Montelukast Sodium is indicated in the treatment of asthma as add-on therapy in those
patients with mild to moderate persistent asthma who are inadequately controlled on
inhaled corticosteroids and in whom “as-needed” short-acting β-agonists provide
inadequate clinical control of asthma.
Montelukast Sodium may also be an alternative treatment option to low-dose inhaled
corticosteroids for patients with mild persistent asthma who do not have a recent history
of serious asthma attacks that required oral corticosteroid use, and who have
demonstrated that they are not capable of using inhaled corticosteroids.
Montelukast Sodium is also indicated in the prophylaxis of asthma in which the
predominant component is exercise-induced bronchoconstriction.

Posology
The recommended dose for paediatric patients 6-14 years of age is one 5 mg chewable
tablet daily to be taken in the evening. If taken in connection with food, Montelukast
Sodium should be taken 1 hour before or 2 hours after food. No dosage adjustment within
this age group is necessary.

General recommendations
The therapeutic effect of Montelukast Sodium on parameters of asthma control occurs
within one day. Patients should be advised to continue taking Montelukast Sodium even if
their asthma is under control, as well as during periods of worsening asthma.
No dosage adjustment is necessary for patients with renal insufficiency, or mild to
moderate hepatic impairment. There are no data on patients with severe hepatic
impairment. The dosage is the same for both male and female patients.
Montelukast Sodium as an alternative treatment option to low-dose inhaled
corticosteroids for mild persistent asthma
Montelukast is not recommended as monotherapy in patients with moderate persistent
asthma. The use of montelukast as an alternative treatment option to low-dose inhaled
corticosteroids for children with mild persistent asthma should only be considered for
patients who do not have a recent history of serious asthma attacks that required oral
corticosteroid use and who have demonstrated that they are not capable of using inhaled
corticosteroids (see section 4.1). Mild persistent asthma is defined as asthma symptoms
more than once a week but less than once a day, nocturnal symptoms more than twice a
month but less than once a week, normal lung function between episodes. If satisfactory
control of asthma is not achieved at follow-up (usually within one month), the need for
an additional or different anti-inflammatory therapy based on the step system for asthma
therapy should be evaluated. Patients should be periodically evaluated for their asthma
control.
Therapy with Montelukast Sodium in relation to other treatments for asthma
When treatment with Montelukast Sodium is used as add-on therapy to inhaled
corticosteroids, Montelukast Sodium should not be abruptly substituted for inhaled
corticosteroids.
10 mg tablets are available for adults and adolescents 15 years of age and older.
Paediatric population
Do not give Montelukast Sodium 5 mg chewable tablets to children less than 6 years of
age. The safety and efficacy of Montelukast Sodium 5 mg chewable tablets in children
less than 6 years of age has not been established.
4 mg chewable tablets are available for paediatric patients 2 to 5 years of age.
4 mg granules are available for paediatric patients 6 months to 5 years of age.

Method of administration
Oral use.
The tablets are to be chewed before swallowing.

Patients should be advised never to use oral montelukast to treat acute asthma attacks
and to keep their usual appropriate rescue medication for this purpose readily available. If
an acute attack occurs, a short-acting inhaled β-agonist should be used. Patients should
seek their doctors' advice as soon as possible if they need more inhalations of short-acting
β-agonists than usual.
Montelukast should not be abruptly substituted for inhaled or oral corticosteroids.
There are no data demonstrating that oral corticosteroids can be reduced when
montelukast is given concomitantly.
In rare cases, patients on therapy with anti-asthma agents including montelukast may
present with systemic eosinophilia, sometimes presenting with clinical features of
vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with
systemic corticosteroid therapy. These cases have been sometimes associated with the
reduction or withdrawal of oral corticosteroid therapy. Although a causal relationship with
leukotriene receptor antagonism has not been established, physicians should be alert to
eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications,
and/or neuropathy presenting in their patients. Patients who develop these symptoms
should be reassessed and their treatment regimens evaluated.
Treatment with montelukast does not alter the need for patients with aspirin-sensitive
asthma to avoid taking aspirin and other non-steroidal anti-inflammatory drugs.
Montelukast Sodium contains aspartame, a source of phenylalanine. Patients with
phenylketonuria should take into account that each 5 mg chewable tablet contains
phenylalanine in an amount equivalent to 0.842 mg phenylalanine per dose.

Montelukast may be administered with other therapies routinely used in the prophylaxis
and chronic treatment of asthma.

