Montelukast

1 INDICATIONS AND USAGE Montelukast sodium tablets are a leukotriene receptor antagonist indicated for: • Prophylaxis and chronic treatment of asthma in patients 15 years of age and older (1.1). • Acute prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older (1.2). • Relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) in patients 15 years of age and older, and perennial allergic rhinitis (PAR) in patients 15 years 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 Montelukast sodium tablets are indicated for the prophylaxis and chronic treatment of asthma in adults and adolescents 15 years of age and older. 1.2 Exercise-Induced Bronchoconstriction (EIB) Montelukast sodium tablets are indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older. 1.3 Allergic Rhinitis Montelukast sodiumtablets are indicated for the relief of symptoms of seasonal allergic rhinitis in patients 15 years of age and older and perennial allergic rhinitis in patients 15 yearsof age and older. Because the benefits of montelukast sodium tablets 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 Montelukastsodium tablets are 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 15 years and older.( 2.1 ). • Acute prevention of EIB: One tablet at least 2 hours before exercise for patients 15 years of age and older. ( 2.2 ) • Seasonal allergic rhinitis: Once daily for patients 15 years and older ( 2.3 ) • Perennial allergic rhinitis: Once daily for patients 15 years and older ( 2.3 ) Dosage (by age) • 15 years and older: one 10 mg tablet.( 2 ). Patients with both asthma and allergic rhinitis should take only one dose daily in the evening (2.4). 2.1 Asthma Forasthma, administer montelukast sodium tablets orally once daily in the evening, with or without food. There have been no clinical trials in patients with asthma toevaluate the relative efficacy of morning versus evening dosing. The following doses arerecommended: Table 1: RecommendedDosage in Asthma Age Dose Adult and adolescentpatients15 years of age andolder one 10 mg tablet Patientswho 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) Forprevention�of EIB, administer a single dose of montelukast sodium tablets orally at least 2 hours, before exercise. The following doses arerecommended: Table 2: RecommendedDosage in Exercise-Induced Bronchoconstriction (EIB) Dose Adult and adolescent patients15 yearsof age andolder one 10 mg tablet An additional dose of montelukast sodium tablets should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium tablets 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 montelukast sodium tablets for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. 2.3 Allergic Rhinitis For allergic rhinitis, administer montelukast sodium tablets 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 ofseasonal allergic rhinitis are recommended: Table 3: RecommendedDosage in Seasonal Allergic Rhinitis Age Dose Adult and adolescent patients15 years of age andolder one 10 mg tablet The following doses for the treatment of symptoms of perennial allergic rhinitisare recommended: Table 4: Recommended Dosage in Perennial AllergicRhinitis Age Dose Adult and adolescent patients 15 years of age andolder one 10 mgtablet Patients who miss a dose should take the next dose at their regular timeand should not take 2 doses at the same time. 2.4 Asthma and Allergic Rhinitis For patients with both asthma and allergic rhinitis, administer only one montelukast sodium tablets dose orally once daily in the evening. Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time.

5 WARNINGS AND PRECAUTIONS • Do not prescribe montelukast sodium 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 montelukast sodium 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 montelukast sodium (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). 5.1 Neuropsychiatric Events Serious neuropsychiatric (NP) events have been reported with use of montelukast sodium. 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 aprevioushistory of psychiatric disorder. NP events have been reported mostly during montelukast sodium treatment, but some were reported aftermontelukastsodium discontinuation. Animal studies showed that montelukast distributes into the brain in rats [see Clinical Pharmacology (12.3)]; however, the mechanisms underlying montelukast sodium-associated NPeventsare currently not well understood. Based upon the available data, it is difficult to identify riskfactorsfor or quantify the risk of NP events with montelukast sodium use. Because of the risk of NP events, the benefits of montelukast sodium may not outweigh the risks in some patients, particularly when the symptoms of disease may bemildand adequately treated with alternative therapies. Reserve use of montelukast sodium for patients with allergic rhinitis who have an inadequateresponseor intolerance to alternative therapies [see Indications and Usage (1.3)]. In patients with asthma or exercise-induced bronchoconstriction, consider the benefits andrisksbefore prescribing montelukast sodium. Discuss the benefits and risks of montelukast sodium use with patients and caregivers when prescribing montelukast sodium. Advise patients and/or caregivers to bealertfor changes in behavior or for new NP symptoms when taking montelukast sodium. If changes in behavior are observed, or if new NP symptoms or suicidal thoughtsand/orbehavior occur, advise patients to discontinue montelukast sodium and contact a healthcare provider immediately. In many cases, symptomsresolved after stopping montelukast sodium therapy; however, in some cases symptoms persisted after discontinuation of montelukast sodium. Therefore,continue to monitor and provide supportive care until symptoms resolve. Re-evaluate the benefits and risks of restarting treatment withmontelukastsodium if such events occur. 5.2 Acute Asthma Montelukast sodium 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 montelukast sodium 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, montelukast sodium 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-inflamma…

4 CONTRAINDICATIONS Montelukast sodium tablets are contraindicated in patients with hypersensitivity to any of its components. • Hypersensitivity to any component of montelukast sodium tablets (4).

7 DRUG INTERACTIONS No dose adjustment is needed when montelukast sodium 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 to 4% and 15 to 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 montelukast sodium 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 Hetero Labs Limited at 1-866-495-1995 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 Montelukast sodium 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 montelukast sodium 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 Montelukast sodium 10 mg/day (%) (n=1955) Placebo (%) (n=1180) Body As A Whole Pain, abdominal Asthenia/fatigue Fever 2.9 1.8 1.5 2.5 1.2 0.9 Trauma Digestive System Disorders Dyspepsia 1.0 2.1 0.8 1.1 Pain, dental 1.7 1.0 Gastroenteritis, infectious 1.5 0.5 Nervous System/Psychiatric Headache 18.4 18.1 Dizziness 1.9 1.4 Respiratory System Disorders Influenza 4.2 3.9 Cough 2.7 2.4 Congestion, nasal 1.6 1.3 Skin/Skin Appendages Disorder Rash 1.6 1.2 Laboratory Adverse Reactions* ALT increased 2.1 2.0 AST increased 1.6 1.2 Pyuria 1.0 0.9 *Number of patients tested (montelukast sodium and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159. The frequency of less common adverse reactions was comparable between montelukast sodium and placebo. The safety profile of montelukast sodium, 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 montelukast sodium. Cumulatively, 569 patients were treated with montelukast sodium 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. Adults and Adolescents 15 Years of Age and Older with Seasonal Allergic Rhinitis Montelukast sodium has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. Montelukast sodium 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 reaction was reported with montelukast sodium with a frequency ≥1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving montelukast sodium 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. Adults and Adolescents 15 Years of Age and Older with Perennial Allergic Rhin…