Montikop

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONTICOPE (MONTICOPE)

Composition:

Active substances: montelukast sodium, levocetirizine dihydrochloride;

Each tablet contains montelukast sodium equivalent to 10 mg of montelukast and 5 mg of levocetirizine dihydrochloride;

Excipients: microcrystalline cellulose, anhydrous colloidal silicon dioxide, hydroxypropylcellulose, sodium croscarmellose, magnesium stearate, dichloromethane, iron oxide yellow (E 172), butylhydroxytoluene, hypromellose, purified water.

Pharmaceutical form. Tablets.

Main physicochemical properties: Round, biconvex, two-layered tablets, light yellow with speckles on one side and nearly white on the other side, with smooth surface on both sides.

Pharmacotherapeutic group. Medicinal products for the treatment of respiratory diseases. Other drugs for the treatment of obstructive airway diseases for systemic use. Leukotriene receptor antagonists. Montelukast in combination with other agents. ATC code R03DC53.

Pharmacological properties.

Pharmacodynamics.

Levocetirizine

Levocetirizine, the R-enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors. Studies have shown that levocetirizine has high affinity for human H1-receptors (Ki = 3.2 nmol/L). Levocetirizine has an affinity approximately twice that of cetirizine (Ki = 6.3 nmol/L). Levocetirizine dissociates from H1-receptors with a half-life of 115 ± 38 minutes. After single administration, levocetirizine achieves 90% receptor occupancy at 4 hours and 57% at 24 hours.

Pharmacodynamic studies in healthy volunteers have shown that half the dose of levocetirizine has comparable activity to cetirizine in both skin and nasal mucosal responses.

Montelukast

Cysteinyl-leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells, including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl-leukotriene (CysLT) receptors. The CysLT type 1 receptor (CysLT1) is located in human airways, particularly on airway smooth muscle cells and airway macrophages, as well as on other pro-inflammatory cells (including eosinophils and certain myeloid progenitor cells). CysLTs are implicated in the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucus secretion, increased vascular permeability, and increased eosinophil recruitment.

In allergic rhinitis, CysLTs are released from nasal mucosa following allergen exposure during both early and late-phase reactions, contributing to symptoms of allergic rhinitis. Intranasal administration of CysLTs has been shown to increase nasal airway resistance and exacerbate nasal congestion symptoms.

Pharmacodynamic effects

Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor.

In clinical studies, montelukast inhibits LTD4-induced bronchoconstriction at doses starting from 5 mg. Bronchodilation was observed within 2 hours after oral administration. The bronchodilatory effect of β-agonists was additive to that induced by montelukast. Montelukast treatment suppressed both early- and late-phase antigen-induced bronchoconstriction. Montelukast, compared to placebo, reduced the number of eosinophils in peripheral blood in both adult and pediatric patients. In a separate study, montelukast treatment significantly reduced eosinophil counts in the airways (measured in sputum) and in peripheral blood, while improving clinical asthma control.

Pharmacokinetics.

Levocetirizine

The pharmacokinetics of levocetirizine are linear, dose- and time-independent, and show low inter-subject variability. The pharmacokinetic profile of levocetirizine is identical whether administered as a single enantiomer or as part of cetirizine. No chiral inversion occurs during absorption or elimination.

Absorption

Levocetirizine is rapidly and extensively absorbed after oral administration. In adults, maximum plasma concentration (Cmax) is achieved within 0.9 hours after dosing. Steady state is reached within two days. Cmax is typically 270 ng/mL and 308 ng/mL after single and repeated administration of 5 mg once daily, respectively. The extent of absorption is dose-independent and unaffected by food, although Cmax is reduced and delayed when taken with food.

Distribution

There are no data on tissue distribution in humans. Levocetirizine is 90% bound to plasma proteins. Distribution of levocetirizine is limited, with a volume of distribution of 0.4 L/kg.

Biological transformation

The extent of levocetirizine metabolism in humans is less than 14% of the dose; therefore, differences due to genetic polymorphism or concomitant use of enzyme inhibitors are expected to be minimal. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and taurine conjugation. Dealkylation pathways are primarily mediated by CYP3A4, whereas aromatic oxidation involves multiple and/or unidentified CYP isoforms. Levocetirizine did not affect the activity of CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations significantly exceeding peak levels achieved after a 5 mg oral dose.

