Amont

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

Composition:

Active ingredient: sodium montelukast;

1 tablet contains sodium montelukast 10.4 mg, equivalent to montelukast 10 mg;

Excipients: mannite (E 421), sodium croscarmellose, aspartame (E 951), banana flavor, microcrystalline cellulose, low-substituted hydroxypropylcellulose, magnesium stearate;

Film coating Opadry yellow 20A33251: hypromellose, hydroxypropylcellulose, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, creamy-colored, round-shaped, with a biconvex surface.

Pharmacotherapeutic group. Agents for systemic use in obstructive diseases of the respiratory tract. 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) present in human airways (including smooth muscle cells and macrophages) and other pro-inflammatory cells (including eosinophils and certain myeloid progenitor cells). CysLTs play a role in the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucus secretion, increased vascular permeability, and increased eosinophil numbers. In allergic rhinitis, CysLTs are released from the nasal mucosa following allergen exposure during both early and late phases and contribute to the symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction.

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 results in significant blockade of LTD4-stimulated bronchoconstriction. Montelukast produces 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 antigens. Montelukast reduces the number of eosinophils in peripheral blood in adult and pediatric patients, significantly decreases the number of eosinophils in the airways (sputum analysis), and improves clinical control of asthma.

Pharmacokinetics

Absorption

After oral administration, montelukast is rapidly and almost completely absorbed. In adults, following administration of the 10 mg film-coated tablets under fasting conditions, maximum plasma concentration (Cmax) is achieved within 3 hours (Tmax). The average bioavailability is 64%. Administration with food does not affect the Cmax in plasma or the bioavailability of the film-coated tablets.

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, concentrations of montelukast metabolites in steady-state plasma in adults and pediatric patients were not detectable.

In vitro studies using human liver microsomes have demonstrated that cytochrome P450 enzymes 3A4, 2A6, and 2C9 are involved in the metabolism of montelukast. Further in vitro studies with human liver microsomes showed 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

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

Dose adjustment is not required for elderly patients or patients with mild to moderate hepatic impairment. Data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score >9) are not available.

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

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 daily dose of 10 mg once daily.

Clinical characteristics.

Indications.

• Adjunctive treatment of mild to moderate persistent asthma that is not adequately controlled by 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 bronchial asthma, the predominant component of which is exercise-induced bronchospasm.
• Relief of symptoms of seasonal and perennial allergic rhinitis.

Contraindications.

• Hypersensitivity to montelukast or to any other components of the medicinal product.
• 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 prevention or long-term management of bronchial 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 concurrently taking phenobarbital, the area under the plasma 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 coadministered 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. Drug interaction studies involving 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 CYP 2C8 (e.g., paclitaxel, rosiglitazone, and repaglinide).

In vitro studies have shown that montelukast is a substrate of CYP 2C8 and, to a lesser extent, of CYP 2C9 and 3A4. In a clinical interaction study, concomitant administration of montelukast with gemfibrozil (an inhibitor of CYP 2C8 and 2C9) increased systemic exposure to montelukast by 4.4-fold. When montelukast is used concomitantly with gemfibrozil or other potent inhibitors of CYP 2C8, dosage 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 are not expected with less potent inhibitors of CYP 2C8 (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 case of an acute attack, short-acting inhaled β-agonists should be used. Patients should seek immediate medical advice if they find they need a greater than usual amount of short-acting inhaled β-agonists.

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

In isolated cases, systemic eosinophilia, sometimes presenting with clinical features 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 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 be aware of the possibility of eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiovascular 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 eliminate the need for patients with aspirin-induced bronchial asthma to avoid acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

Asmont contains aspartame, a phenylalanine derivative, which may be harmful to patients with phenylketonuria. Patients with phenylketonuria should be advised that one 10 mg tablet of Asmont contains 1.5 mg of aspartame.

This medicinal product contains the excipient mannitol, which may have a mild laxative effect.

Use during pregnancy or breastfeeding.

Animal studies have not shown any harmful effects on pregnancy or embryonic/fetal development.

Limited information on the use of montelukast during pregnancy does not indicate a causal relationship between its use and the occurrence of malformations (such as congenital limb defects), which have been rarely reported based on worldwide post-marketing experience. Asmont may be used during pregnancy only if considered absolutely necessary.

Animal studies have demonstrated that montelukast passes into breast milk. It is unknown whether montelukast passes into human breast milk. Asmont may be used during breastfeeding only if considered absolutely necessary.

Ability to affect reaction speed when driving vehicles or operating machinery.

Montelukast is not expected to affect a patient's ability to drive vehicles or operate machinery. However, dizziness or drowsiness may occur in isolated cases; therefore, patients should refrain from driving a car or operating machinery during treatment with this medication.

Dosage and Administration

The medication should be taken orally, regardless of food intake.

Adults and children aged 15 years and older: For the treatment of asthma or asthma associated with seasonal allergic rhinitis, one tablet (10 mg) should be taken once daily in the evening.

For relief of allergic rhinitis symptoms, the time of administration should be individually adjusted.

General recommendations.

The therapeutic effect of the medication regarding control of bronchial asthma is achieved within 1 day. Patients should be advised to continue taking the medication even after achieving control of bronchial asthma, as well as during asthma exacerbations. The medication should not be taken concomitantly with other medicinal products containing montelukast.

Dosage adjustment is not required in elderly patients, patients with renal impairment, or patients with mild to moderate hepatic impairment. There are no data regarding use of the medication in patients with severe hepatic impairment.

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

Treatment with montelukast in relation to other treatments for bronchial asthma.

Asmon can be prescribed in addition to an existing treatment regimen.

Inhaled corticosteroids.

Asmon can be used as add-on therapy when inhaled corticosteroids in combination with short-acting β-agonists as rescue medications do not provide adequate clinical control of the disease.

Inhaled corticosteroids must not be abruptly replaced by Asmon.

Children.

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

Overdose.

During long-term studies in 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 occurring.

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 established 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 montelukast and included abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity.

Treatment. There is no specific information available 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 trials, 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 clinical trials with prolonged treatment in various age groups, 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, drowsiness, paresthesia/hypoesthesia, seizures.

Cardiac disorders: rare – palpitations.

Respiratory, thoracic and mediastinal disorders: uncommon – epistaxis; very rare – Churg-Strauss syndrome (see section "Special precautions for use"), 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 – angioneurotic edema; 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, malaise, edema.

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 very commonly in patients treated with montelukast as well as in patients receiving placebo during clinical trials.

** This adverse reaction was observed commonly in patients treated with montelukast as well as in patients receiving placebo during clinical trials.

§ 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 pack, 4 blisters in a carton.

Prescription status.

Prescription only.

Manufacturer.

Limited Liability Company "Agrofarm".

Limited Liability Company "Natur+".

Manufacturer's address and location of business activity.

113-A Centralna St., Irpin, Kyiv Oblast, 08200, Ukraine.

3 Tarasa Shevchenka St., Irpin, Kyiv Oblast, 08200, Ukraine.