Pharmacological properties
Pharmacodynamics. Cysteinyleukotrienes (LTC4, LTD4, LTE4) are potent pro-inflammatory eicosanoids released from various cells, including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyleukotriene receptors (CYSLT) found in the human airways and are responsible for the bronchoconstriction response, sputum production, vascular permeability, and eosinophil recruitment. CYSLTs are correlated with the pathophysiology of BA and allergic rhinitis. In allergic rhinitis, cysteinyleukotrienes are released from nasal mucus after allergen exposure during the early or late phase of the reaction and are associated with the symptoms of allergic rhinitis.
Montelukast is an active compound that binds with high affinity and selectivity to CysLT 1 receptors. Montelukast significantly blocks cysteine leukotriene receptors in the airways, as demonstrated by its ability to inhibit bronchoconstriction in patients with bronchial asthma induced by inhalation of LTD 4.
Montelukast, even at a dose of up to 5 mg, inhibits bronchoconstriction after inhalation of LTD 4. Bronchodilation is observed within 2 hours after oral administration. The bronchodilating effect caused by agonist β-blockers is summed up with the effect caused by montelukast. Treatment with montelukast inhibits the early and late phases of bronchoconstriction due to the effect on antigens. Treatment with montelukast significantly reduced the number of eosinophils in the respiratory tract (when determined in sputum). Montelukast also reduces the number of eosinophils in adults and children aged 2-14 years in peripheral blood and improves clinical control of asthma.
In a study of children 2 to 5 years of age, montelukast 4 mg reduced daytime symptoms (including cough, wheezing, shortness of breath, and activity limitation) and nighttime symptoms, as well as the frequency of as-needed β-agonist use and the need for corticosteroid rescue for worsening asthma. Patients treated with montelukast had more days without asthma symptoms.
In a study of children aged 2 to 5 years with mild asthma and episodic exacerbations, montelukast 4 mg reduced the annual frequency of asthma exacerbation episodes.
In a study of children aged 6 months to 5 years with intermittent (but not persistent) asthma, there was no significant difference between patients treated with montelukast 4 mg and those treated with placebo in the number of asthma episodes that progressed to an asthma attack (defined as an asthma episode requiring an unscheduled visit to a doctor, emergency room, or hospital; or treatment with oral, IV, or IM corticosteroids).
In a study of children aged 6 to 14 years, montelukast 5 mg significantly improved respiratory function and reduced the frequency of use of β-agonists when needed.
In a study comparing the effectiveness of montelukast and inhaled fluticasone for asthma control in children aged 6 to 14 years with mild persistent asthma, montelukast was non-inferior to fluticasone in increasing the number of days without the use of rapid-acting rescue medications.
A significant reduction in exercise-induced bronchospasm was demonstrated in a study in adults. This effect was observed over the 12-week study period. A reduction in exercise-induced bronchospasm was also demonstrated in a short-term study in children aged 6 to 14 years. The effect in both studies was demonstrated at the end of this period.
In studies in adults, montelukast 10 mg demonstrated significant improvements in morning forced expiratory volume in 1 s (FEV1), morning peak expiratory flow, and a significant reduction in total β-agonist use. There was a significantly greater reduction in patient-reported daytime and night-time asthma symptoms.
Pharmacokinetics. Absorption. Montelukast is rapidly and almost completely absorbed after oral administration. After administration of 4 mg chewable tablets on an empty stomach to children aged 2-5 years, Cmax is achieved 2 hours after administration. The Cmax value is 66% higher and Cmin is lower than in adults who took 10 mg tablets.
After administration of 5 mg chewable tablets to children aged 5-14 years on an empty stomach, Cmax is achieved 2 hours after administration. Bioavailability was 73% and decreased to 63% with regular food.
For 10 mg film-coated tablets taken on an empty stomach in adults, the mean Cmax is reached after 3 hours (Tmax). The mean bioavailability is 64% when taken with a normal meal. The mean bioavailability and Cmax are independent of the normal meal. The efficacy and safety of this dosage form have been demonstrated in clinical studies in which 10 mg film-coated tablets were administered without regard to food.
Metabolism. Montelukast is almost completely metabolized. In studies of therapeutic doses, steady-state plasma concentrations of montelukast metabolites in adults and children could not be determined. In vitro studies using human liver microsomes have shown that cytochrome P450 3A4, 2A6, and 2C9 are involved in the metabolism of montelukast. Based on further in vitro tests using human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochrome P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.
Elimination: The plasma clearance of montelukast averages 45 mL/min in healthy adult subjects.
After oral administration, approximately 86% of the radiolabeled montelukast is excreted in the feces within 5 days and less than 0.2% in the urine. Since montelukast and its metabolites are almost completely eliminated in the bile, dose adjustment is not required in patients with renal impairment.
