Consumer medicine information

APO-Montelukast

Montelukast

BRAND INFORMATION

Brand name

APO-Montelukast

Active ingredient

Montelukast

Schedule

What is in this leaflet

This leaflet answers some common questions about montelukast. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What this medicine is used for

Montelukast is used to:

prevent asthma symptoms, including those that occur during the day and at night-time
prevent the narrowing of airways triggered by exercise
seasonal allergic rhinitis (hay fever) symptoms.

Montelukast tablets are not used to treat an acute attack of asthma. If an acute attack occurs, follow your doctor's instructions for your reliever medicine, and keep taking your montelukast tablets each night or as prescribed.

As a preventive medicine for asthma, montelukast can be used alone or in combination with other preventive medicines, such as inhaled corticosteroids. Your doctor may reduce your dose of inhaled corticosteroid while you are taking montelukast.

How it works

Montelukast belongs to a group of medicines called leukotriene receptor antagonists. It works by blocking substances in your lungs called leukotrienes that cause narrowing and swelling of airways. Blocking leukotrienes improves asthma symptoms and helps prevent asthma attacks. Leukotrienes also cause allergic rhinitis symptoms. By blocking leukotrienes, montelukast improves seasonal allergic rhinitis symptoms.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

This medicine is not addictive.

Montelukast should not be used in children under 2 years of age. Safety and effectiveness in children younger than 2 years of age have not been studied.

Before you take this medicine

When you must not take it

Do not take this medicine if you have had an allergy to:

montelukast
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking montelukast, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant, plan to become pregnant or are breastfeeding. Do not take this medicine until you and your doctor have discussed the risks and benefits involved.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without prescription from your pharmacy, supermarket or health food shop.

Some medicines may affect how montelukast works, or montelukast may affect how your other medicines work.

How to take this medicine

Follow carefully all directions given to you by your doctor. They may differ to the information contained in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take, depending on your condition and if you are taking any other medicines.

For patients with asthma and/or seasonal allergic rhinitis, take montelukast only when prescribed by your doctor.

Asthma: take one tablet once a day in the evening.

Seasonal allergic rhinitis: take one tablet once a day.

For children 2 to 5 years old: take one 4 mg chewable tablet each day.

For children 6 to 14 years old: take one 5 mg chewable tablet each day.

For adults and teenagers 15 years and older: take one 10 mg tablet each day.

How to take it

Chew the 4 mg or 5 mg chewable tablets thoroughly and swallow. Do not swallow chewable tablets whole.

Swallow the 10 mg tablet whole with a glass of water.

When to take it

Asthma: Take your montelukast at bedtime each day. Taking your tablet at bedtime each day is expected to have the best effect. It will also help you remember when to take the tablets.

Seasonal allergic rhinitis: Your doctor will advise you on the best time of the day to take your tablet.

Asthma and seasonal allergic rhinitis: Take your montelukast at bedtime each day if you have both asthma and seasonal allergic rhinitis.

It does not matter if you take it with or without food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you, even if you have no asthma symptoms or if you have an asthma attack.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

Skip the missed dose and take your next dose as usual.

Do not take a double dose to make up for missed doses. This may increase the chance of unwanted side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to the Emergency Department at your nearest hospital if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

The most common symptoms reported with overdose in adults and children include thirst, sleepiness, dilated pupils, hyperactivity, and stomach pain.

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

If you become pregnant whilst taking montelukast, tell your doctor immediately.

Go to your doctor regularly for a check-up.

Tell your doctor if your asthma gets worse while taking montelukast If an acute attack of asthma occurs, follow your doctor's instructions on what reliever medicine to use to relieve the attack.

Things you must not do

If you have been prescribed the 10 mg tablets, do not take two 5 mg chewable tablets in its place.

If you have been prescribed the 5 mg tablets, do not take half a 10 mg tablet in its place. The different strength tablets may not have the same effect, as they are absorbed slightly differently in the body.

Do not take montelukast to relieve an acute asthma attack. In case of an acute asthma attack, follow your doctor's instructions on what reliever medicine to use.

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not take your medicine to treat any other complaint unless your doctor tells you to.

Do not stop taking your medicine, or change the dosage, without first checking with your doctor.

Side effects

Tell your doctor and pharmacist as soon as possible if you do not feel well while you are taking montelukast.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor or pharmacist if you notice any of the following.

This list includes the more common side effects. Mostly, these are mild:

fluid retention
nose bleed
headache, dizziness, drowsiness
feeling unusually weak or tired
upper respiratory tract infection.
bedwetting in children

Muscle or nerve problems:

muscle aches or cramps, joint pain
decreased feeling or sensitivity, especially in the skin
pins and needles.

Stomach or bowel problems:

stomach pain
nausea, vomiting
diarrhoea.

Behaviour and mood-related changes have been reported in patients taking montelukast. If you experience these changes while taking montelukast, tell your doctor.

