Asmont

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ASMONT (ASmont)

Composition:

Active substance: montelukast sodium;

1 tablet contains montelukast sodium 5.2 mg, equivalent to 5 mg of montelukast;

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

Pharmaceutical form. Chewable tablets.

Main physicochemical properties: pink-colored, flat cylindrical tablets with beveled edges*.

*Speckles may be present due to manufacturing technology.

Pharmacotherapeutic group. Systemic drugs used 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) located in human airways and cause responses such as bronchoconstriction, mucus secretion, vascular permeability, and increased eosinophil recruitment.

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

Treatment with montelukast suppresses bronchospasm in both early and late phases, reducing the response to allergens. Montelukast reduces the number of eosinophils in peripheral blood in adult and pediatric patients, significantly decreases eosinophil counts in the airways (sputum analysis), and improves clinical asthma control.

Pharmacokinetics.

Absorption

After administration, montelukast is rapidly and almost completely absorbed. Following a single 5 mg dose of chewable tablets taken on an empty stomach, Cmax is reached within 2 hours. The mean oral bioavailability is 73% and decreases to 63% when taken with food.

Distribution

Over 99% of montelukast is bound to plasma proteins. The steady-state volume of distribution of montelukast averages from 8 to 11 liters. In studies using radiolabeled montelukast, penetration 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 were 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. At therapeutic concentrations, montelukast does not inhibit these cytochromes. The contribution of metabolites to the therapeutic effect of montelukast is considered minimal.

Excretion

The 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

Dosage adjustment is not required in elderly patients or in patients with mild to moderate hepatic impairment. There are no data on the pharmacokinetic profile of montelukast in patients with severe hepatic impairment (Child-Pugh score >9).

Studies in patients with renal impairment have not been conducted. However, since montelukast and its metabolites are primarily excreted via bile, dosage adjustment in patients with renal impairment is not considered necessary.

With administration of high doses of montelukast (20- and 60-fold higher than the recommended adult dose), a decrease in plasma theophylline concentrations was observed. This effect was not observed with the recommended daily dose of 10 mg once daily.

Pharmacokinetic studies have shown that the concentration profiles of 5 mg chewable tablets in children aged 6 to 14 years are similar to those of 10 mg film-coated tablets in adults.

Clinical characteristics.

Indications.

For children aged 6 to 14 years:

• as add-on therapy for mild to moderate persistent asthma inadequately controlled with inhaled corticosteroids, and in patients with inadequate clinical control of asthma symptoms using short-acting β-agonists on an as-needed basis;
• as an alternative to low-dose inhaled corticosteroids in patients with mild persistent asthma who have not recently experienced severe asthma attacks requiring oral corticosteroids, and in those patients who cannot use inhaled corticosteroids;
• prevention of asthma where bronchospasm induced by physical exercise is the predominant component;
• relief of symptoms of seasonal and perennial allergic rhinitis.

Contraindications.

Hypersensitivity to montelukast or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Montelukast may be administered concomitantly with other medicinal products used for the prevention or long-term treatment of asthma. The recommended clinical dose of montelukast has no significant clinical effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients who were concomitantly taking phenobarbital, the area under the concentration-time curve (AUC) for montelukast was reduced by approximately 40%. Since montelukast is metabolized by CYP 3A4, 2C8, and 2C9, caution should be exercised, especially in children, when montelukast is coadministered with inducers of CYP3A4, 2C8, and 2C9, such as phenytoin, phenobarbital, rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. Drug interaction studies involving montelukast and rosiglitazone (a drug metabolized via 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 CYP 2C8 (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 between 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 be aware of the increased risk of adverse reactions.

Based on in vitro studies, clinically significant interactions are not expected with weaker inhibitors of CYP2C8 (e.g., trimethoprim).

Concomitant administration of montelukast with itraconazole (a potent 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 Asmont should not be used to relieve acute asthmatic attacks, and that they must always have a suitable rescue medication available. In the event of an acute attack, short-acting inhaled β-agonists should be used. Patients should seek immediate medical advice if they find they need more short-acting β-agonist inhalations than usual.

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

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

Psychoneuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking montelukast (see section "Adverse reactions"). Patients and physicians should be aware of the possibility of such events. Physicians should discuss the potential for these events with their patients and/or their caregivers. Patients and/or caregivers should be instructed to inform their physician if any psychoneuropsychiatric symptoms occur. Physicians should carefully evaluate the risks and benefits of continuing montelukast therapy if such events occur.

In rare cases, systemic eosinophilia, sometimes manifesting clinically as vasculitis (Churg-Strauss syndrome, also known as allergic granulomatous angiitis), has been observed in patients receiving anti-asthma treatments, including montelukast. This condition is typically treated with systemic corticosteroids. These cases have usually, but not always, been associated with a reduction in dose or discontinuation of oral corticosteroids. A causal relationship between leukotriene receptor antagonists and the development of Churg-Strauss syndrome cannot be either ruled out or confirmed. Therefore, physicians should remain alert to the possible development of eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiovascular complications, and/or neuropathy in their patients. Patients who develop the aforementioned symptoms should undergo re-evaluation, and their treatment regimen should be reassessed.

