Montular® kids

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONTULAR® KIDS

Composition:

Active ingredient: montelukast sodium;

Each chewable tablet contains 4 mg of montelukast sodium calculated as montelukast;

Excipients: microcrystalline cellulose (PH 112), hydroxypropylcellulose, sodium croscarmellose, iron oxide red (E 172), aspartame (E 951), cherry flavor 501027AP0551, mannitol (E 421), magnesium stearate.

Pharmaceutical form. Chewable tablets.

Main physicochemical characteristics: round, biconvex, uncoated tablets ranging in color from light pink to pink, with visible specks, smooth 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 airway responses such as bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil recruitment.

Montelukast, following oral administration, is an active compound that binds with high selectivity and affinity to CysLT1 receptors. Clinical studies have shown that montelukast at a dose of 5 mg inhibits LTD4 inhalation-induced bronchoconstriction. Bronchodilation is observed within 2 hours after oral administration. This effect is additive to bronchodilation caused by β-agonists. Treatment with montelukast suppresses both early and late phases of bronchoconstriction induced by antigen stimulation. Compared to placebo, montelukast reduces the number of eosinophils in peripheral blood in both adult and pediatric patients. In a separate study, montelukast intake 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 the number of peripheral blood eosinophils and improves clinical asthma control.

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) was achieved at 3 hours (Tmax). The mean oral bioavailability is 64%. Consumption of a standard meal does not affect bioavailability or Cmax following oral administration. Safety and efficacy have been confirmed in clinical trials with administration of 10 mg film-coated tablets regardless of the time of food intake.

For 5 mg chewable tablets, the Cmax in adults is achieved within 2 hours after administration under fasting conditions. 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 achieved within 2 hours after dosing. 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 volume of distribution at steady state averages between 8 and 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, plasma concentrations of montelukast metabolites at steady state were undetectable in both adults and pediatric patients.

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 of 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.

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 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. However, since montelukast and its metabolites are 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).

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

• As add-on therapy for asthma in patients aged 2 to 5 years with mild to moderate persistent asthma that is not adequately controlled by inhaled corticosteroids, and in patients with inadequate clinical control of asthma using short-acting β-agonists as needed.
• As an alternative treatment option 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 the recent past and who cannot use inhaled corticosteroids (see section "Dosage and administration").
• Prophylaxis 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. Since the benefit of montelukast in patients with allergic rhinitis may not outweigh the risk of neuropsychiatric symptoms (see section "Special precautions"), Montelar® Kids should be used as a reserve medication in patients who have an inadequate response to or cannot tolerate alternative therapies.

Contraindications

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

Interaction with other medicinal products and other forms of interaction

Montelukast may be administered together with other medicinal products commonly used for the prevention or long-term management 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 taking phenobarbital concomitantly, 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 should be exercised, particularly 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 studies involving montelukast and rosiglitazone (a marker substrate representing drugs primarily 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 medicinal products metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

In vitro studies have shown that montelukast is a substrate of CYP 2C8, 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 consider the increased risk of adverse reactions.

Based on in vitro studies, clinically significant interactions with less potent inhibitors of CYP 2C8 (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 advised that the medicinal product Montular® Kids for oral use must not be used for the treatment of acute asthma attacks, and that they should 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 than usual number of inhalations of short-acting β-agonists.

Inhaled or oral corticosteroids 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 has been observed in patients receiving anti-asthma medications, including montelukast, sometimes together with clinical signs of vasculitis consistent with Churg-Strauss syndrome, which is treated with systemic corticosteroids. Such cases have sometimes been associated with reduction in dose or withdrawal of corticosteroid therapy. The possibility that leukotriene receptor antagonists may be related to the occurrence of Churg-Strauss syndrome cannot be 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 who develop 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.

Excipients:

The medicinal product Montular® Kids contains aspartame (E 951) – a source of phenylalanine, which is hazardous for patients with phenylketonuria.

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

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

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

Montelukast may be used during breastfeeding only if considered absolutely necessary.

Ability to affect driving performance and use of machinery

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

Method of Administration and Dosage

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

Dosage

Patients with asthma and allergic rhinitis (seasonal and perennial) should take 1 chewable tablet of 4 mg once daily. The time of administration for relief of allergic rhinitis symptoms should be individually adjusted.

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

General Recommendations

The therapeutic effect of montelukast on asthma control parameters develops within 1 day. Patients should be advised to continue taking montelukast even when asthma is well controlled, 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.

Alternative treatment option 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 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 evaluated subsequently (usually within 1 month), based on a stepwise asthma treatment approach. 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

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

Use of montelukast in relation to other asthma treatments

When montelukast is used as add-on therapy to inhaled corticosteroids, inhaled corticosteroids should not be abruptly discontinued (see section "Special Warnings and Precautions for Use").

Children

The safety and efficacy of the medicinal product Montelar® Kids, 4 mg chewable tablets, have not been established in children under 2 years of age. The product is administered to children aged 2 to 5 years.

Overdose

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, reports of acute montelukast overdose have been received. These data included administration in 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.

Symptoms

The most commonly observed adverse reactions were consistent with the drug's safety profile and included abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity.

Treatment

There is no specific information on the treatment of montelukast overdose. It is not known whether montelukast is removed 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 more frequently 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.

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 remained unchanged.

Post-marketing period

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

Table 2

Reporting of suspected adverse reactions

Reporting of adverse reactions following the registration of a medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the use of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are requested to report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

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 or 9 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

Kusum Healthcare Pvt Ltd.

Manufacturer's address and location of its business operations

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.