You should immediately inform your doctor if you start to have any:

agitation, including aggressive behaviour and/or hostility (such as temper tantrums in children)
suicidal thoughts and actions
tremors
irritability, restlessness
anxiousness, depression (sad mood)
disorientation (inability to know correct time, place or person)
disturbance in attention, memory impairment
seeing, feeling or hearing things that are not there (also called hallucinations)
insomnia, dream abnormalities, difficulty sleeping
obsessive-compulsive symptomstics or unusual movements
sleep walking.

Tell your doctor immediately if you notice any of the following.

skin rash or itchiness
increased tendency to bleed, bruising
fast or irregular heartbeats (palpitations)
inflammation of the lungs
nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine (signs of liver disease)
suicidal thoughts and actions

The above list includes serious side effects that may need medical attention.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Emergency department at your nearest hospital:

cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; hay fever-like symptoms (signs of an allergic reaction)
seizure

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor and pharmacist if you notice any other effects.

Other side effects not listed above may occur in some patients.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it. If you take your medicine out of its packaging it may not keep well.

Keep your medicine in a cool dry place, away from light, where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine left over.

Product description

What it looks like

4mg chewable tablet: Pink coloured, oval shaped, biconvex tablets, engraved with "APO" on one side and "M 4" on the other side. The tablets may be mottled.

Blister packs of 14 and 28 tablets. AUST R 179118

Bottles of 28, 30 and 100 tablets: AUST R 179111.

5 mg chewable tablet: Pink coloured, round shaped, biconvex tablets, engraved with "APO" on one side and "M 5" on the other side. The tablets may be mottled.

Blister packs of 14 and 28 tablets. AUST R 179115

Bottles of 28, 30 and 100 tablets: AUST R 179110.

10mg Tablet: Beige coloured, rounded square shaped, biconvex film coated tablets, with engraved "APO" on one side and "M10" on the other side.

Blister packs of 14 and 28 tablets. AUST R 170248.

Bottles of 14, 28 and 100 tablets: AUST R 170246

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 4 mg, 5 mg or 10mg of montelukast sodium as the active ingredient.

The 4mg and 5mg tablets also contains the following inactive ingredients:

mannitol
microcrystalline cellulose
croscarmellose sodium
aspartame
magnesium stearate
artificial cherry flavour
iron oxide red

The 10mg tablets also contains the following inactive ingredients:

anhydrous lactose
microcrystalline cellulose
croscarmellose sodium
anhydrous colloidal silica
magnesium stearate
hypromellose
hyprolose
iron oxide yellow
iron oxide red and titanium dioxide

This medicine does not contain gluten, sucrose, tartrazine or any other azo dyes.

The 10mg tablets contains lactose.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

Apotex Pty Ltd is the licensee of the registered trademarks APO and APOTEX from the registered proprietor, Apotex Inc.

This leaflet was prepared in June 2019.

Published by MIMS August 2019

BRAND INFORMATION

Brand name

APO-Montelukast

Active ingredient

Montelukast

Schedule

1 Name of Medicine

Montelukast sodium.

6.7 Physicochemical Properties

Montelukast sodium is a hygroscopic, optically active, white to off-white, free-flowing powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile. Montelukast is the optically active R stereoisomer.
Chemical Name: [R-(E)]-1-[[[1- [3-[2-(7-chloro-2-quinolinyl) ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl) phenyl]propyl]thio]methyl] cyclopropane acetic acid, monosodium salt.
Molecular Formula: C₃₅H₃₅ClNNaO₃S. Molecular Weight: 608.18.

Chemical structure.

CAS number.

151767-02-1.

2 Qualitative and Quantitative Composition

Each 10 mg film-coated tablet contains 10.4 mg montelukast sodium, which is equivalent to 10.0 mg of montelukast, the free acid.
Each 4 mg chewable tablet contains montelukast sodium equivalent to 4.0 mg of montelukast, the free acid.
Each 5 mg chewable tablet contains montelukast sodium equivalent to 5.0 mg of montelukast, the free acid.

Excipients with known effect.

10 mg film-coated tablet: lactose.
4 mg and 5 mg chewable tablet: aspartame.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

10 mg film-coated tablets.

APO-Montelukast montelukast 10 mg (as sodium) film-coated tablets: Beige coloured, rounded square shaped, biconvex film coated tablets, with engraved “APO” on one side and “M10” on the other side.

4 mg chewable tablets.

APO-Montelukast montelukast 4 mg (as sodium) chewable tablets: Pink coloured, oval shaped, biconvex tablets, engraved with “APO” on one side and “M 4” on the other side. The tablets may be mottled.

5 mg chewable tablets.

