Montlezir, 5 mg+10 mg 30 pcs

Indications

Treatment of symptoms of year-round (persistent) and seasonal (intermittent) allergic rhinitis.

Pharmacological effect

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 respiratory tract epithelium. Cysteinyl leukotriene receptor type 1 (CysLT receptors) is present in the human airways, including bronchial smooth muscle cells, macrophages, and other proinflammatory cells (including eosinophils and some myeloid stem cells). Cysteinyl leukotrienes (LTС4, LTD4, LTE4) belong to the class of eicosanoids formed from arachidonic acid and are mediators of inflammation formed in various cells of the body, including mast cells and eosinophils. Cysteinyl leukotrienes correlate with the pathophysiology of bronchial asthma and allergic rhinitis. In allergic rhinitis, after exposure to an allergen, cysteinyl leukotrienes are released from anti-inflammatory cells of the nasal mucosa during the early and late phases of the allergic reaction, which is manifested by symptoms of allergic rhinitis. An intranasal test with cysteinyl leukotrienes demonstrated an increase in symptoms of nasal obstruction. Montelukast binds with high affinity and selectivity to CysLTl receptors, reduces the number of eosinophils in the peripheral blood and respiratory tract.
Levocetirizine is the R enantiomer of cetirizine; competitive histamine antagonist; blocks Hl histamine receptors, the affinity for which is 2 times higher than that of cetirizine. Levocetirizine has an effect on the histamine-dependent stage of allergic reactions; reduces the migration of eosinophils, reduces vascular permeability, limits the release of inflammatory mediators and cytokines (VCAM 1 and others).
Levocetirizine prevents the development and alleviates the course of allergic reactions, has an antiexudative and antipruritic effect; has virtually no anticholinergic and antiserotonin effects. In therapeutic doses it has virtually no sedative effect.
The action begins 12 minutes after taking a single dose in 50% of patients, after 1 hour in 95%, and continues for 24 hours.

Pharmacokinetics
Absorption
Montelukast is rapidly and almost completely absorbed after oral administration. Eating regular food does not affect the bioavailability and maximum plasma concentration (Cmax) of montelukast. In adults, when taking montelukast on an empty stomach in the form of film-coated tablets at a dosage of 10 mg, Cmax is achieved after 3 hours. Bioavailability when taken orally is 64%.
Levocetirizine is quickly and completely absorbed from the gastrointestinal tract when taken orally; food intake does not affect the completeness of absorption, but reduces its speed. Bioavailability reaches 100%. The time to reach the maximum concentration in the blood plasma (TCmax) is 0.9 hours, the maximum concentration in the blood plasma (Cmax) is 270 ng/ml, the equilibrium concentration is achieved after 2 days.

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

Metabolism
Montelukast is actively metabolized in the liver. When using therapeutic doses, the concentrations of montelukast metabolites in plasma at steady state in adults and children are not determined.
It is assumed that the cytochrome P450 CYP isoenzymes (ZA4 and 2C9) are involved in the metabolism of montelukast, while at therapeutic concentrations montelukast does not inhibit the cytochrome P450 CYP isoenzymes: 3A4, 2C9, 1A2, 2A6, 2C19 and 2D6.
In humans, less than 14% of a dose of levocetirizine is metabolized, as the expected differences in the pharmacokinetic profile of levocetirizine due to genetic polymorphisms or concomitant use of enzyme inhibitors are negligible. 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 through many and/or unidentified CYP isoforms. Levocetirizine, when taken orally at a dose of 5 mg and/or when maximum plasma concentrations are exceeded, does not affect the activity of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, 3A4. Due to limited metabolism and the absence of metabolic inhibitory activity, interaction of levocetirizine at the metabolic level with other substances is unlikely.

Removal
The clearance of montelukast averages 45 ml/min in healthy adults. After oral administration of montelukast, 86% of the dose taken is excreted by the intestines within 5 days and less than 0.2% by the kidneys, confirming that montelukast and its metabolites are excreted almost exclusively in bile. The half-life in healthy adults ranges from 2.7 to 5.5 hours. The pharmacokinetics of montelukast remains almost linear when administered orally at doses above 50 mg. When taking montelukast in the morning and evening hours, no differences in pharmacokinetics are observed. When taking montelukast once a day in the dosage form of film-coated tablets, 10 mg, a moderate (about 14%) cumulation of the active substance in plasma is observed.
The 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 taken dose of the drug is excreted by the kidneys, about 12.9% through the intestines. In case of renal failure (creatinine clearance (CC) less than 40 ml/min), clearance decreases (in patients on hemodialysis by 80%, which requires a change in the appropriate dosage regimen), the half-life (T1/2) is extended. Less than 10% is removed during a standard 4 hour hemodialysis procedure.

