M-cast

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

Composition:

Active substance: montelukast;

1 chewable tablet contains 4.15 mg of montelukast sodium (equivalent to 4 mg of montelukast);

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

Pharmaceutical form. Chewable tablets.

Main physico-chemical properties: pinkish, mottled, oval, biconvex uncoated tablets with "X" imprinted on one side and "52" on the other.

Pharmacotherapeutic group. Drugs 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 and provoke responses such as bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil recruitment.

Montelukast, when administered orally, 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; this effect is additive to the bronchodilation caused by β-agonists.

Montelukast treatment suppresses both early and late phases of bronchoconstriction induced by antigen challenge. Compared to placebo, montelukast reduces the number of peripheral blood eosinophils in adult and pediatric patients. In one study, montelukast significantly reduced the number of eosinophils 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 (PEF) (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 have demonstrated montelukast's ability to complement the clinical effect of inhaled corticosteroids (change (%) 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 to inhaled beclomethasone (200 mcg twice daily, via spacer), montelukast showed a faster initial response, although over the 12-week study period, beclomethasone resulted in a greater mean therapeutic effect (change (%) from baseline for inhaled beclomethasone plus montelukast vs. beclomethasone alone for 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 beclomethasone (50%) compared to those receiving montelukast (42%).

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 measures compared to placebo, regardless of concomitant controller therapy (inhaled/nebulized corticosteroids, inhaled/nebulized sodium cromoglycate). 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 to placebo. Montelukast also reduced the frequency of as-needed β-agonist use and emergency use of corticosteroids during asthma exacerbations compared to placebo. Patients receiving montelukast had more asthma-symptom-free days 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 exacerbations (AE) compared to placebo (1.60 AE vs. 2.34 AE, respectively) [AE defined as ≥3 consecutive days of daytime symptoms requiring β-agonist or corticosteroid (oral or inhaled) use, or hospitalization for asthma treatment]. The percentage reduction in annual AE rate was 31.9%, with 95% CI 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 at 4 mg once daily or in 12-day courses initiated at the onset of intermittent symptoms, for 12 months. No significant difference was observed between patients receiving 4 mg montelukast and those receiving placebo in the number of asthma episodes progressing to an asthma attack (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, compared to placebo, significantly improved respiratory function (change from baseline in FEV1: 8.71% vs. 4.16%; change in morning peak expiratory flow: 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 was shown to be non-inferior to fluticasone in increasing the percentage of days without use of fast-acting 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 percentage increase in 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 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 worsening of 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 at 1.38 (1.04; 1.84).

The proportion of patients using 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).

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 dosing interval with once-daily administration.

In patients with aspirin sensitivity receiving ongoing inhaled and/or oral corticosteroid therapy, montelukast treatment, 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

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 reached at 3 hours (Tmax). The mean oral bioavailability is 64%. A typical meal does not affect bioavailability or Cmax following oral administration. Safety and efficacy have been confirmed in clinical trials 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 fasting administration. The mean oral bioavailability is 73% and decreases to 63% when taken with a standard meal.

After administration of 4 mg chewable tablets under fasting conditions in children aged 2 to 5 years, Cmax is reached within 2 hours. The mean Cmax is 66% higher and the mean Cmin is lower than in adults after administration of 10 mg tablets.

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, 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 its 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, and 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 oral bioavailability, 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 to moderate hepatic impairment. Studies in patients with renal impairment have not been conducted. Since montelukast and its metabolites are primarily excreted 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).

When administered at doses 20 and 60 times higher than the recommended adult dose, a decrease in plasma theophylline concentration was 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 aged 2 to 5 years with mild to moderate persistent asthma that is not adequately controlled by inhaled corticosteroids, as well as in cases of inadequate clinical control of asthma with short-acting β-adrenergic agonists used on an as-needed basis.

As an alternative treatment instead of low-dose inhaled corticosteroids, for patients aged 2 to 5 years 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, 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 benefits of M-Kast; therefore, M-Kast 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 drug. Pediatric age under 2 years.

Interaction with other medicinal products and other forms of interactions.

M-Kast can be prescribed together with other drugs 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 agents: 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 is advised, 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 study 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. 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 CYP2C8 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 consider the increased risk of adverse reactions.

Based on in vitro studies, clinically significant interactions with weaker inhibitors of CYP2C8 (e.g., trimethoprim) are not expected. 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 M-Kast for oral use is never to be used for the treatment of acute asthma attacks, and that they must always have a suitable emergency medication available. In acute attacks, short-acting inhaled β-agonists should be used. Patients should seek medical advice as soon as possible if they require a greater amount of short-acting β-agonist than usual.

Inhaled or oral corticosteroid medications 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.

In isolated cases, systemic eosinophilia, sometimes manifesting with clinical features of vasculitis, known as 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 dose 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. Physicians should remain aware of the potential for eosinophilia, vasculitic rash, worsening of pulmonary symptoms, or cardiac and/or neurological complications in patients. Patients presenting with such symptoms should be re-evaluated and their treatment regimen reviewed.

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 aware that one 4 mg tablet contains phenylalanine equivalent to 0.674 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 major congenital malformations in children have not established a risk associated with the use of the medicinal product. However, these studies have methodological limitations, including small sample sizes, retrospective data collection in some cases, and non-comparable control groups.

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

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 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 medicinal product should be used in 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 time 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. M-Kast should be taken 1 hour before or 2 hours after a meal. Dose adjustment is not required for this age group. The medicinal product M-Kast in the form of chewable tablets (4 mg) is not recommended for children under 2 years of age.

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 periods of asthma exacerbation.

Dose adjustment is not necessary 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 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 should be made only for patients who have not experienced severe asthma attacks requiring oral corticosteroids in the recent past, and for those who cannot use inhaled corticosteroids (see section "Indications").

Mild persistent asthma is defined as asthma with 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.

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

M-Kast is recommended for patients 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 M-Kast in relation to other asthma treatments
If 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 2 to 5 years.

Overdose

There is no specific antidote or particular treatment for overdose with M-Kast. In chronic asthma studies, montelukast was administered at doses up to 200 mg daily in 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 montelukast 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 safety profile of M-Kast in adults and children.

In most overdose cases, no adverse events were observed. The most commonly reported adverse effects were consistent with the known 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 administered during clinical studies to patients with persistent asthma:

Chewable tablets, 4 mg – 851 children aged 2 to 5 years.

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

During clinical studies, the following adverse reactions 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 up to 2 years and children aged 6 to 14 years for up to 12 months, the safety profile did not change.

Overall, 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 did not change.

Post-marketing period

Adverse reactions reported during the post-marketing period are listed according to system organ classes and using the preferred terms from 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.

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.