APO-Montelukast montelukast 5 mg (as sodium) chewable tablets: Pink coloured, round shaped, biconvex tablets, engraved with “APO” on one side and “M 5” on the other side. The tablets may be mottled.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The cysteinyl leukotrienes (LTC4, LTD4, LTE4), are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important proasthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other proinflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene mediated effects include a number of airway actions, including bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. In allergic rhinitis, CysLTs are released from the nasal mucosa after 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. The clinical relevance of intranasal challenge studies is unknown.
Montelukast is an orally active compound which has been shown in asthmatic patients to reduce peripheral blood eosinophil counts and sputum eosinophils, which are parameters of asthmatic inflammation. The effect of montelukast on reduction of peripheral blood eosinophils was comparable to inhaled corticosteroids. Based on biochemical and pharmacological bioassays, it binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast potently inhibits physiologic actions of LTC4, LTD4, and LTE4 at the CysLT1 receptor without any agonist activity.
In asthmatic patients, montelukast causes potent inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4.
A dose of 5 mg causes substantial blockage of LTD4 induced bronchoconstriction.
Montelukast causes bronchodilation within 2 hours of oral administration. β-agonists caused additive effects when added to montelukast.

Clinical trials.

Clinical trials - asthma.

In clinical studies, montelukast is effective in adult and paediatric patients for the prophylaxis and chronic treatment of asthma, including protection against day and night time symptoms, the treatment of aspirin sensitive asthmatic patients, and the prevention of exercise induced bronchoconstriction. Montelukast is effective alone or in combination with other prophylactic agents used in the maintenance treatment of asthma. Montelukast and inhaled corticosteroid may be used concomitantly with additive effects to control asthma or to reduce the inhaled corticosteroid dose while maintaining clinical stability. Montelukast is a preventative agent which should be used in addition to other drugs for the management of asthma.

Adults 15 years of age and older.

In two similarly designed 12 week double blind placebo controlled studies in adults asthmatic patients 15 years of age and older, montelukast, 10 mg once daily in the evening, demonstrated significant improvements in parameters of asthma control measuring asthma symptoms, asthma related outcomes, respiratory function and as-needed β-agonist use.
Montelukast significantly improved patient reported daytime symptoms and nocturnal awakenings, compared with placebo. Asthma specific outcomes, including asthma attacks, corticosteroid rescue, discontinuations due to worsening asthma, asthma exacerbations and asthma free days were also significantly better than placebo.
Physicians' and patients' global asthma evaluations and asthma specific quality of life evaluations (in all domains, including normal daily activity and asthma symptoms) were significantly better than placebo.
Montelukast caused significant improvements in morning forced expiratory volume in 1 second (FEV₁), AM and PM peak expiratory flow rate (PEFR) and significantly decreased the use of as-needed β-agonist, compared with placebo.
A comparison of montelukast and inhaled beclomethasone (200 microgram twice daily with a spacer device) demonstrated that montelukast had a more rapid initial response (within the first day compared with 7-10 days for beclomethasone). While both treatments provided significantly and clinically important changes, the overall beclomethasone effect was larger over the 12 weeks duration of the study. The difference in response is, in part, a result of a small percentage of patients treated with beclomethasone (16.7%) that had a ≥ 30% increase in FEV₁). However in a high proportion of patients the response was comparable, for example, 42% of patients taking montelukast compared with 50% of patients taking beclomethasone achieved an 11% or more increase in FEV₁.
The treatment effect was achieved after the first dose and was maintained throughout the 24 hour dosing interval. Treatment effect also remained constant during continuous once daily administration in extension studies for up to one year. Withdrawal of montelukast after 12 weeks of use did not cause rebound worsening of asthma.

Paediatric patients 6 to 14 years of age.

In paediatric patients 6 to 14 years of age, one 5 mg chewable tablet daily in the evening, significantly decreased asthma exacerbations, and improved parents' global evaluations and the paediatric asthma specific quality of life evaluations, compared with placebo.
Montelukast also significantly improved morning FEV₁ and decreased total daily as-needed β-agonist use. Treatment effect was achieved after the first dose and remained constant during once daily administration for up to 6 months.

Growth rate in paediatric patients.

Two controlled clinical studies have demonstrated that montelukast did not affect the growth rate in paediatric patients with asthma. In a short-term study of children aged 6 to 11 years, growth rate as measured by lower leg length growth was similar in patients treated with montelukast 5 mg once daily for 3 weeks compared with placebo, and was significantly lower in patients treated with inhaled budesonide (200 microgram twice daily) for 3 weeks, compared with placebo. In a 56 week study in children aged 6 to 8 years, linear growth rate was similar in patients treated with montelukast 5 mg once daily and placebo (LS means for montelukast and placebo: 5.67 and 5.64 cm/year, respectively), and was significantly lower (LS mean: 4.86 cm/year) in patients treated with inhaled beclomethasone (200 microgram twice daily), compared with placebo [difference in LS means (95% CI): -0.78 (-1.06, -0.49) cm/year]. The long-term clinical relevance of these studies is unknown.

Paediatric patients 2 to 5 years of age.

