AIRING - PACKAGE LEAFLET - LEAFLETS

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Airing - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Montelukast

AIRING 4 mg chewable tablets

Airing package inserts are available for pack sizes:

AIRING 4 mg chewable tablets
AIRING 5 mg chewable tablets
AIRING 10 mg film-coated tablets

Indications Why is Airing used? What is it for?

AIRING is a leukotriene receptor antagonist that blocks substances called leukotrienes. Leukotrienes cause the airways in the lungs to narrow and swell. By blocking leukotrienes, AIRING improves the symptoms of asthma and helps to control it.

The doctor prescribed AIRING for the treatment of asthma, to prevent asthma symptoms both during the day and at night.

AIRING is used to treat patients who are not adequately controlled on their medications and need additional medications.
AIRING can also be used as an alternative treatment to inhaled corticosteroids for patients 2 to 5 years of age who have not recently taken oral corticosteroids for asthma and who have been shown to be unable to use corticosteroids for asthma. by inhalation.
AIRING also prevents exercise-induced narrowing of the airways in patients 2 years and older.

Your doctor will determine how to use AIRING depending on the symptoms and severity of your child's asthma.

What is asthma?

Asthma is a long-term disease.

Asthma includes:

Difficulty breathing due to narrowing of the airways. The narrowing of the airways worsens and improves in response to various conditions.
The airways that react to many irritating stimuli, such as cigarette smoke, pollen, cold air, or exercise.
Swelling (inflammation) of the airways.

Symptoms of asthma include: cough, shortness of breath and chest tightness.

Contraindications When Airing should not be used

Do not give your child AIRING if he is allergic (hypersensitive) to montelukast or any of the other ingredients of AIRING (see 6. FURTHER INFORMATION).

Precautions for use What you need to know before taking Airing

Tell your doctor about any current or past illness and any allergies.

Take special care with AIRING

if your asthma or breathing gets worse, contact your doctor immediately.
AIRING by mouth should not be used for the treatment of acute asthma attacks.If seizures occur, follow your doctor's instructions. Always keep your child's emergency inhaled medications for asthma attacks with you.
It is important that your child takes all asthma medications prescribed by the doctor. AIRING should not be used in place of other asthma medicines that your doctor has prescribed for your child.
If your child is taking anti-asthma medications, you should be aware that if he / she has a combination of symptoms such as flu-like syndrome, tingling or decreased touch in the arms or legs, worsening of lung symptoms and / or redness of the skin, they should consult the doctor.
You should not take acetylsalicylic acid (aspirin) or anti-inflammatory drugs (also called non-steroidal anti-inflammatory drugs or NSAIDs) if they worsen asthma.

Use in children

For children 2 to 5 years, AIRING 4 mg chewable tablets are available.

For children 6 to 14 years, AIRING 5 mg chewable tablets are available.

Interactions Which drugs or foods can modify the effect of Airing

Some drugs can interfere with how AIRING works, or AIRING can interfere with how other drugs work.

Tell your doctor if your child is taking or has recently taken any other medicines, even those without a prescription.

Tell your doctor if your child is taking the following medicines before starting AIRING:

Phenobarbital (used to treat epilepsy).
Phenytoin (used to treat epilepsy).
Rifampicin (used to treat tuberculosis and some other infections).

Using AIRING with food and drink

AIRING 4 mg chewable tablets should not be taken immediately before or after meals. It must be taken at least 1 hour before or 2 hours after meals.

Warnings It is important to know that:

Pregnancy and breastfeeding

This section is not applicable because AIRING 4 mg chewable tablets are to be used in children between the ages of 2 and 5 years. However, the following information refers to the active substance, montelukast.

Use in pregnancy

If you are pregnant or would like to become pregnant, you must consult your doctor before taking AIRING. Your doctor will determine if you can or cannot take AIRING under these circumstances.

Use while breastfeeding

It is not known if AIRING can appear in human milk. If you are breast-feeding or planning to breast-feed, you must consult your doctor before taking AIRING.

