SINGULAIR 5 MG CHEWABLE TABLETS

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS' REGULATIONS

(PREPARATIONS) – 1986

This medicine can be sold under doctor's prescription only

SINGULAIR

4mg GRANULES

FOR KIDDIES

SINGULAIR

4mg

CHEWABLE TABLETS

FOR PRE-SCHOOL

KIDS

SINGULAIR

5mg

CHEWABLE

TABLETS

SINGULAIR

10mg

TABLETS

Each sachet of

granules contains:

Each chewable tablet

contains:

Each chewable tablet

contains:

Each tablet contains:

Montelukast 4 mg

Montelukast 4 mg

Montelukast 5 mg

Montelukast 10 mg

(as sodium salt)

(as sodium salt)

(as sodium salt)

(as sodium salt)

For a list of inactive ingredients please refer to section 6.

Read all of this leaflet carefully before you start using this medicine.

This leaflet contains concise information about SINGULAIR. If you have any further questions, ask

your doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their

ailment seems similar to yours.

1. WHAT SINGULAIR IS AND WHAT IT IS USED FOR?

1.1 What is SINGULAIR?

THERAPEUTIC GROUP

:

SINGULAIR is a selective antagonist of the leukotriene receptor.

SINGULAIR acts by blocking receptors in the airway for substances known as leukotrienes, which cause

bronchoconstriction, and swelling of the airways. Leukotrienes also cause allergy symptoms.

1.2 What is SINGULAIR used for?

SINGULAIR is indicated for the treatment of chronic asthma, including the prevention of daytime and

nighttime symptoms, the treatment of aspirin-sensitive asthmatic patients

and the prevention of exercise-

induced bronchoconstriction in adult and pediatric patients 12 months of age and older.

SINGULAIR is indicated for the relief of symptoms of seasonal allergic rhinitis in adults and in pediatric

patients 2 years of age and older.

What is asthma?

Asthma is a chronic lung disease. It cannot be cured – only controlled.

Characteristics of asthma include:

Narrowed airways causing breathing to become difficult. This narrowing worsens and improves in

response to various conditions.

Inflamed airways; that is, the lining of airways become swollen.

Sensitive airways that react to many things, such as cigarette smoke, pollen, or cold air.

Symptoms of asthma include:

Coughing, wheezing, and chest tightness. Not all people with asthma wheeze. For some, coughing may be

the only symptom of asthma. Symptoms often occur during the night or after exercise.

What is exercise-induced asthma?

Exercise-induced asthma, more accurately called exercise-induced bronchoconstriction (EIB) occurs when

exercise triggers symptoms of asthma.

What is seasonal allergic rhinitis?

Seasonal allergic rhinitis (also known as hay fever) is triggered by outdoor allergens such as airborne

pollens from trees, grasses, and weeds.

The daytime and nighttime symptoms of seasonal allergic rhinitis typically may include:

stuffy, runny, itchy nose

sneezing

watery, swollen, red, itchy eyes

2. BEFORE USING SINGULAIR

2.1 Do not use SINGULAIR if you:

are sensitive (allergic) to the active substance or any of the other ingredients of the medicine.

2.2 Special Warnings concerning use of SINGULAIR

Before starting treatment with SINGULAIR, tell your doctor:

about any medical problems or allergies you or your child has now or has had including allergy to

Aspirin.

If you are sensitive to any type of food or medicine

If you are suffering or have suffered in the past from impaired function of the liver

If you are pregnant, plan to become pregnant or if you are breast feeding

Additional warnings:

If your or your child's asthma symptoms get worse, you should contact your doctor immediately.

This medicine is not intended for use in acute asthmatic attacks; in such cases, follow the instructions

your doctor has given you for such situations. Always have with you the inhaler medicines that the

doctor told you to use for acute attack.

Rarely, patients taking SINGULAIR have experienced a condition that includes a combination of certain

symptoms that do not go away or that get worse. These symptoms may include:

a flu-like illness

rash

a feeling of pins and needles or numbness of arms or legs

breathing difficulties

severe inflammation (pain and swelling) of the sinuses (sinusitis)

These have occurred usually, but not always, in patients who were taking oral corticosteroid pills for

asthma and those corticosteroids were being slowly lowered or stopped. Although SINGULAIR has not

been shown to cause this condition, you must tell your doctor right away if you develop one or more of

these symptoms.

Behavior and mood-related changes have been reported in patients taking SINGULAIR. If you or your

child experience these changes while taking SINGULAIR (see section 4, "Possible Side Effects"), tell

your doctor.

2.3 Taking Other Medicines

If

you

take

or

have

taken

other

medicines

recently,

including

non-prescription

medicines

and

nutritional supplements, or if you have just finished treatment with another medicine, inform the

attending

doctor

or

pharmacist,

in

order

to

prevent

hazards

or

inefficacy

arising

from

drug

interactions.

Especially inform your doctor if you are taking: antiasthmatic preparations such as bronchodilators and

steroids for inhalation or for oral use.

2.4 Taking SINGULAIR with food and drink

SINGULAIR may be taken with or without food.

2.5 Pregnancy and Breast-feeding

Do not take this medicine without consulting a doctor before starting treatment: if you are pregnant, intend to

become pregnant, or breastfeeding.

2.6 Use in Children

Safety and effectiveness of SINGULAIR in children less than 12 months old have not been established.

Studies have shown that SINGULAIR does not affect the growth rate of children

2.7 Driving and using machines

SINGULAIR is not expected to affect your ability to drive a car or operate machinery. However, individual

responses to medications may vary. Certain side effects (such as dizziness and drowsiness), that have been

reported very rarely with SINGULAIR may affect some patients' ability to drive or operate machinery.

2.8 Important information about some of the ingredients of SINGULAIR

SINGULAIR 10 mg film-coated tablets contain lactose. If you have been told by your doctor that you have an

intolerance to some sugars, contact your doctor before taking this medicinal product (see section 6).

If your child has phenylketonuria, you should note that 5 mg chewable tablets and 4 mg chewable tablets

contain aspartame, which is a source of phenylalanine (see section 6).

3. HOW DO YOU USE SINGULAIR?

Always take SINGULAIR exactly as your doctor has told you. You should check with your doctor or

pharmacist if you are not sure.

The dosage and method of treatment will be determined by the doctor only. The recommended dose is:

Adults and adolescents 15 years of age and older with Asthma and/or Seasonal Allergic Rhinitis:

one 10-mg

tablet daily.

Children 6 to 14 years of age with Asthma and/or Seasonal Allergic Rhinitis: one 5-mg chewable tablet daily.

Children 2 to 5 years of age with Asthma and/or Seasonal Allergic Rhinitis: one 4-mg chewable tablet daily or

one sachet of 4-mg oral granules daily.

Children 12 months of age to 2 years with Asthma: one sachet of 4-mg oral granules daily.

Do not exceed the recommended dosage.

SINGULAIR should be taken once daily with or without food, according to doctor's instructions.

For asthma, SINGULAIR should be taken once daily, in the evening.

