Consumer medicine information

Montelukast Sandoz

Montelukast

BRAND INFORMATION

Brand name

Montelukast Sandoz Tablets

Active ingredient

Montelukast

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Montelukast Sandoz.

What is in this leaflet

This leaflet answers some common questions about MONTELUKAST SANDOZ® 4, 5, 10. 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 taking MONTELUKAST SANDOZ® 4, 5, 10 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 MONTELUKAST SANDOZ® 4, 5, 10 is used for

MONTELUKAST SANDOZ® 4, 5, 10 is used to prevent asthma symptoms, including those that occur during the day and at night-time. It also prevents the narrowing of airways triggered by exercise.

If you have seasonal allergic rhinitis (hay fever), MONTELUKAST SANDOZ® 4, 5, 10 also treats your allergic rhinitis symptoms.

It can be used in children 2 years of age and older, teenagers and adults.

MONTELUKAST SANDOZ® 4, 5, 10 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 SANDOZ® 4, 5, 10 each night or as prescribed.

As a preventive medicine for asthma, MONTELUKAST SANDOZ® 4, 5, 10 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 SANDOZ® 4, 5, 10.

Asthma is a lung disease and has the following characteristics:

  • narrowed airways causing breathing to become difficult
  • inflamed airways, which means the lining of airways become swollen
  • sensitive airways that react to many things, such as cigarette smoke, pollen, or cold air.

Symptoms of asthma include coughing, wheezing and chest tightness. Not all people with asthma wheeze. For some, coughing may be the only symptom of asthma.

Symptoms often occur during the night or after exercise.

For further information about asthma, contact the Asthma Foundation in your state on 1800 645 130, or www.asthmaaustralia.org.au

Seasonal allergic rhinitis (also known as hay fever) is an allergic response often caused by airborne pollens from trees, grasses, and weeds. The daytime and nighttime symptoms of seasonal allergic rhinitis typically may include: stuffy, runny, itchy nose; sneezing; watery, swollen, red, itchy eyes.

How MONTELUKAST SANDOZ® 4, 5, 10 works

MONTELUKAST SANDOZ® 4, 5, 10 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 SANDOZ® 4, 5, 10 improves seasonal allergic rhinitis symptoms.

Your doctor may have prescribed MONTELUKAST SANDOZ® 4, 5, 10 for another reason. Ask your doctor if you have any questions about why MONTELUKAST SANDOZ® 4, 5, 10 has been prescribed for you.

MONTELUKAST SANDOZ® 4, 5, 10 is not addictive.

Before you take it

When you must not take it

Do not take MONTELUKAST SANDOZ® 4, 5, 10 if:

  • you have an allergy to MONTELUKAST SANDOZ® 4, 5, 10 or any of the ingredients listed at the end of this leaflet
  • the packaging is torn or shows signs of tampering
  • the expiry date on the pack has passed.

If you take this medicine after the expiry date has passed, it may not work.

If you are not sure whether you should start taking MONTELUKAST SANDOZ®, 4, 5, 10 talk to your doctor.

Do not give MONTELUKAST SANDOZ® 4, 5, 10 to children under 2 years of age.

Safety and effectiveness in children younger than 2 years of age have not been studied.

In studies investigating the effect of MONTELUKAST SANDOZ® 4, 5, 10 on the growth rate of children, it was shown that MONTELUKAST SANDOZ® 4, 5, 10 did not affect the growth rate of children when given for up to 56 weeks in one study.

Before you start to take it

Tell your doctor if:

  1. you are pregnant or intend to become pregnant
    MONTELUKAST SANDOZ® 4, 5, 10 has not been studied in pregnant women.
  2. you are breast-feeding or plan to breast-feed
    It is not known if MONTELUKAST SANDOZ® 4, 5, 10 passes into breast milk.
  3. you have or have had any medical conditions
  4. your child has a condition called phenylketonuria
    The 5 mg and 4 mg chewable tablets contain aspartame, corresponding to 0.842 mg phenylalanine in each 5 mg tablet and 0.674 mg in each 4 mg tablet.
  5. you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell them before you take any MONTELUKAST SANDOZ® 4, 5, 10.

