Montemac 5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONTMAK 4 MONTMAK 5

Composition:

Active substance: montelukast;

One chewable tablet contains montelukast sodium equivalent to 4 mg or 5 mg of montelukast;

Excipients: mannite (E 421), microcrystalline cellulose, sodium croscarmellose, hydroxypropylcellulose, aspartame (E 951), cherry flavoring (FL SD No. 594), iron oxide red (E 172), magnesium stearate, disodium edetate.

Pharmaceutical form. Chewable tablets.

Main physicochemical properties:

4 mg tablets: oval, biconvex, uncoated tablets, pink in color with speckles, engraved with «CL 55» on one side and smooth on the other;

5 mg tablets: round, biconvex, uncoated tablets, pink in color with speckles, engraved with «CL 56» on one side and smooth on the other.

Pharmacotherapeutic group.

Agents for systemic use in obstructive respiratory diseases. Leukotriene receptor antagonists. ATC code R03DC03.

Pharmacological properties.

Pharmacodynamics.

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released by various cells, including mast cells and eosinophils.
These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors (CysLT) present in human airways and cause bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil influx. Montelukast is an active compound that binds with high selectivity and chemical affinity to CysLT1 receptors. Montelukast induces significant blockade of airway CysLT, as confirmed by its ability to inhibit LTD4-induced bronchoconstriction in asthmatic patients. Even a low dose of 5 mg causes significant blockade of LTD4-stimulated bronchoconstriction. Montelukast produces bronchodilation within 2 hours after oral administration; this effect is additive to the bronchodilation caused by β-agonists. Treatment with montelukast suppresses both early- and late-phase bronchoconstriction, reducing the response to allergens. Montelukast, compared to placebo, reduces the number of eosinophils in peripheral blood in both adult and pediatric patients. In a separate study, montelukast significantly reduced eosinophil counts in the airways (measured in sputum). In adults and children aged 2 to 14 years, montelukast, compared to placebo, reduces peripheral blood eosinophil counts and improves clinical control of bronchial asthma.

Pharmacokinetics.

Absorption

After oral administration, montelukast is rapidly and almost completely absorbed. Following administration of the 4 mg chewable tablet formulation on an empty stomach, maximum plasma concentration (Cmax) in children aged 2 to 5 years is achieved within 2 hours. Cmax is 66% higher and minimum concentration (Cmin) lower compared to values in adults receiving 10 mg tablets.

Distribution

Over 99% of montelukast is bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 L. In studies using radiolabeled montelukast, penetration across the blood-brain barrier was minimal. In all other tissues, concentrations of radiolabeled material 24 hours after dose administration were also found to be minimal.

Metabolism

Montelukast is extensively metabolized. In studies using therapeutic doses, metabolite concentrations of montelukast in steady-state plasma in adults and children are not detectable.

In vitro studies using human liver microsomes have shown that cytochrome P450 enzymes 3A4, 2A6, and 2C9 are involved in the metabolism of montelukast. At therapeutic concentrations, montelukast does not inhibit cytochrome P450 enzymes 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Excretion

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

Pharmacokinetics in specific patient populations

Dose adjustment is not required for patients with mild to 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 pharmacokinetic profile of montelukast in patients with severe hepatic impairment (Child-Pugh score >9).

Administration of high doses of montelukast (20 and 60 times the recommended adult dose) has been associated with decreased plasma theophylline concentrations. This effect is not observed with the recommended daily dose of 10 mg once daily.

Pharmacokinetic studies have shown that the concentration profiles of 4 mg chewable tablets in children aged 2 to 5 years and 5 mg chewable tablets in children aged 6 to 14 years are comparable to the concentration profile of 10 mg film-coated tablets in adults. The 5 mg chewable tablets should be administered to patients aged 6 to 14 years, and the 4 mg chewable tablets to patients aged 2 to 5 years.

Clinical characteristics.

Indications.

Chewable tablets 4 mg are indicated for children aged 2 to 5 years.

Chewable tablets 5 mg are indicated for children aged 6 to 14 years.

