Glemont chewable tablets

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLEMONT CHEWABLE TABLETS (GLEMONT CHEWABLE TABLETS)

Composition:

Active substance: montelukast;

1 tablet contains montelukast sodium equivalent to 4 mg or 5 mg of montelukast;

Excipients: microcrystalline cellulose, mannitol (E 421), sodium croscarmellose, hydroxypropyl cellulose, magnesium stearate, aspartame (E 951), cherry flavor.

Pharmaceutical form. Chewable tablets.

Main physico-chemical properties:

4 mg chewable tablets: oval, white or almost white, biconvex tablets, engraved with "G" on one side and "390" on the other;

5 mg chewable tablets: round, white or almost white, biconvex tablets, engraved with "G" on one side and "391" on the other.

Pharmacotherapeutic group.

Antiasthmatic agents for systemic use. 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, vascular permeability, and increased eosinophil recruitment.

Montelukast is an active compound that binds selectively and with high affinity to CysLT1 receptors. It produces significant blockade of cysteinyl leukotriene receptors in the airways, as demonstrated by its ability to inhibit LTD4-induced bronchoconstriction in patients with asthma. Even a low dose of 5 mg results in significant inhibition of LTD4-stimulated bronchoconstriction. Montelukast produces bronchodilation within 2 hours after oral administration; this effect is additive to the bronchodilation produced by β-agonists.

Treatment with montelukast suppresses both early- and late-phase bronchoconstriction, reducing the response to allergens. Compared with 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 with placebo, reduces peripheral blood eosinophil counts and improves clinical asthma control.

Pharmacokinetics

Absorption

After oral administration, montelukast is rapidly and almost completely absorbed. Following administration of 5 mg chewable tablets on an empty stomach, Cmax in adult patients is reached within 2 hours. Bioavailability is 73% and decreases to 63% when taken with a standard meal.

Distribution

Over 99% of montelukast is bound to plasma proteins. The steady-state volume of distribution averages between 8 and 11 liters. In studies using radiolabeled montelukast, passage across the blood-brain barrier was minimal. In all other tissues, concentrations of radiolabeled material 24 hours after dose administration were also found to be minimal.

Metabolism

Montelukast is extensively metabolized. In studies using therapeutic doses, plasma concentrations of montelukast metabolites at steady state are not detectable in adults or pediatric patients.

In vitro studies using human liver microsomes have shown that cytochrome P450 enzymes 3A4, 2A6, and 2C9 are involved in the metabolism of montelukast. Further in vitro studies with human liver microsomes indicate that at therapeutic concentrations, montelukast does not inhibit cytochrome P450 enzymes 3A4, 2C9, 1A2, 2A6, 2C19, and 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 an oral dose 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 its metabolites are almost exclusively eliminated via bile.

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) has been associated with decreased plasma theophylline concentrations. This effect is not observed at the recommended daily dose of 10 mg once daily.

Pharmacokinetic studies have shown that the concentration profiles of 4 mg chewable tablets in children aged 2 to 5 years and 5 mg chewable tablets in children aged 6 to 14 years are comparable to the concentration profile of 10 mg film-coated tablets in adults.

Chewable tablets of 5 mg should be used in patients aged 6 to 14 years, and chewable tablets of 4 mg should be used in patients aged 2 to 5 years.

Clinical characteristics.

Indications.

Chewable tablets Montelukast 4 mg are recommended for children aged 2 to 5 years;

chewable tablets Montelukast 5 mg are recommended for children aged 6 to 14 years:

• as add-on therapy for bronchial asthma in patients with mild to moderate persistent asthma not adequately controlled by inhaled corticosteroids, and in patients with inadequate clinical asthma control using short-acting β-agonists as needed;
• as an alternative treatment option instead of low-dose inhaled corticosteroids in patients with mild persistent asthma who have not recently experienced severe asthma attacks requiring oral corticosteroids, and in patients who are intolerant to inhaled corticosteroids;
• for prevention of asthma, the predominant component of which is exercise-induced bronchospasm;
• for 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 montelukast use; therefore, montelukast 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.

Interaction with other medicinal products and other forms of interaction.