In a 12 week, placebo controlled study in paediatric patients 2 to 5 years of age, montelukast 4 mg once daily consistently improved parameters of asthma control irrespective of concomitant controller therapy use compared with placebo. Sixty percent of patients were not on any other controller therapy. Montelukast significantly improved daytime symptoms (including coughing, wheezing, trouble breathing and activity limitation) and night time symptoms compared with placebo (mean baseline daytime scores were montelukast 0.98 and placebo 0.95 on a 0-5 scale; mean change from baseline: montelukast -0.37 vs placebo -0.25 [p = 0.003] and mean baseline night time scores were montelukast 1.18 and placebo 1.20 on a 0-4 scale; mean change from baseline: montelukast -0.41 vs placebo -0.30 [p = 0.026]).
Montelukast also significantly decreased as-needed β-agonist use (percentage of days used, montelukast 50.09 vs placebo 56.34 [p = 0.001]) and corticosteroid rescue (percentage of patients with corticosteroid rescue, montelukast 19.09 vs placebo 28.07 [p = 0.008]) compared with placebo. Patients receiving montelukast had significantly more days without asthma than those receiving placebo (percentage of days without, montelukast 30.50 vs placebo 23.63 [p = 0.002]). A treatment effect was achieved after the first dose. In addition, total blood eosinophil counts were significantly decreased (for total blood eosinophil counts, the between group difference in LS means was -0.04 10³/microL, p = 0.034).

Effects in patients on concomitant inhaled corticosteroids.

Separate studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled corticosteroid and allow steroid tapering when used concomitantly. In a placebo controlled study, stable, asthmatic patients taking initial inhaled corticosteroid doses of approximately 1600 microgram per day reduced their steroid use by approximately 37% during a placebo run in period. Montelukast allowed a further 47% reduction of the inhaled corticosteroid dose, compared with 30% for placebo. In another study, montelukast provided additional clinical benefit to a similar population of patients maintained but not adequately controlled on inhaled corticosteroid (beclomethasone 400 microgram per day). Complete abrupt removal of beclomethasone in patients receiving both montelukast and beclomethasone caused clinical deterioration in some patients, suggesting that tapering as tolerated rather than abrupt removal is preferred.

Aspirin sensitive patients.

In aspirin sensitive patients, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, montelukast resulted in significant improvement in the parameters of asthma control.
The effect of montelukast on the bronchoconstrictor response to aspirin challenge or other nonsteroidal anti-inflammatory drugs in aspirin sensitive asthmatic patients has not been evaluated (see Section 4.4 Special Warnings and Precautions for Use).

Effects on exercise induced bronchoconstriction.

Montelukast, 10 mg once daily, protected against exercise induced bronchoconstriction (EIB) in adults 15 years of age and older. In a 12 week study, montelukast significantly inhibited the extent and duration of fall in FEV₁ over 60 minutes after exercise, the maximal percent fall in FEV₁ after exercise, and the time to recovery to within 5% of the pre-exercise FEV₁. Protection was consistent through the treatment period indicating that tolerance did not occur. In a separate crossover study, protection was observed after two once daily doses.
In paediatric patients 6 to 14 years of age, using the 5 mg chewable tablet, a similarly designed crossover study demonstrated similar protection and the protection was maintained throughout the dosing interval (24 hours).

Effects on antigen challenge and eosinophils.

In clinical studies montelukast inhibited both early and late phase bronchoconstriction due to antigen challenge. Because inflammatory cell (eosinophil) infiltration is an important feature of asthma, the effects of montelukast on eosinophils in the peripheral blood and airway were examined. In phase IIb/III clinical studies, montelukast significantly decreased peripheral blood eosinophils approximately 15% from baseline, compared with placebo. In paediatric patients 6 to 14 years of age, montelukast decreased peripheral blood eosinophils 13% over the 8 week treatment period, compared with placebo. Montelukast also significantly decreased airway eosinophils in sputum, compared with placebo. In this study, peripheral blood eosinophils decreased and clinical asthma endpoints improved with treatment with montelukast.

Effects in patients with asthma and seasonal allergic rhinitis.

In a two week, placebo controlled, double blind, clinical study in adult asthmatic patients 15 years of age and older with concomitant seasonal allergic rhinitis, montelukast 10 mg tablets administered once daily demonstrated a statistically significant improvement in the primary composite variable, Daily Rhinitis Symptoms score (average of the Daytime Nasal Symptoms score [mean of nasal congestion, rhinorrhea, sneezing, nasal itching] and the Night time Symptoms score [mean of nasal congestion upon awakening, difficulty going to sleep, and night time awakenings scores]) (see Table 2). The mean difference in improvement between the two treatments was 0.12 points (95% CI: -0.18, -0.06) on a scale of 0.00 to 3.00. A change of 1.00 would correspond to an improvement of symptoms from moderate to mild, or from severe to moderate.

Clinical trials - seasonal allergic rhinitis.

Adults 15 years of age and older.