Pharmacokinetics in different patient groups. No dose adjustment is required for elderly patients and patients with mild to moderate hepatic impairment. No dose adjustment is required for patients with renal impairment, since montelukast and its metabolites are almost completely eliminated in the bile. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment.
When taking montelukast in high doses (20-60 times higher than the therapeutic dose), a decrease in theophylline concentration in blood plasma was observed. When taken in therapeutic doses, this effect was not observed.
Indication
Milukant 4 mg
For children aged 2-5 years
As an add-on treatment for asthma in patients aged 2 to 5 years with persistent mild to moderate asthma inadequately controlled with inhaled corticosteroids, and with inadequate clinical control of asthma with short-acting β-adrenergic agonists used as needed.
As an alternative treatment to low-dose inhaled corticosteroids for patients aged 2 to 5 years with mild persistent asthma who have not had a recent serious asthma attack requiring oral corticosteroids and who are unable to use inhaled corticosteroids (see Method of Administration).
Prevention of asthma in patients aged 2 years and older whose predominant component of asthma is exercise-induced bronchospasm.
Reducing symptoms of seasonal and perennial allergic rhinitis.
Milukant 5 mg
Children aged 6 to 14 years
As an add-on treatment for asthma in patients with persistent mild to moderate asthma inadequately controlled with inhaled corticosteroids, and with inadequate clinical control of asthma with short-acting β-adrenergic agonists used as needed.
As an alternative treatment to low-dose inhaled corticosteroids for patients with mild persistent asthma who have not had a recent serious asthma attack requiring oral corticosteroids and who are unable to use inhaled corticosteroids (see Method of administration).
Prevention of asthma, the dominant component of which is exercise-induced bronchospasm.
Reducing symptoms of seasonal and perennial allergic rhinitis.
Milukant 10 mg
As an additional treatment for asthma in patients with persistent mild to moderate asthma, inadequately controlled by inhaled corticosteroids, and in patients with insufficient clinical control of asthma with short-acting β-adrenergic agonists used as needed. In patients with bronchial asthma taking Milukant, this drug also relieves symptoms of seasonal allergic rhinitis.
Prevention of asthma, the dominant component of which is exercise-induced bronchospasm.
Reducing symptoms of seasonal and perennial allergic rhinitis.
Application
Milukant 4 mg
The drug must be used in children under adult supervision.
Patients with bronchial asthma and allergic rhinitis (seasonal and perennial) should take 1 chewable tablet (4 mg) once a day. To relieve symptoms of allergic rhinitis, the time of administration should be selected individually.
For the treatment of asthma, the dose for children aged 2 to 5 years is 1 chewable tablet (4 mg) per day, in the evening. Milukant should be taken 1 hour before or 2 hours after a meal. There is no need for dose adjustment for this age group. Milukant chewable tablet (4 mg) is not recommended for children under 2 years of age.
General recommendations for use of the drug. The therapeutic effect of Milukant on the control of asthmatic manifestations is observed within 1 day. Patients should be advised to continue taking Milukant, even if asthma is under control, as well as during periods of asthma exacerbation.
Milukant as an alternative treatment to low-dose inhaled corticosteroids in mild persistent asthma. Montelukast is not recommended for monotherapy in patients with moderate persistent asthma. Montelukast should only be considered as an alternative to low-dose inhaled corticosteroids in children with mild persistent asthma in patients who have not had a recent serious asthma attack requiring oral corticosteroids or who are unable to take inhaled corticosteroids. Mild persistent asthma is defined as asthma with 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 (usually within 1 month), the need for additional or different anti-inflammatory therapy should be assessed based on the asthma step-by-step system. Patients should be periodically assessed for asthma control.
Prevention of asthma in patients aged 2 to 5 years whose main component of asthma is exercise-induced bronchospasm. Milukant is recommended for patients aged 2 to 5 years for the prevention of exercise-induced bronchospasm, which may be the main manifestation of persistent asthma requiring the use of inhaled corticosteroids.
The patient's condition should be evaluated 2-4 weeks after starting treatment with montelukast. If a satisfactory result of therapy is not achieved, a decision should be made about additional or alternative treatment.
Treatment with Milukant compared to other treatments. In cases where Milukant treatment is additional to inhaled corticosteroid therapy, Milukant should not be abruptly administered instead of inhaled corticosteroids.
Milukant 5 mg
Patients with bronchial asthma and allergic rhinitis (seasonal and perennial) should take 1 chewable tablet (5 mg) once a day. To relieve symptoms of allergic rhinitis, the time of administration should be selected individually.
