively). Patient-reported daytime and nighttime asthma symptoms were significantly improved compared to placebo.

Studies in adults have demonstrated that montelukast provides additional clinical benefit when combined with 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 to inhaled beclomethasone (200 μg twice daily, via spacer device), montelukast showed a faster initial response, although over a 12-week study period, beclomethasone produced a greater mean therapeutic effect (change from baseline % for inhaled beclomethasone with montelukast vs. beclomethasone alone: 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 greater proportion of patients receiving montelukast compared to beclomethasone (50% of patients on beclomethasone vs. 42% on montelukast).

In an 8-week study in children aged 6 to 14 years, montelukast 5 mg once daily, compared to placebo, significantly improved respiratory function (change from baseline FEV1: 8.71% vs. 4.16%; change in morning peak expiratory flow rate: 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 the percentage 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 percentage 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 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 requiring 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 resulted in significant improvement in asthma control (change from baseline 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. Following administration of 10 mg film-coated tablets to adults under fasting conditions, the mean peak plasma concentration (Cmax) is achieved within 3 hours (Tmax). The mean oral bioavailability is 64%. A standard 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 under fasting conditions. The mean oral bioavailability is 73% and decreases to 63% when taken with a standard meal.

Distribution

Over 99% of montelukast is protein-bound in plasma. The steady-state volume of distribution averages 8 to 11 liters. In rat studies using radiolabeled montelukast, penetration across the blood-brain barrier was minimal. Additionally, concentrations of radiolabeled material in all other tissues 24 hours after dosing were also minimal.

Metabolism

Montelukast undergoes extensive metabolism. In studies using therapeutic doses, metabolite concentrations in plasma at steady state are undetectable in both adults and pediatric patients.

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

Elimination

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 its oral bioavailability, 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 in 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, dose adjustment in patients with renal impairment is not considered necessary. Pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9) are not available.

At doses 20 and 60 times higher than the recommended adult dose, a decrease in plasma theophylline concentration has been observed. This effect is not seen 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 which is not adequately controlled by inhaled corticosteroids, as well as in cases of insufficient 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 the predominant component is bronchospasm induced by physical exertion.

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 using M-Kast; therefore, M-Kast 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. Children under 6 years of age.

Interaction with other medicinal products and other types of interactions.

M-Kast can be prescribed together with other drugs 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 drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients who concurrently took 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 should be exercised, 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 studies 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. 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 times. When 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 with weaker inhibitors of CYP 2C8 (e.g., trimethoprim) are not expected. 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 warned that M-Kast for oral use should never be used to treat acute asthma attacks, and that they must always have a suitable emergency 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 find they need to use a short-acting β-agonist more frequently than usual.

It is not recommended to abruptly discontinue inhaled or oral corticosteroid therapy and replace it with montelukast.

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

In isolated cases, systemic eosinophilia has been observed in patients receiving anti-asthma medications, including montelukast, sometimes accompanied by clinical features of vasculitis, known as Churg-Strauss syndrome, which is treated with systemic corticosteroid therapy. These cases have typically (but not always) been associated with a reduction in dose or discontinuation of corticosteroid treatment.

It is not possible to definitively rule out or confirm a potential association between leukotriene receptor antagonists and the occurrence of Churg-Strauss syndrome. Physicians should be aware of the possibility of 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 reconsidered.

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

M-Kast contains aspartame, which is a source of phenylalanine. Patients with phenylketonuria should be informed that one 5 mg 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., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not shown 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 significant 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 sizes, in some cases retrospective data collection, and non-comparable control groups.

M-Kast should be used during pregnancy only if clearly needed.

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

M-Kast may be used during breastfeeding only if it is considered absolutely necessary.

Ability to influence the speed of reactions 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 drowsiness 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 should be individually adjusted to relieve symptoms of allergic rhinitis.

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

General recommendations.

Therapeutic effect of M-Kast on asthma control parameters develops within 1 day. Patients should be advised to continue taking M-Kast even after 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 to low-dose inhaled corticosteroids in mild persistent asthma.

Montelukast is not recommended as monotherapy for patients with moderate persistent asthma. The decision to use montelukast as an alternative to low-dose inhaled corticosteroids in children aged 2 to 5 years with mild persistent asthma may be considered only for patients who have not experienced severe asthma attacks requiring oral corticosteroids recently, and for those who are unable to use inhaled corticosteroids (see section "Indications").

Mild persistent asthma is characterized by asthma symptoms occurring more than once a week but less than once a day, nocturnal symptoms 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 based on a stepwise asthma treatment approach should be evaluated after a period of time (usually within 1 month). Patients should be periodically assessed for asthma control.

Use of M-Kast in relation to other asthma treatments. When M-Kast is used as add-on therapy to inhaled corticosteroids, inhaled corticosteroids should not be abruptly discontinued (see section "Special precautions").

Children.

For use in children aged 6 to 14 years.

Overdose.

There is no specific information on the treatment of M-Kast overdose. In chronic asthma studies, 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 montelukast overdose 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 M-Kast in adults and children.

In most reported overdose cases, no adverse events were observed. The most commonly reported adverse effects were consistent with the safety profile of M-Kast and included abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity.

It is unknown whether montelukast is eliminated by peritoneal dialysis or hemodialysis. Treatment is symptomatic.

Adverse reactions

Montelukast was evaluated in clinical studies: approximately 1,750 children aged 6 to 14 years received the 5 mg chewable tablets.

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 specific terms presented in Table 2.

Table 2

Shelf life. 2 years.

Storage conditions.

Store in a dry, light-protected place, out of reach of children, at a temperature not exceeding 25 °C.

Packaging. 10 chewable tablets per blister, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Limited – Unit VII, India / Aurobindo Pharma Limited – Unit VII, India.

Manufacturer's address and place of business.

Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India / Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India.