In drug-interactions studies, the recommended clinical dose of montelukast did not have
clinically important effects on the pharmacokinetics of the following medicinal products:
theophylline, prednisone, prednisolone, oral contraceptives (ethinyl
oestradiol/norethindrone 35/1), terfenadine, digoxin and warfarin.
The area under the plasma concentration curve (AUC) for montelukast was decreased
approximately 40% in subjects with co-administration of phenobarbital. Since montelukast
is metabolised by CYP 3A4, 2C8, and 2C9, caution should be exercised, particularly in
children, when montelukast is co-administered with inducers of CYP 3A4, 2C8, and 2C9,
such as phenytoin, phenobarbital and rifampicin.
In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However,
data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a
probe substrate representative of medicinal products primarily metabolised by CYP 2C8)
demonstrated that montelukast does not inhibit CYP 2C8 in vivo. Therefore, montelukast
is not anticipated to markedly alter the metabolism of medicinal products metabolised by
this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).
In vitro studies have shown that montelukast is a substrate of CYP 2C8, and to a less
significant extent, of 2C9, and 3A4. In a clinical drug-drug interaction study involving
montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) gemfibrozil increased
the systemic exposure of montelukast by 4.4-fold. No routine dosage adjustment of
montelukast is required upon co-administration with gemfibrozil or other potent inhibitors
of CYP 2C8, but the physician should be aware of the potential for an increase in adverse
reactions.
Based on in vitro data, clinically important drug interactions with less potent inhibitors of
CYP 2C8 (e.g., trimethoprim) are not anticipated. Co-administration of montelukast with
itraconazole, a strong inhibitor of CYP 3A4, resulted in no significant increase in the
systemic exposure of montelukast.

Pregnancy
Animal studies do not indicate harmful effects with respect to effects on pregnancy or
embryonal/foetal development.

Limited data from available pregnancy databases do not suggest a causal relationship
between Montelukast Sodium and malformations (i.e. limb defects) that have been rarely
reported in worldwide post-marketing experience.
Montelukast Sodium may be used during pregnancy only if it is considered to be clearly
essential.
Breast-feeding
Studies in rats have shown that montelukast is excreted in milk. It is unknown whether
montelukast/metabolites are excreted in human milk.
Montelukast Sodium may be used in breast-feeding mothers only if it is considered to be
clearly essential.

Montelukast Sodium has no or negligible influence on the ability to drive and use
machines. However, individuals have reported drowsiness or dizziness.

Montelukast has been evaluated in clinical studies as follows:
 10 mg film-coated tablets in approximately 4,000 adult and adolescent patients 15 years
of age and older, and
 5 mg chewable tablets in approximately 1,750 paediatric patients 6 to 14 years of age.
The following drug-related adverse reactions in clinical studies were reported commonly
(≥1/100 to <1/10) in patients treated with montelukast and at a greater incidence than in
patients treated with placebo

Body System Class
Adult and Adolescent
Patients 15 years and older
(two 12-week studies;
n=795)
Paediatric Patients
6 to 14 years old
(one 8-week study; n=201)
(two 56-week studies; n=615)
Nervous system
disorders
headache headache
Gastro-intestinal
disorders
abdominal pain
With prolonged treatment in clinical trials with a limited number of patients for up to 2
years for adults, and up to 12 months for paediatric patients 6 to 14 years of age, the
safety profile did not change.

Tabulated list of Adverse Reactions
Adverse reactions reported in post-marketing use are listed, by System Organ Class and
specific Adverse Reactions, in the table below. Frequency Categories were estimated based
on relevant clinical trials.
system Organ Class Adverse Reaction Frequency Category*
Infections and infestations upper respiratory infection† Very Common
Blood and lymphatic system
disorders
increased bleeding tendency Rare
Immune system disorder
hypersensitivity reactions
including anaphylaxis
Uncommon
hepatic eosinophilic infiltration Very Rare
Gastrointestinal disorders diarrhoea‡, nausea‡, vomiting‡ Common
dry mouth, dyspepsia Uncommon
Psychiatric disorders
dream abnormalities including
nightmares, insomnia,
somnambulism, anxiety,
agitation including aggressive
behaviour or hostility,
depression, psychomotor
hyperactivity (including
irritability, restlessness,
tremor§)
Uncommon
disturbance in attention,
memory impairment
Rare
hallucinations, disorientation,
suicidal thinking and behaviour
(suicidality)
Very Rare
Nervous system disorder
dizziness, drowsiness
paraesthesia/hypoesthesia,
seizure
Uncommon
Cardiac disorders palpitations Rare
Respiratory, thoracic and
mediastinal disorders
epistaxis Uncommon
Churg-Strauss Syndrome (CSS) Very Rare
Pulmonary eosinophilia Very Rare