For the treatment of asthma, the dose for children aged 6 to 14 years is 1 chewable tablet (5 mg) per day, in the evening. Milukant should be taken 1 hour before or 2 hours after a meal. No dose adjustment is necessary for this age group.
General recommendations for use of the drug. The therapeutic effect of Milukant on the control of asthmatic manifestations is noted within 1 day. Patients should be advised to continue taking Milukant, even if asthma is under control, as well as during periods of asthma exacerbation.
No dose adjustment is necessary for patients with renal impairment or mild or moderate hepatic impairment. There are no data on dose adjustment for patients with severe hepatic impairment. The dosage for male and female patients is identical.
Milukant as an alternative treatment to low-dose inhaled corticosteroids in mild persistent asthma. Montelukast is not recommended for use as monotherapy in patients with moderate to severe persistent asthma. Montelukast should only be considered as an alternative to low-dose inhaled corticosteroids in children with mild persistent asthma in patients who have not had a recent serious asthma attack requiring oral corticosteroids or who are unable to take inhaled corticosteroids. Mild persistent asthma is defined as asthma with 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 (usually within 1 month), the need for additional or different anti-inflammatory therapy should be assessed based on the asthma step-by-step system. Patients should be periodically assessed for asthma control.
Treatment with Milukant compared to other treatments. In cases where Milukant treatment is additional to inhaled corticosteroid therapy, Milukant should not be abruptly administered instead of inhaled corticosteroids.
Milukant 10 mg
The dose for patients (aged 15 years and over) with bronchial asthma or with BA and concomitant seasonal allergic rhinitis is 10 mg (1 tablet) per day, in the evening. To relieve the symptoms of allergic rhinitis, the time of administration should be selected individually.
No dose adjustment is required for patients with mild or moderate hepatic impairment. No dose adjustment data are available for patients with severe hepatic impairment. No dose adjustment is required for elderly patients.
general recommendations
The therapeutic effect of Milukant on asthma control parameters is observed within 1 day. The drug can be used regardless of meals. Patients should be advised to continue taking the drug even if asthma is under control, as well as during periods of asthma exacerbation.
No dose adjustment is required for elderly patients. No dose adjustment is required for patients with renal insufficiency, mild to moderate hepatic impairment. There are no data available for patients with severe hepatic impairment. The dosage for male and female patients is identical.
Treatment with Milukant compared to other asthma treatments. Milukant can be added to a patient's existing treatment regimen.
Inhaled corticosteroids: Treatment with Milukant may be used as add-on therapy for patients in whom inhaled corticosteroids together with the necessary short-acting β-agonists do not provide adequate clinical control of asthma.
Inhaled corticosteroids should not be abruptly replaced with Milukant.
Contraindication
Hypersensitivity to the active substance or any auxiliary component.
Side effects
Milukant is well tolerated. In clinical studies, long-term treatment in different age groups demonstrates a consistent safety profile.
Infections and infestations: upper respiratory tract infections.
From the circulatory and lymphatic systems: tendency to increase bleeding.
Immune system disorders: hypersensitivity reactions, including anaphylaxis, eosinophilic infiltration of the liver.
On the part of the psyche: impaired attention, memory impairment, sleep disturbances, including nightmares, insomnia, somnambulism, irritability, anger, impatience, anxiety, agitation, including aggressive behavior or hostility, depression, tremor; very rarely - hallucinations, disorientation, suicidal thoughts and behavior (suicide attempt).
From the nervous system: dizziness and lethargy, drowsiness, paresthesia/hypoesthesia, seizures, headache.
Cardiovascular system: palpitations.
Respiratory, thoracic and mediastinal disorders: epistaxis, Churg-Strauss syndrome (CSS).
On the part of the digestive system: diarrhea, dry mouth, dyspepsia, nausea, vomiting, abdominal pain.
On the part of the hepatobiliary system: increased serum transaminase levels (ALT, AST), hepatitis, including cholestatic, hepatocellular and mixed types, liver damage.
Renal and urinary disorders: enuresis in children.
Skin and subcutaneous tissue disorders: angioedema, hematoma, urticaria, pruritus, rash, erythema nodosum, erythema multiforme.
Musculoskeletal and connective tissue disorders: arthralgia, myalgia, including muscle cramps.
General disorders and administration site conditions: fever, asthenia/fatigue, malaise, edema, thirst.
Special instructions
Patients should be advised not to use milucant to relieve an acute attack and to have their usual first aid preparations available for these cases. If an acute attack develops, inhaled short-acting β-blockers should be used. Patients should consult their doctor as soon as possible if they require more inhalations of short-acting β-adrenergic agonists than usual.
Montelukast should not be abruptly substituted for inhaled or oral corticosteroids. There is no evidence to suggest that oral corticosteroids can be reduced while taking montelukast.
