Glemont

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

Composition:

Active substance: montelukast;

One film-coated tablet contains montelukast sodium equivalent to 10 mg of montelukast;

Excipients: microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, hydroxypropylcellulose, magnesium stearate, Opadry Yellow (hypromellose, hydroxypropylcellulose, titanium dioxide (E 171), yellow iron oxide (E 172), carnauba wax, red iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, beige-colored film-coated tablets, engraved with "G" on one side and "392" on the other.

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 key pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT). The CysLT type 1 receptor (CysLT1) is located in human airways (including airway smooth muscle cells and airway macrophages), as well as on other pro-inflammatory cells (including eosinophils and certain myeloid progenitor cells). The presence of CysLT receptors correlates with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucus secretion, vascular permeability, and eosinophilia. In allergic rhinitis, CysLT protein is released from the nasal mucosa following allergen exposure during both early- and late-phase reactions, which is associated with symptoms of allergic rhinitis. According to clinical studies, intranasal administration of CysLT leads to increased nasal airway resistance and enhanced nasal congestion symptoms.

Montelukast, administered orally, is an active compound that selectively and with high affinity binds to CysLT1 receptors. Clinical studies have shown that montelukast at a dose of 5 mg inhibits bronchoconstriction induced by inhaled LTD4. Bronchodilation is observed within 2 hours after oral administration, and 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 peripheral blood eosinophils in adult and pediatric patients. In a separate study, montelukast significantly reduced the number of eosinophils in the airways (measured in sputum) and in peripheral blood, and improved clinical asthma control.

In studies involving adults, montelukast at a dose of 10 mg once daily, compared to placebo, demonstrated significant improvement in morning forced expiratory volume in 1 second (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 the ability of montelukast to complement the clinical effect of inhaled corticosteroids (change (% baseline) for inhaled beclomethasone plus montelukast vs. beclomethasone alone: for FEV1: 5.43% vs. 1.04%; for β-agonist use: –8.70% vs. 2.64%). Compared to inhaled beclomethasone (200 mcg twice daily, via spacer device), montelukast showed a more rapid initial response, although over a 12-week study, beclomethasone produced a greater average therapeutic effect (% change from baseline for montelukast vs. beclomethasone: for FEV1: 7.49% vs. 13.3%; for β-agonist use: –28.28% vs. –43.89%). However, a greater proportion of patients receiving montelukast achieved a similar clinical response compared to those receiving beclomethasone (i.e., 50% of patients receiving beclomethasone achieved an improvement in FEV1 of approximately 11% or more from baseline, while 42% of patients receiving montelukast achieved the same response).

A clinical study was conducted to evaluate montelukast as a symptomatic treatment for seasonal allergic rhinitis in patients aged 15 years and older with asthma and concomitant seasonal allergic rhinitis. In this study, montelukast tablets at a dose of 10 mg once daily demonstrated statistically significant improvement in the daytime rhinitis symptom score compared to placebo. The daytime rhinitis symptom score is the average value obtained from assessing nasal symptoms during the day (nasal congestion, rhinorrhea, sneezing, nasal itching) and at night (average nasal congestion upon awakening, difficulty falling asleep, frequency of nocturnal awakenings). Significantly better results were obtained for overall patient and physician assessment of allergic rhinitis treatment compared to placebo. Evaluation of the efficacy of this treatment for asthma was not the primary objective of this study.

In an 8-week study involving children aged 6 to 14 years, montelukast at a dose of 5 mg once daily significantly improved respiratory function compared to placebo (change from baseline in FEV1: 8.71% vs. 4.16%; change in morning PEF: 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%).

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 once-daily dosing interval.

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 in 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 to adults under fasting conditions, the mean peak plasma concentration (Cmax) is achieved within 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 studies with administration of 10 mg film-coated tablets regardless of meal timing.

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.

Distribution

Over 99% of montelukast is protein-bound in plasma. The mean volume of distribution at steady state is 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 the metabolism of montelukast. Additionally, cytochromes CYP3A4 and 2C9 play a minor role in montelukast metabolism, although itraconazole (a CYP3A4 inhibitor) did not alter the pharmacokinetic parameters of montelukast in healthy volunteers receiving 10 mg montelukast daily. According to in vitro studies using human liver microsomes, 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.

Elimination

The mean plasma clearance of montelukast in healthy adult volunteers is approximately 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 the biliary route, dose adjustment in patients with renal impairment is not considered necessary. Data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score >9) are not available.

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.

