Montelukast-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONTELUKAST-TEVA (MONTELUKAST-TEVA)

Composition:

Active substance: montelukast sodium;

One chewable tablet contains 4 mg or 5 mg of montelukast in the form of montelukast sodium;

Excipients: mannitol (E 421), sodium lauryl sulfate, hydroxypropylcellulose, iron oxide red (E 172), cherry flavoring RHS-143671, aspartame (E 951), sodium starch glycolate (type A), magnesium stearate.

Pharmaceutical form. Chewable tablets.

Main physicochemical properties:

4 mg tablets: pink tablet with specks, triangular-shaped with rounded edges, embossed with "93" on one side and "7424" on the other, without visible cracks or chips;

5 mg tablets: pink tablet with specks, square-shaped, embossed with "93" on one side and "7425" on the other, without visible cracks or chips.

Pharmacotherapeutic group. Drugs for systemic use in obstructive airway 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 responses such as bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil recruitment.

Orally administered montelukast is an active compound that binds with high selectivity and affinity to CysLT1 receptors. In clinical studies, montelukast at a dose of 5 mg inhibits LTD4-induced bronchoconstriction following inhalation. Bronchodilation was observed within 2 hours after oral administration, and this effect was additive to that caused by β-agonists. Montelukast treatment inhibits both early and late phases of bronchoconstriction induced by antigen challenge. Compared to placebo, montelukast reduces peripheral blood eosinophil counts in adult and pediatric patients. In one 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 asthma control.

In studies involving adults, montelukast at a dose of 10 mg once daily demonstrated significant improvement compared to placebo in morning forced expiratory volume in 1 second (FEV1) (change from baseline: 10.4% vs. 2.7%, respectively), morning peak expiratory flow rate (PEFR) (change from baseline: 24.5 L/min vs. 3.3 L/min, respectively), and significantly reduced overall use of β-agonists (change from baseline: –26.1% vs. –4.6%, respectively). Patient-reported daytime and nighttime asthma symptoms improved significantly more than with placebo.

Studies in adults demonstrated that montelukast enhances the clinical effect of inhaled corticosteroids (change from baseline (%) for inhaled beclomethasone with montelukast vs. beclomethasone alone: FEV1: 5.43% vs. 1.04%; β-agonist use: –8.70% vs. 2.64%). Compared to inhaled beclomethasone (200 mcg twice daily, via spacer), montelukast showed a faster initial response, although over a 12-week study, beclomethasone produced a greater mean therapeutic effect (change from baseline for montelukast vs. beclomethasone: FEV1: 7.49% vs. 13.3%; β-agonist use: –28.28% vs. –43.89%). However, a similar clinical response (i.e., improvement in FEV1 of approximately 11% or more from baseline) was achieved in a higher proportion of patients receiving montelukast compared to beclomethasone (50% of patients on beclomethasone vs. 42% on montelukast).

In a 12-week, placebo-controlled study in children aged 2 to 5 years, montelukast 4 mg once daily improved asthma control compared to placebo, regardless of concomitant controller therapy (inhaled/nebulized corticosteroids, inhaled/nebulized sodium cromoglicate). Sixty percent of patients received no other controller therapy. Montelukast improved daytime symptoms (including cough, wheezing, shortness of breath, and activity limitation) and nighttime symptoms compared to placebo. It also reduced the need for rescue β-agonists and emergency use of corticosteroids during asthma exacerbations compared to placebo. Patients receiving montelukast had more asthma symptom-free days than those receiving placebo. Therapeutic effect was achieved after the first dose.

In a 12-month, placebo-controlled study in children aged 2 to 5 years with mild asthma and episodic exacerbations, montelukast 4 mg once daily significantly reduced (p≤0.001) the annual rate of asthma exacerbation episodes (AE) compared to placebo (1.60 AE vs. 2.34 AE, respectively) [AE defined as ≥3 consecutive days of daytime symptoms requiring β-agonists or corticosteroids (oral or inhaled), or hospitalization for asthma treatment]. The percentage reduction in annual AE rate was 31.9%, with 95% CI 16.9, 44.1.

