MONTELUKAST GH montelukast (as sodium) 5 mg chewable tablet blister pack

Main information

  • Trade name:
  • MONTELUKAST GH montelukast (as sodium) 5 mg chewable tablet blister pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • MONTELUKAST GH montelukast (as sodium) 5 mg chewable tablet blister pack
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 189229
  • Last update:
  • 22-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

189229

MONTELUKAST GH montelukast (as sodium) 5 mg chewable tablet blister pack

ARTG entry for

Medicine Registered

Sponsor

Torrent Australasia Pty Ltd

Postal Address

Coleman & Greig L9/10 George St,PARRAMATTA, NSW, 2150

Australia

ARTG Start Date

1/08/2012

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. MONTELUKAST GH montelukast (as sodium) 5 mg chewable tablet blister pack

Product Type

Single Medicine Product

Effective date

26/03/2014

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

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

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Blister Pack

PA/Al/PVC/Al -

polyamide-aluminium

foil-polyvinylchloride/al

uminium foil

36 Months

Store below 30

degrees Celsius

Not recorded

Protect from Light

Protect from Moisture

Pack Size/Poison information

Pack Size

Poison Schedule

28 tablets

(S4) Prescription Only Medicine

Components

1. MONTELUKAST GH montelukast (as sodium) 5 mg tablet blister pack

Dosage Form

Tablet, chewable

Route of Administration

Oral

Visual Identification

pink coloured, round shaped, uncoated tablets with score line on both sides

Active Ingredients

montelukast sodium

5.2 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 29.11.2017 at 12:36:01 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

Page 1 of 23

PRODUCT INFORMATION

Montelukast GH 4mg, 5mg and 10mg

NAME OF MEDICINE

Montelukast sodium

DESCRIPTION

Montelukast sodium, the active ingredient in Montelukast GH, is a selective and orally active

leukotriene receptor antagonist that inhibits the cysteinylleukotriene

CysL

T1 receptor.

Montelukast

sodium

described

chemically

sodium

[1-[[[(1

R

)-1-[3-[(

E

)-2-(7-

chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-

methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetate.

empirical

formula

ClNNaO

S, and

molecular

weight

608.18.

structural formula is:

CAS Number: 151767-02-1

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.

Each 10-mg tablet contains 10.4 mg montelukast sodium, which is equivalent to 10.0 mg of

montelukast, the free acid. Each 5-mg chewable tablet contains 5.2 mg montelukast sodium,

which is equivalent to 5.0 mg of montelukast, the free acid. Each 4-mg chewable tablet

contains 4.16 mg montelukast sodium, which is equivalent to 4.0 mg of montelukast, the free

acid.

Each 10-mg tablet contains the following inactive ingredients: mannitol, microcrystalline

cellulose,

croscarmellose

sodium,

iron

oxide

red,

iron

oxide

yellow,

cherry

flavour,

aspartame and magnesium stearate. Each 4-mg and 5-mg chewable tablet contains the

following

inactive

ingredients:

mannitol,

microcrystalline

cellulose,

iron

oxide

red,

croscarmellose sodium, cherry flavour, aspartame, and magnesium stearate.

Page 2 of 23

PHARMACOLOGY

Pharmacodynamics

cysteinyl

leukotrienes

(LTC

potent

inflammatory

eicosanoids

released from various cells including mast cells and eosinophils. These important pro-

asthmatic 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 pro-inflammatory 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,

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.

effect

montelukast

reduction

peripheral

blood

eosinophils

comparable

inhaled

corticosteroids.

Based

biochemical

pharmacological bioassays, it binds with high affinity and selectivity to the CysLT

receptor

(in preference to other pharmacologically important airway receptors such as the prostanoid,

cholinergic, or β-adrenergic receptor). Montelukast potently inhibits physiologic actions of

, LTD

, and LTE

at the CysLT

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 LTD

dose

5-mg

causes

substantial

blockage

-induced

bronchoconstriction.

Montelukast causes bronchodilation within 2 hours of oral administration. β-agonists caused

additive effects when added to montelukast.

Page 3 of 23

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

) is achieved 3 hours

) after administration in adults in the fasted state. The mean oral bioavailability is 64%.

The oral bioavailability and C

are not influenced by a standard meal.

For the 5-mg chewable tablet, the C

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

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 liters. 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 ng/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

.

Page 4 of 23

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

Clinical Studies-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 nighttime 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.