In rare cases, patients receiving anti-asthma drugs, including montelukast, may develop systemic eosinophilia, sometimes accompanied by clinical signs of vasculitis, the so-called Churg-Strauss syndrome, a condition that is eliminated with the help of systemic corticosteroids. These cases are usually, but not always, associated with a decrease or withdrawal of oral corticosteroid therapy. It is not possible to exclude or establish the possibility that leukotriene receptor antagonists may be associated with the development of Churg-Strauss syndrome. Therefore, physicians should be warned about the possibility of eosinophilia, vasculitic rashes, increased severity of pulmonary symptoms, cardiac complications and / or neuropathy in patients. Patients who develop the above symptoms should be re-examined, and their treatment regimen should be reviewed. Treatment with montelukast does not eliminate the need to avoid taking acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs in patients with aspirin-induced asthma.
Milukant, chewable tablets 4 and 5 mg, contain aspartame, a source of phenylalanine. This may have adverse effects on patients with phenylketonuria. Patients with phenylketonuria should take into account that 1 chewable tablet 4 mg contains phenylalanine in an amount equivalent to 0.674 mg / dose, and 1 chewable tablet 5 mg contains phenylalanine in an amount equivalent to 0.842 mg / dose.
Milukant, film-coated tablets, 10 mg, contain lactose, therefore patients with rare hereditary diseases of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take it.
Limited data from available pregnancy databases do not suggest a causal relationship between montelukast and malformations (such as limb defects), which have been rarely reported in postmarketing surveillance worldwide. Most of these women were also taking other anti-asthma medications. A causal relationship between these cases and montelukast has not been established.
When prescribing Milukant to pregnant women, the benefit/risk ratio should be considered.
Breastfeeding: Studies in rats have shown that montelukast passes into breast milk.
There is no data on the penetration of Milukant into breast milk of breastfeeding women, therefore, it is necessary to consider the benefit/risk ratio when prescribing the drug Milukant during breastfeeding.
Fertility: In animal studies, montelukast had no effect on fertility or reproductive function at systemic exposures that exceeded the clinical systemic exposure by more than 24 times.
Children. Milukant 4 mg chewable tablets are intended for use in children aged 2-5 years. Milukant 5 mg chewable tablets are indicated for use in children aged 6-14 years. Milukant 10 mg is used in children over 15 years of age and adults.
Ability to influence the speed of reaction when driving vehicles or operating other mechanisms. Milukant usually does not affect the ability to drive vehicles or operate other mechanisms, but very rarely drowsiness has been observed in patients taking the drug, so while taking the drug you should refrain from driving vehicles or operating other mechanisms.
Interactions
Montelukast can be used concomitantly with other drugs for the prevention and treatment of chronic BA. In drug interaction studies, the recommended clinical dose of montelukast had no clinically important effect on the pharmacokinetics of the following drugs: theophylline, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.
Montelukast AUC was decreased by approximately 40% in subjects receiving concomitant phenobarbital. Montelukast is metabolized by CYP 3A4, 2C8, and 2C9, and caution should be exercised, especially in children, when administered 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 studies with montelukast and rosiglitazone (a marker substrate representing drugs primarily metabolized by CYP 2C8) have shown that montelukast does not inhibit CYP 2C8 in vivo. Therefore, montelukast is not expected to significantly alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).
In vitro studies have shown that montelukast is a substrate of CYP 2C8 and, to a lesser extent, 2C9 and 3A4. In a clinical drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9), gemfibrozil increased the systemic exposure of montelukast by 4.4-fold. Usually, no dose adjustment of montelukast is required when gemfibrozil or other potent inhibitors of CYP 2C8 are administered, but the physician should be aware of the possibility of increased adverse reactions.
Based on in vitro studies, no clinically significant drug interactions are anticipated with less potent CYP 2C8 inhibitors (e.g., trimethoprim). Coadministration of montelukast with itraconazole, a potent CYP 3A4 inhibitor, did not result in a significant increase in systemic exposure to montelukast.
Overdose
There is no specific information on the treatment of overdose with montelukast. In studies with BA, montelukast was administered at doses up to 200 mg/day to adult patients for 22 weeks, and in short-term studies - up to 900 mg/day for about 1 week, without clinically significant adverse reactions.
Acute overdoses of montelukast have been reported in postmarketing experience and in clinical trials. These cases involved adults and children taking doses up to 1000 mg (approximately 61 mg/kg in a 42-month-old child). The clinical and laboratory findings were consistent with the safety profile in adults and children.
In most reports of overdose, no adverse events were observed. The most common adverse events were consistent with the safety profile of the drug and included abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity. Treatment is symptomatic. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.
Storage conditions
In original packaging.