Musculoskeletal, connective tissue
and bone disorders
arthralgia, myalgia including
muscle cramps
Uncommon
Hepatobiliary disorders
elevated levels of serum
transaminases (ALT, AST)
Common
Hepatitis (including cholestatic,
hepatocellular, and mixedpattern
liver injury).
Very Rare
General disorders and
administration site conditions
pyrexia‡ Common
asthenia/fatigue, malaise,
oedema
Uncommon
Skin and subcutaneous tissue
disorders
rash‡ Common
bruising, urticaria, pruritus Uncommon
angiooedema Rare
erythema nodosum, erythema
multiforme
Very Rare
*Frequency Category: Defined for each Adverse Experience Term by the incidence reported
in the clinical trials data base: Very Common (≥1/10), Common (≥1/100 to <1/10),
Uncommon (≥1/1000 to <1/100), Rare (≥1/10,000 to <1/1000), Very Rare (<1/10,000).
†This adverse experience, reported as Very Common in the patients who received
montelukast, was also reported as Very Common in the patients who received placebo in
clinical trials.
‡This adverse experience, reported as Common in the patients who received montelukast,
was also reported as Common in the patients who received placebo in clinical trials.
§ Frequency Category: Rare

To report any side effect(s):
• Saudi Arabia:
 The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

 Other GCC States:
Please contact the relevant competent authority.

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 overdose in post-marketing experience and clinical
studies with montelukast. These include reports in adults and children with a dose as high
as 1,000 mg (approximately 61 mg/kg in a 42 month old child). 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 overdose
reports.
Symptoms of overdose
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.
Management of overdose
No specific information is available on the treatment of overdose with montelukast. It is
not known whether montelukast is dialysable by peritoneal- or haemo-dialysis.