Features of the pharmacokinetics of montelukast in different groups of patients
Gender
The pharmacokinetics of montelukast are the same in women and men.

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

Liver failure
In patients with mild to moderate hepatic impairment and clinical manifestations of cirrhosis, a slowdown in the metabolism of montelukast was observed, accompanied by an increase in the area under the concentration-time curve (AUC) by approximately 41% after a single dose of 10 mg of montelukast. The elimination period of montelukast in patients with hepatic impairment is slightly increased compared to healthy volunteers (average half-life 7.4 hours). No dose adjustment of montelukast is required in patients with mild to moderate hepatic impairment. There are no data on the nature of the pharmacokinetics of montelukast in patients with severe liver failure (more than 9 points on the Child Pugh scale).

Kidney failure
Because montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast have not been evaluated in patients with renal impairment.
In patients with renal failure with creatinine clearance less than 40 ml/min, the clearance of levocetirizine is reduced. In patients on hemodialysis, total clearance is reduced by 80%, which requires a change in dosage 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 taken orally as a single dose of 5 mg of levocetirizine, the Cmax and area under the concentration-time curve (AUC) are approximately twice as high as those in healthy adults. Taking levocetirizine at a dose of 1.25 mg in children aged 6 months to 5 years leads to plasma concentrations corresponding to those in adults when taking 5 mg of the drug once a day.

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

Special instructions

Montelukast
In rare cases, systemic eosinophilia may occur in patients taking drugs to treat asthma, including montelukast, sometimes accompanied by clinical manifestations of vasculitis and Charge-Strauss syndrome. This condition is usually treated with systemic corticosteroids. Such cases are usually, but not always, associated with dose reduction or discontinuation of oral corticosteroids. Clinicians should be aware of the possibility that patients may develop eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy.
Patients with a documented allergy to acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (NSAIDs) should not take these drugs during treatment with montelukast, since it, while improving respiratory function in patients with allergic bronchial asthma, however, cannot completely prevent bronchoconstriction caused by NSAIDs.
Neuropsychiatric disorders have been described in patients taking montelukast. Given that these symptoms could be caused by other factors, it is unknown whether they are related to montelukast. Physicians should discuss these adverse events with patients and/or their parents/guardians. Patients and/or their parents/guardians should be advised that if such symptoms occur, they should notify their physician.

Levocetirizine
It is not recommended to take ethanol during treatment with the drug.

Impact on the ability to drive vehicles and machinery
No studies have been conducted on the effect of the drug on the ability to drive vehicles and operate machinery. During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, since the drug can cause weakness, drowsiness and dizziness.

Active ingredient

Levocetirizine, Montelukast

Composition

Composition per tablet:

Core
1st layer:
Active ingredient: levocetirizine dihydrochloride 5.0 mg;
Excipients: lactose monohydrate (Tablettoza 100) 63.5 mg, microcrystalline cellulose (Avicel PH 102) 30.2 mg, colloidal silicon dioxide 0.3 mg, magnesium stearate 1.0 mg;

2nd layer:
Active ingredient: montelukast sodium 10.4 mg, equivalent to montelukast 10.0 mg;
Excipients: lactose monohydrate (Farmatose 200M) 89.3 mg, microcrystalline cellulose (Avicel PH 101) 83.2 mg, yellow iron oxide dye (iron oxide yellow) 0.1 mg, croscarmellose sodium 13.0 mg, hyprolose (hydroxypropylcellulose) 3.0 mg, magnesium stearate 1.0 mg;

Film casing
Opadry yellow (Opadry yellow 13B52204) 6.0 mg (hypromellose 6cP (HPMC 2910) 3.75 mg, titanium dioxide 1.4556 mg, macrogol 400 0.375 mg, iron oxide yellow dye (iron oxide yellow) 0.357 mg, polysorbate 80 0.060 mg, red iron oxide dye (iron oxide red) 0.0024 mg).