For seasonal allergic rhinitis, SINGULAIR should be taken once daily according to doctor's instructions.

Always have your inhaled rescue medicine for asthma attacks with you.

Do not take an additional dose of

SINGULAIR within 24 hours of previous dose.

SINGULAIR chewable tablets are not intended for use in children under 2 years of age.

Directions for use:

SINGULAIR 10 mg tablets

Do not chew! Swallow the tablet, with some water and without regard to meals.

SINGULAIR 4 mg and 5 mg chewable tablets

Chew the tablet before swallowing, without regard to meals.

SINGULAIR 4 mg granules for kiddies

Do not open the sachet until ready to use.

SINGULAIR 4 mg granules for kiddies can be given:

directly in the mouth;

dissolved in 1 teaspoonful (5 mL) of cold or room temperature baby formula or breast milk;

mixed with a spoonful of cold or room temperature soft food (for example, applesauce, rice

or ice cream).

Mix all

of the contents of the SINGULAIR 4 mg granules for kiddies into a spoonful of

cold or room temperature soft food, or 1 teaspoonful of cold or room temperature baby

formula or breast milk, taking care to see that the entire dose is mixed with the food, baby

formula, or breast milk.

Be sure the child is given the entire spoonful of the SINGULAIR 4 mg granules for

kiddies mixed with food, baby formula, or breast milk immediately (within 15 minutes).

IMPORTANT: Never store any SINGULAIR 4 mg granules for kiddies mixed with food,

baby formula, or breast milk for use at a later time.

SINGULAIR 4 mg granules for kiddies are not intended to be dissolved in any liquid other than baby

formula or breast milk. However, your child may take liquids after swallowing the SINGULAIR 4 mg

granules for kiddies.

If you take more SINGULAIR than you should

If you have taken an overdose, or if a child has accidentally swallowed the medicine, proceed immediately

to a hospital emergency room and bring the package of the medicine with you.

Do not induce

vomiting unless explicitly instructed to do so by a doctor!

If you forget to take SINGULAIR

If you forget to take this medicine at the specified time, do not take the missed dose as soon as you

remember, and simply continue to follow your regular schedule as recommended by the attending doctor.

Do not take a double dose to make up for a forgotten dose.

How can you contribute to the success of the treatment?

Complete the full course of treatment as instructed by the doctor.

Even if there is an improvement in your or your child's health, or if you or your child has an asthma attack,

do not discontinue use of this medicine or change the schedule of its administration without consulting your

doctor.

U

Do not take medicines in the dark!

U

Check the label and the dose

U

each time

U

you take your medicine. Wear

glasses if you need them.

Avoid, as far as possible, contact with factors which can potentially cause an asthmatic attack, such as

smoking, mites in dust dander, mold, pollens, animals, changes in weather, exposure to cold air.

If you have asthma and aspirin makes your asthma symptoms worse, continue to avoid taking aspirin or

other medicines called non-steroidal anti-inflammatory drugs (NSAIDs) while taking SINGULAIR.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, SINGULAIR can cause side effects in some of the users.

Do not be alarmed by reading the list of side effects, you may not suffer from any of them.

Refer to the doctor immediately if you or your child develop the following side effects while using

Singulair:

Behavior and mood-related changes [agitation including aggressive behavior or hostility, depression,

disorientation (confusion), attention problems, bad or vivid dreams, feeling anxious, hallucinations

(seeing or hearing things that are not really there), trouble sleeping, irritability, memory problems,

restlessness, sleep walking, suicidal thoughts and actions (including suicide), tremor].

Increase in certain white blood cells (eosinophils ) and possible inflamed blood vessels throughout the

body (systemic vasculitis). The symptoms of these conditions may include: a flu-like illness, rash, a

feeling of pins and needles or numbness of arms or legs and severe inflammation (pain and swelling)

of the sinuses (sinusitis).

These side effects can happen rarely in people with asthma who take SINGULAIR or in people who

also take steroid medicines by mouth, while the dose is being lowered or the administration is being

stopped.

SINGULAIR is generally well-tolerated. In studies, the most common side effects reported were:

upper respiratory infection

fever

headache

sore throat

cough

stomach pain

diarrhea

earache or ear infection

runny nose

sinus infection

Additionally, the following side effects have been reported as well:

increased bleeding tendency, low blood platelet count

allergic reactions [including swelling of the face, lips, tongue, and/or throat (which may cause trouble

breathing or swallowing), hives, rash, and itching]

dizziness, drowsiness, pins and needles/numbness, seizures

palpitations

nose bleed; stuffy nose, swelling (inflammation) of the lungs

heartburn, diarrhea, dyspepsia, nausea, vomiting

hepatitis

bruising,

rash,

severe skin reactions (erythema multiforme) that may occur without warning

joint pain, muscle aches and muscle cramps

bedwetting in children

weakness/tiredness

swelling

If a side effect appears, if any of the side effects gets serious or if you notice any side effects not mentioned

in this leaflet, consult your doctor.

ADVERSE REACTIONS AND DRUG INTERACTIONS IN CHILDREN AND INFANTS:

Parents must inform the attending doctor about any side effect, as well as any additional medicine being

taken by a child.

See above for details of special side effects and drug interactions.

5. HOW TO STORE SINGULAIR?

Avoid Poisoning! This medicine, as all other medicines, must be stored in a safe place out of the reach of

children and/or infants, in order to avoid poisoning. Do not induce vomiting unless explicitly instructed to do so

by a doctor!

Do not use SINGULAIR after the expiry date (exp. date) which is stated on pack. The expiry date refers to the

last day of the indicated month.

Storage conditions:

SINGULAIR 4 mg granules for kiddies: Store in the original package in order to protect from light and

moisture. Do not store above 25°C. After opening, use within 15 minutes.

SINGULAIR 4 mg chewable tablets: Store below 25ºC.

SINGULAIR 5 mg chewable tablets: Store below 30ºC.

Store in the original package in order to protect from

light and moisture.

SINGULAIR 10 mg tablets: Store below 30ºC.

Store in the original package in order to protect from light and

moisture.

Do not store different medications in the same package.

6. FURTHER INFORMATION

6.1 What SINGULAIR contains?

The active substance is montelukast.

The other ingredients are:

Each 10-mg film-coated tablet contains the following inactive ingredients:

Microcrystalline

cellulose,

lactose

monohydrate,

croscarmellose

sodium,

hydroxypropyl

cellulose,

magnesium stearate.

The film coating consists of:

Hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide, yellow ferric oxide,

and carnauba wax.

Each 4-mg and 5-mg chewable tablet contains the following inactive ingredients:

Mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, artificial

cherry flavor, aspartame, and magnesium stearate.

Each sachet of 4-mg oral granules contains the following inactive ingredients:

Mannitol, hydroxypropyl cellulose, and magnesium stearate.

Please note that the 10 mg film-coated tablets contain lactose. Each SINGULAIR 10 mg tablet contains 89.3

mg of lactose monohydrate.

