Glencet Advance film-coated tablets container No. 14

Instructions for Glencet Advance film-coated tablets container No. 14

Composition

active ingredients: montelukast, levocetirizine;

1 film-coated tablet contains montelukast sodium equivalent to montelukast 10 mg, levocetirizine dihydrochloride 5 mg;

excipients: lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate anhydrous, croscarmellose sodium, hydroxypropylcellulose, magnesium stearate, Opadry yellow 1ZV52204 (hypromellose, titanium dioxide (E 171), macrogol, yellow iron oxide (E 172), polysorbate 80, red iron oxide (E 172)).

Dosage form

Film-coated tablets.

Main physicochemical properties: yellow, round, biconvex tablets, film-coated, smooth on both sides.

Pharmacotherapeutic group

Agents that act on the respiratory system.

ATX code R07A X.

Pharmacological properties

Pharmacodynamics.

Glencet Advance contains a fixed combination of two active ingredients: montelukast and levocetirizine - therefore, the mechanisms of action of each component described below are inherent to the Glencet Advance drug.

Montelukast is a selective leukotriene receptor blocker. Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism released from various cell types, 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 airway smooth muscle cells and airway macrophages) as well as other proinflammatory cells (including eosinophils and certain 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 following allergen challenge during both immediate and delayed hypersensitivity reactions and are associated with the symptoms of allergic rhinitis. Montelukast is an orally active compound that binds with high affinity and selectivity to CysLT1 receptors (which has an advantage over binding to other pharmacologically important airway receptors such as prostanoid, cholinergic, or β-adrenergic receptors). Montelukast inhibits the physiological actions of LTD4 and CysLT1 receptors without any agonist activity.

Montelukast blocks cysteinyl leukotriene receptors in the airways, which has been shown to prevent bronchoconstriction induced by inhaled leukotrienes LTD4 in patients with bronchial asthma. Even at doses as low as 5 mg, montelukast reliably blocks LTD4-induced bronchoconstriction.

Levocetirizine is the 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 receptor binding studies have shown that the affinity of levocetirizine for 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 not yet known.

Pharmacokinetics.

Montelukast

Absorption

Montelukast is rapidly absorbed after oral administration. When 10 mg film-coated tablets were administered to adults in the fasted state, mean peak plasma concentrations (Cmax) of montelukast were achieved 3 to 4 hours after dosing (Tmax). The mean oral bioavailability is 64%. A standard morning meal does not affect the oral bioavailability and Cmax of montelukast. A high-fat meal in the morning did not alter the AUC of montelukast oral granules, but Cmax was decreased by 35% and Tmax was delayed from 2.3 ± 1.0 hours to 6.4 ± 2.9 hours.

Distribution

Montelukast is more than 99% bound to plasma proteins. The volume of distribution of montelukast at steady state averages 8 to 11 liters. In studies with radiolabeled montelukast in rats, minimal penetration of the blood-brain barrier was demonstrated. In addition, radiolabeled montelukast concentrations were minimal in all other tissues of the rat 24 hours after dosing.

Montelukast is extensively metabolized. In studies using therapeutic doses, plasma concentrations of metabolites of montelukast at steady state were not detected in adult patients or children. In vitro studies using human liver microsomes have shown that cytochromes CYP3A4 and 2C9 are involved in the metabolism of montelukast. Clinical studies of the effect of known inhibitors of CYP3A4 (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 inhibit cytochromes CYP3A4, 2C9, 1A2, 2A6, 2C19, and 2D6. In vitro studies have shown that montelukast is a potent inhibitor of cytochrome CYP2C8. However, data from clinical drug interaction studies of montelukast with rosiglitazone (a marker substrate for drugs primarily metabolized by CYP2C8) indicate that montelukast does not inhibit CYP2C8 in vivo and is therefore not expected to have any effect on the metabolism of drugs metabolized by this cytochrome.