Pregnancy

There have been no adequate and strictly controlled clinical studies on the safety of the drug during pregnancy.
The use of the drug during pregnancy is contraindicated.
There is no data on the excretion of montelukast in human breast milk.
Levocetirizine is excreted in breast milk. Therefore, if it is necessary to use the drug during lactation, it is recommended to stop breastfeeding.

Contraindications

Hypersensitivity to montelukast, levocetirizine (including piperazine derivatives), as well as to other components of the drug;
Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
End-stage renal failure (creatinine clearance below 10 ml/min);
Children under 15 years of age (due to limited data on safety and effectiveness);
Pregnancy and breastfeeding.

With caution
Chronic renal failure (dosage regimen adjustment required); old age (possibly decreased glomerular filtration rate); patients with spinal cord injury, prostatic hyperplasia, or other predisposing factors to urinary retention, since levocetirizine may increase the risk of urinary retention; when used simultaneously with alcohol (see section “Interaction with other drugs”).

Side Effects

The adverse events listed below are distributed according to the frequency of occurrence according to the following gradation: very often (≥ 1/10), often (from ≥ 1/100 to < 1/10), infrequently (from ≥ 1/1000 to < 1/100), rarely (from ≥ 1/10000 to < 1/1000), very rarely (< 1/10000), frequency unknown (frequency cannot be calculated from available data).Montelukast
Disorders of the blood and lymphatic system: frequency unknown – increased tendency to bleeding, thrombocytopenia.
Immune system disorders: rarely – hypersensitivity reaction, including anaphylaxis, very rarely – eosinophilic infiltration of the liver.
Mental disorders: frequency unknown – agitation, including aggressive behavior or hostility, anxiety, depression, disorientation, pathological dreams, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thoughts and behavior (suicidality), tremor, attention and memory disorders.
Nervous system disorders: rarely – headache, dizziness, drowsiness; very rarely – convulsions; frequency unknown – paresthesia/hypoesthesia.
Cardiac disorders: frequency unknown – palpitations.
Disorders of the respiratory system, chest and mediastinal organs: rarely – nosebleeds, frequency unknown – upper respiratory tract infections, pharyngitis, cough, sinusitis, rhinorrhea, Churg-Strauss syndrome.
Gastrointestinal disorders: rarely – heartburn, belching, abdominal pain; frequency unknown – diarrhea, vomiting, dyspepsia, nausea, constipation, pancreatitis, dry mouth.
Disorders of the liver and biliary tract: rarely – increased activity of “liver” transaminases in the blood serum (alanine aminotransferase (ALT), aspartate aminotransferase (AST)), very rarely – hepatitis (including cholestatic, hepatocellular and mixed liver lesions).
Disorders of the skin and subcutaneous tissues: rarely – skin rash, urticaria; frequency unknown – angioedema, the appearance of ecchymosis, erythema nodosum, erythema multiforme, pruritus.
Musculoskeletal and connective tissue disorders: rarely – arthralgia; frequency unknown – myalgia, including muscle spasms.
Renal and urinary tract disorders: frequency unknown – enuresis in children.
General disorders and disorders at the injection site: rarely – asthenia (weakness)/fatigue; frequency unknown – edema, pyrexia, thirst.

Levocetirizine
Immune system disorders: frequency unknown – hypersensitivity reactions, including anaphylactic reactions.
Metabolic and nutritional disorders: frequency unknown – increased appetite, increased body weight.
Mental disorders: often – headache, drowsiness, fatigue; infrequently – asthenia; frequency unknown – anxiety, aggression, agitation, insomnia, hallucinations, depression, suicidal thoughts.
Nervous system disorders: frequency unknown – convulsions, dural sinus thrombosis, paresthesia, dizziness, fainting, tremor, dysgeusia (taste disturbance).
Visual disorders: frequency unknown – visual impairment, diplopia, inflammation, blurred vision.
Hearing and labyrinthine disorders: frequency unknown – vertigo.
Cardiac disorders: frequency unknown – tachycardia, angina pectoris, palpitations.
Vascular disorders: frequency unknown – jugular vein thrombosis.
Disorders of the respiratory system, chest and mediastinal organs: frequency unknown – dyspnea, increased symptoms of rhinitis.
Gastrointestinal disorders: often – dry mouth; infrequently – abdominal pain; frequency unknown – nausea, diarrhea, vomiting.
Disorders of the liver and biliary tract: frequency unknown – hepatitis.
Skin and subcutaneous tissue disorders: frequency unknown – angioedema, drug-resistant erythema, rash, itching, urticaria, hypotrichosis, fissures, photosensitivity.
Musculoskeletal and connective tissue disorders: frequency unknown – muscle pain, arthralgia.
Renal and urinary tract disorders: frequency unknown – dysuria, urinary retention, urge to urinate.
Laboratory and instrumental data: frequency unknown – changes in liver function tests.
Other: frequency unknown – cross-reactivity, peripheral edema.
If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Interaction