Pharmacotherapeutic group: Leukotriene receptor antagonist
ATC-Code: R03DC03
Mechanism of action
The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids
released from various cells including mast cells and eosinophils. These important proasthmatic
mediators bind to cysteinyl leukotriene receptors (CysLT) found in the human
airway and cause airway actions, including bronchoconstriction, mucous secretion,
vascular permeability, and eosinophil recruitment.
Pharmacodynamic effects
Montelukast is an orally active compound which binds with high affinity and selectivity to
the CysLT1 receptor. In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD4 at doses as low as 5 mg. Bronchodilation was observed within two hours of
oral administration. The bronchodilation effect caused by a β-agonist was additive to that
caused by montelukast. Treatment with montelukast inhibited both early- and late-phase
bronchoconstriction due to antigen challenge. Montelukast, compared with placebo,
decreased peripheral blood eosinophils in adult and paediatric patients. In a separate
study, treatment with montelukast significantly decreased eosinophils in the airways (as
measured in sputum) and in peripheral blood while improving clinical asthma control.
Clinical efficacy and safety
In studies in adults, montelukast, 10 mg once daily, compared with placebo,
demonstrated significant improvements in morning FEV1 (10.4% vs 2.7% change from
baseline), AM peak expiratory flow rate (PEFR) (24.5 L/min vs 3.3 L/min change from
baseline), and significant decrease in total β-agonist use (-26.1% vs -4.6% change from
baseline). Improvement in patient-reported daytime and night-time asthma symptoms
scores was significantly better than placebo.
Studies in adults demonstrated the ability of montelukast to add to the clinical effect of
inhaled corticosteroid (% change from baseline for inhaled beclomethasone plus
montelukast vs beclomethasone, respectively for FEV1 : 5.43% vs 1.04%; β-agonist use:
-8.70% vs 2.64%). Compared with inhaled beclomethasone (200 μg twice daily with a
spacer device), montelukast demonstrated a more rapid initial response, although over
the 12-week study, beclomethasone provided a greater average treatment effect (%
change from baseline for montelukast vs beclomethasone, respectively for FEV1 : 7.49%
vs 13.3%; β-agonist use: -28.28% vs -43.89%). However, compared with
beclomethasone, a high percentage of patients treated with montelukast achieved similar
clinical responses (e.g., 50% of patients treated with beclomethasone achieved an
improvement in FEV1 of approximately 11% or more over baseline while approximately
42% of patients treated with montelukast achieved the same response). In an 8-week study in paediatric patients 6 to 14 years of age, montelukast 5 mg once
daily, compared with placebo, significantly improved respiratory function (FEV1 8.71% vs
4.16% change from baseline; AM PEFR 27.9 L/min vs 17.8 L/min change from baseline)
and decreased “as-needed” β-agonist use (-11.7% vs +8.2% change from baseline).
In a 12-month study comparing the efficacy of montelukast to inhaled fluticasone on
asthma control in paediatric patients 6 to 14 years of age with mild persistent asthma, montelukast was non-inferior to fluticasone in increasing the percentage of asthma
rescue-free days (RFDs), the primary endpoint. Averaged over the 12-month treatment
period, the percentage of asthma RFDs increased from 61.6 to 84.0 in the montelukast
group and from 60.9 to 86.7 in the fluticasone group. The between group difference in LS
mean increase in the percentage of asthma RFDs was statistically significant (-2.8 with a
95% CI of -4.7, -0.9), but within the limit pre-defined to be clinically not inferior. Both
montelukast and fluticasone also improved asthma control on secondary variables
assessed over the 12 month treatment period:
FEV1 increased from 1.83 L to 2.09 L in the montelukast group and from 1.85 L to 2.14 L
in the fluticasone group. The between-group difference in LS mean increase in FEV1 was -
0.02 L with a 95% CI of -0.06, 0.02. The mean increase from baseline in % predicted
FEV1 was 0.6% in the montelukast treatment group, and 2.7% in the fluticasone
treatment group. The difference in LS means for the change from baseline in the %
predicted FEV1 was significant: -2.2% with a 95% CI of -3.6, -0.7.
The percentage of days with β-agonist use decreased from 38.0 to 15.4 in the
montelukast group, and from 38.5 to 12.8 in the fluticasone group. The between group
difference in LS means for the percentage of days with β-agonist use was significant: 2.7
with a 95% CI of 0.9, 4.5.
The percentage of patients with an asthma attack (an asthma attack being defined as a
period of worsening asthma that required treatment with oral steroids, an unscheduled
visit to the doctor's office, an emergency room visit, or hospitalisation) was 32.2 in the
montelukast group and 25.6 in the fluticasone group; the odds ratio (95% CI) being
significant: equal to 1.38 (1.04, 1.84).
The percentage of patients with systemic (mainly oral) corticosteroid use during the study
period was 17.8% in the montelukast group and 10.5% in the fluticasone group. The
between group difference in LS means was significant: 7.3% with a 95% CI of 2.9; 11.7.
Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a
12-week study in adults (maximal fall in FEV1 22.33% for montelukast vs 32.40% for
placebo; time to recovery to within 5% of baseline FEV1 44.22 min vs 60.64 min). This
effect was consistent throughout the 12-week study period. Reduction in EIB was also
demonstrated in a short term study in paediatric patients (maximal fall in FEV1 18.27% vs 26.11%; time to recovery to within 5% of baseline FEV1 17.76 min vs 27.98 min). The
effect in both studies was demonstrated at the end of the once-daily dosing interval.
In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral
corticosteroids, treatment with montelukast, compared with placebo, resulted in
significant improvement in asthma control (FEV1 8.55% vs -1.74% change from baseline
and decrease in total β-agonist use -27.78% vs 2.09% change from baseline).

Absorption
Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated
tablet, the mean peak plasma concentration (Cmax) is achieved three 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. Safety and efficacy were
demonstrated in clinical trials where the 10 mg film-coated tablet was administered
without regard to the timing of food ingestion.
For the 5 mg chewable tablet, the Cmax is achieved in two hours after administration in
adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63%
by a standard meal.
Distribution
Montelukast is more than 99% bound to plasma proteins. The steady-state volume of
distribution of montelukast averages 8-11 litres. Studies in rats with radiolabeled
montelukast indicate minimal distribution across the blood-brain barrier. In addition,
concentrations of radiolabelled material at 24 hours post-dose were minimal in all other
tissues.
Biotransformation
Montelukast is extensively metabolised. In studies with therapeutic doses, plasma
concentrations of metabolites of montelukast are undetectable at steady state in adults
and children.
Cytochrome P450 2C8 is the major enzyme in the metabolism of montelukast. Additionally
CYP 3A4, and 2C9 may have a minor contribution, although itraconazole, an inhibitor of
CYP 3A4, was shown not to change pharmacokinetic variables of montelukast in healthy
subjects that received 10 mg montelukast daily. Based on in vitro results in human liver
microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes

