Singulair Description

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 C35 H35 ClNNaO3 S, 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 Indications And Usage

SINGULAIR is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older.

SINGULAIR is indicated for prevention of exercise-induced bronchoconstriction in patients 15 years of age and older.

SINGULAIR is indicated for the relief of symptoms of allergic rhinitis (seasonal allergic rhinitis in adults and pediatric patients 2 years of age and older, and perennial allergic rhinitis in adults and pediatric patients 6 months of age and older).

Singulair Contraindications

Hypersensitivity to any component of this product.

Singulair Precautions

General

SINGULAIR is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus.

Patients should be advised to have appropriate rescue medication available. Therapy with SINGULAIR can be continued during acute exacerbations of asthma. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled ?-agonist.

While the dose of 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 PHARMACOLOGY, Clinical Studies).

Eosinophilic Conditions

In rare cases, 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 usually, but not always, have been 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. A causal association between SINGULAIR and these underlying conditions has not been established (see ADVERSE REACTIONS).

Information For Patients

• Patients should be advised to take SINGULAIR daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, 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 short-acting inhaled ?-agonist medication available to treat asthma exacerbations. Patients who have exacerbations of asthma after exercise should be instructed to have available for rescue a short-acting inhaled ?-agonist. Daily administration of SINGULAIR for the chronic treatment of asthma has not been established to prevent acute episodes of exercise-induced bronchoconstriction.
• Patients should be advised that, while using SINGULAIR, medical attention should be sought if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed.
• Patients receiving SINGULAIR should be instructed not to decrease the dose or stop taking any other anti-asthma medications unless instructed by a physician.
• Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking SINGULAIR.

Chewable Tablets

• Phenylketonurics : 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.

Drug Interactions

SINGULAIR has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction 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 (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin.

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, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants.

Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for SINGULAIR is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with SINGULAIR.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of tumorigenicity was seen in carcinogenicity studies of either 2 years in Sprague-Dawley rats or 92 weeks in mice at oral gavage doses up to 200 mg/kg/day or 100 mg/kg/day, respectively. The estimated exposure in rats was approximately 120 and 75 times the area under the plasma concentration versus time curve (AUC) for adults and children, respectively, at the maximum recommended daily oral dose. The estimated exposure in mice was approximately 45 and 25 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose.

Montelukast demonstrated no evidence of mutagenic or clastogenic activity in the following assays: the microbial mutagenesis assay, the V-79 mammalian cell mutagenesis assay, the alkaline elution assay in rat hepatocytes, the chromosomal aberration assay in Chinese hamster ovary cells, and in the in vivo mouse bone marrow chromosomal aberration assay.

In fertility studies in female rats, montelukast produced reductions in fertility and fecundity indices at an oral dose of 200 mg/kg (estimated exposure was approximately 70 times the AUC for adults at the maximum recommended daily oral dose). No effects on female fertility or fecundity were observed at an oral dose of 100 mg/kg (estimated exposure was approximately 20 times the AUC for adults at the maximum recommended daily oral dose). Montelukast had no effects on fertility in male rats at oral doses up to 800 mg/kg (estimated exposure was approximately 160 times the AUC for adults at the maximum recommended daily oral dose).

Pregnancy

Teratogenic Effects

Pregnancy Category B

No teratogenicity was observed in rats at oral doses up to 400 mg/kg/day (estimated exposure was approximately 100 times the AUC for adults at the maximum recommended daily oral dose) and in rabbits at oral doses up to 300 mg/kg/day (estimated exposure was approximately 110 times the AUC for adults at the maximum recommended daily oral dose). Montelukast crosses the placenta following oral dosing in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, 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.

Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women exposed to SINGULAIR while pregnant. Healthcare providers are encouraged to report any prenatal exposure to SINGULAIR by calling the Pregnancy Registry at (800) 986-8999.

Nursing Mothers

Studies in rats have shown that montelukast is excreted in milk. It is not known if montelukast 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

Safety and efficacy of SINGULAIR have been established in adequate and well-controlled studies in pediatric patients with asthma 6 to 14 years of age. Safety and efficacy profiles in this age group are similar to those seen in adults. (See Clinical Studies and ADVERSE REACTIONS.)

