Montelukast-Vertex (Tablets) Instructions for Use

Marketing Authorization Holder

Vertex, JSC (Russia)

ATC Code

R03DC03 (Montelukast)

Active Substance

Montelukast (Rec.INN registered by WHO)

Dosage Form

Montelukast-Vertex

Chewable tablets 5 mg: 10, 14, 15, 28, 30, 56 or 60 pcs.

Dosage Form, Packaging, and Composition

Chewable tablets white or almost white, round, biconvex, with a cherry odor.

Excipients: mannitol – 203.3 mg, microcrystalline cellulose 112 – 81 mg, hypromellose (hydroxypropyl cellulose) – 3 mg, magnesium stearate – 3 mg, cherry flavor – 3 mg, aspartame – 1.5 mg.

5 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
14 pcs. – blister packs (1) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
15 pcs. – blister packs (1) – cardboard packs.
15 pcs. – blister packs (2) – cardboard packs.
15 pcs. – blister packs (4) – cardboard packs.
30 pcs. – blister packs (1) – cardboard packs.
30 pcs. – blister packs (2) – cardboard packs.

Clinical-Pharmacological Group

Leukotriene receptor antagonist. Drug for the treatment of bronchial asthma and allergic rhinitis

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; other systemic agents for the treatment of obstructive airway diseases; leukotriene receptor antagonists

Pharmacological Action

Cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) are potent inflammatory mediators – eicosanoids that are released by various cells, including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene receptors. Cysteinyl leukotriene type 1 receptors (CysLT₁ receptors) are present in human airways (including bronchial smooth muscle cells, macrophages) and other pro-inflammatory cells (including eosinophils and some myeloid stem cells). Cysteinyl leukotrienes correlate with the pathophysiology of bronchial asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchospasm, increased mucus secretion, increased vascular permeability, and increased eosinophil count. In allergic rhinitis, after allergen exposure, cysteinyl leukotrienes are released from pro-inflammatory cells of the nasal mucosa during the early and late phases of the allergic reaction, which manifests as symptoms of allergic rhinitis. Intranasal challenge with cysteinyl leukotrienes has demonstrated increased airway resistance and symptoms of nasal obstruction.

Montelukast is a highly active oral drug that significantly improves inflammation parameters in bronchial asthma. According to biochemical and pharmacological analysis, the drug binds with high selectivity and chemical affinity to CysLT₁ receptors (instead of other pharmacologically important airway receptors, such as prostanoid, cholinergic, or β-adrenergic receptors). Montelukast inhibits the physiological action of cysteinyl leukotrienes LTC₄, LTD₄, LTE₄ by binding to CysLT₁ receptors without exerting an agonist effect on these receptors.

Montelukast inhibits CysLT receptors of the airway epithelium, thereby having the ability to inhibit bronchospasm induced by inhalation of cysteinyl leukotriene LTD₄ in patients with bronchial asthma. A montelukast dose of 5 mg is sufficient to block LTD₄-induced bronchospasm.

Montelukast causes bronchodilation within 2 hours after oral administration and may complement bronchodilation caused by beta₂-adrenergic agonists. The use of montelukast in doses exceeding 10 mg/day, taken as a single dose, does not increase the drug’s efficacy.

Pharmacokinetics

Absorption

Montelukast is rapidly and almost completely absorbed after oral administration. When 5 mg chewable tablets are taken on an empty stomach, C_max in plasma in adults is reached in 2 hours. The mean oral bioavailability is 73%.

Distribution

Montelukast is more than 99% bound to plasma proteins. The V_d of montelukast at steady state averages 8-11 L. Studies in rats with radiolabeled montelukast indicate minimal penetration across the BBB. Furthermore, the concentration of radiolabeled montelukast 24 hours after administration was minimal in all other tissues.

Metabolism

Montelukast is extensively metabolized. In studies of therapeutic doses at steady state in plasma in adults and children, the concentrations of montelukast metabolites are not measurable.

In vitro studies using human liver microsomes have shown that cytochromes P450 3A4, 2C8, and 2C9 are involved in the metabolism of montelukast. Based on further results from in vitro studies in human liver microsomes, the therapeutic plasma concentration of montelukast does not inhibit the cytochrome P450 isoenzymes CYP: 3A4, 2C9, 1A2, 2A6, 2C19, and 2D6.

Excretion

The plasma clearance of montelukast in healthy adults averages 45 ml/min. After oral administration of radiolabeled montelukast, 86% of the amount is excreted via the intestine within 5 days and less than 0.2% via the kidneys, confirming that Montelukast and its metabolites are excreted almost exclusively in the bile. The T_1/2 of montelukast in young healthy adults ranges from 2.7 to 5.5 hours. The pharmacokinetics of montelukast remain almost linear after oral administration of doses above 50 mg. No differences in pharmacokinetics are observed when montelukast is taken in the morning or evening. When taking 10 mg of montelukast daily, there is a moderate (about 14%) accumulation of the active substance in the plasma.

