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Composition:


active ingredients: montelukast, levocetirizine;


1 film-coated tablet contains Montelukast Sodium equivalent to montelukast10 mg, Levocetirizine Dihydrochloride 5 mg;


excipients: lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium croscarmellose, hydroxypropylcellulose, magnesium stearate, Opadri yellow 13b52204 (hypromellose, titanium dioxide (e 171), macrogol, iron oxide yellow (E 172), polysorbate 80, Iron Oxide Red (E 172)).


Dosage form. Film-coated tablets.


Basic physical and chemical properties: yellow, round, biconvex tablets, film-coated, smooth on both sides.


Pharmacotherapeutic group. Drugs that affect the respiratory system.


ATX code R07A X.


Pharmacological properties.


Pharmacodynamics.


Glencet Advans contains a fixed combination of two active ingredients: Montelukast and Levocetirizine – therefore, the mechanisms of action of each component described below are inherent in the drug Glencet Advans.


Montelukast is a selective leukotriene receptor blocker. Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism released from various types of cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. CysLT type 1 receptors (CysLT1) in humans are found in airway cells (including smooth muscle cells and airway macrophages), as well as in other pro-inflammatory cells (including eosinophils and some red bone marrow stem cells). CysLT receptors are involved in the pathogenesis of bronchial asthma and allergic rhinitis. Leukotriene-mediated effects in bronchial asthma include airway edema, smooth muscle contraction, and changes in cellular activity associated with the inflammatory process. In allergic rhinitis, CysLT receptors are released from the nasal mucosa after exposure to an allergen during hypersensitivity reactions of both immediate and delayed types and are associated with symptoms of allergic rhinitis. Montelukast is an active compound that binds with a high degree of affinity and selectivity to CysLT1 receptors (which has an advantage over binding to other pharmacologically important airway receptors, such as prostanoid, cholinergic or beta-adrenergic receptors). Montelukast inhibits the physiological action of LTD4 and CysLT1 receptors without any agonistic activity.


Montelukast blocks cysteinyl-leukotriene receptors of the respiratory tract, which was confirmed by its ability to prevent the development of bronchoconstriction caused by inhalation of ltd4 leukotrienes in patients with bronchial asthma. Even at low doses such as 5 mg, Montelukast reliably blocks ltd4-induced bronchoconstriction.


Levocetirizine is an active R-enantiomer of cetirizine, an antihistamine. Its main effects are mediated by selective inhibition of H1 receptors. The antihistamine effect of Levocetirizine has been confirmed in various studies using experimental models in animals and humans. In vitro studies on receptor binding revealed that the affinity of Levocetirizine to the human H1 receptor is 2 times higher than that of cetirizine (Ki = 3 nmol/L versus 6 nmol/L). The clinical significance of these data is still unknown.


Pharmacokinetics.


Montelukast


Absorption


Montelukast is rapidly absorbed after oral administration. When using film – coated tablets of 10 mg for adults on an empty stomach, the average value of the maximum concentration of Montelukast in blood plasma (Cmax) was reached 3 to 4 hours after administration (Tmax). The average oral bioavailability is 64%. Standard meals in the morning do not affect the bioavailability and Cmax of Montelukast when taken orally. Taking fat-rich foods in the morning did not change the AUC of Montelukast in the form of oral granules, but the Cmax concentration after meals decreased by 35%, and the Tmax time was extended from 2.3 ± 1.0 hours to 6.4 ± 2.9 hours.


Distribution


More than 99% of Montelukast binds to plasma proteins. The volume of distribution of Montelukast at steady state averages from 8 to 11 liters. In studies using radioactive isotope-labeled Montelukast, rats were shown to penetrate the blood-brain barrier in minimal amounts. In addition, in all other rat tissues, concentrations of radioactive isotope-labeled Montelukast were minimal 24 hours after dose administration.