Please note that the 4 mg and 5 mg chewable tablets contain aspartame, which is a source of phenylalanine.

Each 4 mg chewable tablet contains 0.674 mg phenylalanine and each 5 mg chewable tablet contains 0.842

mg phenylalanine.

6.2 What SINGULAIR looks like and contents of the pack

SINGULAIR 4 mg granules for kiddies are white, granular, coarse, free flowing homogeneous solid, with no

extraneous particles present.

SINGULAIR 4 mg chewable tablets are pink, oval, biconvex tablets with SINGULAIR debossed on one side

and MSD 711 on the other.

SINGULAIR 5 mg chewable tablets are pink, round, biconvex tablets with SINGULAIR engraved on one

side and MSD 275 on the other.

SINGULAIR 10 mg tablets are beige, rounded square, film-coated tablets with SINGULAIR engraved on one

side an MSD 117 on the other.

Pack sizes:

SINGULAIR 4 mg granules for kiddies: 7, 10, 28, 30 sachets per pack.

SINGULAIR 4 mg chewable tablets: 7, 10, 28, 30 chewable tablets per pack.

SINGULAIR 5 mg chewable tablets: 7, 10, 28, 30 chewable tablets per pack.

SINGULAIR 10 mg tablets: 7, 10, 28, 30 tablets per pack.

Not all pack sizes may be marketed.

Marketing authorization holder:

Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O. Box 7121, Petah-Tikva 49170.

This leaflet was checked and approved by the Ministry of Health in June 2015.

Drug registration no. listed in the official registry of the Ministry of Health

SINGULAIR 4 mg granules for kiddies: 130.14.30912

SINGULAIR 4 mg chewable tablets for pre-school kids: 121.67.30155

SINGULAIR 5 mg chewable tablets: 109.90.29316

SINGULAIR 10 mg tablets: 109.91.29317

SINGULAIR

®

TABLETS/CHEWABLE TABLETS/ORAL GRANULES

INDICATIONS

SINGULAIR is indicated in adult and pediatric patients 12 months of age and older for the prophylaxis and

chronic treatment of asthma, including prevention of daytime and nighttime symptoms, the treatment of aspirin-

sensitive asthmatic patients, and the prevention of exercise-induced bronchoconstriction.

SINGULAIR is effective alone or in combination with other agents used in the maintenance treatment of

chronic asthma. SINGULAIR and inhaled corticosteroids may be used concomitantly with additive effects to

control asthma or to reduce the inhaled corticosteroid dose while maintaining clinical stability.

SINGULAIR is indicated for the relief of daytime and nighttime symptoms of seasonal allergic rhinitis in adults

and in pediatric patients 2 years of age and older.

DOSAGE AND ADMINISTRATION

General Recommendations

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

tablets, chewable tablets and oral granules can be taken with or without food. Patients should be advised to

continue taking SINGULAIR while their asthma is controlled, as well as during periods of worsening asthma.

No dosage adjustment is necessary for pediatric patients, for the elderly, for patients with renal insufficiency or

mild-to-moderate hepatic impairment or for patients of either gender.

SINGULAIR should be taken once daily. For asthma, the dose should be taken in the evening. For seasonal

allergic rhinitis, the time of administration may be individualized to suit patient needs.

Patients with both asthma and seasonal allergic rhinitis should take only one tablet daily in the evening.

Adults 15 Years of Age and Older

with Asthma and/or Seasonal Allergic Rhinitis

The dosage for adults 15 years of age and older is one 10-mg tablet daily.

Pediatric Patients 6 to 14 Years of Age

with Asthma and/or Seasonal Allergic Rhinitis

The dosage for pediatric patients 6 to 14 years of age is one 5-mg chewable tablet daily.

Pediatric Patients 2 to 5 Years of Age

with Asthma and/or Seasonal Allergic Rhinitis

The dosage for pediatric patients 2 to 5 years of age is one 4-mg chewable tablet daily or one sachet of 4-mg

oral granules daily.

Pediatric Patients 12 Months to 2 Years of Age with Asthma

The dosage for pediatric patients 12 months to 2 years of age is one sachet of 4-mg oral granules daily.

Administration of oral granules:

SINGULAIR oral granules can be administered either directly in the mouth, mixed with a spoonful of cold or

room temperature soft food (e.g., applesauce), or dissolved in 1 teaspoonful (5 mL) of cold or room

temperature baby formula or breast milk. The sachet should not be opened until ready to use. After opening

the sachet, the full dose of SINGULAIR oral granules must be administered immediately (within 15 minutes). If

mixed with food, or dissolved in baby formula or breast milk, SINGULAIR oral granules must not be stored for

future use. SINGULAIR oral granules are not intended to be dissolved in any liquid other than baby formula or

breast milk for administration. However, liquids may be taken subsequent to administration.

Therapy with SINGULAIR in Relation to Other Treatments for Asthma

SINGULAIR can be added to a patient’s existing treatment regimen.

Reduction in Concomitant Therapy:

U

Bronchodilator Treatments

U

: SINGULAIR can be added to the treatment regimen of patients who are not

adequately controlled on bronchodilator alone. When a clinical response is evident (usually after the first dose),

the patient’s bronchodilator therapy can be reduced as tolerated.

U

Inhaled Corticosteroids

U

: Treatment with SINGULAIR provides additional clinical benefit to patients treated with

inhaled corticosteroids. A reduction in the corticosteroid dose can be made as tolerated. The dose should be

reduced gradually with medical supervision. In some patients, the dose of inhaled corticosteroids can be

tapered off completely.

SINGULAIR should not be abruptly substituted for inhaled corticosteroids.

COMPOSITION

Each tablet/chewable tablet/sachet contains:

Active Ingredient

Each 10 mg film-coated tablet contains 10.4 mg montelukast sodium, which is the molar equivalent to 10.0 mg

of free acid.

Each 5 mg chewable tablet contains 5.2 mg montelukast sodium, which is the molar equivalent to 5.0 mg of

free acid.

Each 4 mg chewable tablet and each sachet of 4 mg oral granules contains 4.2 mg montelukast sodium, which

is the molar equivalent to 4.0 mg of free acid.

Inactive Ingredients

Each 10 mg film-coated tablet contains the following inactive ingredients

: microcrystalline cellulose, lactose

monohydrate (89.3 mg), croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The film

coating consists of: hydroxypropyl methylcellulose,

hydroxypropyl cellulose

titanium dioxide, red ferric oxide,

yellow ferric oxide, and carnauba wax.

Each 4 mg and 5 mg chewable tablet contains the following inactive ingredients: mannitol, microcrystalline

cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and

magnesium stearate.

Each sachet of 4 mg oral granules contains the following inactive ingredients: mannitol, hydroxypropyl

cellulose, and magnesium stearate.

CONTRAINDICATIONS

Hypersensitivity to any component of this product.

PRECAUTIONS

The efficacy of oral SINGULAIR for the treatment of acute asthma attacks has not been established.

Therefore, oral SINGULAIR should not be used to treat acute asthma attacks. Patients should be advised to

have appropriate rescue medication available.