The efficacy of SINGULAIR for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age and for the treatment of perennial allergic rhinitis in pediatric patients 6 months to 14 years of age is supported by extrapolation from the demonstrated efficacy in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug?s effect are substantially similar among these populations.

The safety of SINGULAIR 4-mg chewable tablets in pediatric patients 2 to 5 years of age with asthma has been demonstrated by adequate and well-controlled data (see ADVERSE REACTIONS). Efficacy of SINGULAIR in this age group is extrapolated from the demonstrated efficacy in patients 6 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 drug?s effect are substantially similar among these populations. Efficacy in this age group is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients 2 to 5 years of age.

The safety of SINGULAIR 4-mg oral granules in pediatric patients 12 to 23 months of age with asthma has been demonstrated in an analysis of 172 pediatric patients, 124 of whom were treated with SINGULAIR, in a 6-week, double-blind, placebo-controlled study (see ADVERSE REACTIONS). Efficacy of SINGULAIR in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma based on similar mean systemic exposure (AUC), and that the disease course, pathophysiology and the drug?s effect are substantially similar among these populations, supported by efficacy data from a safety trial in which efficacy was an exploratory assessment.

The safety of SINGULAIR 4-mg and 5-mg chewable tablets in pediatric patients aged 2 to 14 years with allergic rhinitis is supported by data from studies conducted in pediatric patients aged 2 to 14 years with asthma. A safety study in pediatric patients 2 to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile (see ADVERSE REACTIONS). The safety of SINGULAIR 4-mg oral granules in pediatric patients as young as 6 months of age with perennial allergic rhinitis is supported by extrapolation from safety data obtained from studies conducted in pediatric patients 6 months to 23 months of age with asthma and from pharmacokinetic data comparing systemic exposures in patients 6 months to 23 months of age to systemic exposures in adults.

The safety and effectiveness in pediatric patients below the age of 12 months with asthma and 6 months with perennial allergic rhinitis have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of montelukast, 3.5% were 65 years of age and over, and 0.4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Singulair Overdosage

No mortality occurred following single oral doses of montelukast up to 5000 mg/kg in mice (estimated exposure was approximately 335 and 210 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose) and rats (estimated exposure was approximately 230 and 145 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose).

No specific information is available on the treatment of overdosage with SINGULAIR. 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 a 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 of acute overdosage in post-marketing experience and 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 removed by peritoneal dialysis or hemodialysis.

Singulair Supplemental Patient Material

SINGULAIR® (SING-u-lair) Tablets, Chewable Tablets, and Oral Granules

Generic name: montelukast (mon-te-LOO-kast) sodium

Read this information before you start taking SINGULAIR® . Also, read the leaflet you get each time you refill SINGULAIR, since there may be new information in the leaflet since the last time you saw it. This leaflet does not take the place of talking with your doctor about your medical condition and/or your treatment.

• SINGULAIR is a medicine called a leukotriene receptor antagonist. It works by blocking substances in the body called leukotrienes. Blocking leukotrienes improves asthma and allergic rhinitis. SINGULAIR is not a steroid. Studies have shown that SINGULAIR does not affect the growth rate of children. (See the end of this leaflet for more information about asthma and allergic rhinitis.)

SINGULAIR is prescribed for the treatment of asthma, the prevention of exercise-induced asthma, and allergic rhinitis:

• Asthma.
  SINGULAIR should be used for the long-term management of asthma in adults and children ages 12 months and older.
  
  Do not take SINGULAIR for the immediate relief of an asthma attack. If you get an asthma attack, you should follow the instructions your doctor gave you for treating asthma attacks.
  
  
• Prevention of exercise-induced asthma.
  SINGULAIR is used for the prevention of exercise-induced asthma in patients 15 years of age and older.
  
  
• Allergic Rhinitis.
  SINGULAIR is used to help control the symptoms of allergic rhinitis (sneezing, stuffy nose, runny nose, itching of the nose). SINGULAIR is used to treat seasonal allergic rhinitis (outdoor allergies that happen part of the year) in adults and children ages 2 years and older, and perennial allergic rhinitis (indoor allergies that happen all year) in adults and children ages 6 months and older.