Adjunctive treatment of bronchial asthma in patients with mild to moderate persistent asthma that is not adequately controlled with inhaled corticosteroids, as well as in cases of insufficient clinical control of asthma with short-acting β-agonists used as needed. Symptomatic treatment of seasonal allergic rhinitis in patients with bronchial asthma.

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

Relief of symptoms of seasonal and perennial allergic rhinitis.

Contraindications.

Hypersensitivity to any of the components of the drug. Children under 15 years of age (for the 10 mg dose).

Interaction with other medicinal products and other types of interactions.

Montelukast may be administered together with other medications used for the prevention or long-term treatment of asthma and treatment of allergic rhinitis. In drug interaction studies, the recommended 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 concurrently taking phenobarbital, the area under the concentration-time curve (AUC) for montelukast was reduced by approximately 40%. Since montelukast is metabolized by CYP 3A4, caution is advised, especially in children, when montelukast is coadministered with CYP 3A4 inducers 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 drug metabolized by CYP 2C8) have 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 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-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 data, 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 result in a significant increase in systemic exposure to montelukast.

Special precautions for use.

Patients should be advised that Glemont should not be used to treat acute asthmatic attacks. Treatment with conventional appropriate medications for relief of attacks should be continued. In case of an acute attack, 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.

Montelukast should not be used to abruptly replace inhaled or oral corticosteroid therapy.

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, so-called Churg-Strauss syndrome (allergic granulomatous angiitis), which is treated with systemic corticosteroid therapy. Such cases have usually (but not always) been associated with reduction or withdrawal of corticosteroid therapy. The possibility that leukotriene receptor antagonists may be linked to the emergence of Churg-Strauss syndrome cannot be either ruled out or confirmed; therefore, physicians should be alerted to the potential development of eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy in patients. Patients who develop the aforementioned symptoms should undergo re-evaluation, and their treatment regimen should be reviewed.

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

This medicinal product should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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.

Limited data from pregnancy registries do not indicate a causal relationship between montelukast use and the occurrence of malformations (such as limb defects), which have been rarely reported during worldwide post-marketing experience.

Montelukast should be used during pregnancy only if clearly necessary.

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

Montelukast should be used during breastfeeding only if clearly necessary.

Ability to influence the speed of reactions while 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.

Method of Administration and Dosage

The medication is intended for use in adults and children aged 15 years and older.

For the treatment of asthma or asthma associated with seasonal allergic rhinitis, the recommended dose for adults and children aged 15 years and older is 1 tablet of 10 mg once daily in the evening. To relieve symptoms of allergic rhinitis, the time of administration should be individually adjusted.

Dosage adjustment is not required for elderly patients or for patients with mild to moderate hepatic impairment or renal impairment. Data regarding dosage adjustment in patients with severe hepatic impairment are lacking. There are no data on the pharmacokinetic profile of montelukast in patients with severe hepatic impairment (Child–Pugh score >9); therefore, no dosage adjustment recommendations can be made.

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

Treatment with Glemont in relation to other asthma therapies

Glemont may be added to a patient's existing treatment regimen.

Inhaled corticosteroids. Glemont can be used as add-on therapy in patients in whom inhaled corticosteroids combined with short-acting β-agonists used as needed do not provide adequate clinical control of the disease.

Glemont should not be used to abruptly displace inhaled corticosteroids (see section "Special Warnings and Precautions for Use").

Children

To be used in children aged 15 years and older. Children under 15 years of age should receive the medication in the form of chewable tablets with appropriate dosing.

Overdose

There is no specific antidote or treatment for montelukast overdose. In chronic asthma studies, montelukast was administered at doses up to 200 mg/day in adult patients 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, 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 clinical and laboratory findings were consistent with the safety profile observed 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 Glemont 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

Montelukast was evaluated in clinical trials:

• 10 mg film-coated tablets – in approximately 4000 asthma patients aged 15 years and older;
• 10 mg film-coated tablets – in approximately 400 asthma patients with seasonal allergic rhinitis aged 15 years and older;
• 5 mg chewable tablets – in approximately 1750 asthma patients aged 6 to 14 years.

During clinical trials, 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. Frequencies are based on data from relevant clinical studies.

Table 2

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

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

30 tablets in a plastic container, in a cardboard box. Each container includes a polymer cylinder with a desiccant (silica gel) placed together with the tablets.

Prescription status.

Prescription only.

Manufacturer.

Glenmark Pharmaceuticals Ltd./Glenmark Pharmaceuticals Ltd.

Manufacturer's address and location of business operations.

Plot № S-7, Colvale Industrial Estate, Colvale, Bardez, Goa – 403 513, India/
Plot № S-7, Colvale Industrial Estate, Colvale, Bardez, Goa – 403 513, India.