Milucant

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

Composition:

Active substance: montelukast sodium;

1 tablet contains 10.4 mg of montelukast sodium equivalent to 10 mg of montelukast;

Excipients: microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, disodium edetate, magnesium stearate; coating: Opadry® Yellow 20A82938 (hypromellose 6 cP, hydroxypropyl cellulose, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: beige, round, biconvex film-coated 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 key 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 from the nasal mucosa following allergen exposure during both early and late phases of the reaction 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 confirmed 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 a β-agonist is additive to the effect produced by montelukast. Treatment with montelukast inhibits both early and late phases of antigen-induced bronchoconstriction. Montelukast reduces the number of eosinophils in peripheral blood. Treatment with montelukast significantly reduces eosinophil counts in the airways (measured in sputum) and in peripheral blood, correlating with improved clinical control of asthma.

In studies involving adults, montelukast at a dose of 10 mg demonstrated significant improvement in morning FEV1, morning peak expiratory flow rate, and a statistically significant reduction in overall use of β-agonists. Improvement in patient-reported daytime and nighttime asthma symptoms was significantly greater.

Pharmacokinetics.

Absorption.

Montelukast is rapidly absorbed after oral administration. For the 10 mg film-coated tablets administered under fasting conditions, the mean peak plasma concentration (Cmax) is achieved within 3 hours (Tmax) after dosing in adults under fasted conditions. The average bioavailability is 64% when taken with a standard meal. The average bioavailability and Cmax are not affected by a standard meal. The efficacy and safety of this dosage form have been demonstrated in clinical trials in which the 10 mg film-coated tablets were administered regardless of food intake.

Distribution.

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

Metabolism.

Montelukast is almost completely metabolized. In studies of therapeutic doses, plasma concentrations of montelukast metabolites at steady state in adults and children were not detectable.

In vitro studies using human liver microsomes have shown that cytochrome P450 3A4, 2A6, and 2C9 are involved in the metabolism of montelukast. Based on further in vitro results using human liver microsomes, it has been demonstrated that therapeutic plasma concentrations of montelukast do not inhibit cytochrome P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Elimination.

The mean plasma clearance of montelukast is approximately 45 mL/min in healthy adult subjects.

Following oral administration, 86% of radiolabeled montelukast is excreted in feces within 5 days, and less than 0.2% is excreted in urine. Considering 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 for patients with mild to moderate hepatic impairment. Since montelukast and its metabolites are almost completely eliminated via bile, dose adjustment is not necessary for patients with renal impairment. There are no data available regarding the pharmacokinetics of montelukast in patients with severe hepatic impairment.

When high doses of montelukast (20–60 times the therapeutic dose) were administered, a decrease in plasma theophylline concentration was observed. This effect was not observed with therapeutic doses.

Clinical characteristics.

Indications.

• As add-on therapy for bronchial asthma in patients with mild to moderate persistent asthma not adequately controlled by inhaled corticosteroids, and in patients with inadequate clinical control of asthma using short-acting β-adrenoceptor agonists as needed. In patients with asthma receiving Milukant, this medication also relieves symptoms of seasonal allergic rhinitis.
• Prophylaxis of asthma in which exercise-induced bronchospasm 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 of the medicinal product. Age under 15 years.

Interaction with other medicinal products and other types of interactions.

Montelukast may be used concomitantly with other medications 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 drugs: 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 individuals 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 systemic exposure to montelukast by 4.4-fold. Generally, dose adjustment of montelukast is not required when coadministered with gemfibrozil or other potent inhibitors of CYP 2C8; however, in such cases, physicians should consider the potential for increased adverse reactions.

Based on in vitro data, clinically significant drug interactions with less potent inhibitors of CYP 2C8 (e.g., trimethoprim) are not anticipated. 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 advised never to use Miluquant for the treatment of acute asthma attacks and to keep their usual rescue medication readily available 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 β-agonists than usual.

Montelukast should not be introduced as a sudden replacement for inhaled or oral corticosteroid therapy. There are no data to suggest that oral corticosteroid dosage can be reduced when montelukast is administered concomitantly.

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 events. Patients and/or caregivers should be instructed to inform their physician if such reactions occur. Physicians should evaluate the risks and benefits of continuing Miluquant therapy if such reactions arise.