Pharmacokinetics in special patient groups

The pharmacokinetics of montelukast are similar in women and men.

After a single oral dose of 10 mg montelukast, the pharmacokinetic profile and bioavailability are similar in elderly patients and young patients. The T_1/2 of montelukast from plasma is somewhat longer in elderly patients. No dose adjustment of the drug is required in elderly patients.

No clinically significant differences in pharmacokinetic effects were identified in patients of different races.

In patients with mild to moderate hepatic impairment and clinical manifestations of liver cirrhosis, a slowdown in the metabolism of montelukast was noted, accompanied by an increase in AUC of approximately 41% after a single dose of the drug at a dose of 10 mg. The T_1/2 of montelukast in these patients increases somewhat (mean T_1/2 – 7.4 hours). Dose adjustment of montelukast is not required for patients with mild to moderate hepatic impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale).

Since Montelukast and its metabolites are not excreted by the kidneys, the pharmacokinetics of montelukast have not been evaluated in patients with renal impairment. No dose adjustment of the drug is required for this group of patients.

Indications

• Prophylaxis and long-term treatment of bronchial asthma, including prevention of daytime and nighttime symptoms of the disease;
• Treatment of bronchial asthma in patients with hypersensitivity to acetylsalicylic acid;
• Prevention of exercise-induced bronchospasm;
• Relief of daytime and nighttime symptoms of seasonal allergic rhinitis and perennial allergic rhinitis.

ICD codes

Dosage Regimen

Montelukast is taken orally once a day, regardless of meals.

For the treatment of bronchial asthma Montelukast should be taken in the evening. For the treatment of allergic rhinitis Montelukast can be taken at any time of the day.

Children aged 6 to 14 years are prescribed 5 mg once a day. Dose selection for this age group is not required.

The dose for adults and children over 15 years is 10 mg/day.

The therapeutic effect of montelukast on parameters reflecting the course of bronchial asthma develops within the first day. The patient should continue taking the drug both during the period of achieving control of bronchial asthma symptoms and during the period of exacerbation of the disease.

For elderly patients, patients with renal impairment, patients with mild or moderate hepatic impairment, special dose selection is not required.

Montelukast can be added to treatment with bronchodilators and inhaled corticosteroids.

Adverse Reactions

Side effects are usually mild and generally do not require discontinuation of the drug.

Nervous system disorders headache, dizziness, drowsiness, paresthesia/hypoesthesia, seizures.

Cardiovascular system disorders palpitations.

Respiratory system disorders epistaxis, pulmonary eosinophilia.

Psychiatric disorders agitation, including aggressive behavior or hostility, anxiety, depression, disorientation, attention disturbance, abnormal dreams, hallucinations, insomnia, memory impairment, psychomotor hyperactivity (including irritability, restlessness, and tremor), somnambulism, suicidal thoughts and behavior (suicidality).

Gastrointestinal disorders diarrhea, dyspepsia, nausea, vomiting, pancreatitis, abdominal pain.

Hepatobiliary disorders increased ALT and AST activity, hepatitis (including cholestatic, hepatocellular, and mixed liver injury).

Musculoskeletal and connective tissue disorders arthralgia, myalgia, muscle cramps.

Blood and lymphatic system disorders increased bleeding tendency, thrombocytopenia.

Skin and subcutaneous tissue disorders bruising tendency, erythema nodosum, erythema multiforme, pruritus, rash, urticaria, angioedema.

Immune system disorders hypersensitivity reactions, including anaphylaxis, hepatic eosinophilic infiltration.

Infections and infestations upper respiratory tract infections.

General disorders and administration site conditions asthenia (weakness)/fatigue, edema, pyrexia.

Contraindications

• Hypersensitivity to any component of the drug;
• Children under 6 years of age;
• Phenylketonuria.

Use in Pregnancy and Lactation

No clinical studies of montelukast involving pregnant women have been conducted. Montelukast should be used during pregnancy and breastfeeding only if the expected benefit to the mother outweighs the potential risk to the fetus or infant. Post-marketing use of montelukast has reported the development of limb defects in newborns whose mothers took Montelukast during pregnancy. Most of these women also took other medications for the treatment of bronchial asthma during pregnancy. A causal relationship between the use of montelukast and the development of limb defects has not been established.

It is not known whether Montelukast is excreted in breast milk. Since many drugs are excreted in breast milk, this should be considered when prescribing montelukast to breastfeeding women.

Use in Hepatic Impairment

For patients with mild or moderate hepatic impairment, special dose selection is not required.

There are no data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale).

Use in Renal Impairment

For patients with renal impairment, special dose selection is not required.

Pediatric Use

Use in children under 6 years of age is prohibited.

Geriatric Use

For elderly patients, special dose selection is not required.

Special Precautions

The efficacy of oral montelukast for the treatment of acute attacks of bronchial asthma has not been established. Therefore, Montelukast tablets are not recommended for the treatment of acute attacks of bronchial asthma. Patients should be instructed to always have emergency medication for the relief of asthma attacks (short-acting inhaled beta₂-agonists) with them.