Montelukast may be administered concomitantly with other medications used for 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 agents: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients taking phenobarbital concomitantly, the area under the concentration-time curve (AUC) of montelukast decreased by approximately 40%. Since montelukast is metabolized by CYP3A4, caution should be exercised, especially in children, when montelukast is co-administered with CYP3A4 inducers such as phenytoin, phenobarbital, and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP2C8. However, clinical drug interaction data involving montelukast and rosiglitazone (a drug metabolized by CYP2C8) have demonstrated that montelukast is not an inhibitor of CYP2C8 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 CYP2C8 and, to a lesser extent, of CYP2C9 and CYP3A4. In a clinical drug interaction study using montelukast and gemfibrozil (an inhibitor of CYP2C8 and CYP2C9), gemfibrozil increased systemic exposure to montelukast by 4.4-fold. When montelukast is used concomitantly with gemfibrozil or other potent inhibitors of CYP2C8, dose adjustment of montelukast is not required; however, physicians should consider the increased risk of adverse reactions.

Based on in vitro data, clinically significant interactions with less potent inhibitors of CYP2C8 (e.g., trimethoprim) are not expected. Concomitant administration of montelukast with itraconazole, a strong inhibitor of CYP3A4, did not result in a significant increase in systemic exposure to montelukast.

Special precautions for use

Patients should be advised that Montelukast should not be used for the relief of acute asthmatic attacks. Appropriate rescue medication should be continued. In case of an acute attack, short-acting inhaled beta-agonists should be used. Patients should consult their physician as soon as possible if they require a greater than usual number of inhalations of short-acting β-agonists.

Inhaled or oral corticosteroid therapy should not be abruptly replaced with montelukast.

In isolated cases, systemic eosinophilia, sometimes accompanied by clinical signs of vasculitis, such as Churg-Strauss syndrome (allergic granulomatous angiitis), has been observed in patients receiving anti-asthmatic medications, including montelukast. This condition is treated with systemic corticosteroid therapy. These cases have usually been associated with a reduction or withdrawal of corticosteroid therapy. A causal relationship between leukotriene receptor antagonists and the occurrence of Churg-Strauss syndrome cannot be either ruled out or confirmed. Therefore, physicians should be alerted to the possibility of eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy in patients. Patients who develop the aforementioned symptoms should undergo reassessment, and their treatment regimen should be reviewed.

Glemont chewable tablets contain aspartame, a phenylalanine derivative, which may be harmful for patients with phenylketonuria.

The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Montelukast treatment does not permit patients with aspirin-sensitive asthma to take aspirin or other nonsteroidal anti-inflammatory drugs.

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. The available studies have methodological limitations, including small sample size, retrospective data collection in some cases, and non-comparable control groups.

Montelukast may be used during pregnancy only if it is considered absolutely necessary.

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

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

Ability to affect reaction speed when driving or operating machinery.

The drug is intended for use in children.

Montelukast is not expected to affect the ability to drive a vehicle or operate machinery. However, in isolated cases, drowsiness or dizziness have been reported.

Dosage and Administration.

The medication should be administered to children under adult supervision.

Children aged 2 to 5 years.

For patients with asthma and allergic rhinitis (seasonal and perennial), the recommended dose is one 4 mg chewable tablet once daily.

Children aged 6 to 14 years.

For patients with asthma and allergic rhinitis (seasonal and perennial), the recommended dose is one 5 mg chewable tablet once daily.

For asthma treatment, the chewable tablet should be taken in the evening, 1 hour before or 2 hours after a meal. For relief of allergic rhinitis symptoms, the time of administration should be individually selected.

General recommendations for drug use.

The therapeutic effect of the medication in controlling asthmatic parameters persists throughout the day. Patients should be advised to continue taking the medication even when asthma is well-controlled, as well as during asthma exacerbations.

Dose adjustment is not required in patients with mild to moderate hepatic impairment or renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score above 9); therefore, no dosage adjustment recommendations can be made.

Dosage of the medication is the same for male and female patients.

Montelukast 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. Montelukast may be used as an alternative medication instead of low-dose inhaled corticosteroids in children with mild persistent asthma only in patients who have not recently experienced severe asthma attacks requiring systemic corticosteroid therapy, and in those who cannot use inhaled corticosteroids.