Driving and using machines

No effects on the ability to drive and use machines are expected.

Individual responses to medications, however, may vary. Some side effects (such as dizziness and somnolence) which have been reported very rarely with AIRING may affect the ability to drive and use machines.

Important information about some of the ingredients of AIRING

AIRING chewable tablets contain aspartame, a source of phenylalanine. If your child has phenylketonuria (a rare inherited disorder of metabolism) please note that the 4 mg chewable tablet contains phenylalanine in an amount equivalent to 0.674 mg of phenylalanine per tablet.

Dose, Method and Time of Administration How to use Airing: Posology

This medicine should be given to the child under adult supervision.
The child should only take one AIRING tablet per day as prescribed by the doctor.
The tablet should also be taken if your child has no symptoms or has an acute asthma attack.
Always take AIRING exactly as your doctor has told you. If in doubt, you should consult your doctor or pharmacist.
Have the tablet taken by mouth.

For children from 2 to 5 years

One 4 mg chewable tablet to be taken every day in the evening. AIRING 4 mg chewable tablets should not be taken immediately before or after meals. It must be taken at least 1 hour before or 2 hours after meals.

If your child is taking AIRING, make sure he does not take other products that contain the same active substance, montelukast.

If you forget to give your child AIRING

Try to take AIRING as it was prescribed. However, if you forget to take a tablet, continue taking the medicine at the usual dosage. Do not give a double dose to make up for a forgotten tablet.

If your child stops taking AIRING

Treatment with AIRING can only be effective against asthma if your child continues to take it. It is important to continue taking AIRING for as long as your doctor has prescribed it. This will help control your baby's asthma.

If you have any further questions on the use of AIRING, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Airing

Consult your doctor immediately. In the majority of overdose reports there were no undesirable effects. Symptoms most frequently reported with overdose in adults and children include abdominal pain, drowsiness, thirst, headache, vomiting and hyperactivity.

Side Effects What are the side effects of Airing

Like all medicines, AIRING can cause side effects, although not everybody gets them.

In clinical trials with montelukast 4 mg chewable tablets, the most commonly reported side effects believed to be related to montelukast (occurring in at least 1 in 100 patients and in less than 1 in 10 pediatric patients treated) were:

abdominal pain
thirst

In addition, the following side effect was reported in clinical studies with montelukast 10 mg film-coated tablets and 5 mg chewable tablets:

headache

These side effects were usually mild and occurred more frequently in patients treated with montelukast than in those treated with placebo (a tablet that contains no drug substance).

The frequency of possible side effects listed below is defined using the following convention:

Very common (affects at least 1 user in 10)
Common (affects 1 to 10 users in 100)
Uncommon (affects 1 to 10 users in 1,000)
Rare (affects 1 to 10 users in 10,000)
Very rare (affects less than 1 user in 10,000)

In addition, the following side effects have been reported with commercial use of the medicine:

upper respiratory tract infection (Very common)
increased bleeding tendency (Rare)
allergic reactions including skin rash, swelling of the face, lips, tongue and / or throat which may cause difficulty in breathing or swallowing (Uncommon)
behavior and mood changes [altered dreams, including nightmares, insomnia, sleepwalking, irritability, feeling anxious, restless, agitation including aggressive behavior or hostility, depression (Uncommon); tremor (Rare); hallucinations, thoughts and actions suicide (Very rare)]
dizziness, somnolence, tingling, convulsions (Uncommon)
palpitations (Rare)
nosebleed (Uncommon)
diarrhea, nausea, vomiting (Common); dry mouth, digestive disturbances (Uncommon)
hepatitis (inflammation of the liver) (Very rare)
bruising, pruritus, urticaria (Uncommon), red painful swelling of the subcutaneous tissue most commonly located on the anterior surface of the legs (erythema nodosum) (Very rare)
joint or muscle pain, muscle cramps (Uncommon)
fever (Common); feeling tired, sick, swollen (Uncommon)

A complex of symptoms such as a flu-like form, tingling or numbness in the arms or legs, worsening of lung symptoms and / or skin rash has been reported in very rare cases during the treatment of asthmatic patients with montelukast. Churg-Strauss). If one or more of these symptoms occur, the patient should stop taking the medicine and contact their doctor immediately.

