Montegen

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONTegen (MONTEGEN)

Composition:

Active substance: montelukast (montelukast);

1 tablet contains 10 mg of montelukast (as montelukast sodium);

Excipients: lactose monohydrate, mannitol (E 421), sodium croscarmellose, hydroxypropylcellulose, microcrystalline cellulose, magnesium stearate, Opadry yellow 20A520007 coating: hypromellose, hydroxypropylcellulose, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: beige square tablets with rounded edges, film-coated, marked with "I" on one side and "114" on the other.

Pharmacotherapeutic group. Drugs for systemic use in obstructive airway 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 present 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, cysteinyl leukotriene protein is released from nasal mucosa following allergen exposure during both early- and late-phase reactions, and this is associated with symptoms of allergic rhinitis. According to studies, intranasal administration of CysLT leads to increased nasal airway resistance and enhanced symptoms of nasal congestion.

Montelukast, following oral administration, is an active compound that binds with high selectivity and affinity to CysLT1 receptors. Clinical studies have shown that montelukast inhibits LTD4-induced bronchoconstriction at a dose of 5 mg. 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 with placebo, montelukast reduces the number of eosinophils in peripheral blood 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 10 mg once daily, compared with 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 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 demonstrated montelukast’s ability 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%; β-agonist use: –8.70% vs. 2.64%). Compared with inhaled beclomethasone (200 mcg twice daily, via spacer device), montelukast showed a faster initial response, although over the 12-week study period, beclomethasone produced a greater mean therapeutic effect (% change from baseline for montelukast vs. beclomethasone for FEV1: 7.49% vs. 13.3%; β-agonist use: –28.28% vs. –43.89%). However, a greater proportion of patients receiving montelukast achieved a similar clinical response compared with 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 administered at a dose of 10 mg once daily demonstrated a statistically significant improvement in the average daily rhinitis symptom score compared with placebo. The average daily rhinitis symptom score is a mean value derived from assessments of nasal symptoms during the day (average nasal congestion, rhinorrhea, sneezing, nasal itching) and at night (average nasal congestion upon awakening, difficulty falling asleep, and frequency of nocturnal awakenings). Significantly better results were obtained for overall patient and physician assessment of allergic rhinitis treatment compared with placebo. Evaluation of the efficacy of this treatment for asthma was not a primary objective of this study.

In an 8-week study involving children aged 6 to 14 years, montelukast 5 mg once daily significantly improved respiratory function compared with placebo (change from baseline in FEV1: 8.71% vs. 4.16%; change in morning PEFR: 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 minutes vs. 60.64 minutes). This effect was observed throughout the 12-week study period. Reduction in EIB was also demonstrated in a short-term study involving 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 minutes vs. 27.98 minutes). The effect in both studies was demonstrated at the end of the dosing interval after once-daily administration.

In patients with aspirin sensitivity receiving ongoing therapy with inhaled and/or oral corticosteroids, treatment with montelukast, compared with placebo, led to 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 fasting adults, the mean peak plasma concentration (Cmax) was achieved within 3 hours (Tmax). The mean oral bioavailability is 64%. A standard meal does not affect the bioavailability or Cmax of montelukast after oral administration. Safety and efficacy were demonstrated in clinical trials with 10 mg film-coated tablets administered regardless of meal timing.

For 5 mg chewable tablets, the Cmax in adults is reached 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. The mean Cmax is 66% higher, and the mean Cmin is lower, compared with adults after administration of 10 mg tablets.

Distribution

Over 99% of montelukast is bound to plasma proteins. The mean volume of distribution at steady state is 8–11 L. Studies in rats using radiolabeled montelukast demonstrated minimal penetration across the blood-brain barrier. Additionally, concentrations of radiolabeled material 24 hours after administration were minimal in all other tissues.

Metabolism

Montelukast is extensively metabolized. In studies with therapeutic doses, metabolite concentrations of montelukast in plasma at steady state in adults and pediatric patients were not detectable.

In vitro studies using human liver microsomes have shown that cytochrome P450 enzymes 3A4, 2A6, and 2C9 are involved in the metabolism of montelukast. Based on further in vitro studies using human liver microsomes, montelukast at therapeutic plasma concentrations 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.

Excretion

The plasma clearance of montelukast averages 45 mL/min in healthy adult volunteers. After oral administration of isotopically labeled 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 bile.

Pharmacokinetics in Specific Patient Populations

Dose adjustment is not required for elderly patients or for 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. There are no data on the pharmacokinetic profile 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 was not observed with the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

As add-on therapy in patients with mild to moderate persistent asthma that is not adequately controlled with inhaled corticosteroids, and in patients who require additional clinical asthma control with short-acting β-adrenoceptor agonists used as needed. In patients with asthma receiving montelukast, this medication also relieves symptoms of seasonal allergic rhinitis.