While the dose of concomitant inhaled corticosteroid may be reduced gradually under medical supervision,

SINGULAIR should not be abruptly substituted for inhaled or oral corticosteroids.

Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory

agents while taking SINGULAIR. Although SINGULAIR is effective in improving airway function in asthmatics

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

and other non-steroidal anti-inflammatory drugs in aspirin sensitive asthmatic patients [see Clinical Studies].

Neuropsychiatric events have been reported in patients taking SINGULAIR. Post-marketing reports with

SINGULAIR use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation,

disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment,

restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details

of some post-marketing reports involving SINGULAIR appear consistent with a drug-induced effect.

Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify

their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of

continuing treatment with SINGULAIR if such events occur (see Side Effects).

In rare cases patients receiving anti-asthma agents, including leukotriene receptor antagonists, have

experienced one or more of the following:

eosinophilia, vasculitic rash, worsening pulmonary symptoms,

cardiac complications, and/or neuropathy sometimes diagnosed as Churg-Strauss syndrome, a systemic

eosinophilic vasculitis. 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, caution and appropriate clinical monitoring are recommended in patients receiving SINGULAIR.

Phenylketonuric patients should be informed that the 4-mg and 5-mg chewable tablets contain phenylalanine

(a component of aspartame), 0.674 and 0.842 mg per 4-mg and 5-mg chewable tablet, respectively.

SIDE EFFECTS

SINGULAIR has been generally well tolerated. Side effects, which usually were mild, generally did not require

discontinuation of therapy. The overall incidence of side effects reported with SINGULAIR was comparable to

placebo.

Adults 15 Years of Age and Older with Asthma

SINGULAIR has been evaluated for safety in approximately 2600 adult patients 15 years of age and older in

clinical

studies.

placebo-controlled

clinical

studies,

following

adverse

experiences

reported

with

SINGULAIR occurred in

1% of patients and at an incidence greater than or equal to that in patients treated

with placebo, regardless of drug relationship:

Table 1: Adverse Experiences Occurring in

1% of Patients

with an Incidence Greater than that in Patients Treated with Placebo

SINGULAIR

10 mg/day

(n = 1955)

Placebo

(n = 1180)

Body As A Whole

Asthenia/fatigue

Fever

Pain, abdominal

Trauma

Digestive System Disorders

Dyspepsia

Gastroenteritis, infectious

Pain, dental

Nervous System/Psychiatric

Dizziness

Headache

18.4

18.1

Respiratory System Disorders

Congestion, nasal

Cough

Influenza

Skin/Skin Appendages Disorder

Rash

Laboratory Adverse Experiences*

ALT increased

AST increased

Pyuria

* Number of patients tested (SINGULAIR and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159.

Cumulatively, 569 patients were treated with SINGULAIR for at least 6 months, 480 for one year and 49 for 2

years in clinical studies. With prolonged treatment, the adverse experience profile did not change.

Pediatric Patients 6 to 14 Years of Age with Asthma

SINGULAIR has been evaluated in approximately 476 pediatric patients 6 to 14 years of age. The safety profile

in pediatric patients is generally similar to the adult safety profile and to placebo.

In pediatric patients 6 to 14 years of age receiving SINGULAIR, the following events occurred with a frequency

≥2% and more frequently than in pediatric patients who received placebo: pharyngitis, influenza, fever,

sinusitis, nausea, diarrhea, dyspepsia, otitis, viral infection, and laryngitis.

In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety

profile previously described for SINGULAIR. In a 56-week, double-blind study evaluating growth rate in

pediatric patients 6 to 8 years of age receiving SINGULAIR, the following events not previously observed with

the use of SINGULAIR in this age group occurred with a frequency ≥2% and more frequently than in pediatric

patients who received placebo: headache, rhinitis (infective), varicella, gastroenteritis, atopic dermatitis, acute

bronchitis, tooth infection, skin infection, and myopia. Cumulatively, 289 pediatric patients 6 to 14 years of age

were treated with SINGULAIR for at least 6 months and 241 for one year or longer. With prolonged treatment,

the adverse experience profile did not change.

Pediatric Patients 2 to 5 Years of Age with Asthma

SINGULAIR has been evaluated in 573 pediatric patients 2 to 5 years of age. In pediatric patients 2 to 5 years

of age receiving SINGULAIR, the following events occurred with a frequency ≥2% and more frequently than in

pediatric patients who received placebo: fever, cough, abdominal pain, diarrhea, headache, rhinorrhea,

sinusitis, otitis, influenza, rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis,

and conjunctivitis.

Cumulatively, 426 pediatric patients 2 to 5 years of age were treated with SINGULAIR for at least 3 months,

230 for 6 months or longer, and 63 patients for 12 months or longer. With prolonged treatment, the adverse

experience profile did not change.

Pediatric Patients 6 Months to 2 Years of Age with Asthma

Safety and effectiveness in pediatric patients younger than 12 months of age with asthma have not been

established.

SINGULAIR has been evaluated for safety in 175 pediatric patients 6 months to 2 years of age.

The safety profile of SINGULAIR in a 6-week, double-blind, placebo-controlled clinical study was generally

similar to the safety profile in adults and pediatric patients 2 to 14 years of age. In pediatric patients 6 to 23

months of age receiving SINGULAIR, the following events occurred with a frequency ≥2% and more frequently

than in pediatric patients who received placebo: upper respiratory infection, wheezing; otitis media; pharyngitis,

tonsillitis, cough; and rhinitis. The frequency of less common adverse events was comparable between

SINGULAIR and placebo.

Adults 15 Years of Age and Older with Seasonal Allergic Rhinitis

SINGULAIR has been evaluated in 2199 adult patients 15 years of age and older for the treatment of seasonal

allergic rhinitis in clinical studies. SINGULAIR administered once daily in the morning or in the evening was

generally well tolerated with a safety profile similar to that of placebo. In placebo-controlled clinical studies,

the following event was reported with SINGULAIR with a frequency ≥1% and at an incidence greater than

placebo: upper respiratory infection, 1.9% of patients receiving SINGULAIR vs. 1.5% of patients receiving

placebo.

In a 4-week, placebo-controlled clinical study, the safety profile was consistent with that observed in 2-week

studies. The incidence of somnolence was similar to that of placebo in all studies.

Pediatric Patients 2 to 14 Years of Age with Seasonal Allergic Rhinitis

SINGULAIR has been evaluated in 280 pediatric patients 2 to 14 years of age for the treatment of seasonal

allergic rhinitis in a 2-week, placebo-controlled, clinical study. SINGULAIR administered once daily in the

evening was generally well tolerated with a safety profile similar to that of placebo. In this study, the following

events occurred with a frequency ≥2% and at an incidence greater than placebo: headache, otitis media,

pharyngitis, and upper respiratory infection.