Metabolism


Montelukast is largely metabolized. In studies using therapeutic doses, plasma concentrations of Montelukast metabolites at steady state were not detected in adult patients and in children. In vitro studies using human liver microsomes have shown that cytochromes CYP3A4 and 2c9 are involved in Montelukast metabolism. Clinical studies of the effect of known CYP3A4 inhibitors (e.g. ketoconazole, erythromycin) or 2c9 (e.g. fluconazole) on the pharmacokinetics of Montelukast have not been conducted. According to the results of in vitro studies using human liver microsomes, therapeutic plasma concentrations of Montelukast do not have an inhibitory effect on cytochromes CYP3A4, 2c9, 1A2, 2A6, 2c19 and 2d6. In vitro studies have shown that montelukast is a potent inhibitor of cytochrome CYP2C8. However, data obtained in clinical studies of the drug interaction of Montelukast with rosiglitazone (the marker substrate is a representative of the group of drugs metabolized mainly by cytochrome CYP2C8) indicate that Montelukast does not inhibit CYP2C8 in vivo and therefore is not expected to show any effect on the metabolism of drugs metabolized by this cytochrome.


Output


The plasma clearance of Montelukast in a healthy adult is on average 45 mL/min. After oral administration of a dose of radioactive isotope – labeled Montelukast, 86% of the label was detected in the stool obtained within 5 days of administration, and less than 0.2% of the label was detected in the urine. These data, combined with the results of the bioavailability assessment of Montelukast, indicate that Montelukast and its metabolites are almost completely excreted in the bile. According to the results of several studies, the average plasma half-life of Montelukast in young healthy adults is from 2.7 to 5.5 hours. The pharmacokinetics of Montelukast are almost linear with oral doses up to 50 mg. When using a dose of 10 mg of Montelukast 1 time a day, a small accumulation of the initial substance in the blood plasma was observed (14 %).


Patients with hepatic insufficiency. Patients with mild to moderate hepatic insufficiency do not need to adjust the dose. The pharmacokinetic profile of Montelukast in patients with more severe hepatic impairment has not been evaluated.


Patients with renal insufficiency. Montelukast and its metabolites are not excreted in the urine, so the pharmacokinetic profile of Montelukast in patients with renal insufficiency has not been evaluated. Dose adjustment is not required for such patients.


Levocetirizine


The pharmacokinetics of Levocetirizine when used in the therapeutic dose range in healthy adults are linear.


Absorption


Levocetirizine is rapidly and significantly absorbed after oral administration. In adults, the maximum concentration in blood plasma is reached 0.9 hours after oral administration of the tablet. The accumulation rate after daily oral administration is 1.12; at the same time, the equilibrium state is reached 2 days after the start of use. Maximum concentrations are usually 270 ng/mL and 308 ng / mL, respectively, after a single and multiple daily dose of 5 mg. Food intake did not affect the degree of exposure (AUC) of Levocetirizine in tablet form, but when used together with fat-rich foods, Tmax was prolonged by about 1.25 hours, and Cmax was reduced by about 36 %. Thus, Levocetirizine can be used regardless of food intake.


Distribution


The average binding rate of Levocetirizine to plasma proteins during in vitro studies ranged from 91 to 92%, regardless of concentrations ranging from 90 to 5000 ng/mL and including therapeutic plasma concentrations. After oral administration of the dose, the average apparent volume of distribution was approximately 0.4 L/kg, which is a typical indicator of the distribution of total body fluid.


Metabolism


In humans, less than 14% of the dose of Levocetirizine taken is metabolized, so it is expected that differences resulting from genetic polymorphism or simultaneous administration of liver enzyme inhibitors that metabolize this drug can be ignored. Metabolic pathways include aromatic oxidation, N-and O-dealkylation, and conjugation with taurine. Dealkylation pathways are mainly mediated by cytochrome CYP3A4, whereas multiple and/or unidentified CYP isoforms are involved in aromatic oxidation.


Output


The plasma half-life in healthy adults is 8 to 9 hours after oral administration. The average total clearance of Levocetirizine after oral administration is about 0.63 ml/kg/min. The main route of excretion of Levocetirizine and its metabolites – together with the urine, this route is excreted on average 85.4% of the dose taken. Only 12.9% of the dose is excreted in the faeces. Levocetirizine is excreted by both glomerular filtration and active tubular secretion. Renal clearance of Levocetirizine correlates with creatinine clearance. In patients with impaired renal function, the clearance of Levocetirizine decreases.

Clinical characteristics.