Prevention of asthma in which bronchospasm induced by physical exertion is the predominant component.

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, the medicinal product should be used as a reserve option in patients who have inadequate response to or intolerance of alternative therapies.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients. Age under 15 years (for the 10 mg dose).

Interaction with other medicinal products and other forms of interaction.

Montelukast may be administered concomitantly with other medications used for the prevention and long-term management of asthma. In drug interaction studies, the recommended clinical dose of montelukast had no clinically significant 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 decreased by approximately 40%. Since montelukast is metabolized by CYP 3A4, 2C8, and 2C9, caution is advised, especially 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 data with montelukast and rosiglitazone (a marker substrate metabolized by CYP 2C8) indicate 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; however, physicians should be aware of 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 warned that Montegen for oral use must not be used to treat acute asthma attacks, and that they should always have appropriate emergency medication available. In the event of an acute attack, short-acting inhaled β-agonists should be used. Patients should consult their physician as soon as possible if they find they need to use short-acting β-agonists more frequently than usual.

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

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

Cases of neuropsychiatric reactions such as behavioral changes, depression, and suicidal ideation have been reported in patients of all age groups receiving montelukast (see section "Side effects"). These manifestations may be serious and may persist if treatment is not discontinued. Therefore, montelukast therapy should be discontinued if neuropsychiatric symptoms occur.

Patients and/or caregivers should be alert to neuropsychiatric reactions and should inform their physician of any behavioral changes.

In rare cases, systemic eosinophilia, sometimes accompanied by clinical signs of vasculitis, known as Churg-Strauss syndrome, may develop 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 oral corticosteroid therapy. A causal relationship between leukotriene receptor antagonists and the occurrence of Churg-Strauss syndrome cannot be ruled out or confirmed. Physicians should be aware of the possibility of 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 reconsidered.

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

Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine because it contains lactose monohydrate.

The medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e. essentially "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 in pregnant women using montelukast, 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 size, retrospective data collection in some cases, and non-comparable control groups.

Montegen may be used during pregnancy only if clearly needed.

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

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

Ability to affect reaction speed when driving or operating machinery.

Montelukast is not expected to affect a patient's ability to drive or operate machinery. However, in very rare cases, somnolence or dizziness may occur in individual patients.

Method of Administration and Dosage.

The recommended dose for patients (aged 15 years and older) with asthma or asthma with concomitant seasonal allergic rhinitis is 10 mg (1 tablet) once daily in the evening. For relief of allergic rhinitis symptoms, the time of administration may be individually adjusted.

General recommendations. The therapeutic effect of Montegen on asthma control parameters develops within 1 day. Montegen may be taken regardless of food intake. Patients should be advised to continue taking Montegen even if asthma control is achieved, as well as during asthma exacerbations. Montegen should not be used concomitantly with medicinal products containing montelukast as the active ingredient. Dose adjustment is not required for elderly patients, patients with renal impairment, or patients with mild to moderate hepatic impairment. There are no data available regarding patients with severe hepatic impairment. Dosage is the same for men and women.

Treatment with Montegen in relation to other asthma therapies.

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

Inhaled corticosteroids. Montegen can be used as add-on therapy in patients in whom inhaled corticosteroids together with short-acting β-agonists used as needed do not provide adequate clinical control of the disease. Montegen must not be abruptly substituted for inhaled corticosteroids (see section "Special Instructions").

Children.

To be used in children aged 15 years and older. For children under 15 years of age, the drug should be administered in the form of chewable tablets.

Overdose.

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

Cases of acute montelukast overdose have been reported. These involved adults and children who ingested doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). Clinical and laboratory findings remained within the known safety profile of the drug in adults and children. In most cases, no adverse reactions were reported. 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.

It is unknown whether montelukast is removed by peritoneal dialysis or hemodialysis.

Adverse reactions

Montelukast was evaluated in clinical trials:

film-coated tablets, 10 mg – in approximately 4000 asthma patients aged 15 years and older;

film-coated tablets, 10 mg – in approximately 400 patients with asthma and seasonal allergic rhinitis aged 15 years and older;

chewable tablets, 5 mg – in approximately 1750 pediatric patients with asthma aged 6 to 14 years.

During clinical trials, the adverse reactions listed below were reported commonly (≥1/100 to <1/10) in asthma patients treated with montelukast and more frequently than in patients treated with placebo.

Table 1

During clinical studies with prolonged treatment of a small number of adult patients over 2 years and children aged 6 to 14 years over 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 in Table 2. Frequencies are based on data from relevant clinical studies.

Table 2

Reporting of suspected adverse reactions

Reporting adverse reactions after the medicinal product has been registered is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through 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 ºC. Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 3 blisters per box.

Prescription status. Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of business operations.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.