Ask your doctor or pharmacist for more information on side effects. Report to your doctor or pharmacist any side effects other than those listed above or if any symptoms persist or worsen.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep AIRING out of the reach and sight of children.

Do not use AIRING after the expiry date indicated on the label with the six numbers after the word EXP. The first two numbers indicate the month; the last four indicate the year. The expiry date refers to the last day of the month.

Store at a temperature not exceeding 25 ° C in the original package to protect it from light and moisture.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Other information

What AIRING contains

The active ingredient is montelukast. Each tablet contains montelukast sodium which corresponds to 4 mg of montelukast.
The other ingredients are: Mannitol (E421), microcrystalline cellulose, croscarmellose sodium, red iron oxide (E172), hydroxypropylcellulose, cherry flavor (also contains glycerol triacetate (E1518)), aspartame (E951) and magnesium stearate.

Description of the appearance of AIRING and contents of the package

Box of 28 tablets: 4 blisters of 7 tablets each.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information about Airing can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

AIRING 4 MG

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One chewable tablet contains:

Active ingredient: montelukast sodium, equivalent to 4 mg of montelukast.

Excipient: aspartame (E951) 1.2 mg per tablet.

For the complete list of excipients, see section "List of excipients".

03.0 PHARMACEUTICAL FORM

Chewable tablet.

Pink, rounded, biconvex, 8.5mm in diameter, debossed with "4" on one side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

AIRING is indicated for the treatment of asthma as adjunctive therapy in those patients with persistent mild / moderate asthma who are inadequately controlled with inhaled corticosteroids and in whom short-acting? need "provide inadequate clinical control of asthma.

AIRING may also be an alternative treatment option to low-dose inhaled corticosteroids for patients 2 to 5 years of age with mild persistent asthma who do not have a recent history of serious asthma attacks requiring the use of oral corticosteroids, and who have been shown to be unable to use inhaled corticosteroids (see section "Posology and method of administration").

AIRING is also indicated for the prophylaxis of asthma from 2 years of age where the predominant component is exercise-induced bronchoconstriction.

04.2 Posology and method of administration

This medicine should be given to the child under adult supervision. The dosage for pediatric patients aged 2 to 5 years is one 4 mg chewable tablet per day, taken in the evening. When taken with a meal, AIRING should be taken either one hour before or two hours after it. No dosage adjustment is necessary in this age group. The 4 mg chewable tablet formulation is not recommended in the general public pediatric under 2 years of age.

General recommendations. The therapeutic effect of AIRING on asthma control parameters becomes evident within one day. Advise the patient to continue taking AIRING even when asthma is under control, as well as during periods of worsening asthma.

No dosage adjustments are required in patients with renal insufficiency or mild to moderate hepatic impairment. There are no data on patients with severe hepatic impairment. The dosage is the same for patients of both genders.

AIRING as an alternative treatment option to low-dose inhaled corticosteroids for persistent mild asthma:

The use of montelukast is not recommended as monotherapy in patients with moderate persistent asthma. The use of montelukast as an alternative treatment option to low-dose inhaled corticosteroids for children with mild persistent asthma should only be considered. for those patients who do not have a recent history of serious asthma attacks requiring oral corticosteroids, and who have been shown to be unable to use inhaled corticosteroids (see "Therapeutic indications"). Persistent mild asthma is defined as asthma symptoms that occur more than once a week but less than once a day and nocturnal symptoms that occur more than twice a month but less than once a week. Lung function between episodes is normal. If satisfactory control of asthma is not achieved during follow-up (usually within one month), the need for additional or different anti-inflammatory therapy should be considered, based on the gradual treatment approach of asthma. patients should undergo periodic assessment of asthma control.