In a placebo-controlled study in children aged 6 months to 5 years with intermittent (but not persistent) asthma, treatment with montelukast was administered for 12 months either as 4 mg once daily or in 12-day courses initiated at the onset of each intermittent symptom episode. No significant difference was observed between patients receiving 4 mg montelukast and those receiving placebo in the number of asthma episodes progressing to an asthma attack (defined as an asthma episode requiring unscheduled physician visit, emergency department visit, or hospitalization; or treatment with oral, intravenous, or intramuscular corticosteroids).

In an 8-week study in children aged 6 to 14 years, montelukast 5 mg once daily significantly improved respiratory function compared to placebo (change from baseline in FEV1: 8.71% vs. 4.16%; change in morning PEFR: 27.9 L/min vs. 17.8 L/min) and reduced the need for rescue β-agonists (change from baseline: –11.7% vs. +8.2%).

In a 12-month comparative efficacy study of montelukast and inhaled fluticasone for asthma control in children aged 6 to 14 years with mild persistent asthma, montelukast was not inferior to fluticasone in increasing the percentage of days without use of rescue medication (primary endpoint). Over the 12-month treatment period, the percentage of days without rescue medication increased from 61.6% to 84.0% in the montelukast group and from 60.9% to 86.7% in the fluticasone group. The between-group difference in least squares (LS) mean percentage increase in days without rescue medication was statistically significant (–2.8 with 95% CI –4.7, –0.9), but within the pre-specified margin for non-inferiority.

Montelukast and fluticasone also improved asthma control on secondary endpoints assessed over the 12-month treatment period.

FEV1 increased from 1.83 L to 2.09 L in the montelukast group and from 1.85 L to 2.14 L in the fluticasone group. The between-group LS mean difference in FEV1 increase was –0.02 L (95% CI –0.06, 0.02). The mean percent increase from baseline predicted FEV1 was 0.6% in the montelukast group and 2.7% in the fluticasone group. The LS mean difference from baseline predicted FEV1 was significant: –2.2% (95% CI –3.6, –0.7).

The percentage of days with β-agonist use decreased from 38.0% to 15.4% in the montelukast group and from 38.5% to 12.8% in the fluticasone group. The between-group LS mean difference in percentage of days with β-agonist use was significant: 2.7 (95% CI 0.9, 4.5).

The proportion of patients experiencing an asthma attack (defined as a period of worsening asthma requiring oral steroids, unscheduled physician visit, emergency care, or hospitalization) was 32.2% in the montelukast group and 25.6% in the fluticasone group; the risk ratio (95% CI) was significant: 1.38 (1.04, 1.84).

The proportion of patients using systemic (mainly oral) corticosteroids during the study period was 17.8% in the montelukast group and 10.5% in the fluticasone group. The between-group LS mean difference was significant: 7.3% (95% CI 2.9, 11.7).

Significant reduction in exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximum decrease in FEV1: 22.33% with montelukast vs. 32.40% with placebo; time to recovery within 5% of baseline FEV1: 44.22 min vs. 60.64 min). This effect was maintained throughout the 12-week study period. Reduction in EIB was also demonstrated in a short-term study in children aged 6 to 14 years (maximum decrease in FEV1: 18.27% vs. 26.11%; time to recovery within 5% of baseline FEV1: 17.76 min vs. 27.98 min). The effect in both studies was demonstrated at the end of the once-daily dosing interval.

In patients with aspirin sensitivity receiving ongoing therapy with inhaled and/or oral corticosteroids, montelukast treatment significantly improved asthma control compared to placebo (change from baseline in FEV1: 8.55% vs. –1.74%; change from baseline in total β-agonist use: –27.78% vs. 2.09%).

Pharmacokinetics.

Absorption. Montelukast is rapidly absorbed after oral administration. Following administration of 10 mg film-coated tablets to adults under fasting conditions, the mean peak plasma concentration (Cmax) is achieved at 3 hours (Tmax). The mean oral bioavailability is 64%. A normal meal does not affect bioavailability or Cmax following oral administration. Safety and efficacy were confirmed in clinical trials with 10 mg film-coated tablets administered regardless of meal timing.

