SINGULAIR

1 INDICATIONS AND USAGE SINGULAIR is a leukotriene receptor antagonist indicated for: Prophylaxis and chronic treatment of asthma in patients 12 months of age and older ( 1.1 ). Acute prevention of exercise-induced bronchoconstriction (EIB) in patients 6 years of age and older ( 1.2 ). Relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) in patients 2 years of age and older, and perennial allergic rhinitis (PAR) in patients 6 months of age and older. Reserve use for patients who have an inadequate response or intolerance to alternative therapies ( 1.3 ). Limitations of Use: Not indicated to treat an acute asthma attack ( 5.2 ). 1.1 Asthma SINGULAIR ® is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older. 1.2 Exercise-Induced Bronchoconstriction (EIB) SINGULAIR is indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 6 years of age and older. 1.3 Allergic Rhinitis SINGULAIR is indicated for the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 6 months of age and older. Because the benefits of SINGULAIR may not outweigh the risk of neuropsychiatric symptoms in patients with allergic rhinitis [see Warnings and Precautions (5.1) ] , reserve use for patients who have an inadequate response or intolerance to alternative therapies. 1.4 Limitations of Use SINGULAIR is not indicated for the treatment of an acute asthma attack.

2 DOSAGE AND ADMINISTRATION Administration (by indications): Asthma: Once daily in the evening for patients 12 months and older ( 2.1 ). Acute prevention of EIB: One tablet at least 2 hours before exercise for patients 6 years of age and older ( 2.2 ). Seasonal allergic rhinitis: Once daily for patients 2 years and older ( 2.3 ). Perennial allergic rhinitis: Once daily for patients 6 months and older ( 2.3 ). Dosage (by age): 15 years and older: one 10-mg tablet ( 2 ). 6 to 14 years: one 5-mg chewable tablet ( 2 ). 2 to 5 years: one 4-mg chewable tablet or one packet of 4-mg oral granules ( 2 ). 6 to 23 months: one packet of 4-mg oral granules ( 2 ). Patients with both asthma and allergic rhinitis should take only one dose daily in the evening ( 2.4 ). For oral granules: Must administer within 15 minutes after opening the packet (with or without mixing with food) ( 2.5 ). 2.1 Asthma For asthma, administer SINGULAIR orally once daily in the evening, with or without food. There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The following doses are recommended: Table 1: Recommended Dosage in Asthma Age Dose Adult and adolescent patients 15 years of age and older one 10 mg tablet Pediatric patients 6 to 14 years of age one 5 mg chewable tablet Pediatric patients 2 to 5 years of age one 4 mg chewable tablet or one packet of oral granules Pediatric patients 12 to 23 months of age Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established. one packet 4 mg oral granules Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time. 2.2 Exercise-Induced Bronchoconstriction (EIB) For prevention of EIB, administer a single dose of SINGULAIR orally at least 2 hours, before exercise. The following doses are recommended: Table 2: Recommended Dosage in Exercise-Induced Bronchoconstriction (EIB) Age Dose Adult and adolescent patients 15 years of age and older one 10 mg tablet Pediatric patients 6 to 14 years of age Safety and effectiveness in patients younger than 6 years of age have not been established. one 5 mg chewable tablet An additional dose of SINGULAIR should not be taken within 24 hours of a previous dose. Patients already taking SINGULAIR daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting β-agonist. Daily administration of SINGULAIR for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. 2.3 Allergic Rhinitis For allergic rhinitis, administer SINGULAIR orally once daily without regard to time of food ingestion. Time of administration in patients with allergic rhinitis can be individualized to suit patient needs. The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended: Table 3: Recommended Dosage in Seasonal Allergic Rhinitis Age Dose Adult and adolescent patients 15 years of age and older one 10 mg tablet Pediatric patients 6 to 14 years of age one 5 mg chewable tablet Pediatric patients 2 to 5 years of age Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established. one 4 mg chewable tablet or one packet of 4 mg oral granules The following doses for the treatment of symptoms of perennial allergic rhinitis are recommended: Table 4: Recommended Dosage in Perennial Allergic Rhinitis Age Dose Adult and adolescent patients 15 years of age and older one 10 mg tablet Pediatric patients 6 to 14 years of age one 5 mg chewable tablet Pediatric patients 2 to 5 years of age one 4 mg chewable tablet or one packet of 4 mg oral granules Pediatric patients 6 to 23 months of age Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been esta…