AIRING as prophylaxis of asthma in patients aged between 2 and 5 years in which the predominant component is exercise-induced bronchoconstriction :

In patients 2 to 5 years of age, exercise-induced bronchoconstriction may be the predominant manifestation of persistent asthma requiring treatment with inhaled corticosteroids. Patients should be evaluated after 2-4 weeks of treatment. with montelukast If a satisfactory response is not achieved, additional or different therapy should be considered.

AIRING therapy in relation to other treatments for asthma:

When AIRING treatment is used as add-on therapy to inhaled corticosteroids, AIRING should not be abruptly substituted for inhaled corticosteroids (see section "Special warnings and precautions for use").

10 mg film-coated tablets are available for adults and adolescents aged 15 years and over.

5 mg chewable tablets are available for patients between 6 and 14 years of age.

Method of administration

The tablet must be chewed.

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

04.4 Special warnings and appropriate precautions for use

Advise the patient not to use oral montelukast for the treatment of acute asthma attacks and to have appropriate emergency medications commonly used in such conditions on hand. In the case of an acute attack, an inhaled? -Adrenergic agonist should be used. In case the patient needs more inhalations of agonist? -Adrenergic than usual, he should contact the treating physician as soon as possible.

Montelukast should not be abruptly substituted for inhaled or oral corticosteroids.

There are no data demonstrating that the oral dose of corticosteroids can be reduced by concomitant administration of montelukast.

In rare cases, patients on anti-asthma medication including montelukast may experience systemic eosinophilia, sometimes manifesting as the clinical features of vasculitis similar to that of Churg-Strauss syndrome, a condition often treated with therapy. systemic corticosteroid. These cases have generally, but not always, been associated with the reduction or discontinuation of oral corticosteroid therapy.

The possibility that leukotriene receptor antagonists may be associated with the onset of Churg-Strauss syndrome cannot be ruled out or established. Physicians should monitor patients for eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications and / or neuropathy. Patients who develop these symptoms need to be evaluated and their treatment regimens reconsidered.

The safety and efficacy of the 4 mg chewable tablets have not been established in the pediatric population below 2 years of age. Therefore, their use is not recommended under 2 years of age.

AIRING contains aspartame, a source of phenylalanine. Patients with phenylketonuria should note that each 4 mg chewable tablet contains phenylalanine in an amount equivalent to 0.674 mg per dose.

04.5 Interactions with other medicinal products and other forms of interaction

Montelukast can be administered with other drugs commonly used in the prophylaxis and chronic treatment of asthma. In drug interaction studies, the recommended clinical dosage of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, contraceptives oral (ethinylestradiol / norethindrone 35/1), terfenadine, digoxin and warfarin.

The area under the plasma concentration curve (AUC) of montelukast was decreased by approximately 40% in subjects co-administered with phenobarbital. Since montelukast is metabolised by CYP 3A4, use caution, especially in children, when administering montelukast. concomitantly with inducers of CYP 3A4, such as phenytoin, phenobarbital and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP2C8. However, data from a clinical drug interaction study with montelukast and rosiglitazone (a substrate used as a representative test for drugs metabolised primarily by CYP2C8) have however shown that montelukast does not inhibit CYP2C8 in vivo. Montelukast is therefore not expected to significantly alter the metabolism of drugs metabolised by this enzyme (eg, paclitaxel, rosiglitazone and repaglinide).

04.6 Pregnancy and breastfeeding

Use during pregnancy

Animal studies do not indicate the presence of harmful effects on pregnancy or embryofoetal development.

The limited data available in pregnancy databases do not suggest the existence of a causal relationship between AIRING and malformations (limb defects) rarely reported in post-marketing experience worldwide.

AIRING can only be used in pregnancy if clearly considered essential.

Use while breastfeeding

Studies in rats have shown that montelukast is excreted in human milk (see section "Preclinical safety data"). It is not known whether montelukast is excreted in the milk of lactating women.

AIRING can be used during breastfeeding only if clearly considered essential.