Taking other medicines

Some medicines may affect how MONTELUKAST SANDOZ® 4, 5, 10 works, or MONTELUKAST SANDOZ® 4, 5, 10 may affect how your other medicines work.

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

How to take it

How much to take

For patients with asthma and/or seasonal allergic rhinitis, take MONTELUKAST SANDOZ® 4, 5, 10 only when prescribed by your doctor.

  • For adults and teenagers 15 years and older, the dose is one 10 mg tablet taken each day.
  • For children 6 to 14 years old, the dose is one 5 mg chewable tablet taken each day.
  • For children 2 to 5 years old, the dose is one 4 mg chewable tablet taken each day.

For patients with asthma, take MONTELUKAST SANDOZ® 4, 5, 10 once a day in the evening.

For patients with seasonal allergic rhinitis, take MONTELUKAST SANDOZ® 4, 5, 10 once a day as prescribed by your doctor.

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How to take it

MONTELUKAST SANDOZ® 4, 5, 10 comes as three types of tablets:

  • 10 mg tablets for adults and teenagers 15 years and older
  • 5 mg chewable tablets for children 6-14 years old
  • 4 mg chewable tablets for children 2-5 years old.

Swallow the 10 mg tablet with a glass of water.

Chew the 5 mg or 4 mg chewable tablets thoroughly and swallow.

When to take it

Asthma:
Take your MONTELUKAST SANDOZ® 4, 5, 10 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:
Take your MONTELUKAST SANDOZ® 4, 5, 10 once a day as prescribed by your doctor.

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

Asthma and seasonal allergic rhinitis:
Take your MONTELUKAST SANDOZ® 4, 5, 10 at bedtime each day if you have both asthma and seasonal allergic rhinitis.

It does not matter if you take MONTELUKAST SANDOZ® 4, 5, 10 before or after food.

How long to take it

MONTELUKAST SANDOZ® 4, 5, 10 helps control your asthma. Therefore MONTELUKAST SANDOZ® 4, 5, 10 must be taken every day. Continue taking MONTELUKAST SANDOZ® 4, 5, 10 for as long as your doctor prescribes.

If you forget to take it

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

Do not take a double dose to make up for the dose that you missed.

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, if you think that you or anyone else may have taken too much MONTELUKAST SANDOZ®. 4, 5, 10 Do this even if there are no signs of discomfort or poisoning.

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

While you are using it

Things you must do

Continue taking MONTELUKAST SANDOZ® 4, 5, 10 every day as directed by your doctor, even if you have no asthma symptoms or if you have an asthma attack.

If your asthma gets worse while taking MONTELUKAST SANDOZ® 4, 5, 10, tell your doctor immediately.

If an acute attack of asthma occurs, follow your doctor's instructions on what reliever medicine to use to relieve the attack.

If you experience behaviour and mood-related changes while taking MONTELUKAST SANDOZ® 4, 5, 10, tell your doctor immediately.

If you become pregnant while taking MONTELUKAST SANDOZ® 4, 5, 10, tell your doctor immediately.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking MONTELUKAST SANDOZ® 4, 5, 10.

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 SANDOZ® 4, 5, 10 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 MONTELUKAST SANDOZ® 4, 5, 10 to anyone else, even if they have the same condition as you.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking MONTELUKAST SANDOZ® 4, 5, 10.

MONTELUKAST SANDOZ® 4, 5, 10 helps most people with asthma and/or seasonal allergic rhinitis, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • fluid retention
  • nose bleed
  • headache, dizziness, drowsiness
  • feeling unusually weak or tired
  • upper respiratory tract infection

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

Tell your doctor if you notice any of the following behaviour and mood-related changes :

  • agitation, including aggressive behaviour and/or hostility
  • tremor
  • irritability, restlessness, feeling anxious
  • depression
  • disorientation
  • seeing, feeling or hearing things that are not there (also called hallucinations)
  • dream abnormalities, difficulty sleeping
  • sleep walking

These are usually mild side effects of MONTELUKAST SANDOZ® 4, 5, 10.

