Airfast Pediatrics is indicated in the treatment of asthma as add-on therapy in those 6

months to 5 year old 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.

Airfast Pediatrics may also be an alternative treatment option to low-dose inhaled

corticosteroids for 2 to 5 year old 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).

Airfast Pediatrics is also indicated in the prophylaxis of asthma from 2 years of age and

older in which the predominant component is exercise-induced bronchoconstriction.

Posology

This medicinal product is to be given to a child under adult supervision. The recommended

dose for paediatric patients 6 months to 5 years of age is one sachet of 4 mg granules daily to

be taken in the evening. No dosage adjustment within this age group is necessary. Efficacy

data from clinical trials in paediatric patients 6 months to 2 years of age with persistent asthma

are limited. Patients should be evaluated after 2 to 4 weeks for response to montelukast

treatment. Treatment should be discontinued if a lack of response is observed. The Airfast

Pediatrics Paediatric 4 mg granules formulation is not recommended below 6 months of age.

Administration of Airfast Pediatrics granules:

Airfast Pediatrics granules can be administered either directly in the mouth, or mixed with a

spoonful of cold or room temperature soft food (e.g., applesauce, ice cream, carrots and rice).

The sachet should not be opened until ready to use. After opening the sachet, the full dose of

Airfast Pediatrics granules must be administered immediately (within 15 minutes). If mixed

with food, Airfast Pediatrics granules must not be stored for future use. Airfast Pediatrics

granules are not intended to be dissolved in liquid for administration. However, liquids may be

taken subsequent to administration. Airfast Pediatrics granules can be administered without

regard to the timing of food ingestion.

General recommendations

The therapeutic effect of Airfast Pediatrics on parameters of asthma control occurs within one

day. Patients should be advised to continue taking Airfast Pediatrics 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.

Airfast Pediatrics 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 2 to 5 years old 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.

Airfast Pediatrics as prophylaxis of asthma for 2 to 5 year old patients in whom the

predominant component is exercise-induced bronchoconstriction

In 2 to 5 year old patients, exercise-induced bronchoconstriction may be the predominant

manifestation of persistent asthma that requires treatment with inhaled corticosteroids. Patients

should be evaluated after 2 to 4 weeks of treatment with montelukast. If satisfactory response

is not achieved, an additional or different therapy should be considered.

Therapy with Airfast Pediatrics in relation to other treatments for asthma

When treatment with Airfast Pediatrics is used as add-on therapy to inhaled corticosteroids,

Airfast Pediatrics should not be abruptly substituted for inhaled corticosteroids (see section

4.4).

10 mg film-coated tablets are available for adults and adolescents 15 years of age and older.

Paediatric population

Do not give Airfast Pediatrics 4 mg granules to children less than 6 months of age. The safety

and efficacy of Airfast Pediatrics 4 mg granules in children less than 6 months of age 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 as an alternative formulation for paediatric patients 2 to 5

years of age.

Method of administration

Oral use.

The diagnosis of persistent asthma in very young children (6 months – 2 years) should be

established by a paediatrician or pulmonologist.

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 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 coadministered 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 Airfast Pediatrics and malformations (i.e. limb defects) that have been rarely

reported in worldwide post-marketing experience.

Airfast Pediatrics 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.

Airfast Pediatrics may be used in breast-feeding mothers only if it is considered to be

Airfast Pediatrics 4 mg Granules

clearly essential.

Airfast Pediatrics 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 in patients with persistent asthma as follows:

▪ 10 mg film-coated tablets in approximately 4,000 adult and adolescent patients 15 years of age and older

▪ 5 mg chewable tablets in approximately 1,750 paediatric patients 6 to 14 years of age

▪ 4 mg chewable tablets in 851 paediatric patients 2 to 5 years of age, and

▪ 4 mg granules in 175 paediatric patients 6 months to 2 years of age.

Montelukast has been evaluated in a clinical study in patients with intermittent asthma as follows:

▪ 4 mg granules and chewable tablets in 1,038 paediatric patients 6 months to 5 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.

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 534 patients for 12 months or longer. With prolonged treatment, the safety profile did not change in these patients either.

