Singulair

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

• Singulair^®

The recommended dose of montelukast in adults is 10 mg daily for treating asthma and allergic rhinitis and 10 mg two hours before exercising for prevention of exercise induced bronchospasm. Montelukast should be taken in the evening with or without food when used for asthma or allergic rhinitis. The 4 and 5 mg tablets are used in children.

Most people who use Singulair do not have serious side effects.

Singulair does have some common side effects that should decrease or go away in time. These include:

• Headache
• Stomach pain, heartburn, upset stomach, nausea, diarrhea
• Tooth pain
• Tired feeling
• Dizziness
• Fever, stuffy nose, sore throat, cough, hoarseness
• Mild rash
• Upper respiratory infection
• Earache or ear infection
• Score throat or cough

If these symptoms continue or get worse, call your doctor.

Serious Side Effects of Singulair

Tell your doctor immediately or get emergency help if you have any of these rare but serious side effects:

• Skin rash, severe tingling, numbness, pain, muscle weakness
• Mood or behavior changes, anxiety, depression, or thoughts about suicide or hurting yourself
• Tremors or shaking
• Easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin
• Severe sinus pain, swelling, or irritation
• Worsening asthma symptoms

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any of the symptoms of a serious allergic reaction, including:

• Rash or hives
• Itching or swelling, especially of the face, tongue, or throat
• Severe dizziness
• Trouble breathing

If you notice other side effects, contact your doctor.

Other drugs may interact with montelukast.

Tell your doctor about all the medications you use, including prescription, over-the-counter (OTC), vitamin, and herbal products.

Do not start a new medication without telling your doctor.

You should especially let your doctor know if you are using drugs containing phenobarbital or rifampin.

The chewable tablets of Singulair may contain aspartame. If you have phenylketonuria (PKU) or any other condition where your doctor has told you to avoid aspartame, ask your doctor or pharmacist about using montelukast safely.

If your asthma symptoms get worse when you take aspirin, avoid taking aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) while taking montelukast.

NSAIDs include ibuprofen, which is commonly found in over-the-counter medications such as Motrin and Advil, and naproxen, the key ingredient in Aleve and Naprosyn.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the following description of clinical trials experience, adverse reactions are listed regardless of causality assessment.

The most common adverse reactions (incidence ≥ 5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.

SINGULAIR has been evaluated for safety in approximately 2950 adult and adolescent patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with SINGULAIR occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:

Table 1: Adverse Experiences Occurring in ≥ 1% of Patients with an Incidence Greater than that in Patients Treated with Placebo

The frequency of less common adverse events was comparable between SINGULAIR and placebo.

The safety profile of SINGULAIR, when administered as a single dose for prevention of EIB in adult and adolescent patients 15 years of age and older, was consistent with the safety profile previously described for SINGULAIR.

Cumulatively, 569 patients were treated with SINGULAIR for at least 6 months, 480 for one year, and 49 for two years in clinical trials. With prolonged treatment, the adverse experience profile did not significantly change.

SINGULAIR has been evaluated for safety in 476 pediatric patients 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with SINGULAIR for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of SINGULAIR in the 8-week, double-blind, pediatric efficacy trial was generally similar to the adult safety profile. 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. The frequency of less common adverse events was comparable between SINGULAIR and placebo. With prolonged treatment, the adverse experience profile did not significantly change.

The safety profile of SINGULAIR, when administered as a single dose for prevention of EIB in pediatric patients 6 years of age and older, was consistent with the safety profile previously described for SINGULAIR.

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.

SINGULAIR has been evaluated for safety in 573 pediatric patients 2 to 5 years of age in single- and multiple-dose studies. 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 one year or longer in clinical trials. 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.

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 to 23 months 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.

SINGULAIR has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. SINGULAIR administered once daily in the morning or in the evening had a safety profile similar to that of placebo. In placebo-controlled clinical trials, 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, placebocontrolled 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.

SINGULAIR has been evaluated in 280 pediatric patients 2 to 14 years of age in a 2-week, multicenter, double-blind, placebo-controlled, parallel-group safety study. SINGULAIR administered once daily in the evening had 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.

SINGULAIR has been evaluated for safety in 3357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1632 received SINGULAIR in two, 6-week, clinical studies. SINGULAIR administered once daily had a safety profile consistent with that observed in patients with seasonal allergic rhinitis and similar to that of placebo. In these two studies, the following events were reported with SINGULAIR with a frequency ≥ 1% and at an incidence greater than placebo: sinusitis, upper respiratory infection, sinus headache, cough, epistaxis, and increased ALT. The incidence of somnolence was similar to that of placebo.

The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis. The safety in patients 6 to 23 months of age is supported by data from pharmacokinetic and safety and efficacy studies in asthma in this pediatric population and from adult pharmacokinetic studies.

Post-Marketing 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.