Due to low metabolism and lack of metabolic inhibition potential, drug interactions involving levocetirizine are unlikely.

Elimination

The plasma elimination half-life in adults is 7.9 ± 1.9 hours. The half-life is shorter in children. The mean apparent total clearance in adults is 0.63 mL/min/kg. The primary route of elimination of levocetirizine and its metabolites is via urine (85.4% of the dose). Fecal excretion accounts for only 12.9% of the dose. Levocetirizine is eliminated by both glomerular filtration and active tubular secretion.

Special populations

Renal impairment

The apparent systemic clearance of levocetirizine correlates with creatinine clearance. Therefore, dosage intervals of levocetirizine should be adjusted according to creatinine clearance in patients with moderate to severe renal impairment. In patients with anuric end-stage renal disease, total clearance is reduced by approximately 80% compared to patients with normal renal function. The amount of levocetirizine removed during a standard 4-hour hemodialysis session is less than 10%.

Montelukast

Absorption

Montelukast is rapidly absorbed after oral administration. In adults, following administration of 10 mg film-coated tablets on an empty stomach, Cmax in plasma is reached within 3 hours (Tmax). The mean oral bioavailability is 64%. A normal meal does not affect the bioavailability or Cmax of orally administered montelukast. Safety and efficacy have been confirmed in clinical trials with 10 mg film-coated tablets administered regardless of meal timing.

Following administration of 5 mg chewable tablets on an empty stomach, Cmax in adults is reached within 2 hours. The mean oral bioavailability is 73% and decreases to 63% when taken with a standard meal.

Distribution

Over 99% of montelukast is bound to plasma proteins. The volume of distribution at steady state averages between 8 and 11 liters. Studies in rats using radiolabeled montelukast showed minimal passage across the blood-brain barrier. Furthermore, concentrations of radiolabeled material in all other tissues 24 hours after dosing were also minimal.

Biological transformation

Montelukast is actively metabolized. In studies using therapeutic doses, plasma concentrations of montelukast metabolites at steady state in adults and pediatric patients were not detectable.

Cytochrome P450 2C8 is the primary enzyme involved in montelukast metabolism. Additionally, cytochromes CYP3A4 and 2C9 play minor roles in its metabolism, although itraconazole (a CYP3A4 inhibitor) did not alter the pharmacokinetic parameters of montelukast in healthy volunteers receiving 10 mg daily. In vitro studies using human liver microsomes indicate that therapeutic plasma concentrations of montelukast do not inhibit cytochrome P450 enzymes 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Elimination

Plasma clearance of montelukast in healthy adult volunteers averages 45 mL/min. After oral administration of radiolabeled montelukast, 86% is excreted in feces within 5 days and less than 0.2% in urine. Combined with oral bioavailability, this indicates that montelukast and its metabolites are almost entirely eliminated via bile.

Pharmacokinetics in different patient groups

Dose adjustment is not required for patients with mild or moderate hepatic impairment. Studies in patients with renal impairment have not been conducted. Since montelukast and its metabolites are eliminated via bile, dose adjustment in patients with renal impairment is not considered necessary. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score > 9).

When large doses of montelukast (20 and 60 times the recommended adult dose) were administered, a decrease in plasma theophylline concentration was observed. This effect is not seen with the recommended dose of 10 mg once daily.

Clinical characteristics.

Indications.

For symptomatic treatment of seasonal and perennial allergic rhinitis.

Contraindications.

Hypersensitivity to montelukast sodium, levocetirizine, cetirizine, hydroxyzine, to any other piperazine derivatives, or to any of the excipients of the medicinal product.

Severe form of chronic renal insufficiency (creatinine clearance < 15 mL/min).

Rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Children under 15 years of age.

Interaction with other medicinal products and other forms of interactions.

