Montegen

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

Composition:

Active substance: montelukast;

One chewable tablet contains montelukast sodium equivalent to 5 mg of montelukast;

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

Pharmaceutical form. Chewable tablets.

Main physicochemical characteristics: round, biconvex chewable tablets ranging from light pink to pink in color with speckles, marked with the letter "I" on one side and "113" on the other.

Pharmacotherapeutic group. Systemic agents for 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 responses such as bronchoconstriction, mucus secretion, increased vascular permeability, and increased numbers of eosinophils.

Montelukast, following oral administration, is an active compound that binds with high selectivity and affinity to CysLT1 receptors. According to clinical studies, montelukast inhibits LTD4-induced bronchoconstriction at a dose of 5 mg. Bronchodilation is observed within 2 hours after oral administration; this effect is additive to the 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 adult and pediatric patients. In a separate study, montelukast treatment significantly reduced the number of eosinophils in the airways (measured in sputum) and in peripheral blood, and improved clinical asthma control.

Pharmacokinetics.

Absorption

Montelukast is rapidly absorbed after oral administration. Following administration of 10 mg film-coated tablets on an empty stomach to adults, the mean peak plasma concentration (Cmax) was reached 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 demonstrated in clinical studies with 10 mg film-coated tablets administered regardless of timing of food intake.

For 5 mg chewable tablets, the Cmax in adults was achieved within 2 hours after administration on an empty stomach. The mean oral bioavailability is 73% and decreases to 63% when taken with a standard meal.

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 have shown minimal penetration across the blood-brain barrier. Furthermore, concentrations of radiolabeled material 24 hours after administration were minimal in all other tissues.

Metabolism

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

Cytochrome P450 2C8 is the primary enzyme involved in the metabolism of montelukast. 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. Based on further in vitro studies using human liver microsomes, montelukast at therapeutic plasma concentrations does not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Excretion

The mean plasma clearance of montelukast is approximately 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. Together 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

Dosage adjustment is not required for elderly patients or 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, dosage 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 was not observed with the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

As add-on therapy for bronchial asthma in patients with mild to moderate persistent asthma that is not adequately controlled by inhaled corticosteroids, and in cases of inadequate clinical control of asthma with short-acting β-adrenergic agonists used as needed.

As an alternative treatment instead of low-dose inhaled corticosteroids in patients 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").

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, Montegen should be used as a reserve medication for patients with inadequate response or intolerance to alternative therapies.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Montegen may be prescribed concomitantly with other medications used for the prevention and long-term treatment of asthma. In drug interaction studies, the recommended clinical dose of montelukast had no clinically significant effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/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 administering montelukast 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 data for montelukast and rosiglitazone (a marker substrate; a drug 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 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 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 times. When coadministered with gemfibrozil or other potent inhibitors of CYP 2C8, dosage adjustment of montelukast is not required, but physicians should be aware of the increased risk of adverse reactions.

Based on in vitro studies, clinically significant interactions are not expected with less potent inhibitors of CYP 2C8 (e.g., trimethoprim). 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 for the treatment of acute asthma attacks, and that they should always have a suitable emergency relief medication available. In the event of an acute attack, short-acting inhaled β-agonists should be used. Patients should seek medical advice from their physician as soon as possible if they find they need to use their short-acting β-agonist more frequently than usual.

Montelukast therapy must not be abruptly substituted for inhaled or oral corticosteroids.

There are no data to support reducing oral corticosteroid dosage when montelukast is used concomitantly.

In rare cases, systemic eosinophilia, sometimes manifesting with clinical features of vasculitis (Churg-Strauss syndrome), may develop in patients receiving anti-asthma medications, including montelukast. This condition is treated with systemic corticosteroid therapy. These cases have usually, but not always, been associated with a reduction in dose or discontinuation of oral corticosteroid therapy. The possibility that leukotriene receptor antagonists may be associated with the emergence of Churg-Strauss syndrome cannot be definitively ruled out or confirmed. Therefore, physicians should remain vigilant for the development 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 treatment does not permit patients with aspirin-sensitive asthma to take acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

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

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

Psychoneurological events have been reported in patients taking montelukast (see section "Adverse reactions"). Patients and physicians should remain alert to such psychoneurological events. Patients and/or caregivers should be advised to inform their physician if such changes occur. Physicians should carefully evaluate the risks and benefits of continuing treatment if such events occur.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not demonstrated any harmful effects of the medicinal product on pregnancy or embryonal/fetal development.

Available data from published prospective and retrospective cohort studies on montelukast use in pregnant women, assessing major congenital malformations in offspring, have not established a risk associated with the use of the medicinal product. However, existing 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 period. Studies in rats have shown that montelukast passes into breast milk. It is unknown whether montelukast is excreted in human breast milk.

Montegen may be used during breastfeeding only if clearly needed.

Ability to influence the speed of reactions when driving vehicles or operating machinery.

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

Method of Administration and Dosage

Chewable tablets should be chewed before swallowing.

For patients with asthma and allergic rhinitis (seasonal and perennial), the recommended dose is 1 chewable tablet of 5 mg once daily. The timing of administration for relief of allergic rhinitis symptoms may be individualized.

The recommended dose for asthma treatment in children aged 6 to 14 years is 1 chewable 5 mg tablet once daily 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.

Patients aged 15 years and older should be prescribed Montegen, film-coated tablets, 10 mg.

General Recommendations

Therapeutic effects of Montegen on asthma control parameters develop within 1 day. Patients should be advised to continue taking Montegen even after asthma is controlled, as well as during asthma exacerbations.

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 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 with mild persistent asthma should only be considered for patients who have not had 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 over time (usually within 1 month), the need for additional or alternative anti-inflammatory therapy should be assessed based on a stepwise asthma treatment approach. Patients should be periodically evaluated for asthma control.

Use of Montegen depending on other asthma treatments

When montelukast treatment is used as add-on therapy to inhaled corticosteroids, Montegen should not be abruptly substituted for inhaled corticosteroids (see section "Special Instructions").

Children

Montegen is indicated for use in children aged 6 to 14 years. Montegen 5 mg chewable tablets are not recommended for children under 6 years of age. The safety and efficacy of montelukast in children under 6 years of age have not been established.

Overdose

In clinical trials of chronic asthma, 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. These cases involved ingestion of the drug by adults and children at 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 effects were consistent with the drug's safety profile and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

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

Adverse reactions.

Montelukast was evaluated in clinical studies: 5 mg chewable tablets – in approximately 1750 pediatric patients with asthma aged 6 to 14 years.

During clinical studies, the adverse reactions listed below were reported commonly (≥1/100 to <1/10) in patients with asthma treated with montelukast and at a higher frequency than in patients treated with placebo:

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.

Adverse reactions are listed according to system organ classes and preferred terms, presented in the table below. Frequency is based on data from the relevant clinical studies:

Shelf life. 2 years.

Storage conditions.

Store in the original packaging in a dry, light-protected, and child-proof place at a temperature not exceeding 25 °C.

Packaging.

10 tablets per blister pack, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and place of business.

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