• As add-on therapy for bronchial asthma with mild-to-moderate persistent asthma inadequately controlled by inhaled corticosteroids, and in cases of insufficient clinical control of asthma with short-acting β-agonists used as needed;
• as an alternative to low-dose inhaled corticosteroids for treatment of mild persistent asthma, provided there have been no recent severe asthma attacks requiring oral corticosteroids, and in cases of intolerance to inhaled corticosteroids;
• prevention of bronchial asthma in which exercise-induced bronchospasm is the predominant component;
• relief of symptoms of seasonal and perennial allergic rhinitis; the risk of developing neuropsychiatric symptoms in patients with allergic rhinitis may outweigh the benefit of montelukast use; therefore, the medicinal product should be used as a reserve option for patients with inadequate response or intolerance to alternative therapies.

Contraindications.

Hypersensitivity to any component of the medicinal product. Children under 2 years of age.

Interaction with other medicinal products and other forms of interaction.

Montelukast may be administered concomitantly with other medicinal products commonly used for prevention or long-term treatment of bronchial asthma. 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 concurrently taking phenobarbital, the area under the concentration-time curve (AUC) of montelukast decreased by approximately 40%. Since montelukast is metabolized by CYP 3A4, 2C8, and 2C9, caution is advised—especially in children—when montelukast is administered concomitantly 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 studies involving montelukast and rosiglitazone (a marker substrate 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 shown 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 coadministered 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 studies, clinically significant interactions with weaker inhibitors of CYP 2C8 (e.g., trimethoprim) are not expected. Concomitant administration of montelukast with itraconazole, a strong inhibitor of CYP 3A4, did not result in a significant increase in systemic exposure to montelukast.

Special precautions.

Patients should be advised that montelukast for oral use must never be used for the treatment of acute asthma attacks, and that they should always have a suitable emergency relief medication available. In acute attacks, short-acting inhaled β-agonists should be used. Patients should seek medical advice as soon as possible if they require a greater amount of short-acting β-agonist than usual.

Inhaled or oral corticosteroid therapy should not be abruptly replaced by montelukast therapy.

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

Neuropsychiatric events have been reported in patients taking montelukast. It is unknown whether these events are related to the use of montelukast. Physicians should discuss these adverse events with patients and/or their caregivers. Patients and/or their caregivers should be instructed to report such events to their physician.

In rare cases, patients receiving anti-asthma medications, including montelukast, may develop systemic eosinophilia, sometimes accompanied by clinical signs of vasculitis, known as Churg-Strauss syndrome, which is treated with systemic corticosteroid therapy. Such cases have usually been associated with a reduction in dose or discontinuation of corticosteroid therapy. A connection between leukotriene receptor antagonists and the occurrence of Churg-Strauss syndrome cannot be ruled out or confirmed. Physicians should be aware of the possibility 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.

Treatment with montelukast does not allow patients with aspirin-sensitive asthma to use acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

The product contains aspartame, a source of phenylalanine. For patients with phenylketonuria, it should be noted that 1 tablet of 4 mg contains phenylalanine equivalent to 0.674 mg phenylalanine per dose, and 1 tablet of 5 mg contains phenylalanine equivalent to 0.842 mg phenylalanine per dose.

Use during pregnancy or breastfeeding.

The product is intended for use in children.

Ability to affect reaction speed when driving or operating machinery.

Montelukast is not expected to affect psychomotor reaction speed. However, very rare cases of somnolence or dizziness have been reported.

Method of Administration and Dosage

The medication should be administered to children under adult supervision.

For children aged 2 to 5 years, the recommended dose is one 4 mg chewable tablet taken orally once daily in the evening.

For children aged 6 to 14 years, the recommended dose is one 5 mg chewable tablet taken orally once daily in the evening.

For the treatment of asthma or allergic rhinitis (seasonal or perennial), the medication should be taken 1 hour before or 2 hours after food intake.

For relief of allergic rhinitis symptoms, the timing of administration may be individually adjusted. However, individual dose adjustment within this age group is not required.