Page 5 of 23

Adults 15 years of age and older

similarly-designed

12-week

double-blind

placebo-controlled

studies

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

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’

patients’

global

asthma

evaluations

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 (FEV

), 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 mcg 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 FEV

). However in a high proportion of patients the response was comparable, for

example,

patients

taking

montelukast

compared

with

patients

taking

beclomethasone achieved an 11% or more increase in FEV

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

Page 6 of 23

paediatric

asthma-specific

quality-of-life

evaluations,

compared

with

placebo.

Montelukast also significantly improved morning FEV

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 μg 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)

patients

treated

with

inhaled

beclomethasone

(200

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

asthma

control

irrespective

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 nighttime 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

Page 7 of 23

[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 10

/ μL, 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 μg per day reduced their steroid use by approximately 37% during a

placebo

run-in

period.

Montelukast

allowed

further

reduction

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 μg 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

non-steroidal anti- inflammatory drugs in aspirin-sensitive asthmatic patients has not been

evaluated (see PRECAUTIONS)

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 FEV

over 60 minutes after exercise, the maximal percent

fall in FEV

after exercise, and the time to recovery to within 5% of the pre-exercise FEV

Protection was consistent through the treatment period indicating that tolerance did not occur.

In a separate cross-over 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

Page 8 of 23

designed cross-over 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

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, rhinorrhoea, 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.

Page 9 of 23

TABLE 1

Daily Rhinitis Symptom Score

Treatment Group

Change

from

Baseline

Mean

(SD)

Treatment Difference:

Montelukast Minus Placebo

LS Mean Difference

(95% CI)

p-Value

Montelukast

-0.35 (0.48)

-0.12

(-0.18, -0.06)

≤ 0.001

Placebo

-0.24 (0.46)

Clinical Studies - 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,

active

symptoms

seasonal

allergic

rhinitis

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, rhinorrhoea, nasal itching, and sneezing); nighttime symptoms score, and its

individual components (nasal congestion upon awakening, difficulty going to sleep, and

nighttime awakenings); daytime eye symptoms score, and its individual components (tearing,

itchy,

red,

puffy

eyes);

global

evaluation

allergic

rhinitis

patients

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,

Page 10 of 23

loratadine

placebo

shown

TABLE

mean

change

from

baseline

montelukast was 50% larger than the mean change from baseline for placebo.

TABLE 2

Effects of Montelukast on Daytime Nasal Symptoms Score* in a Placebo- and Active-

controlled Trial in Patients with Seasonal Allergic Rhinitis

Treatment Group (N)

Baseline

Mean Score

Mean

Change

from

Baseline

Difference

Between

Treatment

Placebo (95% CI)

Least-Squares

Mean

Montelukast 10 mg (344)

2.09

-0.39

-0.13

(-0.21,

0.06)

Placebo (351)

2.10

-0.26

N.A.

Active Control

(Loratadine 10 mg) (599)

2.06

-0.46

-0.24

(-0.31,

0.17)

*Average of individual scores of nasal congestion, rhinorrhoea, nasal itching, sneezing as assessed by patients on a 0-3 categorical scale.

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

Statistically different from placebo (p≤0.001).

Page 11 of 23

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

effect

observed

studies

using

evening

dosing

(see

TABLE

Additionally, the effect over the entire 4 weeks was consistent with the 2-week results (see

Figure 1).

TABLE 3

Effects of Montelukast on Daytime Nasal Symptoms Score* in a Placebo- and Active-

controlled Trial in Patients with Seasonal Allergic Rhinitis

Treatment Group (N)

Baseline

Mean Score

Mean

Change

from Baseline

Difference

Between

Treatment

Placebo (95% CI)

Least-Squares

Mean

Montelukast 10 mg (445)

2.19

-0.32

-0.10

††

(-0.16,

0.03)

Placebo (448)

2.16

-0.20

N.A.

Active Control

(Loratadine 10 mg) (180)

2.23

-0.45

-0.22

(-0.31,

0.13)

* Average of individual scores of nasal congestion, rhinorrhoea, nasal itching, sneezing as assessed by patients on a 0-3

categorical scale.

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

†† Statistically different from placebo (p=0.003); ‡ Statistically different from placebo (p≤0.001).

Page 12 of 23

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.

Page 13 of 23

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 the active substance or to any of the excipients.

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 Studies - Asthma

Neuropsychiatric Events

Neuropsychiatric events have been reported in adult, adolescent, and paediatric patients

taking

montelukast.