5 WARNINGS AND PRECAUTIONS Do not prescribe SINGULAIR to treat an acute asthma attack ( 5.2 ). Advise patients to have appropriate rescue medication available ( 5.2 ). Inhaled corticosteroid may be reduced gradually. Do not abruptly substitute SINGULAIR for inhaled or oral corticosteroids ( 5.3 ). Patients with known aspirin sensitivity should continue to avoid aspirin or non-steroidal anti-inflammatory agents while taking SINGULAIR ( 5.4 ). Systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, has been reported. These events have been sometimes associated with the reduction of oral corticosteroid therapy ( 5.5 and 6.2 ). Inform patients with phenylketonuria that the 4-mg and 5-mg chewable tablets contain phenylalanine ( 5.6 ). 5.1 Neuropsychiatric Events Serious neuropsychiatric (NP) events have been reported with use of SINGULAIR. These postmarketing reports have been highly variable and included, but were not limited to, agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thoughts and behavior (including suicide), tic, and tremor. NP events have been reported in adult, adolescent, and pediatric patients with and without a previous history of psychiatric disorder. NP events have been reported mostly during SINGULAIR treatment, but some were reported after SINGULAIR discontinuation. Animal studies showed that montelukast distributes into the brain in rats [see Clinical Pharmacology (12.3) ] ; however, the mechanisms underlying SINGULAIR-associated NP events are currently not well understood. Based upon the available data, it is difficult to identify risk factors for or quantify the risk of NP events with SINGULAIR use. Because of the risk of NP events, the benefits of SINGULAIR may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with alternative therapies. Reserve use of SINGULAIR for patients with allergic rhinitis who have an inadequate response or intolerance to alternative therapies [see Indications and Usage (1.3) ] . In patients with asthma or exercise-induced bronchoconstriction, consider the benefits and risks before prescribing SINGULAIR. Discuss the benefits and risks of SINGULAIR use with patients and caregivers when prescribing SINGULAIR. Advise patients and/or caregivers to be alert for changes in behavior or for new NP symptoms when taking SINGULAIR. If changes in behavior are observed, or if new NP symptoms or suicidal thoughts and/or behavior occur, advise patients to discontinue SINGULAIR and contact a healthcare provider immediately. In many cases, symptoms resolved after stopping SINGULAIR therapy; however, in some cases symptoms persisted after discontinuation of SINGULAIR. Therefore, continue to monitor and provide supportive care until symptoms resolve. Re-evaluate the benefits and risks of restarting treatment with SINGULAIR if such events occur. 5.2 Acute Asthma 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 β-agonist. 5.3 Concomitant Corticosteroid Use While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, SINGULAIR should not be abruptly substituted for inhaled or oral corticosteroids. 5.4 Aspirin Sensitivity Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking SINGULAIR. Although SINGULA…

4 CONTRAINDICATIONS SINGULAIR is contraindicated in patients with hypersensitivity to any of its components. Hypersensitivity to any component of SINGULAIR ( 4 ).

7 DRUG INTERACTIONS No dose adjustment is needed when SINGULAIR is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, fexofenadine, digoxin, warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers [see Clinical Pharmacology (12.3) ].

8.1 Pregnancy Risk Summary Available data from published prospective and retrospective cohort studies over decades with montelukast use in pregnant women have not established a drug-associated risk of major birth defects [see Data ] . In animal reproduction studies, no adverse developmental effects were observed with oral administration of montelukast to pregnant rats and rabbits during organogenesis at doses approximately 100 and 110 times, respectively, the maximum recommended human daily oral dose (MRHDOD) based on AUCs [see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly or moderately controlled asthma in pregnancy increases the maternal risk of perinatal adverse outcomes such as preeclampsia and infant prematurity, low birth weight, and small for gestational age. Data Human Data Published data from prospective and retrospective cohort studies have not identified an association with SINGULAIR use during pregnancy and major birth defects. Available studies have methodologic limitations, including small sample size, in some cases retrospective data collection, and inconsistent comparator groups. Animal Data In embryo-fetal development studies, montelukast administered to pregnant rats and rabbits during organogenesis (gestation days 6 to 17 in rats and 6 to 18 in rabbits) did not cause any adverse developmental effects at maternal oral doses up to 400 and 300 mg/kg/day in rats and rabbits, respectively (approximately 100 and 110 times the AUC in humans at the MRHDOD, respectively).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Neuropsychiatric Events [see Warnings and Precautions (5.1) ] Most common adverse reactions (incidence ≥5% and greater than placebo listed in descending order of frequency): upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., Inc., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Adults and Adolescents 15 Years of Age and Older with Asthma 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 reactions 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 5: Adverse Reactions 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 Pain, abdominal Asthenia/fatigue Fever Trauma 2.9 1.8 1.5 1.0 2.5 1.2 0.9 0.8 Digestive System Disorders Dyspepsia Pain, dental Gastroenteritis, infectious 2.1 1.7 1.5 1.1 1.0 0.5 Nervous System/Psychiatric Headache Dizziness 18.4 1.9 18.1 1.4 Respiratory System Disorders Influenza Cough Congestion, nasal 4.2 2.7 1.6 3.9 2.4 1.3 Skin/Skin Appendages Disorder Rash 1.6 1.2 Laboratory Adverse Reactions Number of patients tested (SINGULAIR and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159. ALT increased AST increased Pyuria 2.1 1.6 1.0 2.0 1.2 0.9 The frequency of less common adverse reactions 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 reaction profile did not significantly change. Pediatric Patients 6 to 14 Years of Age with Asthma 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 reactions 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 reactions was comparable between SINGULAIR and placebo. With prolonged treatment, the adverse reaction profile did not significantly change. The safety profile of SINGULAIR, when admi…