04.7 Effects on ability to drive and use machines

Montelukast is not thought to interfere with the ability to drive or use machines. However, in very rare cases, some people have reported drowsiness or dizziness.

04.8 Undesirable effects

Montelukast has been evaluated in clinical studies as follows:

• 10 mg film-coated tablets in approximately 4,000 adult patients ≥ 15 years of age

• 5 mg chewable tablets in approximately 1,750 pediatric patients aged 6 to 14 years

• 4 mg chewable tablets in 851 pediatric patients aged 2 to 5 years.

The following drug-related adverse reactions were reported commonly (> 1/100, placebo:

Apparatus Adult Patients 15 years and older (two 12-week studies; n = 795) Pediatric Patients 6 to 14 years (one 8-week study; n = 201) (two 56-week studies n = 615) Pediatric patients 2 to 5 years (one 12-week study, n = 461) (one 48-week study, n = 278) Nervous system disorders headache headache Gastrointestinal disorders abdominal pain abdominal pain General disorders and administration site conditions thirst

With continued therapy in clinical trials for up to 2 years in a limited number of adult patients and up to 12 months in pediatric patients aged 6 to 14 years, the safety profile did not change.

Cumulatively, 502 pediatric patients aged 2 to 5 years were treated with montelukast for at least 3 months, 338 patients for 6 months or more, and 534 patients for 12 months or more. With prolonged treatment the safety profile remained unchanged even in these patients.

Post-marketing experience

Adverse reactions reported from post-marketing use are listed in the table below, based on system organ class and specific adverse experience terminology. The frequency categories were estimated on the basis of relevant clinical studies.

System and organ classification Adverse Experience Terminology Frequency category * Infections and infestations upper respiratory tract infection † Very common Disorders of the blood and lymphatic system increased bleeding tendency Rare Disorders of the immune system hypersensitivity reactions including anaphylaxis Uncommon hepatic eosinophilic infiltration Very rare Psychiatric disorders change in dream activity including nightmares, insomnia, sleepwalking, irritability, anxiety, restlessness, agitation including aggressive behavior or hostility, depression Uncommon Tremor Rare hallucinations, suicidal thoughts and behavior (propensity to commit suicide) Very rare Nervous system disorders dizziness, somnolence, paraesthesia / hypoesthesia, convulsions Uncommon Cardiac pathologies Palpitations Rare Respiratory, thoracic and mediastinal disorders Epistaxis Uncommon Churg-Strauss syndrome (CSS) (see section 4.4) Very rare Gastrointestinal disorders diarrhea ‡, nausea ‡, vomiting ‡ common dry mouth, dyspepsia Uncommon Hepatobiliary disorders elevated levels of serum transaminases (ALT, AST) common hepatitis (including cholestatic, hepatocellular, and mixed-type liver injury) Very rare Skin and subcutaneous tissue disorders rash ‡ common bruising, hives, itching Uncommon Angioedema Rare erythema nodosum Very rare Disorders of the musculoskeletal system, connective tissue and bone tissue arthralgia, myalgia including muscle cramps Uncommon General disorders and administration site conditions pyrexia ‡ common asthenia / fatigue, malaise, edema Uncommon * Frequency category: defined for each adverse experience terminology based on the incidence reported in the clinical trial database: Very common (≥1 / 10), Common (≥1 / 100, † This adverse experience, reported as Very Common in patients who received montelukast, was also reported as Very Common in patients who received placebo in clinical trials. ‡ This adverse experience, reported as Common in patients who received montelukast, was also reported as Common in patients who received placebo in clinical trials.

04.9 Overdose

No specific information is available on the treatment of overdose with montelukast. In chronic asthma studies, montelukast has been 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 one week, with no clinically important adverse events.

There have been reports of acute overdose in post-marketing experience and in clinical trials with montelukast. These include reports in adults and children with doses up to 1000 mg (approximately 61 mg / kg in a 42 month old child). observed laboratory results were consistent with the safety profile in adults and pediatric patients. There were no adverse experiences in the majority of overdose cases. The most frequently observed adverse experiences were consistent with the safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity.