Montelukast
Montelukast can be prescribed together with other drugs traditionally used for the prevention and long-term treatment of bronchial asthma and/or allergic rhinitis. The recommended therapeutic dose of montelukast does not have a clinically significant effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisone, oral contraceptives (ethinyl estradiol/norethisterone 35/1), terfenadine, digoxin and warfarin.
The AUC value decreases when taking phenobarbital concomitantly (by approximately 40%), however, no adjustment of the montelukast dosage regimen is required. Since montelukast is metabolized by the CYP3A4 isoenzyme, caution should be exercised if montelukast is co-administered with drugs that induce the CYP3A4 isoenzyme, such as phenytoin, phenobarbital and rifampicin. However, no change in the dose of montelukast is required.
In vitro studies have shown that montelukast is a potential inhibitor of the CYP 2C8 isoenzyme, however, data from clinical drug-drug interaction studies involving montelukast and rosiglitazone (a pre-substrate of medicinal products primarily metabolized by the CYP 2C8 isoenzyme) have shown that doses of montelukast do not inhibit CYP 2C8 isoenzymes in vivo. Therefore, montelukast has no significant effect on the metabolism of drugs metabolized by this enzyme (for example, paclitaxel, rosiglitazone and repaglinide).
Gemfibrozil (an inhibitor of CYP 2C8 and 2C9) increases the effect of systemic exposure to montelukast by 4.4 times. However, the effect of gemfibrozil on the systemic exposure of montelukast may not be considered clinically significant based on safety data at doses of montelukast greater than the approved dose of 10 mg. Therefore, when co-administered with gemfibrozil, no dose adjustment of montelukast is required. Co-administration of itraconazole, a strong CYP3A4 inhibitor, with gemfibrozil and montelukast did not lead to an additional increase in the effect of systemic exposure to montelukast.

Levocetirizine
When studying the drug interactions of cetirizine racemate with phenazone, pseudoephedrine, cimetidine, ketoconazole, erythromycin, azithromycin, glipizide and diazepam, no clinically significant adverse interactions were identified.
Theophylline (400 mg/day) reduces the total clearance of levocetirizine by 16%, while the kinetics of theophylline does not change.
A study with simultaneous administration of ritonavir (600 mg 2 times a day) and cetirizine (10 mg per day) showed that the exposure of cetirizine increased by 40%, and the exposure of ritonavir changed slightly (-11%).
Combined use with macrolides or ketoconazole did not cause significant changes in the ECG.
In some cases, when levocetirizine is used simultaneously with alcohol or drugs that have a suppressive effect on the central nervous system (CNS), their effect on the central nervous system may be enhanced, although it has not been proven that cetirizine racemate potentiates the effect of alcohol.

Overdose

There have been no reports of drug overdose. However, there is evidence of overdose with individual components of the drug.

Montelukast
Symptoms: The most common adverse events were thirst, drowsiness, vomiting, psychomotor agitation, headache and abdominal pain.
Treatment: treatment is symptomatic. There is no information on specific treatment for montelukast overdose. There is no data on the possibility of removing montelukast by peritoneal dialysis and hemodialysis.

Levocetirizine
Symptoms: drowsiness (in adults), agitation and anxiety, followed by drowsiness (in children).
Treatment: gastric lavage, taking activated carbon, symptomatic therapy. There is no specific antidote. Hemodialysis is not effective.

Storage conditions

Storage temperature 2℃ to 25℃

Shelf life

2 years.

Do not use the drug after the expiration date.

Manufacturer

Glenmark Pharmaceuticals Ltd, India