Montlezir, 5 mg+10 mg 30 pcs

Pharmacotherapeutic group
Leukotriene receptor blocker + H1-histamine receptor blocker

Pharmacodynamics
The drug is a combination of montelukast (leukotriene receptor blocker) and levocetirizine (H1-histamine receptor blocker).
Montelukast selectively inhibits CysLT receptors of cysteinyl leukotrienes of the airway epithelium. Cysteinyl leukotriene receptors type 1 (CysLT receptors) are present in the human airways, including bronchial smooth muscle cells, macrophages and other pro-inflammatory cells (including eosinophils and some myeloid stem cells). Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are a class of eicosanoids formed from arachidonic acid and are mediators of inflammation produced in various cells in the body, including mast cells and eosinophils. Cysteinyl leukotrienes correlate with the pathophysiology of bronchial asthma and allergic rhinitis. In allergic rhinitis, the release of cysteinyl leukotrienes from the anti-inflammatory cells of the nasal mucosa during the early and late phases of the allergic reaction occurs after allergen exposure, which manifests as symptoms of allergic rhinitis. An intranasal test with cysteinyl leukotrienes demonstrated increased symptoms of nasal obstruction. Montelukast binds with high affinity and selectivity to CysLTl receptors, reduces the number of eosinophils in peripheral blood, in the airways.
Levocetirizine – R enantiomer of cetirizine; competitive histamine antagonist; blocks Hl histamine receptors, affinity to which is twice that of cetirizine. Levocetirizine affects histamine-dependent stage of allergic reactions; it decreases eosinophils migration, decreases vascular permeability, restricts release of inflammatory mediators and cytokines (VCAM 1 and others).
Levocetirizine prevents development and facilitates allergic reactions, has antiexudative, antipruritic effects; it has practically no anticholinergic and antiserotonic action. It has practically no sedative action in therapeutic doses.
The action begins 12 minutes after a single dose in 50% of patients, after 1 hour – in 95% of patients and lasts for 24 hours.

Pharmacokinetics
Absorption
Montelukast is rapidly and almost completely absorbed after oral administration. Normal food intake has no effect on the bioavailability and maximum plasma concentration (Cmax) of montelukast. In adults, when taken on an empty stomach in the form of film-coated tablets in a dose of 10 mg, Cmax is reached after 3 hours. Bioavailability when administered orally is 64%.
Levocetirizine is quickly and completely absorbed from the gastrointestinal tract when taken orally; eating has no effect on the completeness of absorption, but reduces its rate. Bioavailability reaches 100%. Time of reaching maximum concentration in blood plasma (TSmax) – 0.9 hours, maximum concentration in blood plasma (Cmax) – 270 ng/ml, equilibrium concentration is reached after 2 days.

Distribution
Montelukast is bound to blood plasma proteins by more than 99 %. The volume of distribution of montelukast averages 8 11 liters.
Levocetirizine is 90% bound to blood plasma proteins. The volume of distribution is 0.4 L/kg.

Metabolism
Montelukast is actively metabolized in the liver. At therapeutic doses, plasma concentrations of montelukast metabolites are not determined at equilibrium in adults and children.
It is assumed that cytochrome P450 CYP isoenzymes (WA4 and 2C9) are involved in metabolism of montelukast, and at therapeutic concentrations montelukast does not inhibit cytochrome P450 CYP isoenzymes: WA4, 2C9, 1A2, 2A6, 2C19 and 2D6.
In humans less than 14% of the dose of levocetirizine is metabolized, since the estimated differences in the pharmacokinetic profile of levocetirizine due to genetic polymorphism or simultaneous administration of enzyme inhibitors are insignificant. Metabolic transformations consist of oxidation of the aromatic ring, N and O dealkylation and conjugation with taurine. The dealkylation process is mainly carried out by the CYP3A4 isoenzyme, while the oxidation of the aromatic ring occurs by many and/or unspecified CYP isoforms. Levocetirizine when administered orally at a dose of 5 mg and/or when exceeding maximum plasma concentrations has no effect on the activity of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, 3A4. Due to limited metabolism and absence of metabolic inhibitory activity, interaction of levocetirizine on the metabolic level with other substances is unlikely.

Elimation
Clearance of montelukast in healthy adults is on average 45 ml/min. After oral administration of montelukast, 86% of the dose taken is excreted by the intestine within 5 days and less than 0.2% by the kidneys, confirming that montelukast and its metabolites are excreted almost exclusively with bile. The half-life in healthy adults is 2.7 to 5.5 hours. Pharmacokinetics of montelukast remains practically linear in oral doses over 50 mg. When taking montelukast in the morning and evening hours no differences in pharmacokinetics are observed. When receiving once daily montelukast in a dosage form of film-coated tablets 10 mg a moderate (about 14%) cumulation of active substance in plasma is observed.
Period of half-life of levocetirizine (T1/2) in adults is 7.9 ± 1.9 hours. The average observed total clearance is 0.63 ml/min/kg. It is completely eliminated from the body within 95 hours. About 85.4% of the administered dose is excreted by the kidneys, about 12.9% via the intestine. In renal insufficiency (creatinine clearance (CK) less than 40 ml/min), clearance is decreased (in patients on hemodialysis by 80%, which requires changing the appropriate dosing regimen), the half-life (T1/2) is prolonged. Less than 10% is eliminated during a standard 4-hour hemodialysis procedure.

Peculiarities of Montelukast pharmacokinetics in different patient groups
Gender
Montelukast pharmacokinetics in women and men are similar.

Elderly patients
When taken orally once daily with film-coated tablets containing 10 mg of montelukast, the pharmacokinetic profile and bioavailability are similar in elderly and younger patients.
There are limited data on the pharmacokinetics of levocetirizine. When levocetirizine was repeatedly administered 30 mg once daily for 6 days in elderly patients, total clearance was approximately 33% lower than that in younger adult patients. The distribution of cetirizine racemate has been shown to be more dependent on renal function than on age, so in elderly patients the dose of the drug should be adjusted according to renal function.

Help failure
. In patients with mild to moderate hepatic impairment and clinical manifestations of liver cirrhosis, a slowing of montelukast metabolism has been noted, accompanied by an increase in the area under the pharmacokinetic concentration-time curve (AUC) of approximately 41% after a single dose of 10 mg of montelukast. The elimination period of montelukast in patients with hepatic impairment is slightly longer compared to healthy volunteers (mean elimination half-life 7.4 hours). Dose adjustment of montelukast in patients with mild to moderate hepatic insufficiency is not required. There are no data on the nature of pharmacokinetics of montelukast in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale).

Renal Impairment
Because montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast in patients with renal impairment have not been evaluated.
In patients with renal impairment with creatinine clearance less than 40 ml/min, clearance of levocetirizine decreases. In patients on hemodialysis total clearance decreases by 80%, which requires a change in dosing regimen. Less than 10% is removed during a standard 4-hour hemodialysis procedure.

Children
In children aged 6 to 11 years with a body weight of 20 to 40 kg when 5 mg of levocetirizine is taken orally once, the Cmax and area under the concentration-time curve (AUC) are approximately twice those of healthy adults. Administration of levocetirizine in dose of 1.25 mg in children aged 6 months to 5 years leads to the same concentration in plasma as in adults while taking 5 mg of the preparation once a day.

Race
No clinically significant differences in pharmacokinetic parameters were found in patients of different racial ethnic groups.