Breeding

The plasma clearance of montelukast in healthy adults averages 45 mL/min. After oral administration of a dose of radiolabeled montelukast, 86% of the label was recovered in feces collected within 5 days of administration, and less than 0.2% of the label was recovered in urine. These data, combined with the results of an assessment of the bioavailability of montelukast, indicate that montelukast and its metabolites are almost completely excreted in the bile. According to the results of several studies, the mean plasma half-life of montelukast in young healthy adults ranges from 2.7 to 5.5 hours. The pharmacokinetics of montelukast are nearly linear with oral doses up to 50 mg. When a dose of 10 mg of montelukast was administered once daily, a small accumulation of the parent compound in plasma (14%) was observed.

Patients with hepatic impairment: No dose adjustment is required for patients with mild or moderate hepatic impairment. The pharmacokinetic profile of montelukast has not been evaluated in patients with more severe hepatic impairment.

Patients with renal impairment: Montelukast and its metabolites are not excreted in the urine; therefore, the pharmacokinetic profile of montelukast has not been evaluated in patients with renal impairment. No dose adjustment is necessary for these patients.

Levocetirizine

The pharmacokinetics of levocetirizine are linear in the therapeutic dose range in healthy adults.

Absorption

Levocetirizine is rapidly and extensively absorbed after oral administration. In adults, peak plasma concentrations are reached 0.9 hours after oral administration of a tablet. The accumulation coefficient after daily oral administration is 1.12; steady state is reached 2 days after the start of administration. Peak concentrations are usually 270 ng/ml and 308 ng/ml after single and multiple daily doses of 5 mg, respectively. Food intake did not affect the exposure (AUC) of levocetirizine tablets, however, when administered with a high-fat meal, Tmax was delayed by approximately 1.25 hours and Cmax was reduced by approximately 36%. Levocetirizine can therefore be administered without regard to food intake.

Distribution

The mean plasma protein binding of levocetirizine in in vitro studies ranged from 91 to 92% over concentrations ranging from 90 to 5000 ng/mL, including therapeutic plasma concentrations. After oral dosing, the mean apparent volume of distribution was approximately 0.4 L/kg, which is typical of distribution in total body fluid.

Metabolism

Less than 14% of the administered dose of levocetirizine is metabolized in humans, so differences due to genetic polymorphisms or concomitant administration of inhibitors of hepatic enzymes that metabolize this drug are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation pathways are primarily mediated by cytochrome CYP3A4, while aromatic oxidation involves multiple and/or unidentified CYP isoforms.

Breeding

The plasma elimination half-life in healthy adults is 8 to 9 hours after oral administration. The mean total oral clearance of levocetirizine is approximately 0.63 ml/kg/min. The main route of excretion of levocetirizine and its metabolites is via the urine, accounting for an average of 85.4% of the dose administered. 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. Levocetirizine clearance is reduced in patients with impaired renal function.

Indication

The fixed combination of montelukast and levocetirizine is indicated for the relief of symptoms associated with seasonal and perennial allergic rhinitis, as well as rhinitis in patients with bronchial asthma.

Contraindication

Hypersensitivity to montelukast sodium, levocetirizine or cetirizine, or to any of the other ingredients of the drug. The drug is also contraindicated in severe renal failure (creatinine clearance < 10 ml/min); in severe hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Interaction with other medicinal products and other types of interactions

Montelukast

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

Oral contraceptives, terfenadine, digoxin, and warfarin: Drug interaction studies with the recommended clinical dose of montelukast revealed no clinically significant effects of this compound on the following agents: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin.

Thyroid hormones, sedative hypnotics, nonsteroidal anti-inflammatory drugs, benzodiazepines and decongestants: no forms of interaction.

Cytochrome P450 (CYP) enzyme inducers: In the presence of phenobarbital, which induces hepatic metabolism, the area under the pharmacokinetic curve (AUC) of montelukast was decreased by approximately 40% following a single 10 mg dose of montelukast. No dose adjustment of montelukast is recommended. Montelukast is a potent inhibitor of cytochrome CYP2C8 in vitro. However, a clinical drug interaction study with montelukast and rosiglitazone (a marker substrate representative of drugs primarily metabolized by CYP2C8) in 12 healthy volunteers showed that the pharmacokinetics of rosiglitazone were unchanged when co-administered with montelukast, indicating that montelukast does not inhibit CYP2C8 in vivo. Therefore, montelukast is not expected to alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, repaglinide).

