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. In those asthmatic patients in whom Montelukast Sodium is
indicated in asthma, Montelukast Sodium can also provide symptomatic relief of seasonal
allergic rhinitis. Montelukast Sodium is also indicated in the prophylaxis of asthma in which
the predominant component is exercise-induced bronchoconstriction.

Posology
The dosage for adults and adolescents 15 years of age and older with asthma, or with
asthma and concomitant seasonal allergic rhinitis, is one 10 mg tablet daily to be taken in
the evening.
General recommendations.
The therapeutic effect of Montelukast Sodium on parameters of asthma control occurs within
one day. Montelukast Sodium may be taken with or without food. Patients should be
advised to continue taking Montelukast Sodium even if their asthma is under control, as well
as during periods of worsening asthma. Montelukast Sodium should not be used
concomitantly with other products containing the same active ingredient, montelukast.

No dosage adjustment is necessary for the elderly, or 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.
Therapy with Montelukast Sodium in relation to other treatments for asthma.
Montelukast Sodium can be added to a patient's existing treatment regimen.
Inhaled corticosteroids: Treatment with Montelukast Sodium can be used as add-on therapy
in patients when inhaled corticosteroids plus "as needed" short acting β-agonists provide
inadequate clinical control. Montelukast Sodium should not be abruptly substituted for
inhaled corticosteroids.
Paediatric population
Do not give Montelukast Sodium to children less than 15 years of age. The safety and
efficacy of Montelukast Sodium tablets in children less than 15 years has not been
established.
5 mg chewable tablets are available for paediatric patients 6 to 14 years of age.
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.

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-a gonist should be used. Patients should seek
their doctor's advice as soon as possible if they need more inhalations of short-acting β-a
gonists than usual.
Montelukast should not be substituted abruptly 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 usually, but not always, have been associated with the
reduction or withdrawal of oral corticosteroid therapy. The possibility that leukotriene
receptor antagonists may be associated with emergence of Churg-Strauss syndrome can
neither be excluded nor established. Physicians should be alert to eosinophilia,
vasculiticrash, 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.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency
or glucose-galactose malabsorption should not take this medicine.

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 estradiol/ 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 metabolized 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
ofmontelukast 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/fetal 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.
Use during lactation
Studies in rats have shown that montelukast is excreted in milk. It is not known if
montelukast is excreted in human milk.
Montelukast Sodium may be used in breast-feeding only if it is considered to be clearly
essential.

Montelukast 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 4000 adult and adolescent asthmatic
patients 15 years of age and older.
 10 mg film-coated tablets in approximately 400 adult and adolescent asthmatic
patients with seasonal allergic rhinitis 15 years of age and older.
 5 mg chewable tablets in approximately 1750 paediatric asthmatic 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 asthmatic 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 Experience Term Frequency Category*
Infections and infestations upper respiratory infection† Very Common
Blood and lymphatic system
disorders
increased bleeding tendency Rare
Immune system disorders
hypersensitivity reactions
including anaphylaxis
Uncommon
hepatic eosinophilic infiltration Very Rare
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
Psychiatric disorders
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
Gastrointestinal disorders
diarrhoea‡, nausea‡, vomiting‡ Common
dry mouth, dyspepsia Uncommon
Hepatobiliary disorders
elevated levels of serum
transaminases (ALT, AST)
Common

system Organ Class Adverse Experience Term Frequency Category*
Hepatitis (including cholestatic,
hepatocellular, and mixed-pattern
liver injury).
Very Rare
Skin and subcutaneous tissue
disorders
rash‡ Common
bruising, urticaria, pruritus Uncommon
angiooedema Rare
erythema nodosum, erythema
multiforme
Very Rare
Musculoskeletal, connective
tissue and bone disorders
arthralgia, myalgia including
muscle cramps
Uncommon
General disorders and
administration site conditions
pyrexia‡ Common
asthenia/fatigue, malaise,
oedema
Uncommon
*Frequency Category: Defined for each Adverse Reaction 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
o 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 1000
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 haemodialysis.

5.1. Pharmacodynamics:
Pharmacotherapeutic group: Leukotriene receptor antagonist
ATC-code: R03D C03
Mechanism of action
The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are 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 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.
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 2 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 nighttime 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 beclometasone plus montelukast
vs beclometasone, respectively for FEV1: 5.43% vs 1.04%; β-agonist use: -8.70% vs
2.64%). Compared with inhaled beclometasone (200 μg twice daily with a spacer device),
montelukast demonstrated a more rapid initial response, although over the 12-week study,
beclometasone provided a greater average treatment effect (% change from baseline for
montelukast vs beclometasone, respectively for FEV1: 7.49% vs 13.3%; β-agonist use: -
28.28% vs -43.89%). However, compared with beclometasone, a high percentage of
patients treated with montelukast achieved similar clinical responses (e.g., 50% of patients
treated with beclometasone achieved an improvement in FEV1 of approximately 11% or
more over baseline while approximately 42% of patients treated with montelukast achieved
the same response).
A clinical study was conducted to evaluate montelukast for the symptomatic treatment of
seasonal allergic rhinitis in adult and adolescent asthmatic patients 15 years of age and
older with concomitant seasonal allergic rhinitis. In this study, montelukast 10 mg tablets
administered once daily demonstrated a statistically significant improvement in the Daily
Rhinitis Symptoms score, compared with placebo. The Daily Rhinitis Symptoms score is the
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). Global evaluations
of allergic rhinitis by patients and physicians were significantly improved, compared with
placebo. The evaluation of asthma efficacy was not a primary objective in this study.
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).
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 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. 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 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.
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 radiolabelled
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), 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, gastrointestinal 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.

S. NO. MATERIAL FUNCTION
Dry Mixing
1. Lactose Monohydrate (Impalpable) Ph.Eur Diluent
2. Mannitol (Pearlitol 25C) Ph.Eur. Diluent
3. Croscarmellose Sodium (Ac-di-Sol) Ph.Eur. Disintegrant
Granulation
4. Hydroxy propyl Cellulose (Klucel LF) Ph.Eur. Binder
5. Purified Water IHS/USP/ Ph.Eur. Solvent
6. Purified Water (If required) IHS/USP/ Ph.Eur. Solvent
Extra Granular
7. Cellulose Microcrystalline (Avicel PH 112) Ph.Eur. Diluent
8. Croscarmellose Sodium (Ac-di-Sol) Disintegrant
9.
Magnesium Stearate (or) Magnesium Stearate (Liga-MF-
2V-VEG) Ph.Eur.
Lubricant
Film Coating (12% w/w Suspension)
10. Opadry Yellow 20A520007 IHS Coating Agent
11. Purified Water@ IHS/USP/Ph.Eur Solvent
COMPOSITION OF OPADRY YELLOW 20A520007
S.
No
Ingredients Function
a) HPMC 2910/Hypromellose 6 Cp USP, Ph.Eur., JP Film-Forming
b) Hydroxypropyl Cellulose NF, Ph.Eur, JP, FCC Film forming
c) Titanium Dioxide USP, FCC, Ph.Eur, JP Opacifier
d) Carnauba wax NF, Ph.Eur Polishing agent
e) Iron Oxide Yellow NF, JPE Colorant
f) Iron Oxide Red NF, JPE Colorant

None known

Store below 30°C

Lukra tablets 10 mg are packed in Alu/Alu blisters and placed in a printed carton along with
a pack insert.
Pack size: 30’

None known