SINGULAIR (montelukast sodium) is indicated in adult and pediatric patients 2 years of age and older for the prophylaxis and chronic treatment of asthma, including prevention of day- and night-time symptoms, the treatment of ASA-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.

In patients who continue to experience asthma symptoms, SINGULAIR can be an additional treatment option following initial management with an “as needed” short-acting beta-agonist (SABA), an inhaled corticosteroid, or inhaled corticosteroid together with a long-acting beta agonist.

In adults, SINGULAIR can be a treatment option after “as needed” SABAs if patients remain symptomatic and cannot or will not use an inhaler device or would prefer not to be treated with an inhaled corticosteroid.

In children, SINGULAIR can be a treatment option after “as needed” SABAs if patients remain symptomatic and cannot appropriately use an inhaler device.

SINGULAIR can be a treatment option in patients who experience exercise-induced bronchoconstriction.

SINGULAIR is indicated for the relief of symptoms of seasonal allergic rhinitis in patients 15 years old or older. SINGULAIR should be considered when other treatments are not effective or not tolerated.

• Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see Dosage Forms, Composition and Packaging .

  
  

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 SINGULAIR is not for the treatment of acute asthma attacks. They should have appropriate rescue medication available.

Phenylketonuric patients should be informed that the 4 mg and the 5 mg chewable tablets contains phenylalanine (a component of aspartame) 0.674 and 0.842 mg per 4 mg and 5 mg chewable tablet.

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

When SINGULAIR is prescribed for the prevention of exercise-induced bronchoconstriction, patients should be advised to always have readily available appropriate rescue medication.

Patients with known acetylsalicylic acid (ASA) sensitivity should continue avoidance of ASA or non-steroidal anti-inflammatory agents while taking SINGULAIR. Although SINGULAIR is effective in improving airway function in asthmatic patients with documented ASA sensitivity, it has not been shown to truncate bronchoconstrictor response to ASA and other non-steroidal anti-inflammatory drugs in ASA-sensitive asthmatic patients.

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. Although there is insufficient evidence to suggest a direct pathological role of SINGULAIR in the development of Churg-Strauss syndrome, the association appears to be due to either unmasking (through a reduction or discontinuation of steroids) or progression of previous disease. Physicians should be alert to eosinophilia, vasculitic rash, arthralgia, 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).

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 of 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).

In post-marketing surveillance, elevations in serum transaminases have been reported in patients who were treated with SINGULAIR. These events were usually asymptomatic and transient. Serious hepatic adverse events such as jaundice have been reported although no deaths or liver transplantations have been attributed to the use of SINGULAIR (see Adverse Reactions).

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.

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.

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 that seen in adults (see Adverse Reactions, Clinical Trial Adverse Drug Reactions).

The safety of SINGULAIR 4 mg chewable tablets in pediatric patients 2 to 5 years of age has been demonstrated in a 12-week double-blind, placebo-controlled study in 689 patients (see Action and Clinical Pharmacology and also Adverse Reactions). Efficacy of SINGULAIR in this age group is based on extrapolation of the demonstrated efficacy in adults 15 years of age and older and pediatric patients 6 to 14 years of age with asthma, and that the disease course, pathophysiology and the drug's effect are substantially similar among these populations. The findings of the exploratory efficacy evaluations along with pharmacokinetics and extrapolation of data from older patients, support the overall conclusion that SINGULAIR is efficacious in the maintenance treatment of asthma in patients 2 to 5 years of age (see Action and Clinical Pharmacology).

SINGULAIR has been evaluated for safety in a 6-week, placebo-controlled clinical study in 175 asthma patients 6 months to 2 years of age receiving 4 mg as oral granules daily in the evening. There were no safety concerns compared to older pediatric patients (see Adverse Reactions, Pediatric Patients 6 Months to 2 Years of Age with Asthma). Since this study was not powered to detect between group differences in efficacy endpoints, the efficacy of SINGULAIR could not be determined in this age group.

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

There is no evidence that SINGULAIR affects the ability to drive and use machines.

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.

SINGULAIR has been evaluated for safety in approximately 2600 adult patients 15 years of age and older in clinical studies. In two similarly designed, 12-week placebo-controlled clinical studies, the only adverse experiences reported as drug-related in ≥1% of patients treated with SINGULAIR and at a greater incidence than in patients treated with placebo were abdominal pain and headache. The incidences of these events were not significantly different in the two treatment groups.

In placebo-controlled clinical trials, the 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 (see Table 1).

Table 1: SINGULAIR

Adverse Experiences Occurring in ≥1% of Patients with an Incidence ≥ to that in Patients Treated with Placebo, Regardless of Drug Relationship

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

Cumulatively, 544 patients were treated with SINGULAIR for at least 6 months, 253 for one year and 21 for two years in clinical trials. With prolonged treatment, the adverse experience profile did not change.

SINGULAIR has been evaluated for safety in approximately 475 pediatric patients 6 to 14 years of age. Cumulatively, 263 pediatric patients 6 to 14 years of age were treated with SINGULAIR for at least 3 months, 164 for 6 months or longer in clinical trials. The safety profile in pediatric patients is generally similar to the adult safety profile and to placebo. With prolonged treatment, the adverse experience profile did not change.

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 occurred with a frequency ≥2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: atopic dermatitis, myopia, rhinitis (infective), skin infection, tooth infection, headache, varicella, gastroenteritis and acute bronchitis.