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 satisfactory asthma control cannot be achieved (usually within 1 month), the need for additional or alternative anti-inflammatory therapy based on a stepwise asthma treatment approach should be evaluated. Asthma control in patients should be periodically assessed.

Use of montelukast before physical exertion to prevent asthma attacks.

In patients aged 2 to 5 years, exercise-induced bronchospasm may be the primary manifestation of persistent asthma requiring treatment with inhaled corticosteroids. The patient's condition should be evaluated within 2 to 4 weeks after initiating montelukast therapy. If an adequate response is not observed, additional or alternative treatment should be considered.

Montelukast treatment compared to other asthma treatments.
When montelukast is used as add-on therapy to inhaled corticosteroids, montelukast should not be introduced abruptly as a replacement for inhaled corticosteroids.

Children.

Do not use in children under 2 years of age.

Overdose.

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

During post-marketing use and clinical trials, reports of acute montelukast overdose were received, involving ingestion by adults and children at doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). The clinical and laboratory findings were consistent with the known safety profile of montelukast in adults and children.

In most overdose cases, adverse effects were consistent with the safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

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

Adverse reactions

The safety of montelukast was evaluated in clinical studies in patients with persistent asthma:

• 5 mg chewable tablets – studies involving approximately 1750 children aged 6 to 14 years;
• 4 mg chewable tablets – studies involving 851 children aged 2 to 5 years.

The safety of montelukast was also evaluated in clinical studies in patients with intermittent asthma:

• 4 mg granules and chewable tablets – studies involving 1038 children aged 6 months to 5 years.

In clinical trials, 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.

Table 1

During clinical studies with long-term treatment of a limited number of adult patients (up to 2 years) and children aged 6–14 years (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 long-term treatment, the safety profile in these patients did not change.

Post-marketing period

The adverse reactions listed below have been reported during the post-marketing period. The frequency of adverse reactions is based on data from relevant clinical studies and is classified as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Infections and infestations: very common – upper respiratory tract infection.

Blood and lymphatic system disorders: rare – tendency to bleed; very rare – thrombocytopenia.

Immune system disorders: uncommon – hypersensitivity reactions, including anaphylaxis; very rare – hepatic eosinophilic infiltration.

Psychiatric disorders: uncommon – sleep disorders, including nightmares, insomnia, somnambulism, anxiety, agitation, including aggressive behavior or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremorc); rare – attention disturbance, memory impairment, tic; very rare – hallucinations, disorientation, suicidal thoughts and behavior (suicidality), obsessive-compulsive symptoms, dysphemia.

Nervous system disorders: uncommon – dizziness, drowsiness, paresthesia/hypoesthesia, seizures.

Cardiac disorders: rare – palpitations.

Respiratory, thoracic and mediastinal disorders: uncommon – epistaxis; very rare – Churg-Strauss syndrome (see section "Special precautions"), pulmonary eosinophilia.

Gastrointestinal disorders: common – diarrheab, nausea b, vomitingb; uncommon – dry mouth, dyspepsia.

Hepatobiliary disorders: common – increased serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]); very rare – hepatitis (including cholestatic, hepatocellular, and mixed liver injury).

Skin and subcutaneous tissue disorders: common – rashb; uncommon – bruising, urticaria, pruritus; rare – angioedema; very rare – erythema nodosum, erythema multiforme.

Musculoskeletal and connective tissue disorders: uncommon – arthralgia, myalgia, including muscle cramps.

Renal and urinary disorders: uncommon – enuresis in children.

General disorders: common – pyrexia b; uncommon – asthenia/fatigue, malaise, swelling.

a This adverse reaction was observed with "very common" frequency in patients receiving montelukast and in patients receiving placebo in clinical studies.

b This adverse reaction was observed with "common" frequency in patients receiving montelukast and in patients receiving placebo in clinical studies.

c Frequency: "rare".

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister, 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Glenmark Pharmaceuticals Ltd.

Manufacturer's address and location of business operations.

Village Kishanpura, Baddi-Nalagarh Road, Tehsil Baddi, Distt. Solan (H.P.) 173 205, India.