The efficacy of montelukast for the treatment of seasonal allergic rhinitis was investigated in seven similarly designed randomised, 2 week, double blind, placebo controlled trials including 4924 patients (1751 patients were treated with montelukast). Patients were 15 years of age and older with a history of seasonal allergic rhinitis, a positive skin test to at least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at study initiation.
Two of the three pivotal studies showed a significant reduction in daytime nasal symptoms scores with montelukast 10 mg tablets compared to placebo.
In a combined analysis of the three pivotal studies, montelukast 10 mg tablets administered to 1189 patients once daily in the evening resulted in a statistically significant improvement in the primary endpoint, daytime nasal symptoms score, and its individual components (nasal congestion, rhinorrhea, nasal itching, and sneezing); night time symptoms score, and its individual components (nasal congestion upon awakening, difficulty going to sleep, and night time awakenings); daytime eye symptoms score, and its individual components (tearing, itchy, red, and puffy eyes); global evaluation of allergic rhinitis by patients and by physicians; and composite symptoms score (composed of the daytime nasal and night time symptoms scores), compared with placebo.
The efficacy results of one trial are shown in Table 3. The mean changes from baseline in daytime nasal symptoms score in the treatment groups that received montelukast tablets, loratadine and placebo are shown in Table 3. The mean change from baseline for montelukast was 50% larger than the mean change from baseline for placebo.

The efficacy of montelukast in the treatment of seasonal allergic rhinitis was investigated in a separate 4 week study in which the primary objective of the study was to determine the treatment effect of montelukast 10 mg administered once daily in the morning, compared to placebo, in patients with seasonal allergic rhinitis over the first 2 weeks of treatment. The efficacy of montelukast over the initial 2 weeks was significantly different from placebo and consistent with the effect observed in studies using evening dosing (see Table 4). Additionally, the effect over the entire 4 weeks was consistent with the 2 week results (see Figure 1).

The study was not designed for statistical comparison between montelukast and the active control (loratadine).

Paediatric patients 2 to 14 years of age.

Efficacy studies have not been conducted in this age group.

5.2 Pharmacokinetic Properties

Absorption.

Montelukast is rapidly and nearly completely absorbed following oral administration.
For the 10 mg film coated tablet, the mean peak plasma concentration (C_max) is achieved 3 hours (T_max) after administration in adults in the fasted state. The mean oral bioavailability is 64%.
The oral bioavailability and C_max are not influenced by a standard meal.
For the 5 mg chewable tablet, the C_max is achieved in 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal. This is unlikely to have any clinical significance with chronic administration. Efficacy was demonstrated in clinical studies in children where the montelukast 5 mg chewable tablet was administered irrespective of food.
For the 4 mg chewable tablet, C_max is achieved 2 hours after the administration in paediatric patients 2 to 5 years of age in the fasted state.
Safety and efficacy were demonstrated in clinical studies where the 4 mg chewable tablet, 5 mg chewable tablet, and 10 mg film coated tablet were administered without regard to the timing of food ingestion.
The 10 mg film coated tablets of montelukast are not bioequivalent to two 5 mg chewable tablets, and these two products should not be used interchangeably.

Distribution.

Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 L. Studies in rats with radiolabelled montelukast indicate minimal distribution across the blood brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.

Metabolism.

Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable (< 20 nanogram/mL) at steady state in adults and children. Further studies showed that relatively high concentrations of montelukast competitively inhibit the activity of cytochromes P450 3A4 and 2C9. However, these concentrations are at least 15-fold higher than the peak plasma concentrations attained following a 10 mg oral dose of montelukast. Based on these and other in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast should not be expected to inhibit cytochromes P450, 3A4, 2C9, 1A2, 2A6, 2C19 or 2D6.

Excretion.

The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5 day faecal collections and < 0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.
In several studies, the mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once daily dosing with 10 mg montelukast, there is little accumulation of the parent drug in plasma (~ 14%).

Characteristics in patients.

No dosage adjustment is necessary for the elderly or for patients with mild to moderate hepatic insufficiency. There are no clinical data in patients with severe hepatic insufficiency (Child-Pugh score > 9). Because montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. Studies in patients with renal impairment have not been undertaken.

5.3 Preclinical Safety Data

Genotoxicity.

Montelukast sodium was found not to be genotoxic. Montelukast sodium was negative in microbial and mammalian cell mutagenesis assays, with and without metabolic activation. There was no evidence of clastogenic activity in the in vitro chromosomal aberration assay in Chinese hamster ovary cells, with or without a microsomal enzyme activation system, or of DNA damage in the in vitro alkaline elution assay in rat hepatocytes. Similarly, there was no induction of chromosomal aberrations in bone marrow cells of male or female mice.

Carcinogenicity.

Montelukast sodium was not carcinogenic when administered at oral doses of up to 200 mg/kg/day in 104 week study in rats, nor at oral doses up to 100 mg/kg/day in a 91 week study in mice. Systemic exposure in these studies, in terms of the plasma AUC for parent drug, was at least 30 times higher than that in humans at recommended dose levels.