Treatment with montelukast does not eliminate the need for patients with aspirin-sensitive bronchial asthma to avoid the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

Asmont chewable tablets contain aspartame, a phenylalanine derivative, which is potentially hazardous for patients with phenylketonuria. Patients with phenylketonuria should be informed that one 5 mg tablet of Asmont contains 0.743 mg of aspartame.

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 during pregnancy, assessing major congenital malformations in offspring, have not established a risk associated with the use of the drug. However, these studies have methodological limitations, including small sample sizes, retrospective data collection in some cases, and non-comparable control groups.

Asmont may be used during pregnancy only if clearly necessary.

Breastfeeding. Studies in rats have shown that montelukast is excreted into milk. It is unknown whether montelukast or its metabolites are excreted in human breast milk.

Asmont may be used during breastfeeding only if clearly 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, very rare cases of somnolence or dizziness have been reported; therefore, caution should be exercised when driving or operating machinery during treatment with this medicinal product.

Method of Administration and Dosage.

Chewable tablets should be chewed before swallowing.

For patients with bronchial asthma and allergic rhinitis (seasonal and perennial), the recommended dose is 1 chewable tablet of 5 mg once daily. For relief of allergic rhinitis symptoms, the time of administration should be individually adjusted.

For treatment of bronchial asthma, the dosage for children aged 6 to 14 years is 1 chewable tablet (5 mg) once daily in the evening, taken 1 hour before or 2 hours after a meal. Dose adjustment is not required for this age group.

General Recommendations.

The therapeutic effect of the drug on bronchial asthma control parameters develops within 1 day. Patients should be advised to continue taking Asmont even after achieving asthma control, as well as during asthma exacerbation periods.

Dose adjustment is not required for patients with renal impairment or mild to moderate hepatic impairment. There are no data regarding dose adjustment in patients with severe hepatic impairment.

The dosage of the drug is the same for male and female patients.

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 bronchial asthma. The decision to use montelukast as an alternative to low-dose inhaled corticosteroids in children with mild persistent asthma may be considered only for patients who have not experienced severe asthma attacks requiring systemic corticosteroids in the recent past, and for patients who have demonstrated inability to use inhaled corticosteroids.

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 satisfactory asthma control is not achieved within 1 month of montelukast therapy, the need for additional or alternative anti-inflammatory treatment should be evaluated according to a stepwise approach to bronchial asthma management. Patients should be periodically monitored to assess asthma control.

Use of montelukast in relation to other asthma treatments.

When montelukast therapy is used as add-on treatment to inhaled corticosteroids, inhaled corticosteroids must not be abruptly replaced by montelukast.

Children.

For use in children aged 6 to 14 years. For children aged 15 years and older, montelukast 10 mg tablets should be used.

Overdose.

In long-term studies of chronic bronchial asthma, montelukast was administered at doses up to 200 mg/day in adult patients, and in short-term studies up to 900 mg/day for approximately one week, without clinically significant adverse reactions.

Symptoms. Acute montelukast overdose has been reported. These cases involved adults and children who ingested doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). Observed clinical and laboratory findings were within the safety profile of montelukast in adult and pediatric patients. Most cases of overdose were not associated with reported adverse reactions. The most commonly observed adverse reactions were consistent with the safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

Treatment. There is no specific information on the treatment of montelukast overdose. Treatment is symptomatic. No antidote is available. It is unknown whether montelukast is eliminated by peritoneal dialysis or hemodialysis.

Adverse Reactions

During clinical studies, the following adverse reactions were reported frequently (≥ 1/100 to < 1/10) in patients receiving montelukast treatment and more frequently than in patients receiving placebo:

Nervous system: headache.

Gastrointestinal system: abdominal pain.

General disorders: thirst.

During long-term clinical studies in various age groups of patients, the safety profile did not change.

Adverse reactions reported during the post-marketing period:

Infections and infestations: very common – upper respiratory tract infections*.

Blood and lymphatic system disorders: rare – tendency to increased bleeding; 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, tremor§); rare – attention disorders, memory impairment, tic; very rare – hallucinations, disorientation, suicidal thoughts and behavior (suicidality), dysphemia, obsessive-compulsive disorders.

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

Cardiovascular system: rare – palpitations.

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

Gastrointestinal disorders: common – diarrhea**, nausea**, vomiting**; uncommon – dry mouth, dyspepsia.

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

Skin and subcutaneous tissue disorders: common – rash**; uncommon – bruising, urticaria, pruritus; rare – angioedema; very rare – nodular erythema, 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**; uncommon – asthenia/fatigue, discomfort (malaise), swelling.

Frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

* This adverse reaction was observed with "very common" frequency in patients treated with montelukast as well as in patients receiving placebo during clinical studies.

** This adverse reaction was observed with "common" frequency in patients treated with montelukast as well as in patients receiving placebo during clinical studies.

§ Frequency category: rare.

Shelf life.

3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of reach of children.

Packaging.

7 tablets in a blister; 4 blisters in a carton.

Prescription category. Prescription only.

Manufacturer.

Limited Liability Company "Agrofarm".

Limited Liability Company "Natur+".

Manufacturer's address and place of business.

113-A Tsentralna Street, Irpin, Kyiv region, Ukraine, 08200.

3 Tarasa Shevchenka Street, Irpin, Kyiv region, Ukraine, 08200.