General recommendations. The therapeutic effect of the medication on asthma control parameters develops within 1 day. Patients should be advised to continue taking the medication even after achieving asthma control, as well as during periods of exacerbation.

There is no need to adjust the dosage in patients with renal impairment or mild to moderate hepatic impairment. Data regarding patients with severe hepatic impairment are lacking. Dosage recommendations are the same for boys and girls.

As an alternative treatment instead of low-dose inhaled corticosteroids in mild persistent asthma. Montelukast is not recommended as monotherapy for patients with moderate persistent asthma. The use of montelukast as an alternative to low-dose inhaled corticosteroids in children with mild persistent asthma should only be considered for patients who have not recently experienced severe asthma attacks requiring oral corticosteroids and who are unable to use inhaled corticosteroids. Mild persistent asthma is defined as asthma symptoms occurring more than once per week but less than once per day, nocturnal symptoms occurring more than twice per month but less than once per week, and normal lung function between episodes. If adequate asthma control is not achieved, the need for additional or alternative anti-inflammatory therapy should be evaluated subsequently (usually within 1 month), based on a stepwise asthma treatment approach. Patients' asthma control should be regularly assessed.

Prevention of asthma in patients aged 2 to 5 years whose primary component of asthma is exercise-induced bronchospasm. The medicinal product Montemak 4 mg is recommended for patients aged 2 to 5 years for the prevention of exercise-induced bronchospasm, which may be the primary manifestation of persistent asthma requiring inhaled corticosteroids. Patients should be evaluated after 2–4 weeks of treatment with montelukast. If an adequate response is not achieved, additional or alternative therapy should be considered.

Use of the medicinal product in relation to other asthma treatments. When the medicinal product is used as add-on therapy to inhaled corticosteroids, montelukast should not be used to abruptly discontinue inhaled corticosteroids.

Children.

The medication is administered to children aged 2 to 5 years at a dose of 4 mg.

The medication is administered to children aged 6 to 14 years at a dose of 5 mg.

Overdose.

There is no specific antidote for montelukast overdose. In chronic asthma studies, montelukast was administered to adult patients at doses up to 200 mg per day for 22 weeks and up to 900 mg per day for approximately 1 week in short-term studies, without clinically significant adverse reactions.

Cases of acute montelukast overdose have been reported, including ingestion by adults and children at doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). The observed data were consistent with the safety profile in adult and pediatric patients. In most cases, no adverse reactions were reported. The most commonly observed adverse reactions were consistent with the known safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

It is unknown whether montelukast is removed by peritoneal dialysis or hemodialysis. Treatment is symptomatic.

Side effects.

Infections and infestations: upper respiratory tract infections.

Nervous system disorders: lethargy, dizziness, paresthesia/hypoesthesia, seizures, headache.

Gastrointestinal disorders: diarrhea, dry mouth, dyspepsia, nausea, vomiting, abdominal pain, thirst.

Blood and lymphatic system disorders: tendency to increased bleeding, thrombocytopenia.

Immune system disorders: hypersensitivity reactions, including anaphylaxis; eosinophilic infiltration of the liver.

Psychiatric disorders: sleep disorders, including nightmares, insomnia, somnambulism, anxiety, agitation, including aggressive behavior or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremor), attention disturbances, memory impairment, hallucinations, disorientation, suicidal thoughts and behavior (suicidality), tic, obsessive-compulsive disorders, dysphemia.

Cardiac disorders: palpitations.

Respiratory system disorders: epistaxis, Churg-Strauss syndrome, pulmonary eosinophilia.

Hepatobiliary disorders: increased serum transaminase levels (ALT, AST); hepatitis, including cholestatic, hepatocellular, and mixed liver injury.

Skin and subcutaneous tissue disorders: angioneurotic edema, hematoma, urticaria, pruritus, erythema nodosum, erythema multiforme, rash.

Musculoskeletal and connective tissue disorders: arthralgia; myalgia, including muscle cramps.

Renal and urinary disorders: enuresis in children.

General disorders: asthenia/fatigue, edema, pyrexia, malaise.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and place of business.

Village Thedda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.