Milucant

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MİLUKANTE (MILUKANTE)

Composition:

Active substance: montelukast sodium;

1 tablet contains 5.20 mg of montelukast sodium equivalent to 5 mg of montelukast;

Excipients: microcrystalline cellulose, mannite (E 421), crospovidone, iron oxide red (E 172), hydroxypropylcellulose, disodium edetate, cherry flavor, aspartame (E 951), talc, magnesium stearate.

Pharmaceutical form. Chewable tablets.

Main physicochemical characteristics: pink, round, biconvex tablets.

Pharmacotherapeutic group. Antiasthmatic agents. Selective oral leukotriene receptor antagonists. ATC code R03DC03.

Pharmacological Properties.

Pharmacodynamics.

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 receptors (CysLT) present in human airways and are responsible for bronchoconstriction, mucus secretion, vascular permeability, and increased eosinophil recruitment. CysLTs are implicated in the pathophysiology of asthma and allergic rhinitis. In allergic rhinitis, cysteinyl leukotrienes are released in nasal secretions following allergen exposure during both early and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction.

Montelukast is an orally active compound that binds with high affinity and selectivity to CysLT1 receptors. Montelukast produces significant blockade of cysteinyl leukotriene receptors in the airways, as demonstrated by its ability to inhibit LTD4-induced bronchoconstriction in patients with asthma.

Montelukast inhibits bronchoconstriction induced by inhaled LTD4 even at doses as low as 5 mg. Bronchodilation is observed within 2 hours after oral administration. The bronchodilatory effect of β-agonists is additive to the effect produced by montelukast. Treatment with montelukast inhibits both early and late phases of bronchoconstriction following antigen challenge. Montelukast treatment significantly reduces the number of eosinophils in the airways (measured in sputum). Montelukast also reduces eosinophil counts in peripheral blood in both adults and children aged 2 to 14 years and improves clinical asthma control.

In a study involving children aged 6 to 14 years, montelukast at a dose of 5 mg significantly improved respiratory function and reduced the frequency of as-needed β-agonist use.

In a comparative study of montelukast versus inhaled fluticasone for asthma control in children aged 6 to 14 years with mild persistent asthma, montelukast was shown to be at least as effective as fluticasone in increasing the number of days without the need for short-acting rescue medication.

A significant reduction in exercise-induced bronchoconstriction (EIB) was demonstrated in studies in adults. 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. The effect in both studies was demonstrated at the end of the dosing interval.

Pharmacokinetics.

Absorption.

Montelukast is rapidly and almost completely absorbed after oral administration. Following administration of 5 mg chewable tablets on an empty stomach to children aged 5 to 14 years, Cmax is achieved within 2 hours after dosing. Bioavailability is 73% and decreases to 63% when taken with a standard meal.

Distribution.

More than 99% of montelukast is bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8–11 L. Studies with radiolabeled montelukast have shown minimal distribution across the blood-brain barrier. Additionally, concentrations of radiolabeled material in all other tissues 24 hours after administration were minimal.

Metabolism.

Montelukast is almost entirely metabolized. In studies of therapeutic doses, plasma concentrations of montelukast metabolites in adults and children at steady state were undetectable. In vitro studies using human liver microsomes have shown that cytochrome P450 enzymes 3A4, 2A6, and 2C9 are involved in the metabolism of montelukast. Based on further in vitro testing using human liver microsomes, 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.

Excretion.

Plasma clearance of montelukast averages 45 mL/min in healthy adult subjects.

After oral administration, approximately 86% of radiolabeled montelukast is excreted in feces within 5 days, with less than 0.2% excreted in urine. Given the bioavailability and elimination characteristics, it can be concluded that montelukast and its metabolites are almost entirely eliminated via bile.

Pharmacokinetics in Specific Patient Populations.

Dose adjustment is not required for elderly patients or patients with mild to moderate hepatic impairment. Since montelukast and its metabolites are almost entirely eliminated via bile, dose adjustment is not necessary in patients with renal impairment. Data on the pharmacokinetics of montelukast in patients with severe hepatic impairment are not available.

Pharmacokinetic studies in adults and children have shown that the concentration profiles of 4 mg chewable tablets in children aged 2–5 years and 5 mg chewable tablets in children aged 6–14 years are similar to the concentration profile of 10 mg film-coated tablets administered to adolescents aged 15 years and older and adults.

Decreased plasma theophylline concentrations have been observed following administration of high doses of montelukast (20–60 times the therapeutic dose). This effect has not been observed with therapeutic doses (10 mg once daily).