Blood and lymphatic system disorders: increased bleeding tendency, thrombocytopenia.

Immune system disorders: hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration.

Psychiatric disorders: agitation including 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 [see WARNINGS AND PRECAUTIONS].

Nervous system disorders: drowsiness, paraesthesia/hypoesthesia, seizures.

Cardiac disorders: palpitations.

Respiratory, thoracic and mediastinal disorders: epistaxis, pulmonary eosinophilia.

Gastrointestinal disorders: diarrhea, dyspepsia, nausea, pancreatitis, vomiting.

Hepatobiliary disorders: Cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with SINGULAIR. Most of these 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, Stevens-Johnson syndrome/toxic epidermal necrolysis, urticaria.

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

Renal and urinary disorders: enuresis in children.

General disorders and administration site conditions: edema.

Patients with asthma on therapy with SINGULAIR 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 events have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients [see WARNINGS AND PRECAUTIONS].

Singulair is part of the drug class:

• Leukotriene receptor antagonists

Administration

Oral Administration

Administer at regular intervals (once daily) without regard to meals.1 31 45

Administer in the evening in patients with asthma with or without coexisting allergic rhinitis.1 31 45

May individualize time of administration in patients with allergic rhinitis; administer at the same time each day.1 125

Administer ≥2 hours before exercise in patients with exercise-induced bronchospasm; do not take an additional dose within 24 hours of previous dose.1 125

Generally used in children 12 months to 5 years of age.1 Do not open packet until ready to use; administer full dose within 15 minutes of opening packet and without regard to meals.1 125

Administer directly in the mouth alone or mix with a teaspoonful (5 mL) of cold or room temperature baby formula, breast milk, or soft food (i.e., applesauce, carrots, rice, ice cream).1 Granules are not intended to be dissolved in liquid other than baby formula or breast milk prior to administration; however, liquids can be taken after administration of the granules.1 125 (See Stability.)

Do not store granules mixed with food for future use; discard any unused portion.1 125

Dosage

Available as montelukast sodium; dosage expressed in terms of montelukast.1

Pediatric Patients

Children 12–23 months: 4 mg once daily as oral granules.1

Children 2–5 years of age: 4 mg once daily as chewable tablets or oral granules.1 109

Children 6–14 years of age: 5 mg once daily as chewable tablets.1

Adolescents ≥15 years of age: 10 mg once daily as film-coated tablets.1 45

Additional dosage not needed for treatment of allergic rhinitis in patients already receiving chronic therapy for asthma.1

Children 6–14 years of age: 5 mg daily has been used for prevention of exercise-induced bronchospasm†.1 48 49 50 52 77 78

Adolescents ≥15 years of age: 10 mg once daily as film-coated tablets.1 48 49 50 52 77 78

Children 2–5 years of age: 4 mg once daily as chewable tablets or oral granules.1

Children 6–14 years of age: 5 mg once daily as chewable tablets.1

Adolescents ≥15 years of age: 10 mg once daily as film-coated tablets.1

Infants 6–23 months of age: 4 mg once daily as oral granules.1

Children 2–5 years of age: 4 mg once daily as chewable tablets or oral granules.1

Children 6–14 years of age: 5 mg once daily as chewable tablets.1

Adolescents ≥15 years of age: 10 mg once daily as film-coated tablets.1

Adults

10 mg once daily as film-coated tablets.1

Additional dosage not needed for treatment of allergic rhinitis in patients already receiving chronic therapy for asthma.1

10 mg as film-coated tablets.1 48 49 50 52 77 78

10 mg once daily as film-coated tablets.1

10 mg once daily as film-coated tablets.1

5–20 mg daily.83

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment.1 Not evaluated in patients with severe hepatic impairment or hepatitis.1

Renal Impairment

No dosage adjustment required.1

Geriatric Patients

No dosage adjustment required.1

Absorption

Bioavailability

Rapidly absorbed from the GI tract; peak plasma concentrations attained within 3–4, 2–2.5, or 2 hours following oral administration in the fasted state of a single 10-mg film-coated tablet (in adults), 5-mg chewable tablet (in adults), or 4-mg chewable tablet (in children 2–5 years of age), respectively.1 13 14 37 53

Oral bioavailability of the 10-mg tablet in adults is 58–66%; bioavailability of the 5-mg chewable tablet in fasting adults is 73%.1

Plasma concentration profile following oral administration of montelukast 10 mg in adolescents ≥15 years of age is similar to that in young adults.1

Plasma concentration profile following oral administration of 4- or 5-mg chewable tablet in children 2–5 or 6–14 years of age, respectively, is similar to the profile in adults receiving 10-mg film-coated tablet.1 37 101

Systemic exposure and variability of plasma concentrations with 4-mg granule formulation in infants 6–11 months of age are greater than the exposure and variability with the 10-mg film-coated tablet in adults.1 Systemic exposure with 4-mg granule formulation in infants 12–23 months of age is less variable than that with the same formulation in younger children but is still greater than that with the 10-mg film-coated tablet in adults.1