Montelukast

In drug interaction studies, the recommended clinical dose of montelukast had no clinically significant effect on the pharmacokinetics of the following medicinal products: theophylline, prednisone, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

In patients taking phenobarbital concomitantly, the area under the concentration-time curve (AUC) of montelukast decreased by approximately 40%. Since montelukast is metabolized via CYP 3A4, 2C8, and 2C9, caution is required, especially in children, when montelukast is coadministered 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 data involving montelukast and rosiglitazone (a marker substrate; a drug metabolized by CYP 2C8) demonstrated that montelukast is not an inhibitor of CYP 2C8 in vivo. Therefore, montelukast does not significantly affect the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

In vitro studies have established that montelukast is a substrate of CYP 2C8 and, to a lesser extent, of CYP 2C9 and 3A4. In a clinical drug interaction study using montelukast and gemfibrozil (an inhibitor of CYP 2C8 and 2C9), gemfibrozil increased systemic exposure to montelukast by 4.4-fold. When montelukast is used concomitantly with gemfibrozil or other potent inhibitors of CYP 2C8, dose adjustment of montelukast is not required, but physicians should consider the increased risk of adverse reactions.

Based on in vitro data, clinically significant interactions with less potent inhibitors of CYP 2C8 (e.g., trimethoprim) are not expected. Concomitant administration of montelukast with itraconazole, a strong CYP 3A4 inhibitor, did not result in a significant increase in systemic exposure to montelukast.

Levocetirizine

Drug interaction studies with levocetirizine (including with CYP3A4 inducers) have not been conducted. Drug interaction studies with cetirizine (the racemic compound) have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not result in clinically significant adverse effects. In a multiple-dose study, concomitant administration with theophylline (400 mg/day) resulted in a slight reduction (by 16%) in the clearance of cetirizine (theophylline distribution was not altered).

In a study of multiple-dose administration of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), exposure to cetirizine increased by approximately 40%, while ritonavir distribution was slightly altered (-11%) with concomitant cetirizine use.

Food intake does not affect the extent of levocetirizine absorption, but coadministration with food reduces the rate of its absorption.

There are no data on the potentiation of sedative effects when used at therapeutic doses. However, concomitant use of sedatives should be avoided during treatment with this medicinal product.

Concomitant use of cetirizine or levocetirizine with alcohol or other CNS depressants in sensitive patients may cause additional impairment of attention and ability to perform tasks.

Special precautions for use.

Montelukast

There are no data confirming that the dose of oral corticosteroids can be reduced when montelukast is used concomitantly.

In isolated cases, systemic eosinophilia has been observed in patients receiving montelukast, sometimes in conjunction with clinical features of vasculitis, known as Churg-Strauss syndrome, which is treated with systemic corticosteroid therapy. Such cases have sometimes been associated with a reduction in dose or discontinuation of corticosteroid treatment. The possibility that leukotriene receptor antagonists may be linked to the emergence of Churg-Strauss syndrome cannot be ruled out or confirmed. Physicians should be aware of the potential for the development of eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy in patients. Patients who develop such symptoms should be re-evaluated and their treatment regimen reviewed.

Psychoneuropsychiatric reactions have been reported in adults and children taking montelukast (see section "Adverse reactions"). Patients and physicians should remain vigilant for signs of psychoneuropsychiatric reactions. Patients and/or their caregivers should be informed of the importance of notifying their physician if such reactions occur. Physicians should carefully evaluate the risks and benefits of continuing the medication if such reactions occur.

Levocetirizine

Use with caution in patients with chronic renal insufficiency (dose adjustment required) and in elderly patients with renal impairment (possible reduction in glomerular filtration rate).

Caution is recommended when using the drug concomitantly with alcohol (see section "Interaction with other medicinal products and other forms of interaction").

The drug should be used with caution in patients with epilepsy or those at risk of seizures, as levocetirizine may lead to seizure exacerbation.

When prescribing the drug to patients with factors predisposing to urinary retention (e.g., spinal cord injury, benign prostatic hyperplasia), it should be noted that levocetirizine increases the risk of urinary retention.

Antihistamines suppress the response to skin allergy testing; drug intake should be discontinued 3 days prior to testing (elimination period).

Pruritus may occur after discontinuation of the drug, even if this symptom was not present before treatment initiation. Symptoms may resolve spontaneously. In some cases, symptoms may be intense and re-initiation of the drug may be required. Symptoms usually resolve after resuming treatment.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

Montelukast

Animal studies have not shown any harmful effects on pregnancy or embryonic/fetal development.