Clinical characteristics.

Indications.

For children aged 6 to 14 years:

• As add-on therapy for bronchial 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-agonists as needed.
• As an alternative treatment option instead of low-dose inhaled corticosteroids for 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 "Dosage and administration").
• Prevention of asthma in which bronchospasm induced by physical exertion is the predominant component.
• Relief of symptoms of seasonal and perennial allergic rhinitis.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients. Children under 6 years of age.

Interaction with other medicinal products and other forms of interaction.

Montelukast may be administered concomitantly with other medications used for the prevention and chronic treatment of asthma. In drug interaction studies, the recommended clinical dose of montelukast did not have a clinically significant effect on the pharmacokinetics of the following agents: theophylline, prednisolone, oral contraceptives (ethinylestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

The area under the concentration-time curve (AUC) for montelukast decreased by approximately 40% in subjects who concurrently received phenobarbital. Montelukast is metabolized by CYP 3A4, 2C8, and 2C9; therefore, caution should be exercised, especially in children, when prescribing it 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 data for montelukast and rosiglitazone (a marker substrate representing drugs primarily metabolized by CYP 2C8) demonstrated that montelukast does not inhibit CYP 2C8 in vivo. Therefore, montelukast is not expected to significantly alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

In vitro studies indicate that montelukast is a substrate of CYP 2C8, and to a lesser extent, of CYP 2C9 and 3A4. In a clinical drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9), gemfibrozil increased the systemic exposure to montelukast by 4.4-fold. Dose adjustment of montelukast is generally not required when coadministered with gemfibrozil or other potent CYP 2C8 inhibitors; however, in such cases, physicians should consider the potential for increased adverse reactions.

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

Special precautions for use.

Patients should be warned not to use Miluquant for the treatment of acute asthma attacks and to keep readily available their usual rescue medications for such cases. In the event of an acute attack, short-acting inhaled β-agonists should be used. Patients should consult their physician as soon as possible if they require more frequent use of short-acting inhaled β-agonists than usual.

Montelukast should not be introduced abruptly to replace inhaled or oral corticosteroid therapy. There are no data to suggest that oral corticosteroid dosage can be reduced when montelukast is co-administered.

Psychoneuropsychiatric reactions have been reported in adults, adolescents, and children taking montelukast (see section "Adverse reactions"). Patients and physicians should be alert to such psychoneuropsychiatric reactions. Patients and/or their caregivers should be instructed to inform their physician if such reactions occur. Physicians should carefully evaluate the risks and benefits of continuing Miluquant treatment if such reactions develop.

Rarely, patients receiving anti-asthma medications, including montelukast, may develop systemic eosinophilia, sometimes accompanied by clinical features of vasculitis—so-called Churg-Strauss syndrome, a condition requiring systemic corticosteroid therapy. These cases typically occur in association with reduction or withdrawal of oral corticosteroid therapy. A possible association between leukotriene receptor antagonists and the development of Churg-Strauss syndrome cannot be ruled out. Therefore, physicians should be alerted to the possibility of eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy in patients. Patients who develop the aforementioned symptoms should undergo re-evaluation and their treatment regimen should be reviewed.

Treatment with montelukast does not alter the necessity of avoiding aspirin and other nonsteroidal anti-inflammatory drugs in patients with aspirin-sensitive asthma.

Miluquant 5 mg chewable tablets contain aspartame, a source of phenylalanine. This may be harmful to patients with phenylketonuria. Patients with phenylketonuria should be advised that one 5 mg chewable tablet contains phenylalanine equivalent to 0.842 mg per dose.

Neuropsychiatric events such as behavioral changes, depression, and suicidal ideation have been reported in patients of all age groups taking montelukast (see section "Adverse reactions"). Symptoms may be severe and persist if treatment is not discontinued. Therefore, if neuropsychiatric symptoms occur, montelukast should be discontinued.

Patients and/or their caregivers should be cautious regarding neuropsychiatric events and should inform their physician if such behavioral changes occur.

Use during pregnancy or breastfeeding.

Pregnancy.

Animal studies have not shown any harmful effects of montelukast on pregnancy or embryonal/fetal development.

Limited data from existing pregnancy registries do not suggest a causal relationship between montelukast and congenital malformations (such as limb defects), which have been rarely reported in post-marketing surveillance worldwide. Most of these women were also taking other asthma medications. A causal relationship between these cases and montelukast use has not been established.