Montelukast should not be discontinued during an exacerbation of bronchial asthma. It should be remembered that it is necessary to use emergency medications to relieve attacks (short-acting inhaled beta₂-agonists).

Patients with confirmed allergy to acetylsalicylic acid and other NSAIDs should not take these drugs during treatment with montelukast, since Montelukast, while improving respiratory function in patients with allergic bronchial asthma, nevertheless cannot completely prevent NSAID-induced bronchoconstriction in them.

The dose of inhaled or oral corticosteroids taken during treatment with montelukast can be gradually reduced under medical supervision. However, corticosteroids should not be abruptly replaced with montelukast. Neuropsychiatric disorders have been described in patients taking Montelukast (see section “Adverse Reactions”). Given that these symptoms could have been caused by other factors, it is not known whether they are related to the use of montelukast. The physician should discuss this adverse event with patients and/or their parents/caregivers. Patients and/or their parents/caregivers should be advised that if such symptoms occur, they should inform their doctor.

In rare cases, patients receiving anti-asthmatic drugs, including leukotriene receptor antagonists, experienced one or more of the following adverse events: eosinophilia, rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy, sometimes diagnosed as Churg-Strauss syndrome, a systemic eosinophilic vasculitis. These cases were sometimes associated with a reduction in dose or withdrawal of oral corticosteroid therapy. Although a causal relationship between these adverse events and leukotriene receptor antagonist therapy has not been established, caution should be exercised and appropriate clinical monitoring should be carried out in patients taking Montelukast.

Patients with phenylketonuria should be informed that each chewable tablet contains aspartame in an amount equivalent to 0.842 mg of phenylalanine. Montelukast in the form of 5 mg chewable tablets should not be taken by patients with phenylketonuria.

Effect on ability to drive vehicles and operate machinery

No data have been identified indicating that taking montelukast affects the ability to drive a car or operate moving machinery. However, side effects such as dizziness and drowsiness may occur when using the drug. In view of this, caution should be exercised when driving vehicles and performing activities that require quick psychomotor reactions.

Drug Interactions

Montelukast can be prescribed concomitantly with other drugs commonly used for the prophylaxis and long-term treatment of bronchial asthma and/or the treatment of allergic rhinitis. The recommended therapeutic dose of montelukast did not have a clinically significant effect on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethisterone 35/1), terfenadine, digoxin, and warfarin. The AUC value of montelukast decreases when taken concomitantly with phenobarbital by approximately 40%, but this does not require a change in the montelukast dosing regimen.

In vitro studies have established that Montelukast inhibits the cytochrome P450 system isoenzyme CYP2C8; however, in an in vivo drug interaction study of montelukast and rosiglitazone (metabolized by the cytochrome system isoenzyme CYP2C8), no confirmation of inhibition of the CYP2C8 isoenzyme by montelukast was obtained. Therefore, in clinical practice, no effect of montelukast on CYP2C8-mediated metabolism of a number of drugs, including paclitaxel, rosiglitazone, repaglinide, and others, is expected.

In vitro studies have shown that Montelukast is a substrate of the CYP2C8, 2C9, and 3A4 isoenzymes. Data from a clinical drug interaction study regarding montelukast and gemfibrozil (an inhibitor of both CYP2C8 and 2C9) demonstrate that gemfibrozil increases the systemic exposure effect of montelukast by 4.4 times. Concomitant administration of itraconazole, a strong inhibitor of the CYP3A4 isoenzyme, together with gemfibrozil and montelukast did not lead to an additional increase in the systemic exposure effect of montelukast. The effect of gemfibrozil on the systemic exposure of montelukast cannot be considered clinically significant based on safety data from the use of doses exceeding the approved 10 mg dose for adult patients (for example, 200 mg/day for adult patients for 22 weeks and up to 900 mg/day for patients taking the drug for about one week, no clinically significant adverse effects were observed). Therefore, when taken concomitantly with gemfibrozil, no dose adjustment of montelukast is required. Based on in vitro studies, no clinically significant drug interaction with other known inhibitors of the CYP2C8 isoenzyme (e.g., trimethoprim) is expected. Furthermore, concomitant administration of montelukast with itraconazole alone did not lead to a significant increase in the systemic exposure effect of montelukast.

Combination Treatment with Bronchodilators

Montelukast is a justified addition to monotherapy with bronchodilators if the latter do not provide adequate control of bronchial asthma.

Once a therapeutic effect is achieved with Montelukast therapy, a gradual reduction in the dose of bronchodilators can be initiated.

Combination Treatment with Inhaled Corticosteroids

Treatment with Montelukast provides an additional therapeutic effect for patients using inhaled corticosteroids.

After the patient’s condition has stabilized, a gradual reduction in the dose of corticosteroids can be initiated under medical supervision.

In some cases, complete discontinuation of inhaled corticosteroids is permissible; however, an abrupt replacement of inhaled corticosteroids with Montelukast is not recommended.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.