Indications.


The fixed combination of Montelukast and Levocetirizine is designed to reduce symptoms associated with seasonal and year-round allergic rhinitis, as well as rhinitis in patients with bronchial asthma.


Contraindications.


Hypersensitivity to Montelukast Sodium, Levocetirizine or cetirizine, as well as to other components of the drug. The drug is also contraindicated in severe renal failure (creatinine clearance


Interactions with other drugs and other types of interactions.


Montelukast


Theophylline, prednisone, and prednisone: no dose adjustment is required when montelukast is co-administered with theophylline, prednisone, prednisone, oral contraceptives, terfenadine, digoxin, warfarin, thyroid hormones, sedative decongestants, and cytochrome P450 (CYP) enzyme inducers.


Oral contraceptives, terfenadine, digoxin and warfarin: in the course of drug interaction studies with the recommended clinical dose of Montelukast, no clinically significant effect of this compound on the following agents was found: oral contraceptives (norethindrone 1 mg/ ethinyl estradiol 35 mcg), terfenadine, digoxin and warfarin.


Thyroid hormones, sedatives, sleeping pills, nonsteroidal anti-inflammatory drugs, benzodiazepines, and decongestants: there are no forms of interaction.


Inducers of the cytochrome P450 enzyme (CYP): against the background of the use of phenobarbital, which induces hepatic metabolism, the area under the pharmacokinetic curve (AUC) of Montelukast decreased by approximately 40% after a single dose of Montelukast 10 mg. Dose adjustment of Montelukast is not recommended. Montelukast is a potent cytochrome CYP2C8 inhibitor in vitro. However, in a clinical study of drug interaction with the use of Montelukast and rosiglitazone (a marker substrate, a representative of drugs metabolized mainly by cytochrome CYP2C8) with the participation of 12 healthy volunteers, it was shown that the pharmacokinetics of rosiglitazone remain unchanged when it is co-administered with Montelukast, which indicates the absence of inhibition of CYP2C8 by Montelukast in vivo. Therefore, montelukast is not expected to alter the metabolism of drugs metabolized by this enzyme in any way (for example, paclitaxel, rosiglitazone, repaglinide).


Levocetirizine


Data from in vitro studies indicate that Levocetirizine should not be expected to cause pharmacokinetic interactions by inhibiting or inducing liver enzymes that metabolize drugs. No in vivo studies have been conducted on the drug interaction of Levocetirizine.


Antipyrine, azithromycin, cimetidine, erythromycin, ketoconazole, theophylline and pseudoephedrine: according to the results of pharmacokinetic interaction studies with racemic cetirizine, the latter did not interact with antipyrine, pseudoephedrine, erythromycin, azithromycin, ketoconazole and cimetidine. In such studies, there was a slight decrease (by 16 %) in the clearance of cetirizine when using theophylline at a dose of 400 mg. It can be assumed that higher doses of theophylline will have a more powerful effect.

Dosage and administration.


For adults and children over 15 years of age, the recommended dose is 1 tablet per day, in the evening, regardless of food intake. Tablets are swallowed whole, without chewing. The course of treatment is 14 days.


Children.


The drug is used for children over 15 years of age.


Overdose.


Montelukast


Currently, there are no specific recommendations for the treatment of Montelukast overdose. Cases of acute overdose with Montelukast have been reported during post-marketing follow-up and during clinical trials. These reports include reports of overdose in adults and children after using high doses such as 1000 mg. Data from clinical and laboratory studies were consistent with the safety profile for adults and children. In most reported cases of overdose, no severe adverse reactions were observed. The most common adverse reactions were consistent with Montelukast's safety profile and included abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity. It is not known whether montelukast is eliminated by peritoneal dialysis or hemodialysis.


Treatment is symptomatic.


Levocetirizine


Cases of Levocetirizine overdose have been reported. Symptoms of overdose may include drowsiness in adults, and in children – first a state of agitation and anxiety, followed by the development of drowsiness. There is no known specific antidote to Levocetirizine. In case of overdose, symptomatic or supportive therapy is recommended. Levocetirizine is not excreted during dialysis.

Tags: Glencet [Levocetirizine, Montelukast]