Post-marketing

reports

with

montelukast

include

agitation,

aggressive

behaviour

hostility,

anxiousness,

depression,

dream

abnormalities,

hallucinations,

insomnia,

irritability,

restlessness,

somnambulism,

suicidal

thinking

behaviour (including suicidality), and tremor. The clinical details of some post-marketing

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

reduction

systemic

corticosteroid

dose

patients

receiving

anti-asthma

agents

including leukotriene receptor antagonists has been followed in rare cases by the occurrence

more

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

Page 14 of 23

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

effective

improving

airway

function

asthmatics

with

documented aspirin sensitivity, it has not been shown to modify bronchoconstrictor response

to aspirin challenge and other non-steroidal anti-inflammatory drugs in aspirin-sensitive

asthmatic

patients.

Therefore,

patients

with

known

aspirin

sensitivity

should

continue

avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast. (see

PHARMACOLOGY, Clinical Studies - Asthma).

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 recommened dose levels.

Use in Pregnancy (Category B1)

(Australian Categorisation B1): Drugs which have been taken by only a limited number of

pregnant women and women of childbearing age, without an increase in the frequency of

malformation or other direct or indirect harmful effects on the human fetus having been

observed. Studies in animals have not shown evidence of an increased occurrence of fetal

damage.

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

Page 15 of 23

women

were

also

taking

other

asthma

medications

during

their

pregnancy.

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.

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.

Gentoxicity

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

Page 16 of 23

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.

INTERACTIONS WITH OTHER MEDICINES

Relatively

high

concentrations

montelukast

competitively

inhibit

activity

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

affected

recommended

dose

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

frequency

plasma

theophylline

monitoring

necessary

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

pharmacokinetics

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

subjects

with

co-administration

phenobarbital.

dosage

adjustment for Montelukast GH 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).

Page 17 of 23

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

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.

placebo-controlled

clinical

studies,

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:

Page 18 of 23

ADVERSE EXPERIENCES OCCURRING IN ≥1% OF PATIENTS WITH AN INCIDENCE GREATER THAN OR

EQUAL TO THAT IN PATIENTS TREATED WITH PLACEBO, REGARDLESS OF DRUG RELATIONSHIP

Montelukast

10-mg/day

(n = 1955)

Placebo

(n = 1180)

Body As A Whole

Asthenia/fatigue

Fever

Pain, abdominal

Trauma

Digestive System Disorders

Diarrhoea

Dyspepsia

Gastroenteritis, infectious

Pain, dental

Nervous System/Psychiatric

Dizziness

Headache

18.4

18.1

Insomnia

Respiratory System Disorders

Congestion, nasal

Cough

Influenza

Skin/Skin Appendages Disorder

Rash

Laboratory Adverse Experiences*

ALT increased

AST increased

Pyuria

Number of patients tested (Montelukast and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924,

1159.

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.

Page 19 of 23

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

seasonal

allergic

rhinitis

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

Page 20 of 23

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

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

subcutaneous

tissue

disorders:

angioedema,

bruising,

erythema

multiforme,

erythema nodosum, pruritus, rash, urticaria

Musculoskeletal

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

vasculitis

consistent with

Churg-Strauss

syndrome. These events usually, but not always, have been associated with the reduction of

Page 21 of 23

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 GH 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

Montelukast GH may be taken with or without food. Tablets are not to be broken prior to

oral administration.

The therapeutic effect of montelukast on parameters of asthma control occurs within one day.

Patients should be advised to continue taking Montelukast GH 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:

Page 22 of 23

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

paediatric

patients.

There

were

adverse

experiences

majority

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 AND STORAGE

Montelukast GH is supplied in three tablet presentations as follows:

10-mg tablet - Light brown colored, round biconvex shaped, uncoated tablets, with a

score line on both sides. Supplied in blister packs of 4 x 7 tablets.

5-mg chewable tablet -

pink colored, round shaped, uncoated, chewable tablets, with a

score line on both sides

. Supplied in blister packs of 4 x 7 tablets.

4-mg chewable tablet - pink colored, oval biconvex shaped, uncoated, chewable

tablets, with a score line on both sides. Supplied in blister packs of 4 x 7 tablets.

Page 23 of 23

Store below 30°C. Store in the original package in order to protect from light and moisture.

NAME AND ADDRESS OF THE SPONSOR

Torrent Australasia Pty Ltd

Level 9, 100 George Street,

Parramatta NSW 2150

Australia

POISON SCHEDULE

Prescription Only Medicine (Schedule 4)

Date of first inclusion in the Australian Register of Therapeutic Goods (ARTG)

: 13

July 2012