It is not known whether montelukast is dialysable by peritoneal dialysis or hemodialysis.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: other systemic drugs for obstructive airway diseases. Leukotriene receptor antagonists.

ATC code: R03D C03.

Cysteinyl-leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released by various cells including mast cells and eosinophils. These important asthma mediators bind to cysteinyl-leukotriene receptors (CysLT), found in humans in the respiratory tract, and cause various effects on the respiratory tract including bronchoconstriction, mucosal secretion, vascular permeability and eosinophil recruitment.

Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT1 receptor. In clinical studies, montelukast at low doses, such as 5 mg, inhibits bronchoconstriction caused by the inhalation of LTD4. Bronchodilation was observed within two hours of oral administration. The bronchodilator effect caused by a beta-adrenergic agonist was additive to the one produced by montelukast. Treatment with montelukast inhibited both the early and late stages of bronchoconstriction caused by 'exposure to' the antigen. Montelukast, compared to placebo, decreased peripheral blood eosinophils in both adult and pediatric patients. In a separate study, montelukast treatment significantly reduced respiratory tract eosinophils (as a result of 'sputum examination'). In adult and pediatric patients 2 to 14 years of age, montelukast, compared with placebo, reduced peripheral blood eosinophils while improving clinical control of asthma.

In studies in adults versus placebo, montelukast, 10 mg once daily, has been shown to significantly improve morning FEV1 (changes from baseline 10.4% vs 2.7%), morning peak expiratory flow (PEFR) (changes from baseline 24.5 l / min vs 3.3 l / min), and significantly decreases the total use of? -adrenergic agonists (changes from baseline -26.1% vs -4.6%). patient-reported day and night symptom score was significantly better than that of the placebo group.

In adult studies, montelukast has been shown to provide an additive clinical effect to that induced by inhaled corticosteroid (percentage changes from baseline for inhaled beclomethasone plus montelukast vs beclomethasone in FEV1, respectively: 5.43% vs 1 04% and use of? -Adrenergic agonists: -8.70% vs 2.64%). Initial response to montelukast was shown to be faster than inhaled beclomethasone (200 mcg twice per day, administered via a spacer device), although beclomethasone provided a greater mean effect over the entire twelve-week study period (percentage changes from baseline for montelukast vs beclomethasone in FEV1, respectively: 7.49% vs 13.3 % and the use of? -adrenergic agonists: -28.28% vs -43.89%). However, a "high percentage of patients treated with montelukast achieved a clinical response similar to that seen with beclomethasone (eg, 50% of patients treated with beclomethasone achieved an improvement in FEV1 of approximately 11% or greater than at baseline, while approximately 42% of patients treated with montelukast achieved the same response).

In a 12-week, placebo-controlled study in pediatric patients aged 2 to 5 years, montelukast 4 mg once daily improved asthma control parameters compared to placebo regardless of concomitant use of control therapies ( inhaled / nebulized corticosteroids or inhaled / nebulized sodium cromoglycate). Sixty percent of patients were not on other control therapies. Montelukast compared with placebo improved daytime symptoms (including cough, wheezing, difficulty breathing and limited motor activity) and nocturnal symptoms. Montelukast compared with placebo also reduced the use of "as needed"? -Agonists and urgent corticosteroids for worsening asthma. Patients on montelukast therapy were asthma-free for more days than those receiving placebo. The treatment produced an effect after the first dose.

In a 12-month placebo-controlled study in pediatric patients aged 2 to 5 years with mild asthma and episodic exacerbations, montelukast 4 mg once daily significantly reduced (p≤0.001) the annual frequency of exacerbations (EE) compared to placebo (1.60 EE vs 2.34 EE, respectively), [EE is defined as ≥3 consecutive days with daytime symptoms requiring the use of? -Agonists, or corticosteroids (oral or inhaled), or hospitalizations for asthma]. reduction in the annual EE rate was 31.9%, with a 95% CI of 16.9, 44.1.