For 5 mg chewable tablets, Cmax in adults is achieved within 2 hours after administration under fasting conditions. The mean oral bioavailability is 73% and decreases to 63% when taken with a standard meal.

After administration of 4 mg chewable tablets under fasting conditions in children aged 2 to 5 years, Cmax is achieved within 2 hours. The mean Cmax is 66% higher, and mean Cmin is lower, than in adults after 10 mg tablet administration.

Distribution. Over 99% of montelukast is protein-bound in plasma. The steady-state volume of distribution averages 8 to 11 liters. In rat studies using radiolabeled montelukast, passage across the blood-brain barrier was minimal. Additionally, concentrations of radiolabeled material in all other tissues 24 hours after dose administration were also minimal.

Metabolism. Montelukast is extensively metabolized. In studies using therapeutic doses, metabolite concentrations in steady-state plasma are not detectable in adults or pediatric patients.

Cytochrome P450 2C8 is the primary enzyme involved in montelukast metabolism. Additionally, CYP 3A4 and 2C9 play minor roles in its metabolism, although itraconazole (a CYP 3A4 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, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Elimination. The 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 Special Populations. Dose adjustment is not required in patients with mild to moderate hepatic impairment. Studies in patients with renal impairment have not been conducted. Since montelukast and its metabolites are excreted via bile, dose adjustment in patients with renal impairment is not considered necessary. Data on the pharmacokinetics of montelukast in patients with severe hepatic impairment (Child-Pugh score >9) are lacking.

When high 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.

Montelukast-Teva chewable tablets 4 mg are recommended for children aged 2 to 5 years;

Montelukast-Teva chewable tablets 5 mg are recommended for children aged 6 to 14 years:

• as add-on therapy for the treatment of asthma in patients with mild to moderate persistent asthma not adequately controlled with inhaled corticosteroids, and in patients with inadequate clinical control of asthma using short-acting β-adrenoceptor agonists on an as-needed basis;
• as an alternative treatment to low-dose inhaled corticosteroids in patients with mild persistent asthma who have not experienced severe asthma attacks requiring oral corticosteroids in the recent past, and who are unable to use inhaled corticosteroids (see section "Method of administration and dosage");
• prevention of asthma with exercise-induced bronchospasm as 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-Teva, therefore Montelukast-Teva should be used as a reserve medication for patients with inadequate response to or intolerance of alternative therapies.

Contraindications.

Hypersensitivity to montelukast or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Montelukast-Teva may be administered concomitantly with other medicinal products commonly used for the prevention or long-term treatment of asthma. In drug interaction studies, the recommended dose of montelukast had no significant clinical 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 was reduced by approximately 40%. Since montelukast is metabolized by CYP 3A4, 2C8, and 2C9, caution should be exercised, 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 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 medicinal products 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, administration of montelukast with gemfibrozil (an inhibitor of CYP 2C8 and 2C9) 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 be aware of the increased risk of adverse reactions.

Based on in vitro studies, clinically significant interactions with less potent 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 for use

Patients should be advised that Montelukast-Teva for oral use is never to be used for the treatment of acute asthma attacks, and that they should always have a suitable emergency medication available. In the event of an acute attack, short-acting inhaled β-agonists should be used. Patients should seek immediate medical advice if they require a greater than usual number of doses of short-acting β-agonists.

Montelukast should not be used to abruptly replace inhaled or oral corticosteroid therapy.

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

In rare cases, systemic eosinophilia has been observed in patients receiving anti-asthma medications, including montelukast, sometimes in association with clinical features of vasculitis, such as Churg-Strauss syndrome, which is treated with systemic corticosteroids. These cases have usually (but not always) been associated with a reduction in dose or discontinuation of corticosteroid therapy. The possibility that leukotriene receptor antagonists may be associated with the occurrence of Churg-Strauss syndrome cannot be definitively ruled out or confirmed. Therefore, physicians should remain vigilant for the emergence of eosinophilia, vasculitic rash, worsening of pulmonary symptoms, or cardiac and/or neuropathic complications in patients. Patients who develop such symptoms should be re-evaluated and their treatment regimen reconsidered.

