Emcast® 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.
Emcast® 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 (see section 4.2).
Emcast® 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, Emcast® 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 Emcast® on parameters of asthma control occurs within one day.
Patients should be advised to continue taking Emcast® 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.
Emcast® 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 Emcast® in relation to other treatments for asthma

When treatment with Emcast® is used as add-on therapy to inhaled corticosteroids, Emcast®
should not be abruptly substituted for inhaled corticosteroids (see section 4.4).
10 mg tablets are available for adults and adolescents 15 years of age and older.
Paediatric population
Do not give Emcast® 5 mg chewable tablets to children less than 6 years of age. The safety
and efficacy of Emcast® 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.
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.
Emcast® 5 mg chewable tablets contain Lactose monohydrate, 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
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 coadministration 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 and malformations (i.e. limb defects) that have been rarely reported in worldwide post-marketing experience.
Emcast® 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 (see section 5.3). It is unknown
whether montelukast/metabolites are excreted in human milk.
Emcast® may be used in breast-feeding mothers only if it is considered to be clearly essential.

Emcast® 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:

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.

To report any side effect(s):
•Saudi Arabia:
The National Pharmacovigilance and Drug Safety Center (NPC):
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2340.
Reporting hotline: 19999
E-mail: npc.drug@sfda.gov.sa
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: 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 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 FEV144.22 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.

Microcrystalline cellulose (Avicel) PH102, lactose monohydrate, mannitol EZ, croscarmellose
sodium, cherry powder flavor, red iron oxide, acesulfame K, magnesium stearate

Not applicable.

Store below 30°C.

Emcast® 5 mg chewable tablets are Pink round normal biconvex tablets with break line
engraved with MD on one face and M|2 on the other face, presented in Alu/Alu blisters, intended
for oral use.
Pack size:
30 Chewable Tablets. 10 tablets/blister, 3 blisters/pack.

No special requirements.