Data from published and retrospective cohort studies evaluating significant congenital malformations in children of pregnant women treated with montelukast have not shown an increased risk associated with the use of the drug. However, these studies have methodological limitations, including small sample size, retrospective data collection in some cases, and non-comparable control groups.

When prescribing Miluquant to pregnant women, the benefit-risk balance should be carefully considered.

Breastfeeding.

Studies in rats have shown that montelukast passes into breast milk.

There are no data on the passage of Miluquant into human breast milk. Therefore, the benefit-risk balance should be considered when prescribing Miluquant during breastfeeding.

Fertility.

Animal studies have shown that montelukast does not affect fertility or reproductive function at systemic exposures exceeding the clinical systemic exposure by more than 24 times.

Ability to affect reaction speed when driving or operating machinery.

Generally, Miluquant does not affect the ability to drive or operate machinery. However, very rare cases of somnolence or dizziness have been reported in patients taking the medicinal product. Therefore, patients should refrain from driving or operating machinery while taking this medication.

Method of Administration and Dosage

The tablet should be chewed before swallowing.

For patients with asthma and allergic rhinitis (seasonal and perennial), the recommended dose is
1 chewable tablet (5 mg) once daily. To alleviate symptoms of allergic rhinitis, the time of administration should be individually adjusted.

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

General Recommendations for Drug Use

The therapeutic effect of Montelukast on asthma control is observed within 1 day. Patients should be advised to continue taking Montelukast even when asthma is under control, as well as during asthma exacerbations.

Dosage adjustment is not required for patients with renal impairment or mild to moderate hepatic impairment. There are no data regarding dosage adjustment in patients with severe hepatic impairment. Dosage is the same for male and female patients.

Montelukast as an Alternative Treatment to Low-Dose Inhaled Corticosteroids in Mild Persistent Asthma

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

Treatment with Montelukast Compared to Other Treatment Approaches

When Montelukast is used as add-on therapy to inhaled corticosteroids, it must not be abruptly substituted for inhaled corticosteroids.

Children. Montelukast 5 mg chewable tablets are indicated for use in children aged 6 to 14 years.

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 1 week, without clinically significant adverse reactions.

During post-marketing use and clinical trials, reports of acute overdose have been received, including cases of ingestion by adults and children at doses exceeding 1000 mg (approximately 61 mg/kg in a 42-month-old child). In most reported overdose cases, no adverse events were observed. The most common adverse effects were consistent with the drug's safety profile and included: abdominal pain, drowsiness, thirst, headache, vomiting, and psychomotor hyperactivity. Treatment is symptomatic. It is unknown whether montelukast is removed by peritoneal dialysis or hemodialysis.

Adverse Reactions

Milucant is generally well tolerated. Long-term treatment across various age groups in clinical studies has demonstrated a consistent safety profile.

Infections and infestations: Upper respiratory tract infections.

Blood and lymphatic system disorders: Tendency towards increased bleeding, thrombocytopenia.

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

Psychiatric disorders: Attention disturbances, memory impairment, sleep disorders, including nightmares, insomnia, somnambulism, irritability, anger, impatience, anxiety, agitation, including aggressive behavior or hostility, depression, tremor, very rare hallucinations, disorientation, suicidal ideation and behavior (suicide attempt), dysphemia, obsessive-compulsive disorders.

Nervous system disorders: Dizziness and lethargy, somnolence, paraesthesia/hypoaesthesia, seizures, headache.

Cardiac disorders: Palpitations.

Respiratory, thoracic and mediastinal disorders: Epistaxis, Churg–Strauss syndrome (CSS) (see section "Special precautions for use"), pulmonary eosinophilia.

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

Hepatobiliary disorders: Increased serum transaminase levels (alanine aminotransferase and aspartate aminotransferase), hepatitis including cholestatic, hepatocellular, and mixed types, liver damage.

Renal and urinary disorders: Enuresis in children.

Skin and subcutaneous tissue disorders: Angioneurotic edema, bruising, urticaria, pruritus, rash, erythema nodosum, erythema multiforme.

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

General disorders and administration site conditions: Fever, asthenia/fatigue, discomfort, edema, thirst.

Shelf life

2 years.

Storage conditions

Store in the original packaging, in a place inaccessible to children.

Packaging

7 tablets per blister. 4 or 12 blisters per cardboard box.

Prescription category
By prescription only.

Manufacturer

Adamed Pharma Ltd., Poland

Manufacturer's address

5 J. Pilsudskiego Marsh. St., 95-200 Pabianice, Poland