Do not take SINGULAIR if you are allergic to SINGULAIR or any of its ingredients.

The active ingredient in SINGULAIR is montelukast sodium.

See the end of this leaflet for a list of all the ingredients in SINGULAIR.

Tell your doctor about:

• Pregnancy : If you are pregnant or plan to become pregnant, SINGULAIR may not be right for you.
• Breast-feeding : If you are breast-feeding, SINGULAIR may be passed in your milk to your baby. You should consult your doctor before taking SINGULAIR if you are breast-feeding or intend to breast-feed.
• Medical Problems or Allergies : Talk about any medical problems or allergies you have now or had in the past.
• Other Medicines : Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, and herbal supplements. Some medicines may affect how SINGULAIR works, or SINGULAIR may affect how your other medicines work.

For adults and children 12 months of age and older with asthma:

• Take SINGULAIR once a day in the evening .
• Take SINGULAIR every day for as long as your doctor prescribes it, even if you have no asthma symptoms.
• You may take SINGULAIR with food or without food.
• If your asthma symptoms get worse, or if you need to increase the use of your inhaled rescue medicine for asthma attacks, call your doctor right away.
• Do not take SINGULAIR for the immediate relief of an asthma attack. If you get an asthma attack, you should follow the instructions your doctor gave you for treating asthma attacks.
• Always have your inhaled rescue medicine for asthma attacks with you.
• Do not stop taking or lower the dose of your other asthma medicines unless your doctor tells you to.

For patients 15 years of age and older for the prevention of exercise-induced asthma:

• Take SINGULAIR at least 2 hours before exercise.
• Always have your inhaled rescue medicine for asthma attacks with you.
• If you are taking SINGULAIR daily for chronic asthma or allergic rhinitis, do not take an additional dose to prevent exercise-induced asthma. Speak to your doctor about your treatment of exercise-induced asthma.
• Do not take an additional dose of SINGULAIR within 24 hours of a previous dose.

For adults and children 2 years of age and older with seasonal allergic rhinitis, or for adults and children 6 months of age and older with perennial allergic rhinitis:

• Take SINGULAIR once a day, at about the same time each day.
• Take SINGULAIR every day for as long as your doctor prescribes it.
• You may take SINGULAIR with food or without food.

Do not open the packet until ready to use.

SINGULAIR 4-mg oral granules 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 one of the following soft foods at cold or room temperature: applesauce, mashed carrots, rice, or ice cream.

Be sure that the entire dose is mixed with the food, baby formula, or breast milk and that the child is given the entire spoonful of the food, baby formula, or breast milk mixture right away (within 15 minutes).

IMPORTANT: Never store any oral granules mixed with food, baby formula, or breast milk for use at a later time. Throw away any unused portion.

Do not put SINGULAIR oral granules in any liquid drink other than baby formula or breast milk. However, your child may drink liquids after swallowing the SINGULAIR oral granules.

For asthma -Take once daily in the evening:

• One 10-mg tablet for adults and adolescents 15 years of age and older,
• One 5-mg chewable tablet for children 6 to 14 years of age,
• One 4-mg chewable tablet or one packet of 4-mg oral granules for children 2 to 5 years of age, or
• One packet of 4-mg oral granules for children 12 to 23 months of age.

For exercise-induced asthma - Take at least 2 hours before exercise, but not more than once daily:

• One 10-mg tablet for adults and adolescents 15 years of age and older.

For allergic rhinitis -Take once daily at about the same time each day:

• One 10-mg tablet for adults and adolescents 15 years of age and older,
• One 5-mg chewable tablet for children 6 to 14 years of age,
• One 4-mg chewable tablet for children 2 to 5 years of age, or
• One packet of 4-mg oral granules for children 2 to 5 years of age with seasonal allergic rhinitis, or for children 6 months to 5 years of age with perennial allergic rhinitis.

If you have asthma and if your asthma is made worse by aspirin, continue to avoid aspirin or other medicines called non-steroidal anti-inflammatory drugs while taking SINGULAIR.

The side effects of SINGULAIR are usually mild, and generally did not cause patients to stop taking their medicine. The side effects in patients treated with SINGULAIR were similar in type and frequency to side effects in patients who were given a placebo (a pill containing no medicine).