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

  • skin rash or itchiness
  • increased tendency to bleed, bruising
  • fast or irregular heart beats, also called palpitations
  • symptoms of liver disease such as nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine
  • suicidal thoughts and actions

These may be serious side effects.

You may need urgent medical attention. Serious side effects are rare.

If any of the following happen, stop taking MONTELUKAST SANDOZ® 4, 5, 10 and tell your doctor immediately or go to accident and emergency at your nearest hospital:

  • swelling of the face, lips, mouth, throat or tongue which may cause difficulty in breathing or swallowing
  • pinkish, itchy swellings on the skin, also called hives or nettlerash, severe skin reactions that may occur without warning
  • seizure

These may be serious side effects. If you have them, you may be having a serious allergic reaction to MONTELUKAST SANDOZ® 4, 5, 10. You may need urgent medical attention. These side effects are rare.

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

Tell your doctor if you notice any other effects.

After using it

Storage

Keep your tablets in the blister pack until it is time to take them.

If you take the tablets out the blister pack they may not keep well.

Keep MONTELUKAST SANDOZ® 4, 5, 10 in a cool dry place, away from light, where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it 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 the tablets, or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

MONTELUKAST SANDOZ® 4, 5, 10 comes as three types of tablets:

  • 10 mg tablet - Beige coloured, rounded square, biconvex, film coated tablet debossed "M10" on one side and plain on other side.
  • 5 mg chewable tablet - Pink colored, mottled, round, biconvex, uncoated chewable tablet, debossed "M5" on one side and plain on other side.
  • 4 mg chewable tablet Pink colored, mottled, oval, biconvex, uncoated chewable tablet, debossed "M4" on one side and plain on other side.

A box of MONTELUKAST SANDOZ® 4, 5, 10 contains 28 tablets.

Ingredients

Active ingredient:

  • 10 mg tablet contains 10 mg Montelukast
  • 5 mg chewable tablet contains 5 mg montelukast
  • 4 mg chewable tablet contains 4 mg montelukast

Inactive ingredients:

10 mg tablets

  • microcrystalline cellulose
  • lactose
  • hydroxypropyl cellulose
  • croscarmellose sodium
  • magnesium stearate
  • hypromellose
  • titanium dioxide
  • macrogol 6000
  • iron oxide red CI77491
  • iron oxide yellow CI77492

5 mg and 4 mg chewable tablets

  • mannitol
  • microcrystalline cellulose
  • croscarmellose sodium
  • aspartame
  • cherry flavour
  • iron oxide red CI77491
  • magnesium stearate

MONTELUKAST SANDOZ® 4, 5, 10 do not contain gluten, sucrose, tartrazine or any other azo dyes.

The 10 mg tablets contain lactose; the 5 mg and 4 mg chewable tablets do not.

Name and Address of the Sponsor

Accord Healthcare Pty Ltd.
Unit 702/23,
Queens Road,
Melbourne, Victoria, 3004
Australia

  • MONTELUKAST SANDOZ® 10:
    AUST R 184830
  • MONTELUKAST SANDOZ® 5:
    AUST R 184833
  • MONTELUKAST SANDOZ® 4:
    AUST R 184832

Date of first inclusion in the ARTG
17th May 2012

Date of preparation
08 October 2012

BRAND INFORMATION

Brand name

Montelukast Sandoz Tablets

Active ingredient

Montelukast

Schedule

S4

 

Name of the medicine

Montelukast sodium.

Excipients.

10 mg tablet.

Microcelac 100 (lactose and microcrystalline cellulose), low substituted HPC (hydroxypropyl cellulose), croscarmellose sodium, and magnesium stearate. The film coating consists of: hydroxypropylcellulose, hypromellose, titanium dioxide, macrogol 6000, iron oxide red CI77491 and iron oxide yellow CI77492.

4 mg and 5 mg chewable tablet.

Mannitol, microcrystalline cellulose, croscarmellose sodium, aspartame, cherry 501027 AP0551 (PI ID. 107148), iron oxide red CI77491 and magnesium stearate.