SINGULAIR has been evaluated for safety in 573 pediatric patients 2 to 5 years of age. In a 12-week, placebo-controlled clinical study, the only adverse experience reported as drug-related in >1% of patients treated with SINGULAIR and at a greater incidence than in patients treated with placebo was thirst. The incidence of thirst was not significantly different in the two treatment groups. Cumulatively, 363 patients 2 to 5 years of age were treated with SINGULAIR. Of these, 338 were continuously treated for at least 6 months and 256 for >1 year. The safety profile of SINGULAIR in pediatric patients 2 to 5 years of age is generally similar to the safety profiles in adults 15 years of age and older in pediatric patients 6 to 14 years of age, and to placebo. With prolonged treatment, the adverse experience profile did not change.

SINGULAIR has been evaluated in 175 pediatric patients 6 months to 2 years of age. In a 6-week, placebo-controlled clinical study, the adverse experiences reported as drug related in >1% of patients treated with SINGULAIR and at a greater incidence than in patients treated with placebo were diarrhea, hyperkinesia, asthma, eczematous dermatitis and rash. The incidences of these adverse experiences were not significantly different in the two treatment groups.

SINGULAIR has been evaluated in 1751 adult patients 15 years of age and older for the treatment of seasonal allergic rhinitis in clinical studies. SINGULAIR administered once daily at bedtime was generally well tolerated with a safety profile similar to that of placebo. In similar designed, 2-week, placebo-controlled, clinical studies, no adverse experience reported as drug related in ≥1% of patients treated with SINGULAIR and at a greater incidence than in patients treated with placebo were observed. The incidence of somnolence was similar to that of placebo.

The following adverse drug reactions have been reported very rarely (<1/10 000) in post-marketing use:

increased bleeding tendency.

hypersensitivity reactions including anaphylaxis, and very rarely, hepatic eosinophilic infiltration.

agitation including aggressive behavior (including temper tantrums in pediatric patients), very rarely reported as serious; sleep disorders including dream abnormalities and insomnia, visual hallucinations, irritability, restlessness.

drowsiness, paraesthesia/hypoesthesia, and very rarely seizure.

palpitations.

diarrhea, dyspepsia, nausea, vomiting.

angioedema, bruising, urticaria, pruritus, rash.

arthralgia, myalgia including muscle cramps.

increased ALT, AST, and isolated cases of hepatitis. In post-marketing surveillance, elevations in serum transaminases have been reported in patients who were treated with SINGULAIR. These events were usually asymptomatic and transient. Serious hepatic adverse events such as jaundice have been reported although no deaths or liver transplantations have been attributed to the use of SINGULAIR (see Warnings and Precautions).

edema.

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, arthralgia, 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. The Churg-Strauss syndrome complicating antileukotriene therapy is thought to relate to unmasking of an underlying vasculitic syndrome associated with moderate or severe asthma treated with corticosteroids (see Warnings and Precautions, Eosinophilic Conditions).

SINGULAIR may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma, and in the treatment of allergic rhinitis (see Drug-Drug Interactions).

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.

In vitro studies have shown that montelukast is an inhibitor of CYP 2C8. Montelukast may inhibit the metabolism of drugs primarily metabolized by CYP 2C8 (e.g., paclitaxel, rosiglitazone, repaglinide); however, no in vivo interaction studies have been performed.

Montelukast 10 mg once daily to pharmacokinetic steady state:

• did not cause clinically significant changes in the kinetics of an intravenous dose of theophylline.

  
  

• did not change the pharmacokinetic profile of warfarin or influence the effect of a single 30 mg oral dose of warfarin on prothrombin time or INR (International Normalized Ratio).

  
  

• did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin.

  
  

• did not change the plasma concentration profile of terfenadine or its carboxylated metabolite and does not prolong the QTc interval following coadministration with terfenadine 60 mg twice daily.

  
  

Montelukast at doses of ≥100 mg daily to pharmacokinetic steady state:

• did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 μg.

  
  

• did not cause any clinically significant change in plasma profiles of either prednisone and prednisolone following administration of either oral prednisone or IV prednisolone.

  
  

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.

The safety and efficacy of SINGULAIR was demonstrated in clinical trials where it was administered in the evening without regard to the time of food ingestion. There have been no clinical trials evaluating the relative efficacy of morning versus evening dosing. However, no difference in pharmacokinetics was noted between morning and evening dosing.

The therapeutic effect of SINGULAIR on parameters of asthma 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.

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

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.

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. It remains to be determined whether the withdrawal from inhaled corticosteroids can be maintained for extended periods, or possibly indefinitely. SINGULAIR should not be abruptly substituted for inhaled corticosteroids.

Limited data suggest that SINGULAIR may provide additional clinical benefit in patients currently treated with oral corticosteroids.

The dosage for adults 15 years of age and older is one 10 mg tablet daily to be taken in the evening.

The dosage for pediatric patients 6 to 14 years of age is one 5 mg chewable tablet daily to be taken in the evening. No dosage adjustment within this age group is necessary.

The dosage for pediatric patients 2 to 5 years of age is one 4 mg chewable tablet daily to be taken in the evening or one packet of 4 mg granules to be taken orally once a day in the evening. No dosage adjustment within this age group is necessary.

No dosage adjustment is necessary for the elderly, for patients with renal insufficiency, or mild to moderate hepatic impairment, or for patients of either gender.

SINGULAIR oral granules can be administered either directly in the mouth, or mixed with a spoonful of cold or room temperature soft food (e.g., apple sauce). The packet should not be opened until ready to use. After opening the packet, the full dose of SINGULAIR oral granules must be administered immediately (within 15 minutes). If mixed with food, SINGULAIR oral granules must not be stored for future use. SINGULAIR oral granules are not intended to be dissolved in liquid for administration. However, liquids may be taken subsequent to administration.

SINGULAIR should be taken as prescribed. However, if a dose is missed, the usual schedule should be resumed as prescribed.