Pooled Analyses of Clinical Trials Experience

A pooled analysis of 41 placebo-controlled clinical studies (35 studies in patients 15 years of age and older; 6

studies in pediatric patients 6 to 14 years of age) was performed using a validated assessment method of

suicidality. Among the 9929 patients who received SINGULAIR and 7780 patients who received placebo in

these studies, there was one patient with suicidal ideation in the group taking SINGULAIR. There were no

completed suicides, suicide attempts or preparatory acts toward suicidal behavior in either treatment group.

A separate pooled analysis of 46 placebo-controlled clinical studies (35 studies in patients 15 years of age and

older; 11 studies in pediatric patients 3 months to 14 years of age) assessing behavior-related adverse

experiences (BRAEs) was performed. Among the 11,673 patients who received SINGULAIR and 8827

patients who received placebo in these studies, the frequency of patients with at least one BRAE was 2.73%

in patients who received SINGULAIR and 2.27% in patients who received placebo; the odds ratio was 1.12

(95% CI [0.93; 1.36]).

The clinical trials included in these pooled analyses were not designed specifically to examine suicidality or

BRAEs.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of SINGULAIR. Because these

reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably

estimate their frequency or establish a causal relationship to drug exposure.

Infections and infestations: upper respiratory infection

Blood and lymphatic system disorders: increased bleeding tendency, thrombocytopenia

Immune system disorders: hypersensitivity reactions including anaphylaxis, very rarely hepatic eosinophilic

infiltration

Psychiatric

disorders:

agitation

including

aggressive

behavior

hostility,

anxiousness,

depression,

disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, memory impairment,

psychomotor hyperactivity (including irritability, restlessness, and tremor), somnambulism, suicidal thinking

and behavior (suicidality)

Nervous system disorders: dizziness, drowsiness, paraesthesia/hypoesthesia, very rarely seizure

Cardiac disorders: palpitations

Respiratory, thoracic and mediastinal disorders: epistaxis; pulmonary eosinophilia

Gastrointestinal disorders: diarrhea, dyspepsia, nausea, vomiting

Hepatobiliary disorders: increased ALT and AST, very rarely hepatitis (including cholestatic, hepatocellular,

and mixed-pattern liver injury). Most of the cases of hepatitis occurred in combination with other confounding

factors, such as use of other medications, or when SINGULAIR was administered to patients who had

underlying potential for liver disease such as alcohol use or other forms of hepatitis.

Skin and subcutaneous tissue disorders: angioedema, bruising, erythema multiforme, erythema nodosum,

pruritus, rash, urticaria

Musculoskeletal and connective tissue disorders: arthralgia, myalgia including muscle cramps

Renal and urinary disorders: enuresis in children

General disorders and administration site conditions: asthenia/fatigue, edema, pyrexia

DRUG INTERACTIONS

SINGULAIR may be administered with other therapies routinely used in the prophylaxis and chronic treatment

of asthma, and in the treatment of allergic rhinitis. In drug-interactions studies, the recommended clinical dose

of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs:

theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine,

digoxin, warfarin, gemfibrozil, itraconazole and Cytochrome P450 (CYP) enzyme inducers.

Although additional specific interaction studies were not performed, SINGULAIR was used concomitantly with

a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions.

These medications included thyroid hormones, sedative hypnotics, nonsteroidal anti-inflammatory agents,

benzodiazepines and decongestants.

The area under the plasma concentration-time curve (AUC) for montelukast was decreased approximately

subjects

with

co-administration

phenobarbital.

dosage

adjustment

SINGULAIR

recommended.

In vitro studies have shown that montelukast is an inhibitor of CYP 2C8. However, data from a clinical drug-

drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs

primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo. Therefore,

montelukast is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g. paclitaxel,

rosiglitazone, and repaglinide).

In vitro studies have shown that montelukast is a substrate of CYP 2C8, 2C9, and 3A4. Data from a clinical

drug-drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9)

demonstrated that gemfibrozil increased the systemic exposure of montelukast by 4.4-fold. Co-administration

of itraconazole, a strong CYP 3A4 inhibitor, with gemfibrozil and montelukast did not further increase the

systemic exposure of montelukast. The effect of gemfibrozil on systemic exposure of montelukast is not

considered to be clinically meaningful based on clinical safety data with doses greater than the 10 mg

approved dose in adults (e.g., 200 mg/day to adult patients for 22 weeks, and up to 900 mg/day to patients for

approximately one week) where clinically important adverse experiences were not observed. Therefore, no

dosage adjustment of montelukast is required upon co-administration with gemfibrozil. Based on in vitro data,

clinically important drug interactions with other known inhibitors of CYP 2C8 (e.g., trimethoprim) are not

anticipated. In addition, co-administration of montelukast with itraconazole alone resulted in no significant

increase in the systemic exposure of montelukast.

USE IN SPECIFIC POPULATIONS

Pregnancy

SINGULAIR has not been studied in pregnant women. SINGULAIR should be used during pregnancy only if

clearly needed.

During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of

women being treated with SINGULAIR during pregnancy. Most of these women were also taking other asthma

medications during their pregnancy. A causal relationship between these events and SINGULAIR has not

been established.

Nursing Mothers

It is not known if SINGULAIR is excreted in human milk. Because many drugs are excreted in human milk,

caution should be exercised when SINGULAIR is given to a nursing mother.

Pediatric Use

SINGULAIR

been

studied

pediatric

patients

months

years

(see

Dosage

Administration). Safety and effectiveness in pediatric patients younger than 6 months of age have not been

studied. Studies have shown that SINGULAIR does not affect the growth rate of pediatric patients.

Use in the Elderly

In clinical studies, there were no age-related differences in the efficacy or safety profiles of SINGULAIR.

OVERDOSAGE

No specific information is available on the treatment of overdosage with SINGULAIR. In chronic asthma

studies, SINGULAIR 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. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g.,

remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive

therapy, if required.

There

have

been

reports

acute

overdosage

postmarketing

experience

clinical

studies

with

SINGULAIR. These include reports in adults and children with a dose as high as 1000 mg. The clinical and

laboratory findings observed were consistent with the safety profile in adults and pediatric patients. There were

no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse

experiences were consistent with the safety profile of SINGULAIR and included abdominal pain, somnolence,

thirst, headache, vomiting, and psychomotor hyperactivity.

It is not known whether montelukast is dialyzable by peritoneal-or hemodialysis.

THERAPEUTIC CLASS

SINGULAIR (montelukast sodium) is a selective and orally active leukotriene receptor antagonist that

specifically inhibits the cysteinyl leukotriene CysLT1 receptor.

CLINICAL PHARMACOLOGY

Mechanism of Action

SINGULAIR is a selective orally active leukotriene receptor antagonist that specifically inhibits the cysteinyl

leukotriene CysLT

receptor.

Pharmacodynamics

The cysteinyl leukotrienes (LTC

, LTD

, LTE

), 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 (CysLT

) receptor is found in the human airway (including

airway

smooth

muscle

cells

airway

macrophages)

other

pro-inflammatory

cells

(including

eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma

and allergic rhinitis. In asthma, leukotriene-mediated effects include a number of airway actions, including

bronchoconstriction, mucous secretion, vascular permeability, 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.