Treatment with montelukast does not enable patients with aspirin-sensitive asthma to take aspirin or other nonsteroidal anti-inflammatory drugs.

Excipients.

Aspartame. Montelukast-Teva contains aspartame, which is a source of phenylalanine. Patients with phenylketonuria should be advised that each 4 mg or 5 mg chewable tablet of Montelukast-Teva contains 0.5 mg of aspartame.

Sodium. This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e. it is practically sodium-free.

Use in pregnancy or breastfeeding.

Pregnancy. Animal studies have not shown any harmful effects on pregnancy or embryonic/fetal development.
Published data from prospective and retrospective cohort studies on the use of montelukast in pregnant women, assessing major congenital malformations in children, do not indicate an increased risk associated with the use of this medicinal product. However, these studies have methodological limitations, including small sample size, retrospective data collection in some cases, and non-comparable control groups.
Montelukast-Teva may be used during pregnancy only if clearly necessary.

Breastfeeding. Animal studies have shown that montelukast is excreted in milk. It is not known whether montelukast is excreted in human breast milk. Therefore, Montelukast-Teva should be used during breastfeeding only if clearly necessary.

Ability to influence reaction speed when driving or operating machinery.

Montelukast is not expected to affect the ability to drive or operate machinery. However, somnolence and dizziness have been reported very rarely.

Method of Administration and Dosage

The medicinal product should be used in children under adult supervision. The tablets should be chewed before swallowing.

Children aged 2 to 5 years

Patients with asthma and allergic rhinitis (seasonal and perennial) should take 1 chewable tablet of 4 mg once daily. The time of administration for relief of allergic rhinitis symptoms should be individually adjusted.

For treatment of asthma, the dose for children aged 2 to 5 years is 1 chewable tablet (4 mg) daily, taken in the evening. Montelukast-Teva should be taken 1 hour before or 2 hours after food. Dose adjustment is not required for this age group. The medicinal product Montelukast-Teva in the dosage form of chewable tablets (4 mg) is not recommended for children under 2 years of age.

Children aged 6 to 14 years

Patients with asthma and allergic rhinitis (seasonal and perennial) should take 1 chewable tablet of 5 mg once daily. The time of administration for relief of allergic rhinitis symptoms should be individually adjusted.

For treatment of asthma, the dose for children aged 6 to 14 years is 1 chewable tablet (5 mg) daily, taken in the evening. Montelukast-Teva should be taken 1 hour before or 2 hours after food. Dose adjustment is not required for this age group.

Patients aged 15 years and older are recommended to use Montelukast-Teva, film-coated tablets, 10 mg.

General recommendations

The therapeutic effect of the medicinal product Montelukast-Teva on asthma control parameters occurs within 1 day. Patients should continue taking Montelukast-Teva even if their asthma symptoms are under control, as well as during asthma exacerbations.

Special patient groups. Dose adjustment is not required in patients with renal impairment or mild to moderate hepatic impairment. There are no data available for patients with severe hepatic impairment. Dosage of the drug is the same for boys and girls.

As an alternative treatment to low-dose inhaled corticosteroids in mild persistent asthma

Montelukast-Teva 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 be considered only for patients who have not had recent severe asthma attacks requiring oral corticosteroids and who cannot use inhaled corticosteroids (see section "Indications"). Mild persistent asthma is defined as asthma with symptoms more than once a week but less than once a day, nocturnal symptoms more than twice a month but less than once a week, with normal lung function between attacks. If satisfactory control of bronchial asthma is not achieved after treatment (usually within one month), additional or alternative anti-inflammatory therapy based on the stepwise asthma treatment approach should be considered. Patients should also be periodically evaluated for asthma control. If children have difficulty taking the chewable tablet, the medicinal product should be administered in granule form.