Available data from published prospective and retrospective cohort studies on montelukast use in pregnant women, assessing major congenital malformations in offspring, have not established a risk associated with the use of the drug. However, the existing studies have methodological limitations, including small sample size, retrospective data collection in some cases, and non-comparable control groups. Montelukast may be considered during pregnancy only if clearly needed.

Levocetirizine

Data on the use of levocetirizine in pregnant women are lacking or limited (fewer than 300 pregnancy outcomes). However, for cetirizine, the racemate of levocetirizine, a large amount of data (over 1000 pregnancy outcomes) in pregnant women indicates no evidence of malformative or fetotoxic/neonatal toxicity. Animal studies do not indicate any direct or indirect harmful effects on pregnancy, embryonic/fetal development, labor, or postnatal development. Levocetirizine may be considered during pregnancy if necessary.

Breastfeeding

Montelukast

Studies in rats have shown that montelukast is excreted into milk. It is unknown whether montelukast is excreted in human breast milk. Montelukast may be used during breastfeeding only if it is considered absolutely necessary.

Levocetirizine

Cetirizine, the racemate of levocetirizine, has been shown to be excreted in humans. Therefore, excretion of levocetirizine into human milk is likely. Adverse reactions related to levocetirizine may occur in breastfed infants. Therefore, levocetirizine should be prescribed with caution to breastfeeding women.

Fertility

Levocetirizine

There are no clinical data on the effect of the medicinal product on fertility.

Ability to affect reaction speed when driving vehicles or operating machinery.

Montelukast

Montelukast is not expected to affect a patient's ability to drive vehicles or operate machinery. However, very rare cases of somnolence or dizziness have been reported.

Levocetirizine

Patients should refrain from driving vehicles or operating potentially hazardous machinery during treatment with this medicinal product.

Dosage and Administration.

The dose for patients with allergic rhinitis is 1 tablet per day. The time of administration for alleviating symptoms of allergic rhinitis should be individually adjusted.

Elderly Patients

Elderly patients with normal renal function should receive the usual recommended dose.

Elderly patients with moderate to severe renal impairment (see section "Renal Impairment") should be treated with caution.

Renal Impairment

For patients with impaired renal function, dosage adjustment should be based on the degree of renal impairment (creatinine clearance) according to Table 1.

To determine the dosage, calculate the patient's creatinine clearance (CrCl) in mL/min from serum creatinine concentration (mg/dL) using the following formula:

Table 1

Dosage adjustment for patients with impaired renal function

In children with renal impairment, dosage adjustment should be individualized based on the patient's renal clearance and body weight.

There are no specific data regarding use in children with renal impairment.

Hepatic impairment

Dosage adjustment is not required in patients with hepatic impairment. Patients with both hepatic and renal impairment should have their dosing regimen adjusted according to Table 1 above.

Administration

The tablet should be taken orally, independent of food intake. The tablet must be swallowed whole with a small amount of water.

Children. The medicinal product is indicated for children aged 15 years and older.

Overdose

Published data from clinical studies in chronic asthma showed that montelukast was administered to adult patients at doses up to 200 mg/day for 22 weeks and up to 900 mg/day in short-term studies lasting approximately one week, without clinically significant adverse reactions.

Cases of acute montelukast overdose in adults and children have been reported at doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). The clinical and laboratory findings were consistent with the safety profile observed in adult and pediatric patients. In most cases, no adverse reactions were reported.

Symptoms of montelukast overdose

The most commonly observed adverse reactions include abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity.

Symptoms of levocetirizine overdose

Symptoms of overdose in adults may include drowsiness. In children, initial symptoms may include excitation and increased irritability, followed by drowsiness.

Treatment

There is no specific information available regarding the treatment of montelukast overdose. Data on elimination of montelukast by peritoneal dialysis or hemodialysis are lacking.

There is no specific antidote for levocetirizine. In case of overdose symptoms, symptomatic and supportive therapy is recommended. Gastric lavage may be considered shortly after drug ingestion. Hemodialysis is ineffective for elimination of levocetirizine from the body.

Adverse reactions.

Montelukast

Montelukast was evaluated in clinical trials:

• film-coated tablets, 10 mg – in approximately 4000 patients with asthma aged 15 years and older;
• film-coated tablets, 10 mg – in approximately 400 patients with asthma and seasonal allergic rhinitis aged 15 years and older;
• chewable tablets, 5 mg – in approximately 1750 patients with asthma aged 6 to 14 years.