Montelukast is a potent, orally active compound with antiinflammatory properties which significantly improves

parameters of asthmatic inflammation. Based on biochemical and pharmacological bioassays, it binds with

high affinity and selectivity to the CysLT

receptor (in preference to other pharmacologically important airway

receptors such as the prostanoid, cholinergic, or

-adrenergic receptor). Montelukast potently inhibits

physiologic actions of LTC

, LTD

, and LTE

at the CysLT

receptor without any agonist activity.

In asthmatic patients, montelukast causes potent inhibition of airway cysteinyl leukotriene receptors, as

demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD

. Doses as low as 5 mg, cause

substantial blockage of LTD

-induced bronchoconstriction.

Montelukast causes bronchodilation within 2 hours of oral administration; these effects were additive to the

bronchodilation caused by a

-agonist.

Pharmacokinetics

Absorption

Montelukast is rapidly and nearly completely absorbed following oral administration. For the 10-mg film-coated

tablet, the mean peak plasma concentration (C

) is achieved 3 hours (T

) after administration in adults in

the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and C

are not influenced by a

standard meal.

For the 5-mg chewable tablet, the C

is achieved 2 hours after administration in adults in the fasted state.

The mean oral bioavailability is 73%. Food does not have a clinically important influence with chronic

administration.

For the 4-mg chewable tablet, C

is achieved 2 hours after administration in pediatric patients 2 to 5 years of

age in the fasted state.

The 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet when administered to adults in

the fasted state. The coadministration of applesauce or a standard meal with the oral 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 standard meal, respectively).

Safety and efficacy were demonstrated in clinical studies where the 4-mg chewable tablet, 5-mg chewable

tablet, and 10-mg film-coated tablet were administered without regard to the timing of food ingestion. The

safety of SINGULAIR was also demonstrated in a clinical study in which the 4-mg oral granules were

administered without regard to the timing of food ingestion.

Distribution

Montelukast is more than 99% bound to plasma proteins.

The steady state volume of distribution

montelukast averages 8 to 11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution

across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were

minimal in all other tissues.

Metabolism

Montelukast

extensively

metabolized.

studies

with

therapeutic

doses,

plasma

concentrations

metabolites of montelukast are undetectable at steady state in adults and pediatric patients.

In vitro studies using human liver microsomes indicate that cytochrome P450 3A4, 2C8, and 2C9 are involved

in the metabolism of montelukast. Based on further in vitro results in human liver microsomes, therapeutic

plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.

Elimination

The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of

radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was

recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates montelukast and

its metabolites are excreted almost exclusively via the bile.

In several studies, the mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young

adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg.

No difference in pharmacokinetics was noted between dosing in the morning or in the evening.

During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma

14%).

Characteristics in Patients

Gender

: The pharmacokinetics of montelukast are similar in males and females.

Elderly: The pharmacokinetic profile and the oral bioavailability of a single 10-mg oral dose of montelukast are

similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No

dosage adjustment in the elderly is required.

Race: Pharmacokinetic differences due to race have not been studied. In clinical studies, there do not appear

to be any differences in clinically important effects.

Hepatic Insufficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had

evidence of decreased metabolism of montelukast, resulting in approximately 41% higher mean montelukast

area

under the plasma concentration curve (AUC) following a single 10-mg dose. The elimination

montelukast is slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage

adjustment is required in patients with mild-to-moderate hepatic insufficiency. There are no clinical data in

patients with severe hepatic insufficiency (Child-Pugh score >9).

Renal Insufficiency: Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics

of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended

in these patients.

Adolescents and Pediatric Patients: The plasma concentration profile of montelukast following administration

of the 10-mg film-coated tablet is similar in adolescents

15 years old and young adults. The 10-mg film-

coated tablet is recommended for use in patients

15 years old.

Pharmacokinetic studies show that the plasma profiles of the 4-mg oral granule formulation in pediatric

patients 6 months to 2 years of age, the 4-mg chewable tablet in pediatric patients 2 to 5 years of age, and the

5-mg chewable tablets in pediatric patients 6 to 14 years of age were similar to the plasma profile of the 10-mg

film-coated tablet in adults. The 5-mg chewable tablet should be used in pediatric patients 6 to 14 years of age

and the 4-mg chewable tablet in pediatric patients 2 to 5 years of age. The 4-mg oral granule formulation

should be used for pediatric patients 12 months to 2 years of age.

Since the 4-mg oral granule formulation is

bioequivalent to the 4-mg chewable tablet, it can also be used as an alternative formulation to the 4-mg

chewable tablet in pediatric patients 2 to 5 years of age.

NONCLINICAL TOXICOLOGY

Carcinogenicity

Montelukast sodium was not carcinogenic when administered at oral doses of up to 200 mg/kg/day in a 106-

week study in rats, or at oral doses of up to 100 mg/kg/day in a 92-week study in mice. These doses are

equivalent to 1000 times and 500 times the recommended adult human dose respectively, based on an adult

patient weight of 50 kg.

Mutagenicity

Montelukast sodium was found to be neither genotoxic nor mutagenic. Montelukast sodium was negative in the

in vitro microbial mutagenesis assay and the V-79 mammalian cell mutagenesis assays, with and without

metabolic activation. There was no evidence of genotoxicity in the in vitro alkaline elution assay in rat

hepatocytes and the in vitro chromosomal aberration assays in Chinese hamster ovary cells, with or without a

microsomal enzyme activation system. Similarly, there was no induction of chromosomal aberrations in bone

marrow cells of male or female mice after the administration of oral doses of up to 1200 mg/kg body weight

(3600 mg/m

), which represent 6000 times the recommended daily adult dose, based on an adult patient

weight of 50 kg.

Reproduction

Fertility and reproductive performance were not affected in studies with male rats given oral doses of up to 800

mg/kg/day or with female rats given doses of up to 100 mg/kg/day. These dosages provide margins of 4000-

fold and 500-fold respectively above the recommended adult human dose, based on an adult patient weight of

50 kg.

Development

developmental

toxicity

studies,

there

were

treatment

related

adverse

effects

doses

400 mg/kg/day in rats and up to 100 mg/kg/day in rabbits. Fetal exposure of montelukast sodium in rats and

rabbits does occur and significant concentrations of drug were observed in milk of lactating rats.

CLINICAL STUDIES

CLINICAL STUDIES - ASTHMA

ADULTS 15 YEARS OF AGE AND OLDER

The efficacy of SINGULAIR for the chronic treatment of asthma in adults 15 years of age and older was

demonstrated in two (US and Multinational) similarly designed 12-week double-blind, placebo-controlled

studies

in 1325

patients

(795 treated

with

SINGULAIR and 530

treated

with placebo).