4-mg oral granule formulation and 4-mg chewable tablet are bioequivalent (fasting adults).1

Bioequivalence of the 10-mg film-coated tablet versus two 5-mg chewable tablets not evaluated.1

Onset

Improvement in asthma symptoms and/or lung function test results and decreased use of β-agonist bronchodilators are evident after the first dose.1 31 45

Duration

Therapeutic effects persist for at least 24 hours.1 31 45

Food

10-mg tablets: Food does not affect absorption.1

5-mg chewable tablet: Food decreases extent of absorption.1 Bioavailability is 63% when administered with a standard meal in the morning.1

4-mg oral granule formulation: High-fat meal decreases rate of absorption and peak plasma concentration; no effect on AUC.1 Applesauce does not appear to have a clinically important effect on the pharmacokinetics of montelukast granules.1

Special Populations

In patients with mild to moderate hepatic impairment, AUC increased 41%.1

Distribution

Extent

Not fully characterized.98 99

Crosses the placenta in animals (rats, rabbits); not known whether montelukast crosses the placenta in humans.1

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

99%.1

Elimination

Metabolism

Extensively metabolized in the GI tract and/or liver.1 12 20 Several pathways have been identified, including acyl glucuronidation and oxidation catalyzed by CYP3A4 and CYP2C9.1 12 20

Elimination Route

Excreted principally in feces (about 86%) via bile as unchanged drug and metabolites.1 12 20

Half-life

Children 6–14 years of age: 3.4–4.2 hours.37

Adults 19–48 years of age: 2.7–5.5 hours.1 13 14 37 51

Special Populations

In patients with mild to moderate hepatic impairment, elimination half-life prolonged (7.4 hours).1 13 51 Pharmacokinetics not evaluated in patients with severe hepatic impairment or hepatitis.1

In geriatric adults 65–73 years of age, elimination half-life prolonged (6.6 hours).1 13 51

Storage

Oral

25°C (may be exposed to 15–30°C).1 125 Protect from moisture and light.1 125

Do not store opened packets or granules mixed with food, baby formula, or breast milk for future use.1 125 Administer contents within 15 minutes of opening packet.1 125

25°C (may be exposed to 15–30°C).1 125 Protect from moisture and light.1 125

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Oral

Granules may be mixed with cold or room temperature soft food; based on stability studies, only applesauce, carrots, rice, or ice cream should be used.1 125

Montelukast sodium, the active ingredient in Singulair, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor.

Montelukast sodium is described chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt.

The empirical formula is C35H35ClNNaO3S, and its molecular weight is 608.18. The structural formula is:

Montelukast sodium is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile.

Each 10-mg film-coated Singulair tablet contains 10.4 mg montelukast sodium, which is equivalent to 10 mg of montelukast, and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, 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 Singulair tablet contains 4.2 and 5.2 mg montelukast sodium, respectively, which are equivalent to 4 and 5 mg of montelukast, respectively. Both chewable tablets contain the following inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate.

Each packet of Singulair 4-mg oral granules contains 4.2 mg montelukast sodium, which is equivalent to 4 mg of montelukast. The oral granule formulation contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, and magnesium stearate.

Singulair is used in addition to other treatments for the maintenance treatment of asthma. It does not relieve acute attacks and may cause neuropsychiatric effects in a small number of people.

Montelukast is a leukotriene (loo-koe-TRY-een) inhibitor. Leukotrienes are chemicals your body releases when you breathe in an allergen (such as pollen). These chemicals cause swelling in your lungs and tightening of the muscles around your airways, which can result in asthma symptoms.

Montelukast is used to prevent asthma attacks in adults and children as young as 12 months old. Montelukast is also used to prevent exercise-induced bronchospasm in adults and children who are at least 6 years old.

Montelukast is also used to treat symptoms of year-round (perennial) allergies in adults and children who are at least 6 months old. It is also used to treat symptoms of seasonal allergies in adults and children who are at least 2 years old.

Do not give this medicine to a child without a doctor's advice.

Montelukast is also used to prevent exercise-induced bronchoconstriction (narrowing of the air passages in the lungs) in adults and teenagers who are at least 15 years old and are not already taking this medicine for other conditions.

If you already take montelukast to prevent asthma or allergy symptoms, do not use an extra dose to treat exercise-induced bronchoconstriction.

Montelukast may also be used for purposes not listed in this medication guide.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• unusual changes in mood or behavior;

• skin rash, bruising, severe tingling, numbness, pain, muscle weakness;

• ear pain, swelling, or warmth; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• stomach pain, diarrhea;

• fever or other flu symptoms;

• cold symptoms such as stuffy nose, sinus pain, cough, sore throat;

• headache; or

• bed-wetting or loss of bladder control in children.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.