During clinical trials, the adverse reactions listed below were reported commonly (≥ 1/100 to < 1/10) in patients receiving montelukast treatment and more frequently than in patients receiving placebo.

Table 2

During clinical studies with prolonged treatment of a small number of adult patients over 2 years and children aged 6 to 14 years over 12 months, the safety profile did not change.

Post-marketing period

Adverse reactions reported during the post-marketing period are listed according to system organ classes and using standard terminology in Table 3. Frequencies are based on data from the relevant clinical studies.

Table 3

Levocetirizine

Clinical trials

Adults and children aged 12 years and older

In therapeutic studies involving males and females aged 12 to 71 years, 15.1% of patients in the group receiving 5 mg of levocetirizine experienced at least one adverse drug reaction compared to 11.3% in the placebo group. 91.6% of these adverse drug reactions were of mild to moderate severity.

In therapeutic trials, the discontinuation rate due to adverse reactions was 1.0% (9/935) with 5 mg levocetirizine and 1.8% (14/771) with placebo.

Clinical therapeutic trials with levocetirizine included 935 individuals who received the drug at the recommended dose of 5 mg once daily. Reports of adverse reactions occurring with an incidence of 1% or greater (common: ≥ 1/100 to < 1/10) during treatment with either 5 mg levocetirizine or placebo are presented.

Table 4

Further uncommon adverse reactions (uncommon: ≥ 1/1000 to < 1/100), such as asthenia or abdominal pain, were observed.

The incidence of sedative adverse reactions, such as somnolence, fatigue, and asthenia, was generally higher (8.1%) with 5 mg of levocetirizine than with placebo (3.1%).

Children

In two placebo-controlled trials involving pediatric patients aged 6 to 11 months and aged 1 to 6 years, 159 patients received levocetirizine at a dose of 1.25 mg once daily and 1.25 mg twice daily, respectively, for 2 weeks, while 83 patients received placebo. Adverse reactions listed in Table 5 were reported at a frequency of 1% or more with levocetirizine or placebo.

Table 5

Double-blind, placebo-controlled trials were conducted in children aged 6–12 years, in which 243 children received 5 mg of levocetirizine once daily over variable periods ranging from less than 1 week to 13 weeks. The adverse reactions listed in Table 6 were reported at a frequency of 1% or more with either levocetirizine or placebo.

Table 6

Post-marketing period

Adverse reactions reported during the post-marketing experience are grouped by system organ class and frequency. Frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

• Immune system disorders

Not known: hypersensitivity, including anaphylaxis.

• Metabolism and nutrition disorders

Not known: increased appetite.

• Psychiatric disorders

Not known: aggression, agitation, hallucinations, depression, insomnia, suicidal thoughts, nightmares.

• Nervous system disorders

Not known: seizures, paraesthesia, dizziness, loss of consciousness, tremor, dysgeusia.

• Ear and labyrinth disorders

Not known: vertigo.

• Eye disorders

Not known: visual disturbance, blurred vision, nystagmus.

• Cardiac disorders

Not known: palpitations, tachycardia.

• Respiratory, thoracic and mediastinal disorders

Not known: dyspnoea.

• Gastrointestinal disorders

Not known: nausea, vomiting, diarrhoea.

• Hepatobiliary disorders

Not known: hepatitis.

• Renal and urinary disorders

Not known: dysuria, urinary retention.

• Skin and subcutaneous tissue disorders

Not known: angioedema, fixed drug eruptions, pruritus, rash, urticaria.

• Musculoskeletal and connective tissue disorders

Not known: myalgia, arthralgia.

• General disorders and administration site conditions

Not known: oedema.

• Investigations

Not known: weight increased, abnormal liver function tests.

Description of selected adverse reactions

After discontinuation of levocetirizine, pruritus has been reported.

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C, in a place protected from light and moisture. Keep out of the reach of children.

Packaging. 10 tablets per blister, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Mankind Pharma Limited, Unit-II.

Manufacturer's address and location of operations.

Village Kishanpura, P.O. Jamniwala, Tehsil Paonta Sahib, District Sirmaur 173025, Himachal Pradesh, India.