P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the
therapeutic effect of montelukast is minimal.
Elimination
The plasma clearance of montelukast averages 45 ml/min in healthy adults. Following an
oral dose of radiolabelled montelukast, 86% of the radioactivity was recovered in 5-day
faecal collections and <0.2% was recovered in urine. Coupled with estimates of
montelukast oral bioavailability, this indicates that montelukast and its metabolites are
excreted almost exclusively via the bile.
Characteristics in Patients
No dosage adjustment is necessary for the elderly or mild to moderate hepatic
insufficiency. Studies in patients with renal impairment have not been undertaken.
Because montelukast and its metabolites are eliminated by the biliary route, no dose
adjustment is anticipated to be necessary in patients with renal impairment.
There are no data on the pharmacokinetics of montelukast in patients with severe hepatic
insufficiency (Child-Pugh score >9).
With high doses of montelukast (20- and 60-fold the recommended adult dose), a
decrease in plasma theophylline concentration was observed. This effect was not seen at
the recommended dose of 10 mg once daily.

In animal toxicity studies, minor serum biochemical alterations in ALT, glucose,
phosphorus and triglycerides were observed which were transient in nature.
The signs of toxicity in animals were increased excretion of saliva, gastro-intestinal
symptoms, loose stools and ion imbalance. These occurred at dosages which provided
>17-fold the systemic exposure seen at the clinical dosage. In monkeys, the adverse
effects appeared at doses from 150 mg/kg/day (>232-fold the systemic exposure seen at
the clinical dose). In animal studies, montelukast did not affect fertility or reproductive
performance at systemic exposure exceeding the clinical systemic exposure by greater
than 24-fold. A slight decrease in pup body weight was noted in the female fertility study
in rats at 200 mg/kg/day (>69-fold the clinical systemic exposure). In studies in rabbits,
a higher incidence of incomplete ossification, compared with concurrent control animals,
was seen at systemic exposure >24-fold the clinical systemic exposure seen at the clinical dose. No abnormalities were seen in rats. Montelukast has been shown to cross
the placental barrier and is excreted in breast milk of animals.
No deaths occurred following a single oral administration of montelukast sodium at doses
up to 5,000 mg/kg in mice and rats (15,000 mg/m2 and 30,000 mg/m2 in mice and rats,
respectively), the maximum dose tested. This dose is equivalent to 25,000 times the
recommended daily adult human dose (based on an adult patient weight of 50 kg).
Montelukast was determined not to be phototoxic in mice for UVA, UVB or visible light
spectra at doses up to 500 mg/kg/day (approximately >200-fold based on systemic
exposure).
Montelukast was neither mutagenic in in vitro and in vivo tests nor tumorigenic in rodent
species.

6.1. List of excipients:
S. NO. MATERIAL FUNCTION
Dry Mixing
1. Mannitol (Pearlitol 25C) Ph.Eur. Diluent
2. Croscarmellose Sodium (Ac-di-Sol) Ph.Eur. Disintegrant
3. Hydroxypropyl Cellulose (Klucel EXF) Ph.Eur. Binder
Granulation
4. Hydroxypropyl Cellulose (Klucel EXF) Ph.Eur. Binder
5. Ferric Oxide (Sicovit Red 30E172)USP/NF Colorant
6. Purified WaterIHS/USP/ Ph.Eur. Solvent
7. Purified Water (If required)IHS/USP/ Ph.Eur. Solvent
Extra Granular
8. Cellulose Microcrystalline (Avicel PH 112) Ph.Eur. Diluent
9. Mannitol (Pearlitol SD 100) Ph.Eur. Diluent
10. Ferric Oxide (Sicovit Red 30E172)USP/NF Colorant
11. Aspartame Ph.Eur. Sweetener
12. ART Cherry Flavor (SD 594) IHS Flavoring Agent
13. Magnesium Stearate Ph.Eur. Lubricant

None known

Store below 30°C

The Chewable tablets are packed in Alu/Alu blisters and placed in a printed carton along
with a pack insert.
Pack size: 30’s (10’s Blister × 3)

None known