Patients

were

symptomatic and using approximately 5 puffs of

-agonist per day on an “as-needed” basis. The mean

baseline percent of predicted forced expiratory volume in 1 second (FEV1 ) was 66% (approximate range, 40

to 90%). In these studies, asthma symptoms, asthma-related outcomes, respiratory function, and “as-needed”

-agonist use, were measured. Endpoints were analyzed in each study and in a combined analysis, according

to a prespecified data analysis plan.

The following clinical results were observed:

Asthma Symptoms and Asthma-related Outcomes

SINGULAIR, 10 mg once daily in the evening, significantly improved measurements of patient-reported

daytime symptoms and nighttime awakenings in each study and in the combined analysis, compared with

placebo. In patients with nocturnal awakenings of at least 2 nights per week, SINGULAIR reduced the

nocturnal awakenings by 34% from baseline, significantly better than the reduction of 14% for the placebo

group (combined analysis).

SINGULAIR, compared with placebo, significantly improved asthma-related outcome measurements. In the

combined analysis, SINGULAIR, compared with placebo, decreased asthma attacks by 37%, corticosteroid

rescue by 39%, discontinuations due to worsening asthma by 65%, asthma exacerbations by 38% and

increased asthma-free days by 42%.

Physicians’ and patients’ global asthma evaluations and asthma-specific quality-of-life evaluations (in all

domains, including normal daily activity and asthma symptoms) were significantly better with SINGULAIR

compared with placebo in each study and in the combined analysis,.

Respiratory Function

Compared with placebo, SINGULAIR caused significant improvements in parameters of respiratory function

(FEV

and peak expiratory flow rate, PEFR) in each study and in the combined analysis:

Table 2Effect of SINGULAIR, 10 mg Daily, on Parameters of Respiratory Function

in Adults 15 Years and Older (Combined Analysis)

SINGULAIR

n = 795

Placebo

n = 530

Morning FEV

(% change from baseline)

10.4*

AM PEFR (L/min change from baseline)

24.5*

PM PEFR (L/min change from baseline)

17.9*

*Significantly better than placebo (p

0.001)

Figure 1

Effect of SINGULAIR on Morning FEV

in Adults 15 Years and Older

(Combined Analysis)

-1

1

3

5

7

9

11

13

0

3

6

9

12

-1

1

3

5

7

9

11

13

SINGULAIR

(n = 795)

Placebo

(n = 530)

Weeks in Treatment

Percent

Change

From

Baseline

-agonist Use

Compared with placebo, SINGULAIR significantly decreased the use of “as-needed”

-agonist by 26.1% from

baseline compared with 4.6% in the placebo group, in the combined analysis. The decreases were also

significant in each of the studies (p

0.001) (see Figure 2).

Figure 2

Effect of SINGULAIR on “As-needed”

-agonist Use

in Adults 15 Years and Older

(Combined Analysis)

-60

-50

-40

-30

-20

-10

0

10

-50

-40

-30

-20

-10

0

10

0

3

6

9

12

-60

-50

-40

-30

-20

-10

0

10

Percent

Change

From

Baseline

Weeks in Treatment

Placebo

n = 530

SINGULAIR

n = 795

Onset of Action and Maintenance of Benefits

In each study and in the combined analysis, the treatment effect of SINGULAIR, measured by daily diary card

parameters, including symptom scores, “as-needed”

-agonist use, and PEFR measurements, was achieved

after the first dose and was maintained throughout the dosing interval (24 hours). Treatment effect also

remained constant during continuous once-daily administration in extension studies for up to one year.

Withdrawal of SINGULAIR in asthmatic patients after 12 weeks of continuous use did not cause rebound

worsening of asthma (See also EFFECTS ON EXERCISE-INDUCED BRONCHOCONSTRICTION.)

Effects Relative to Inhaled Corticosteroids

In one of the two 12-week double-blind studies in adults (Multinational), SINGULAIR was compared with

inhaled beclomethasone (200

g twice daily with a spacer device). SINGULAIR demonstrated a more rapid

initial response, although over the full duration of the study beclomethasone provided a greater average

treatment effect. However, a high percent of patients treated with SINGULAIR achieved similar clinical

responses compared with inhaled beclomethasone.

PEDIATRIC PATIENTS 6 TO 14 YEARS OF AGE

The efficacy of SINGULAIR in pediatric patients 6 to 14 years of age was demonstrated in one 8-week double-

blind, placebo-controlled study in 336 patients (201 treated with SINGULAIR and 135 treated with placebo)

using

-agonist on an “as-needed” basis. The mean baseline percent predicted FEV

was 72% (approximate

range, 45 to 90%) and approximately 36% of the patients were on inhaled corticosteroids.

Compared with placebo, SINGULAIR, one 5-mg chewable tablet daily in the evening, significantly decreased

the percent of days asthma exacerbations occurred. Parents’ global asthma evaluations and the pediatric

asthma-specific

quality-of-life

evaluations

domains,

including

normal

daily

activity

asthma

symptoms) were significantly better with SINGULAIR, compared with placebo.

Compared with placebo, there was a significant improvement in morning FEV

(8.7% versus 4.2% change

from

baseline

placebo

group,

p<0.001)

significant

decrease

total

“as-needed”

-agonist use (11.7% decrease from baseline versus 8.2% increase from baseline in the placebo group,

0.050).

Similar to the adult studies, the treatment effect was achieved after the first dose and remained constant during

continuous once-daily administration in clinical studies for up to 6 months.

Growth Rate in Pediatric Patients

Two controlled clinical studies have demonstrated that montelukast did not affect the growth rate in prepubertal

pediatric patients with asthma. In a study of children aged 6 to 11 years, growth rate as measured by lower leg

length growth, was similar in patients treated with montelukast 5 mg once daily for 3 weeks compared with

placebo, and was significantly lower in patients treated with inhaled budesonide (200

g twice daily) for 3

weeks, compared with placebo. In a 56-week study in children aged 6 to 8 years, linear growth rate was similar

in patients treated with montelukast 5 mg once daily and placebo (LS means for montelukast and placebo:

5.67 and 5.64 cm/year, respectively), and was significantly lower (LS mean: 4.86 cm/year) in patients treated

with inhaled beclomethasone (200

g twice daily), compared with placebo [difference in LS means (95% CI): -

0.78 (-1.06, -0.49) cm/year]. Both montelukast and beclomethasone versus placebo demonstrated significant

benefit in rescue medication use in these patients with mild asthma.

PEDIATRIC PATIENTS 12 MONTHS TO 5 YEARS OF AGE

The efficacy of SINGULAIR, one 4-mg chewable tablet daily in the evening, in pediatric patients 2 to 5 years of

age was demonstrated in a 12-week double-blind, placebo-controlled study in 689 patients (461 treated with

SINGULAIR and 228 treated with placebo). SINGULAIR significantly improved multiple asthma efficacy

endpoints and improved parameters of asthma control.

SINGULAIR was significantly better compared with placebo in the following caregiver asthma diary efficacy

endpoints: days

with daytime asthma symptoms, daytime asthma symptom score (including coughing,

wheezing, trouble breathing, and child activities), beta-agonist use, corticosteroid rescue, days without asthma,

and overnight asthma symptoms (p<0.05). Additionally, there was a favorable trend in treatment effect for the

efficacy endpoint, asthma attack (p=0.107).