The safety profile in paediatric patients 6 months to 2 years of age did not change with treatment up to 3 months.

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.

Post Marketing Experience:

Psychiatric disorders: including, but not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tic, and tremor [see Boxed Warning, Warnings and Precautions].

To report any side effect(s):

• Saudi Arabia:

The National Pharmacovigilance Center (NPC):

Fax: +966-11-205-7662

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

• 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.

Tabuk Pharmaceutical Mfg. Co.

Airfast Pediatrics 4 mg Granules

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).

In adult and paediatric patients 2 to 14 years of age, montelukast, compared with placebo,

decreased peripheral blood eosinophils 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 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

Tabuk Pharmaceutical Mfg. Co.

Airfast Pediatrics 4 mg Granules

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.

In a 12-week, placebo-controlled study in paediatric patients 2 to 5 years of age, montelukast

4 mg once daily improved parameters of asthma control compared with placebo irrespective

of concomitant controller therapy (inhaled/nebulised corticosteroids or inhaled/nebulised

sodium cromoglycate). Sixty percent of patients were not on any other controller therapy.

Montelukast improved daytime symptoms (including coughing, wheezing, trouble breathing

and activity limitation) and nighttime symptoms compared with placebo. Montelukast also

decreased “as-needed” β-agonist use and corticosteroid rescue for worsening asthma

compared with placebo. Patients receiving montelukast had more days without asthma than

those receiving placebo. A treatment effect was achieved after the first dose.

In a 12-month, placebo-controlled study in paediatric patients 2 to 5 years of age with mild

asthma and episodic exacerbations, montelukast 4 mg once daily significantly (p≤ 0.001)

reduced the yearly rate of asthma exacerbation episodes (EE) compared with placebo (1.60

EE vs. 2.34 EE, respectively), [EE defined as ≥ 3 consecutive days with daytime symptoms

requiring β-agonist use, or corticosteroids (oral or inhaled), or hospitalisation for asthma]. The

percentage reduction in yearly EE rate was 31.9%, with a 95% CI of 16.9, 44.1.

In a placebo-controlled study in paediatric patients 6 months to 5 years of age who had

intermittent asthma but did not have persistent asthma, treatment with montelukast was

administered over a 12-month period, either as a once-daily 4 mg regimen or as a series of 12-

day courses that each were started when an episode of intermittent symptoms began. No

significant difference was observed between patients treated with montelukast 4 mg or

placebo in the number of asthma episodes culminating in an asthma attack, defined as an

asthma episode requiring utilization of health-care resources such as an unscheduled visit to a

doctor's office, emergency room, or hospital; or treatment with oral, intravenous, or

intramuscular corticosteroid.

Efficacy of montelukast is supported in paediatric patients 6 months to 2 years of age by

extrapolation from the demonstrated efficacy in patients 2 years of age and older with asthma,

and is based on similar pharmacokinetic data, as well as the assumption that the disease

course, pathophysiology and the medicinal product's effect are substantially similar among

these populations.

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

Airfast Pediatrics 4 mg Granules

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 6 to 14 years of age (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.

After administration of the 4 mg chewable tablet to paediatric patients 2 to 5 years of age in

the fasted state, Cmax is achieved 2 hours after administration. The mean Cmax is 66% higher

while mean Cmin is lower than in adults receiving a 10 mg tablet.

The 4 mg granule formulation is bioequivalent to the 4 mg chewable tablet when

administered to adults in the fasted state. In paediatric patients 6 months to 2 years of age,

Cmax is achieved 2 hours after administration of the 4 mg granules formulation. Cmax is nearly

2-fold greater than in adults receiving a 10 mg tablet. The co-administration of applesauce or

a high-fat standard meal with the granule formulation did not have a clinically meaningful

effect on the pharmacokinetics of montelukast as determined by AUC (1225.7 vs 1223.1

ng.hr/mL with and without applesauce, respectively, and 1191.8 vs 1148.5 ng.hr/mL with and

without a high-fat standard meal, respectively).

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), a decrease in

plasma theophylline concentration was observed. This effect was not seen at the

recommended dose of 10 mg once daily.

Store below 30° C

28 Aluminum sachets packed in a printed carton with folded leaflet.