In an 8-week study in pediatric patients 6 to 14 years of age, montelukast 5 mg once daily compared with placebo significantly improved respiratory function (change from baseline FEV1 8.71% vs 4.16%; change from baseline in AM PEFR 27.9 l / min vs 17.8 l / min) and reduced the "use of? -Agonists" as needed (change from baseline -11.7% vs + 8.2%).

In a 12-month comparative study of the efficacy of montelukast and inhaled fluticasone for asthma control in pediatric patients aged 6 to 14 years with persistent mild asthma, montelukast was non-inferior to fluticasone in increasing the percentage days without the need for rescue therapy (RFD), the primary endpoint. The mean percentage of RFD over the 12-month treatment period increased from 61.6 to 84.0 in the montelukast group and from 60.9 to 86.7 in the fluticasone group. The difference between groups in the least squares (LS) mean increase in the percentage of RFD was statistically significant (-2.8 with a 95% CI of -4.7, -0.9) But within the predefined limit of non-inferiority from the clinical point of view.

Both montelukast and fluticasone also improved asthma control on secondary variables assessed over the 12-month treatment period: VEF1 increased from 1.83 to 2.09 in the montelukast group and from 1.85 to 2. 14 l in the fluticasone group. The difference in LS mean increase in FEV1 between groups was -0.02 l, with a 95% CI of -0.06, 0.02. The increase from baseline in the expected percentage of FEV1 was 0.6% in the montelukast treatment group, and 2.7% in the fluticasone group. The difference between LS means for the change in the expected percentage of FEV1 from baseline was -2.2%, with a 95% CI of -3.6, -0.7. The percentage of days using β-agonists decreased from 38.0 to 15.4 in the montelukast group , and 38.5 to 12.8 in the fluticasone group. The inter-group difference in the LS means of the percentages of days using β-agonists was 2.7, with a 95% CI of 0.9, 4, 5.

The percentage of patients with an asthma attack (defined as a period of worsening of asthma that requires treatment with steroids per os, an unscheduled medical visit, an emergency department visit, or hospitalization) was 32.2 in the montelukast group and 25.6 in the fluticasone group; the odds ratio (95% CI) was 1.38.

The percentage of patients with systemic (predominantly oral) use of corticosteroids during the study was 17.8% in the montelukast group and 10.5% in the fluticasone group. The difference in LS means between groups was 7.3% with a 95% CI of 2.9, 11.7.

A significant reduction in exercise-induced bronchoconstriction (BIE) was demonstrated in a 12-week study in adults (maximum reduction in FEV1: 22.33% for montelukast vs 32.40% for placebo; recovery time of FEV1 to a value that does not differ by more than 5% from baseline: 44.22 min vs 60.64 min.)

This effect repeated consistently throughout the 12-week duration of the study. The reduction in BIE was also demonstrated in a short-term study in pediatric patients aged 6 to 14 years (maximum reduction in FEV1: 18.27% vs 26.11%; recovery time of FEV1 to a value that does not differ by more than 5% from baseline: 17.76 min vs 27.98 min). In both studies, the effect was demonstrated at the end of the once daily dosing interval.

In aspirin-sensitive asthma patients receiving concomitant treatment with inhaled and / or oral corticosteroids, treatment with montelukast, compared to placebo, resulted in a significant improvement in asthma control (percentage changes from baseline in FEV1: 8.55% vs -1.74%; reduction in total use of? -adrenergic agonists compared to baseline: -27.78% vs 2,09%).

05.2 Pharmacokinetic properties

Absorption

Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated tablets, the mean value of the maximum plasma concentration (Cmax) in adults is reached 3 hours (Tmax) after dosing in the fasted state. The mean bioavailability after oral administration is 64%. Oral bioavailability and Cmax are not affected by a meal standard. Safety and efficacy have been demonstrated in clinical trials where the 10 mg film-coated tablets were administered regardless of the timing of food intake.

For 5 mg chewable tablets, adult Cmax is reached after 2 hours dosing in the fasted state. Mean bioavailability after oral administration is 73% and decreases to 63% with a meal. standard.