4 Clinical Particulars

4.1 Therapeutic Indications

Prophylaxis and treatment of chronic asthma in adults and children 2 years of age and older.
Symptomatic treatment of seasonal allergic rhinitis.

4.3 Contraindications

Hypersensitivity to any component of this product.

4.4 Special Warnings and Precautions for Use

The efficacy of oral montelukast for the treatment of acute asthma attacks has not been established. Therefore, oral tablets of montelukast should not be relied upon to treat acute asthma attacks. Patients should be advised to have appropriate rescue medication available.
While the dose of concomitant inhaled corticosteroid may be reduced gradually under medical supervision, montelukast should not be abruptly substituted for inhaled or oral corticosteroids (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical trials - asthma).

Neuropsychiatric events.

Neuropsychiatric events have been reported in adult, adolescent, and paediatric patients taking montelukast. Post-marketing reports with montelukast use include agitation, aggressive behaviour or hostility, anxiousness, depression, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behaviour (including suicidality), and tremor. The clinical details of some postmarketing reports involving montelukast appear consistent with a drug induced effect.
Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with montelukast if such events occur.

Eosinophilic conditions.

In rare cases patients receiving antiasthma agents including leukotriene receptor antagonists have experienced one or more of the following: eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes diagnosed as Churg-Strauss syndrome, a systemic eosinophilic vasculitis. These cases have been sometimes associated with the reduction or withdrawal of oral corticosteroid therapy. Although a causal relationship with leukotriene receptor antagonism has not been established, caution and appropriate clinical monitoring are recommended in patients receiving montelukast.
4 mg and 5 mg chewable tablets contain aspartame which is a source of phenylalanine (APO-Montelukast contains 1.5 mg phenylalanine per 5 mg chewable tablet, and 1.2 mg phenylalanine per 4 mg chewable tablet).
Although montelukast is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to modify bronchoconstrictor response to aspirin challenge and other nonsteroidal anti-inflammatory drugs in aspirin sensitive asthmatic patients. Therefore, patients with known aspirin sensitivity should continue avoidance of aspirin or nonsteroidal anti-inflammatory agents while taking montelukast (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical trials - asthma).

Use in the elderly.

In clinical studies, there were no age-related differences in the efficacy or safety profiles of montelukast.

Paediatric use.

In asthma: montelukast has been studied in paediatric patients six months to 14 years of age (see Section 4.2 Dose and Method of Administration). Safety and effectiveness in paediatric patients younger that six months of age have not been studied. In studies investigating the effect of montelukast on the growth rate of paediatric patients, it has been shown in one study that montelukast does not affect the growth rate of paediatric patients when given for up to 56 weeks. The long-term clinical relevance of the growth rates studies is unknown.
In seasonal allergic rhinitis: montelukast has been studied in paediatric patients 2 to 14 years of age (see Section 4.2 Dose and Method of Administration). Safety in paediatric patients younger than two years of age has not been studied.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Relatively high concentrations of montelukast competitively inhibit the activity of cytochromes P450 3A4 and 2C9. However, these concentrations are at least 15-fold higher than the peak plasma concentrations attained following a 10 mg oral dose of montelukast. Theophylline plasma concentration was not affected by the recommended dose of montelukast (10 mg once daily). At 20 and 60-fold above the recommended dose, plasma concentration of concomitant theophylline was decreased. Theophylline dose adjustment or a change in the frequency of plasma theophylline monitoring is not necessary at the recommended dose of montelukast.
Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma, and in the treatment of allergic rhinitis. In drug interactions studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/ norethisterone 35/1), terfenadine, digoxin and warfarin. The effects of concomitant administration of montelukast and macrolide antimicrobials have not been studied.
The area under the plasma concentration time curve (AUC) for montelukast was decreased approximately 40% in subjects with coadministration of phenobarbital. No dosage adjustment for montelukast is recommended.
In vitro studies have shown that montelukast is an inhibitor of CYP2C8. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo. Therefore, montelukast is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g. paclitaxel, rosiglitazone, repaglinide).
In vitro studies have shown that montelukast is a substrate of CYP2C8, 2C9 and 3A4. Data from a clinical drug-drug interaction study involving montelukast and gemfrozil (an inhibitor of both CYP2C8 and 2C9) demonstrated that gemfibrozil increased the systemic exposure of montelukast by 4.4 fold. Co-administration of itraconazole, a strong CYP3A4 inhibitor, with gemfibrozil and montelukast did not further increase the systemic exposure of montelukast. Based on available clinical experience no dosage adjustment of montelukast is required upon administration with gemfibrozil or other inhibitors of CYP2C8. Specific in vivo data are not available for other known inhibitors of CYP2C8 (e.g. trimethoprim). Although clinically important drug interactions are not anticipated based on these findings, systemic exposure to montelukast is potentially increased and the physician should be aware of a possible increase in adverse reactions (see Section 4.9 Overdose). Co-administration of montelukast with itraconazole alone resulted in no significant increase in the systemic exposure of montelukast.
Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, nonsteroidal anti-inflammatory agents, benzodiazepines and decongestants.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility and reproductive performance were not affected in studies with male rats given oral doses of up to 800 mg/kg/day, but fecundity was slightly reduced in female rats doses orally at 200 mg/kg/day. The no effect dose for the latter effect was 100 mg/kg/day, corresponding to systemic exposure, in terms of plasma AUC for parent drug, at least 20 times higher than that in women at recommended dose levels.
(Category B1)
In animal studies, montelukast sodium had no adverse effects on embryofoetal development at oral doses up to 400 mg/kg/day in rats or up to 100 mg/kg/day in rabbits. Retardation of foetal growth and development was observed in rabbits dosed at 200 mg/kg/day, a dose level associated with severe maternal toxicity. Foetal exposure of montelukast was demonstrated in both species. Montelukast has not been studied in pregnant women. Montelukast should be used during pregnancy only if clearly needed.
During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women being treated with montelukast during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and montelukast has not been established.
Studies in lactating rats have shown that montelukast is excreted into milk following oral doses of 100 and 200 mg/kg/day, and growth of the pups was slightly inhibited at the higher dose level. It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when montelukast is given to a nursing mother.