Prevention of asthma in patients aged 2 to 5 years in whom the main component of asthma is exercise-induced bronchospasm

Montelukast-Teva is recommended for patients aged 2 to 5 years for the prevention of exercise-induced bronchospasm, which may be the main manifestation of persistent asthma requiring inhaled corticosteroids. Patients should be evaluated after 2–4 weeks of montelukast treatment. If an adequate clinical response to therapy is not achieved, additional or alternative therapy should be considered.

Use of the medicinal product Montelukast-Teva in relation to other asthma treatments

When the medicinal product Montelukast-Teva is used as add-on therapy to inhaled corticosteroids, inhaled corticosteroids should not be abruptly replaced by Montelukast-Teva (see section "Special precautions for use").

Children.

The medicinal product is not recommended for use in children under 2 years of age.

Overdose.

There is no specific information on the treatment of montelukast overdose. In chronic asthma studies, montelukast was administered at doses up to 200 mg/day to adult patients for 22 weeks, and in short-term studies up to 900 mg/day for approximately one week, without clinically significant adverse reactions occurring.

Cases of acute montelukast overdose have been reported during post-marketing use and clinical trials. The drug has been taken by adults and children at doses exceeding 1000 mg (including a case of approximately 61 mg/kg in a 42-month-old child). The observed clinical and laboratory 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 drug's safety profile and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

It is unknown whether montelukast is eliminated by peritoneal dialysis or hemodialysis.

Adverse reactions.

The safety of montelukast was evaluated in clinical studies in patients with persistent asthma:

• 5 mg chewable tablets – studies involving approximately 1750 children aged 6 to 14 years;
• 4 mg chewable tablets – studies involving 851 children aged 2 to 5 years.

The safety of montelukast was also evaluated in clinical studies in patients with intermittent asthma:

• 4 mg granules and chewable tablets – studies involving 1038 children aged 6 months to 5 years.

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

Table 1

During clinical studies with long-term treatment of a limited number of adult patients (for 2 years) and children aged 6–14 years (for 12 months), the safety profile did not change.

A total of 502 children aged 2 to 5 years received montelukast treatment for at least 3 months, 338 for 6 months or longer, and 534 for 12 months or longer. With long-term treatment, the safety profile in these patients remained unchanged.

Post-marketing period

The following adverse reactions have been reported during the post-marketing period. The frequency of adverse reactions is based on data from relevant clinical studies and is classified as follows: 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).

Infections and infestations: very common – upper respiratory tract infection.

Blood and lymphatic system disorders: rare – tendency to bleed; very rare – thrombocytopenia.

Immune system disorders: uncommon – hypersensitivity reactions, including anaphylaxis; very rare – hepatic eosinophilic infiltration.

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

Nervous system disorders: uncommon – dizziness, lethargy, paresthesia/hypoaesthesia, convulsions.

Cardiac disorders: rare – palpitations.

Respiratory, thoracic and mediastinal disorders: uncommon – epistaxis; very rare – Churg-Strauss syndrome (see section "Special precautions for use"), pulmonary eosinophilia.

Gastrointestinal disorders: common – diarrheab, nausea b, vomitingb; uncommon – dry mouth, dyspepsia.

Hepatobiliary disorders: common – increased serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]); very rare – hepatitis (including cholestatic, hepatocellular, and mixed liver injury).

Skin and subcutaneous tissue disorders: common – rashb; uncommon – bruising, urticaria, pruritus; rare – angioneurotic edema; very rare – erythema nodosum, erythema multiforme.

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

Renal and urinary disorders: uncommon – enuresis in children.

General disorders: common – pyrexia b; uncommon – asthenia/fatigue, malaise, edema.

a This adverse reaction was observed at a "very common" frequency in patients receiving montelukast and in patients receiving placebo in clinical studies.

b This adverse reaction was observed at a "common" frequency in patients receiving montelukast and in patients receiving placebo in clinical studies.

c Frequency: "rare".

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging to protect from light, in a place inaccessible to children.

Packaging. 7 tablets per blister, 4 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer. Teva Operations Poland Sp. z o.o.

Manufacturer's address and location of operations.

80 Mogilska Street, 31-546 Kraków, Poland.