The physician's global assessment and the average of caregiver's and physician's global assessments of

asthma were significantly better with SINGULAIR compared with placebo (p=0.007 and 0.015, respectively).

A treatment effect was achieved after the first dose. In addition, total blood eosinophil counts were significantly

decreased (p= 0.034).

Efficacy of SINGULAIR is supported in pediatric patients 6 months to 2 years of age by extrapolation from the

demonstrated

efficacy

patients

years

older

with

asthma,

based

similar

pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug’s

effect are substantially similar among these populations.

EFFECTS IN PATIENTS ON CONCOMITANT INHALED CORTICOSTEROIDS

Separate studies in adults demonstrated the ability of SINGULAIR to add to the clinical effect of inhaled

corticosteroids, and to allow steroid tapering when used concomitantly.

Three large studies demonstrated SINGULAIR has additional benefits in patients taking corticosteroids.

In a randomized, placebo-controlled, parallel-group study (n=226), stable asthmatic patients on initial inhaled

corticosteroid doses of approximately 1600

g per day, reduced their steroid use by approximately 37% during

a placebo run-in period. SINGULAIR allowed a further 47% reduction in inhaled corticosteroid dose compared

with 30% for placebo over the 12-week active treatment period (p

0.050).

In another randomized, placebo-controlled, parallel-group study (n=642) in a similar population of patients

maintained

adequately

controlled

inhaled

corticosteroids

(beclomethasone

g/day),

SINGULAIR

provided

additional

clinical

benefit,

compared

with

placebo.

Complete

abrupt

removal

beclomethasone

patients

receiving

both

treatments

caused

clinical

deterioration

some

patients,

suggesting that tapering inhaled corticosteroids as tolerated, rather than abrupt removal of steroids is

preferred.

In aspirin-sensitive asthmatic patients, nearly all of whom were receiving concomitant inhaled and/or oral

corticosteroids, a 4-week randomized, parallel-group study (n=80) demonstrated that SINGULAIR, compared

with placebo, resulted in significant improvement in parameters of asthma control.

EFFECTS ON EXERCISE-INDUCED BRONCHOCONSTRICTION

In a 12-week, parallel group study of 110 adult patients 15 years of age and older, SINGULAIR, 10 mg,

prevented exercise-induced bronchoconstriction (EIB) as demonstrated by significant inhibition of the following,

compared with placebo:

- the extent and duration of fall in FEV

over 60 minutes after exercise (as measured by the area under

the % fall in FEV

versus time curve after exercise, AUC);

- the maximal percent fall in FEV

after exercise;

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

Protection was consistent throughout the 12-week treatment period, indicating that tolerance did not occur. In a

separate crossover study, protection was observed after two once-daily doses.

pediatric

patients

years

age,

using

5-mg

chewable

tablet,

identically

designed

cross-over study demonstrated similar protection and the protection was maintained throughout the dosing

interval (24 hours).

EFFECTS ON ASTHMATIC INFLAMMATION

Several

studies

have

shown

SINGULAIR

inhibits

parameters

asthmatic

inflammation.

a placebo-controlled crossover study (n=12), SINGULAIR inhibited early- and late-phase bronchoconstriction

due to antigen challenge by 75 and 57%, respectively.

Because inflammatory cell (eosinophil) infiltration is an important feature of asthma, the effects of SINGULAIR

on eosinophils in the peripheral blood and airway were examined. In Phase Ilb/III clinical studies in adults,

SINGULAIR significantly decreased peripheral blood eosinophils approximately 15% from baseline, compared

with placebo. In pediatric patients 6 to 14 years of age SINGULAIR also significantly decreased peripheral

blood eosinophils 13% over the 8-week treatment period, compared with placebo.

In a 4-week, randomized, parallel group study (n=40) in adults, SINGULAIR significantly decreased airway

eosinophils (as assessed in sputum) by 48% from baseline compared with an increase of 23% from baseline

with placebo. In this study, peripheral blood eosinophils significantly decreased, and clinical asthma endpoints

improved with treatment with SINGULAIR.

CLINICAL STUDIES - SEASONAL ALLERGIC RHINITIS

The efficacy of SINGULAIR for the treatment of seasonal allergic rhinitis was investigated in similarly designed

randomized, 2-week, double-blind, placebo-controlled trials including 4924 patients (1751 patients were

treated with SINGULAIR). Patients were 15 years of age and older with a history of seasonal allergic rhinitis, a

positive skin test to at least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at

study initiation.

In a combined analysis of three pivotal studies, SINGULAIR 10-mg tablets administered to 1189 patients once

daily in the evening resulted in a statistically significant improvement in the primary endpoint, daytime nasal

symptoms score, and its individual components (nasal congestion, rhinorrhea, nasal itching, and sneezing);

nighttime symptoms score, and its individual components (nasal congestion upon awakening, difficulty going to

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

red, and puffy eyes); global evaluations of allergic rhinitis by patients and by physicians; and composite

symptoms score (composed of the daytime nasal and nighttime symptoms scores), compared with placebo.

In a separate 4-week study in which SINGULAIR was administered once daily in the morning, the efficacy over

the initial 2 weeks was significantly different from placebo and consistent with the effect observed in studies

using evening dosing. Additionally, the effect over the entire 4 weeks was consistent with the 2-week results.

In patients with seasonal allergic rhinitis aged 15 years and older who received SINGULAIR, a median

decrease of 13% in peripheral blood eosinophil counts was noted, compared with placebo, over the double-

blind treatment periods.

The efficacy of SINGULAIR for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of

age is supported by extrapolation from the demonstrated efficacy in patients 15 years of age and older with

seasonal allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug’s

effect are substantially similar among these populations.

STORAGE

SINGULAIR 4 mg granules for kiddies: Store in the original package in order to protect from light and moisture.

Do not store above 25°C. After opening, use within 15 minutes.

SINGULAIR 4 mg chewable tablets for preschool kids: Store below 25ºC

SINGULAIR 5 mg chewable tablets: Store below 30ºC. Store in the original package in order to protect from

light and moisture.

SINGULAIR 10 mg tablets: Store below 30ºC. Store in the original package in order to protect from light and

moisture.

PATIENT COUNSELING INFORMATION

Information for Patients

Patients should be advised to take SINGULAIR daily as prescribed, even when they are asymptomatic as well

as during periods of asthma worsening, and to contact their physicians if their asthma is not well controlled.

Patients should be advised that oral SINGULAIR is not for the treatment of acute asthma attacks.They should

have appropriate rescue medication available.

Manufactured by Merck, Sharp & Dohme B.V., Haarlem, Holland

For Merck, Sharp & Dohme (Israel-1996) Company Ltd., P.O.Box 7121 Petah-Tikva, 49170.

The format of this leaflet was determined by the Ministry of Health and its content was checked and approved

in June 2015.