Description

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. MW: 608.18. CAS: 151767-02-1. Montelukast sodium is a selective and orally active leukotriene receptor antagonist that specifically inhibits the cysteinyl leukotriene CysLT1 receptor. 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.

Pharmacology

Pharmacodynamics.

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.

Pharmacokinetics.

Absorption.

Montelukast is rapidly and nearly completely absorbed following oral administration. For the 10 mg film coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal.
For the 5 mg chewable tablet, the Cmax 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, Cmax 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 radiolabeled 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.

Elimination.

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 fecal 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.

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 tablets, 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 tablets 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 tablets 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 tablets 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 nighttime 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 x 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 Precautions).

Effects on exercise induced bronchoconstriction.

Montelukast tablets, 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 Nighttime Symptoms score [mean of nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings scores]) (see Table 1). 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.

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 nighttime symptoms scores), compared with placebo.
The efficacy results of one trial are shown below. 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 2. 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 3). 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.

Indications

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

Contraindications

Hypersensitivity to any component of this product.

Precautions

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 Clinical Trials, Asthma).

Neuropsychiatric events.

Neuropsychiatric events have been reported in adult, adolescent, and paediatric patients taking montelukast. Postmarketing 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.

The reduction in systemic corticosteroid dose in patients receiving antiasthma agents including leukotriene receptor antagonists has been followed in rare cases by the occurrence of 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. Although a causal relationship with leukotriene receptor antagonism has not been established, caution and appropriate clinical monitoring are recommended when systemic corticosteroid reduction is considered in patients receiving montelukast.
4 mg and 5 mg chewable tablets contain aspartame which is a source of phenylalanine (0.842 mg phenylalanine per 5 mg chewable tablet, and 0.674 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 Clinical Trials, Asthma).

Carcinogenicity, mutagenicity and impairment of fertility.

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.
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.
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.

Use in pregnancy.

(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.

Use in lactation.

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.

Paediatric use.

In asthma.

Montelukast has been studied in paediatric patients six months to 14 years of age (see Dosage and 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 Dosage and Administration). Safety in paediatric patients younger than two years of age has not been studied.

Use in the elderly.

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

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 tablets (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 tablets.
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 (ethinylestradiol/ 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 tablets is recommended.
In vitro studies have shown that montelukast is an inhibitor of CYP 2C8. 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).
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.

Adverse 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.
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 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.

Postmarketing experience.

The following additional side effects have been reported in postmarketing use.

Infections and infestations.

Upper respiratory tract infection.

Blood and lymphatic system disorders.

Increased bleeding tendency.

Immune system disorders.

Hypersensitivity reactions including anaphylaxis, very rarely hepatic eosinophilic infiltration.

Psychiatric disorders.

Agitation including aggressive behaviour or hostility, anxiousness, depression, disorientation, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism (sleep walking), suicidal thinking and behaviour (suicidality), tremor.

Nervous system disorders.

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

Cardiac disorders.

Palpitations.

Respiratory, thoracic and mediastinal disorders.

Epistaxis.

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.

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 Precautions).

Dosage and Administration

Asthma and/or seasonal allergic rhinitis.

Montelukast tablets 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.

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.

General recommendations.

The therapeutic effect of montelukast tablet on parameters of asthma control occurs within one day. Montelukast tablets may be taken with or without food. Patients should be advised to continue taking montelukast tablet 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.

Overdosage

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 hemodialysis.

Presentation

Tablets, 10 mg (≡ 10.4 mg montelukast sodium) (beige, rounded square, biconvex, film coated, marked M10 on one side, plain on reverse): 4's*, 14's*, 28's (blister pack).
Chewable tablets (pink, mottled, biconvex, uncoated, plain on one side), 4 mg (≡ 4.16 mg montelukast sodium) (oval, marked M4 on reverse), 5 mg (≡ 5.2 mg montelukast sodium) (round, marked M5 on reverse): 4's*, 14's*, 28's (blister pack).
*Not currently marketed in Australia.

Storage

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

Poison Schedule

S4.