Levocetirizine

In vitro data indicate that levocetirizine is not expected to cause pharmacokinetic interactions through inhibition or induction of hepatic drug-metabolizing enzymes. No in vivo drug interaction studies have been conducted with levocetirizine.

Antipyrine, azithromycin, cimetidine, erythromycin, ketoconazole, theophylline and pseudoephedrine: Pharmacokinetic interaction studies with racemic cetirizine have shown that racemic cetirizine does not interact with antipyrine, pseudoephedrine, erythromycin, azithromycin, ketoconazole and cimetidine. In these studies, a small decrease (16%) in the clearance of cetirizine was observed when theophylline was administered at a dose of 400 mg. It can be assumed that higher doses of theophylline would have a more potent effect.

Application features

Montelukast

Acute asthma: Montelukast is not indicated for the relief of bronchospasm in acute asthma attacks, including status asthmaticus. In such cases, patients should use available rescue medication. Montelukast therapy may be continued during an asthma exacerbation. Patients who experience exercise-induced asthma should carry a short-acting β-agonist inhaler.

Concomitant use with corticosteroids: While the dose of inhaled corticosteroids may be gradually reduced under medical supervision, montelukast should not be abruptly replaced with inhaled or oral corticosteroids.

Neuropsychiatric disorders: Neuropsychiatric events have been reported in adults, adolescents, and children with montelukast. The following adverse reactions have been reported during post-marketing surveillance with montelukast: agitation, aggressive behavior or hostility, anxiety, depression, disorientation, sleep disturbances, hallucinations, insomnia, irritability, restlessness, tremor, somnambulism, suicidal ideation, and suicidal behavior (including suicide). The clinical features of some of the post-marketing adverse reactions reported with montelukast are consistent with an effect induced by this drug. Prescribers and patients should be aware of the possibility of neuropsychiatric events. Patients should be advised to report any symptoms to their physician. If a patient experiences such events, the physician should carefully weigh the risks and benefits of continuing montelukast therapy.

Eosinophilic conditions: Patients with asthma receiving montelukast may develop systemic eosinophilia, sometimes presenting with clinical signs of vasculitis, suggestive of Churg-Strauss syndrome, a condition for which systemic corticosteroid therapy is often indicated. These events are usually associated with a reduction in the dose of oral corticosteroids. The physician should closely monitor the patient for signs of eosinophilia, vasculitic skin rashes, and worsening pulmonary symptoms, cardiac complications, and/or neuropathy.

Levocetirizine

Use with caution in patients with chronic renal failure (dosage adjustment required) and in elderly patients (possible reduction in glomerular filtration).

When prescribing the drug in patients with certain factors that provoke urinary retention (e.g., spinal cord injuries, prostatic hyperplasia), it should be taken into account that levocetirizine increases the risk of urinary retention.

Antihistamines suppress the response to skin allergy testing, so before conducting it, the drug must be stopped 3 days before the test (withdrawal period).

Itching may occur after discontinuation of levocetirizine, even if these symptoms were not present before treatment. The symptoms may disappear on their own. In some cases, the symptoms may be intense and may require re-treatment with the drug after discontinuation.

During clinical trials, cases of drowsiness, increased fatigue and general weakness in some patients while taking levocetirizine were reported. Patients should be warned that during treatment with the drug, activities requiring increased mental activity and precise coordination of movements, including working with mechanisms or driving vehicles, should be avoided. During therapy with levocetirizine, alcohol consumption and central nervous system (CNS) depressants should be avoided, as additional decrease in activity and increased inhibition of CNS activity may occur.

Glencet Advance contains lactose and should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Use in elderly patients.

Montelukast

No differences in the safety and efficacy profile of this agent have been observed between elderly and younger patients, and there is no evidence in clinical practice to suggest a difference in response to this agent between these two populations, but the possibility of greater sensitivity to this agent in some elderly patients cannot be ruled out.