4.8 Adverse Effects (Undesirable Effects)

Montelukast has been generally well tolerated. Side effects, which usually were mild, generally did not require discontinuation of therapy. The overall incidence of side effects reported with montelukast was comparable to placebo.

Adults 15 years of age and older with asthma.

Montelukast has been evaluated for safety in approximately 2600 adult patients 15 years of age and older in clinical studies. In two similarly designed, 12 week placebo controlled clinical studies, the only adverse experiences reported as drug related in ≥ 1% of patients treated with montelukast and at a greater incidence than in patients treated with placebo were abdominal pain and headache. The incidences of these events were not significantly different in the two treatment groups.
In placebo controlled clinical studies, the following adverse experiences reported with montelukast occurred in ≥ 1% of patients and at an incidence greater than or equal to that in patients treated with placebo, regardless of drug relationship (see Table 1).

Cumulatively, 544 patients were treated with montelukast for at least 6 months, 253 for one year and 21 for two years in clinical studies. With prolonged treatment, the adverse experience profile did not change.

Paediatric patients 6 to 14 years of age with asthma.

Montelukast has been evaluated for safety in approximately 970 paediatric patients 6 to 14 years of age. The safety profile in paediatric patients is generally similar to the adult safety profile and to placebo. Cumulatively, 263 paediatric patients 6-14 years of age were treated with montelukast for at least 3 months, 164 for 6 months or longer in clinical studies. The safety profile in paediatric patients is generally similar to the adult safety profile and to placebo. With prolonged treatment, the adverse experience profile did not change.
In a 56 week active controlled study comparing montelukast to inhaled fluticasone in paediatric patients 6-14 years of age with mild persistent asthma, the safety profile was consistent with the safety profile previously described for montelukast. In the study, the number of patients with asthma symptoms after treatment was 166 (33.5%) patients in the montelukast treatment group and 135 (27.1%) patients in the fluticasone treatment group.
In studies evaluating growth rate, the safety profile in these paediatric patients was consistent with the safety profile previously described for montelukast.

Paediatric patients 2 to 5 years of age with asthma.

Montelukast has been evaluated in 573 paediatric patients 2 to 5 years of age. In a 12 week placebo controlled clinical study, the only adverse experience reported as drug related in > 1% of patients treated with montelukast and at a greater incidence than in patients treated with placebo was thirst. The incidence of thirst was not significantly different in the two treatment groups.
Cumulatively, 502 paediatric patients 2 to 5 years of age were treated with montelukast for at least 3 months, 338 for 6 months or longer, and 256 patients for 12 months or longer. With prolonged treatment, the adverse experience profile did not change.

Adults 15 years of age and older with seasonal allergic rhinitis.

Montelukast has been evaluated in 2199 adult patients 15 years of age and older for the treatment of seasonal allergic rhinitis in clinical studies. Montelukast administered once daily in the morning or in the evening was generally well tolerated with a safety profile similar to that of placebo. In placebo controlled clinical studies, no adverse experiences reported as drug related in ≥ 1% of patients treated with montelukast and at a greater incidence than in patients treated with placebo were observed. In a 4 week, placebo controlled clinical study, the safety profile was consistent with that observed in 2 week studies. The incidence of somnolence was similar to that of placebo in all studies.

Paediatric patients 2 to 14 years of age with seasonal allergic rhinitis.

Montelukast has been evaluated in 280 paediatric patients 2 to 14 years of age for the treatment of seasonal allergic rhinitis in a 2 week, placebo controlled, clinical study.
Montelukast administered once daily in the evening was generally well tolerated with a safety profile similar to that of placebo. In this study, no adverse experiences reported as drug related in ≥ 1% of patients with montelukast and at a greater incidence than in patients treated with placebo were observed.