The most common side effects with SINGULAIR include:

• stomach pain
• stomach or intestinal upset
• heartburn
• tiredness
• fever
• stuffy nose
• cough
• flu
• upper respiratory infection
• dizziness
• headache
• rash

Less common side effects that have happened with SINGULAIR include (listed alphabetically):

• agitation including aggressive behavior, allergic reactions (including swelling of the face, lips, tongue, and/or throat, which may cause trouble breathing or swallowing), hives, and itching, bad/vivid dreams, increased bleeding tendency, bruising, depression, diarrhea, drowsiness, hallucinations (seeing things that are not there), hepatitis, indigestion, inflammation of the pancreas, irritability, joint pain, muscle aches and muscle cramps, nausea, palpitations, pins and needles/numbness, restlessness, seizures (convulsions or fits), suicidal thoughts and actions, swelling, tremor, trouble sleeping, and vomiting.

Rarely, asthmatic patients taking SINGULAIR have experienced a condition that includes certain symptoms that do not go away or that get worse. These occur usually, but not always, in patients who were taking steroid pills by mouth for asthma and those steroids 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 get one or more of these symptoms :

• a feeling of pins and needles or numbness of arms or legs
• a flu-like illness
• rash
• severe inflammation (pain and swelling) of the sinuses (sinusitis)

These are not all the possible side effects of SINGULAIR. For more information ask your doctor or pharmacist.

Talk to your doctor if you think you have side effects from taking SINGULAIR.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use SINGULAIR for a condition for which it was not prescribed. Do not give SINGULAIR to other people even if they have the same symptoms you have. It may harm them. Keep SINGULAIR and all medicines out of the reach of children.

Store SINGULAIR at 25°C (77°F). Protect from moisture and light. Store in original package.

This leaflet summarizes information about SINGULAIR. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about SINGULAIR that is written for health professionals.

Active ingredient: montelukast sodium

SINGULAIR chewable tablets contain aspartame, a source of phenylalanine.
Phenylketonurics: SINGULAIR 4-mg and 5-mg chewable tablets contain 0.674 and 0.842 mg phenylalanine, respectively.

Inactive ingredients:

• 4-mg oral granules : mannitol, hydroxypropyl cellulose, and magnesium stearate.
• 4-mg and 5-mg chewable tablets : mannitol, microcrystalline cellulose, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate.
• 10-mg tablet : microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, red ferric oxide, yellow ferric oxide, and carnauba wax.

Asthma is a continuing (chronic) inflammation of the bronchial passageways which are the tubes that carry air from outside the body to the lungs.

Symptoms of asthma include:

• coughing
• wheezing
• chest tightness
• shortness of breath

Exercise-induced asthma, more accurately called exercise-induced bronchoconstriction occurs when exercise triggers symptoms of asthma.

• Seasonal allergic rhinitis, also known as hay fever, is triggered by outdoor allergens such as pollens from trees, grasses, and weeds.
• Perennial allergic rhinitis may occur year-round and is generally triggered by indoor allergens such as dust mites, animal dander, and/or mold spores.
• Symptoms of allergic rhinitis may include:
  • stuffy, runny, and/or itchy nose
  • sneezing

Rx only

US Patent No.: 5,565,473

Distributed by:

MERCK & CO., INC.

Whitehouse Station, NJ 08889, USA

Issued September 2007

9628410

Singulair Information For Patients

• Patients should be advised to take SINGULAIR daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, 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 short-acting inhaled ?-agonist medication available to treat asthma exacerbations. Patients who have exacerbations of asthma after exercise should be instructed to have available for rescue a short-acting inhaled ?-agonist. Daily administration of SINGULAIR for the chronic treatment of asthma has not been established to prevent acute episodes of exercise-induced bronchoconstriction.
• Patients should be advised that, while using SINGULAIR, medical attention should be sought if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed.
• Patients receiving SINGULAIR should be instructed not to decrease the dose or stop taking any other anti-asthma medications unless instructed by a physician.
• Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking SINGULAIR.

Chewable Tablets

• Phenylketonurics : 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.