Levocetirizine

The number of patients aged 65 years and over in clinical trials with levocetirizine for each approved indication was insufficient to determine whether they would respond differently from younger patients. There is no evidence in clinical practice that elderly patients respond differently to this agent than younger patients. In general, dose selection for elderly patients should be cautious; in general, therapy should be initiated at the low end of the recommended dose range, given that these patients are more likely to have decreased hepatic, renal, or cardiac function, to have comorbid conditions, and to be receiving concomitant medications.

Use during pregnancy or breastfeeding

There are no adequate and well-controlled clinical studies of this medicinal product in pregnant women. Use during pregnancy is contraindicated.

Breastfeeding. Because many drugs are excreted in breast milk in nursing women, breastfeeding should be discontinued if the drug is necessary.

The ability to influence the reaction speed when driving or working with other mechanisms

No studies have been conducted on the effects of a fixed-dose combination of montelukast and levocetirizine on the ability to drive or use machines. Some patients may experience drowsiness, fatigue, and weakness during treatment with levocetirizine. Patients should refrain from driving or operating potentially hazardous machinery during treatment with Glencet Advance.

Method of administration and doses

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

Children.

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

Overdose

Montelukast

There are currently no specific recommendations for the treatment of overdose with montelukast. Cases of acute overdose with montelukast have been reported during post-marketing surveillance and during clinical trials. These reports include cases of overdose in adults and children after administration of doses as high as 1000 mg. Clinical and laboratory findings were consistent with the safety profile in adults and children. In the majority of reported cases of overdose, no serious adverse reactions were observed. The most common adverse reactions were consistent with the safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.

Treatment is symptomatic.

Levocetirizine

Cases of overdose with levocetirizine have been reported. Symptoms of overdose may include drowsiness in adults and, in children, initially agitation and restlessness, followed by drowsiness. There is no known specific antidote for levocetirizine. In case of overdose, symptomatic or supportive treatment is recommended. Levocetirizine is not removed by dialysis.

Side effects

Montelukast

The table below presents the adverse reactions reported during post-marketing surveillance. The frequency of adverse events was estimated based on data from relevant clinical trials.

*Frequency is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Levocetirizine

The following adverse reactions have been reported during clinical trials:

often (from >1/100 to <1/10) - headache, drowsiness, dry mouth, increased fatigue;

In addition to the above adverse reactions reported during clinical trials, rare cases of the following adverse reactions have also been reported during post-marketing surveillance.

Immune system disorders: hypersensitivity reactions, including anaphylaxis.

On the part of the psyche: aggressiveness, agitation, sleep disturbances, hallucinations, depression, insomnia, suicidal thoughts.

Nervous system: convulsions, fainting, tremor, dysgeusia, vertigo, drowsiness, headache, fatigue, weakness, asthenia, paresthesia, dizziness.

On the part of the organs of vision: visual impairment, blurred vision.

From the cardiovascular system: increased heartbeat, tachycardia.

Respiratory, thoracic and mediastinal disorders: dyspnea.

Gastrointestinal: nausea, diarrhea, vomiting, constipation, increased appetite, dry mouth, abdominal pain.

Hepatobiliary disorders: hepatitis.

Renal and urinary disorders: dysuria, urinary retention.

Skin and subcutaneous tissue disorders: angioedema, persistent drug-induced erythema, pruritus, rash, urticaria.

Musculoskeletal, connective tissue and bone disorders: myalgia, arthralgia.

General disorders: edema.

Examination results: weight gain, abnormal liver function tests.

Description of selected adverse reactions: Pruritus has been reported after discontinuation of levocetirizine.

Expiration date

2 years.

Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging

14 or 28 tablets in a plastic container in a cardboard box.

A polymer cylinder with a desiccant (silica gel) is placed in each container along with the tablets.

Vacation category

According to the recipe.

Producer

Glenmark Pharmaceuticals Ltd. / Glenmark Pharmaceuticals Ltd.

Location of the manufacturer and address of its place of business.

Village Kishanpura, Baddi-Nalagarh Road, Tehsil Baddi, Distt. Solan (HP) 173 205, India.

Address

Village Kishanpura, Baddi-Nalagarh Road, Tehsil Baddi, Distt. Solan (HP) 173 205, India.