Adults 15 years of age and older with asthma and seasonal allergic rhinitis.

Montelukast 10 mg film coated tablets have been evaluated in approximately 400 asthmatic patients 15 years of age and older with seasonal allergic rhinitis. The safety profile in asthmatic patients with seasonal allergic rhinitis was consistent with that observed in patients with asthma.

Post-marketing experience.

The following additional side effects have been reported in post-marketing use.

Infections and infestations.

Upper respiratory tract infection.

Blood and lymphatic system disorders.

Increased bleeding tendency, thrombocytopenia.

Immune system disorders.

Hypersensitivity reactions including anaphylaxis, very rarely hepatic eosinophilic infiltration.

Psychiatric disorders.

Agitation including aggressive behaviour or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, memory impairment, obsessive-compulsive symptoms, psychomotor hyperactivity (including irritability, restlessness and tremor), somnambulism (sleep walking), suicidal thinking and behaviour (suicidality), tic.

Nervous system disorders.

Dizziness, drowsiness, paraesthesia/ hypoesthesia, very rarely seizure.

Cardiac disorders.

Palpitations.

Respiratory, thoracic and mediastinal disorders.

Epistaxis, pulmonary eosinophilia.

Gastrointestinal disorders.

Diarrhoea, dyspepsia, nausea, vomiting.

Hepatobiliary disorders.

Increased ALT and AST, very rarely hepatitis (including cholestatic, hepatocellular, and mixed pattern liver injury).

Skin and subcutaneous tissue disorders.

Angioedema, bruising, erythema multiforme, erythema nodosum, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders.

Arthralgia, myalgia including muscle cramps.

Renal and urinary disorders.

Enuresis in children.

General disorders and administration site conditions.

Oedema, pyrexia.
In rare cases, patients on therapy with montelukast may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. A causal association between montelukast and these underlying conditions has not been established (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

APO-Montelukast tablets are intended for oral administration.

Dosage.

Asthma and/or seasonal allergic rhinitis.

Montelukast should be taken once daily.
For asthma, the dose should be taken in the evening.
For seasonal allergic rhinitis, the time of administration may be individualised to suit patient needs.
Patients with both asthma and seasonal allergic rhinitis should take only one tablet daily in the evening.

Adults 15 years of age and older.

The dosage for adults 15 years of age and older is one 10 mg tablet daily.

Paediatric patients 6 to 14 years of age.

The dosage for paediatric patients 6 to 14 years of age is one 5 mg chewable tablet daily.
Chew the tablets. Do not swallow whole.

Paediatric patients 2 to 5 years of age.

The dosage for paediatric patients 2 to 5 years of age is one 4 mg chewable tablet daily.
Chew the tablets. Do not swallow whole.

General recommendations.

The therapeutic effect of montelukast on parameters of asthma control occurs within one day. Montelukast may be taken with or without food. Patients should be advised to continue taking montelukast daily when their asthma is controlled, as well as during periods of worsening asthma.
No dosage adjustment is necessary for paediatric patients, for the elderly, for patients with renal insufficiency, or mild to moderate hepatic impairment, or for patients of either gender.

Therapy with montelukast in relation to other treatments for asthma.

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

Reduction in concomitant therapy.

Bronchodilator treatments.

Montelukast can be added to the treatment regimen of patients who are not adequately controlled on bronchodilator alone. When a clinical response is evident (usually after the first dose), the patient's bronchodilator therapy can be reduced as tolerated.

Inhaled corticosteroids.

Treatment with montelukast provides additional clinical benefit to patients treated with inhaled corticosteroids. A reduction in the corticosteroid dose can be made as tolerated. The dose should be reduced gradually with medical supervision. In some patients, the dose of inhaled corticosteroids can be tapered off completely. Montelukast should not be abruptly substituted for inhaled corticosteroids.

4.7 Effects on Ability to Drive and Use Machines

There is no evidence that montelukast affects the ability to drive and use machines. However, adverse effects of this medicine include dizziness and drowsiness, which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.9 Overdose

No specific information is available on the treatment of overdosage with montelukast. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks and in short-term studies, up to 900 mg/day to patients for approximately one week without clinically important adverse experiences.
There have been reports of acute overdosage in postmarketing experience and clinical studies with montelukast. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and paediatric patients. There were no adverse experiences in the majority of overdosage reports.
The most frequently occurring 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 dialyzable by peritoneal or haemodialysis.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each 10 mg film-coated tablet contains the following inactive ingredients:
Lactose, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, hypromellose, hyprolose, iron oxide yellow, iron oxide red, titanium dioxide.
Each 4 mg and 5 mg chewable tablet contains the following inactive ingredients:
Mannitol, microcrystalline cellulose, croscarmellose sodium, aspartame, magnesium stearate, Cherry 501027 AP0551, iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light and moisture.