After administration of the 4 mg chewable tablet to pediatric patients aged 2 to 5 years in the fasted state, Cmax is reached in 2 hours. The mean C is greater than 66% while the C min is less than that of adults taking a 10 mg tablet.

Distribution

More than 99% of montelukast is bound to plasma proteins. The steady state volume of distribution of montelukast averages 8-11 liters. Rat studies with radiolabelled montelukast indicate minimal distribution across the blood brain barrier. Furthermore, 24 hours after the administration of the dose, the concentrations of radio-labeled substance were found to be minimal in all other tissues.

Biotransformation

Montelukast is extensively metabolised. In studies performed with therapeutic dosages, plasma concentrations of the metabolites of montelukast were not detectable at steady state in both adults and children.

Education in vitro using human liver microsomes indicate that cytochromes P450 3A4, 2A6 and 2C9 are involved in the metabolism of montelukast. Based on further findings in vitro on human liver microsomes, montelukast, at therapeutic plasma concentrations, does not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19 or 2D6. The contribution of the metabolites to the therapeutic effect of montelukast is minimal.

Elimination

In the healthy adult, the clearance plasma concentration of montelukast averages 45 mL / min. After oral administration of a radiolabelled dose of montelukast, 86% of the radioactivity was detected on a five-day stool test, and less than 0.2% was detected in the urine. These data, together with those relating to the bioavailability of montelukast following oral administration, indicate that montelukast and its metabolites are excreted almost exclusively via the bile.

Characteristics of patients

No dosage adjustment is necessary in the elderly or in patients with mild to moderate hepatic impairment. Studies in patients with renal insufficiency have not been conducted. As montelukast and its metabolites are eliminated primarily via the biliary route, no dosage adjustment is anticipated in patients with renal insufficiency. There are no pharmacokinetic data with montelukast in patients with severe hepatic impairment (Child-Pugh score> 9).

At high doses of montelukast (20 - 60 times the recommended adult dose) a reduction in plasma theophylline concentration was observed. This effect was not observed at the recommended dose of 10 mg once daily.

05.3 Preclinical safety data

In animal toxicity studies, mild and transient serum biochemical changes in SGPT (ALT), glucose, phosphorus and triglycerides were observed. Signs of toxicity in the animal were: increased salivation, gastrointestinal symptoms, loose stools and electrolyte imbalance. These occurred at dosages that provided> 17 times the systemic exposure observed with the clinical dose. In monkeys, undesirable effects appeared starting at doses of 150 mg / kg / day (> 232 times the systemic exposure observed with clinical dosage). In animal studies, montelukast did not affect fertility and reproductive capacity at a systemic exposure exceeding the clinical systemic exposure by more than 24 times. In the female rat fertility study, at doses of 200 mg / kg / day (> 69 times the clinical systemic exposure) a slight reduction in the weight of the newborns was observed. In rabbit studies, a "higher incidence of incomplete ossification was observed than in the control group at" systemic exposure> 24 times that observed with clinical dosing. No abnormalities were observed in the rat. Montelukast has been shown to cross the placental barrier and is excreted in the breast milk of animals.

No deaths occurred in mice and rats after single oral doses up to 5,000 mg / kg, the maximum dose tested (15,000 mg / m2 and 30,000 mg / m2 in mice and rats, respectively). The dose is equivalent to 25,000 times the recommended human dose in adults (based on a weight of 50 kg for an adult patient).

Montelukast was found to have no phototoxicity to UVA, UVB or visible light spectrum at dosages up to 500 mg / kg / day (approximately 200 times the systemic exposure observed with clinical dosage) in mice.

Montelukast was neither mutagenic in in vitro and in vivo tests nor oncogenic in the rodent.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Mannitol (E421), microcrystalline cellulose, croscarmellose sodium, red iron oxide (E172), hydroxypropylcellulose, cherry flavor (also contains glycerol triacetate (E1518)), aspartame (E951) and magnesium stearate.