In rare cases, patients treated with anti-asthma medications, including montelukast, may develop systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg–Strauss syndrome, a condition often treated with systemic corticosteroid therapy. These cases have usually, but not always, been associated with reduction or withdrawal of oral corticosteroid therapy. A causal relationship between leukotriene receptor antagonists and the development of Churg–Strauss syndrome cannot be ruled out or confirmed. 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 these symptoms should undergo re-evaluation and their treatment regimen should be reassessed.

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

Miluquant, 10 mg film-coated tablets contain lactose; therefore, patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

The medicinal product contains less than 1 mmol (23 mg) of sodium per tablet; therefore, it is essentially sodium-free.

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

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

Use during pregnancy or breastfeeding.

Pregnancy.

Studies in animals have not shown any harmful effects of montelukast on pregnancy or embryonal/fetal development.

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

Available data from published and retrospective cohort studies evaluating the use of montelukast in pregnant women and major congenital malformations in offspring have not demonstrated a risk associated with the use of the drug. However, these studies have methodological limitations, including small sample sizes, 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 is excreted in breast milk.

There are no data on the excretion of Miluquant into human breast milk during lactation; therefore, the benefit–risk balance should be considered when prescribing Miluquant during breastfeeding.

Fertility.

In animal studies, montelukast did not affect fertility or reproductive function at systemic exposures exceeding 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, somnolence and dizziness have been reported very rarely in patients taking the medicinal product. Therefore, patients should refrain from driving or operating machinery while taking this medicine.

Method of Administration and Dosage

The recommended dose for patients (aged 15 years and older) with asthma or asthma with concomitant seasonal allergic rhinitis is 10 mg (1 tablet) once daily in the evening. To alleviate symptoms of allergic rhinitis, the time of administration should be individually adjusted.

Dose adjustment is not required in patients with mild or moderate hepatic impairment. Data regarding dose adjustment in patients with severe hepatic impairment are lacking. Dose adjustment is not necessary for elderly patients.

General Recommendations

The therapeutic effect of Montelukast in terms of asthma control is observed within 24 hours. The drug may be taken independently of meals. Patients should be advised to continue taking the medication regularly, even when asthma is well-controlled, as well as during periods of asthma exacerbation.

Montelukast should not be used concomitantly with other medicinal products containing the same active substance, montelukast.

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

Treatment with Montelukast compared to other asthma therapies

Montelukast may be added to a patient's existing treatment regimen.

Inhaled Corticosteroids

Montelukast treatment may be used as add-on therapy in patients when inhaled corticosteroids together with required short-acting β-agonists do not provide adequate clinical control of asthma.

Inhaled corticosteroids should not be abruptly replaced by Montelukast.

Children

Montelukast 10 mg film-coated tablets are indicated for patients aged 15 years and older. For children under 15 years of age, chewable tablets of 4 mg or 5 mg should be used according to the child's age.

Overdose

There is no specific information regarding the treatment of montelukast overdose. In chronic asthma studies, montelukast was administered to adult patients at doses up to 200 mg/day 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 in adults and children where doses exceeding 1000 mg were taken (approximately 61 mg/kg in a 42-month-old child). In most reported cases of overdose, no adverse events were observed. The most commonly reported adverse effects were consistent with the drug's safety profile and included: abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity. Treatment is symptomatic. It is unknown whether montelukast is removed by peritoneal dialysis or hemodialysis.

Side effects

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

Infections and infestations: upper respiratory tract infections.

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

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

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 rarely – hallucinations, disorientation, suicidal thoughts and behavior (suicide attempt), dysphemia, obsessive-compulsive disorder.

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

Cardiac disorders: palpitations.

Respiratory, thoracic and mediastinal disorders: epistaxis, Churg-Strauss syndrome (see section "Special precautions"), pulmonary eosinophilia.

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

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

Skin and subcutaneous tissue disorders: angioneurotic edema, hematoma, urticaria, pruritus, rash, nodular erythema, 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. Prescription only.

Manufacturer.

"Adamet Pharma" JSC, Poland.

Manufacturer's location and address of its place of business.

5 J. Pilsudskiego Str., 95-200 Pabianice, Poland.