MONTELUKAST SODIUM

Montelukast sodium, the active ingredient in montelukast sodium tablets USP and montelukast sodium oral granules USP, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT 1 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 C 35 H 35 ClNNaO 3 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 montelukast sodium tablet USP contains 10.4 mg montelukast sodium, which is equivalent to 10 mg of montelukast, and the following inactive ingredients: croscarmellose sodium, ferric oxide red, ferric oxide yellow, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and titanium dioxide. Each 4-mg and 5-mg chewable montelukast sodium tablet USP 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: aspartame, cellulose microcrystalline, cherry flavor, croscarmellose sodium, ferric oxide red, magnesium stearate, mannitol. Each packet of Montelukast sodium oral granules USP 4 mg contains 4.16 mg Montelukast sodium USP, which is equivalent to 4 mg of montelukast. The oral granule formulation contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, tribasic sodium phosphate and magnesium stearate. str

Montelukast sodium 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 Montelukast sodium 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) Montelukast sodium is indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 6 years of age and older. 1.3 Allergic Rhinitis Montelukast sodium 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 montelukast sodium 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 Montelukast sodium is not indicated for the treatment of an acute asthma attack.

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 montelukast sodium 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* one packet 4 mg oral granules *Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established. 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 montelukast sodium 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* one 5 mg chewable tablet *Safety and effectiveness in patients younger than 6 years of age have not been established. An additional dose of montelukast sodium should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium 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 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 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* one 4 mg chewable tablet or one packet of 4 mg oral granules *Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established. 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* one packet of 4 mg oral granules *Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established. Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time. 2.4 Asthma and Allergic Rhinitis For patients with both asthma and allergic rhinitis, administer only one montelukast sodium 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. 2.5 Instructions for Administration of Oral Granules Montelukast sodium 4-mg oral granules can be administered either directly in the mouth, dissolved in 1 teaspoonful (5 mL) of cold or room temperature baby formula or breast milk, or mixed with a spoonful of cold or room temperature soft foods; based on stability studies, only applesauce, carrots, rice, or ice cream should be used. The packet should not be opened until ready to use. After opening the packet, the full dose (with or without mixing with baby formula, breast milk, or food) must be administered within 15 minutes. If mixed with baby formula, breast milk, or food, montelukast sodium oral granules must not be stored for future use. Discard any unused portion. Montelukast sodium oral granules are not intended to be dissolved in any liquid other than baby formula or breast milk for administration. However, liquids may be taken subsequent to administration. Montelukast sodium oral granules can be administered without regard to the time of meals.

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

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 (). To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following clinically significant adverse reactions are described elsewhere in the labeling: • Neuropsychiatric Events [see Warnings and Precautions ( 5.1 )] . 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 2,950 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 * Number of patients tested (montelukast sodium and placebo, respectively): ALT and AST, 1,935, 1,170; pyuria, 1,924, 1,159. Montelukast 10 mg/day (%) (n=1,955) Placebo (%) (n=1,180) Body As A Whole Pain, abdominal 2.9 2.5 Asthenia/fatigue 1.8 1.2 Fever 1.5 0.9 Trauma 1.0 0.8 Digestive System Disorders Dyspepsia 2.1 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 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. Pediatric Patients 6 to 14 Years of Age with Asthma Montelukast sodium has been evaluated for safety in 476 pediatric patients 6 to 14 years of age. Cumulatively, 289 pediatric patients were treated with montelukast sodium for at least 6 months, and 241 for one year or longer in clinical trials. The safety profile of montelukast sodium 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 montelukast sodium, 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 montelukast sodium and placebo. With prolonged treatment, the adverse reaction profile did not significantly change. The safety profile of montelukast sodium, 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 montelukast sodium. In studies evaluating growth rate, the safety profile in these pediatric patients was consistent with the safety profile previously described for montelukast sodium. In a 56-week, double-blind study evaluating growth rate in pediatric patients 6 to 8 years of age receiving montelukast sodium, the following reactions not previously observed with the use of montelukast sodium 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. Pediatric Patients 2 to 5 Years of Age with Asthma Montelukast sodium 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 montelukast sodium 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 montelukast sodium, the following reactions 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. Pediatric Patients 6 to 23 Months of Age with Asthma Safety and effectiveness in pediatric patients younger than 12 months of age with asthma have not been established. Montelukast sodium has been evaluated for safety in 175 pediatric patients 6 to 23 months of age. The safety profile of montelukast sodium 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 montelukast sodium, the following reactions 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 reactions was comparable between montelukast sodium and placebo. Adults and Adolescents 15 Years of Age and Older with Seasonal Allergic Rhinitis Montelukast sodium has been evaluated for safety in 2,199 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. Pediatric Patients 2 to 14 Years of Age with Seasonal Allergic Rhinitis Montelukast sodium 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. Montelukast sodium administered once daily in the evening had a safety profile similar to that of placebo. In this study, the following reactions occurred with a frequency ≥2% and at an incidence greater than placebo: headache, otitis media, pharyngitis, and upper respiratory infection. Adults and Adolescents 15 Years of Age and Older with Perennial Allergic Rhinitis Montelukast sodium has been evaluated for safety in 3,357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1,632 received montelukast sodium in two, 6-week, clinical studies. Montelukast sodium 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 reactions were reported with montelukast sodium 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. Pediatric Patients 6 Months to 14 Years of Age with Perennial Allergic Rhinitis 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of montelukast sodium. 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 including, but 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 thinking and behavior (including suicide), tic, and tremor [see Boxed Warning, Warnings and Precautions ( 5.1 )] 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 montelukast sodium. Most of these occurred in combination with other confounding factors, such as use of other medications, or when montelukast sodium 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 montelukast sodium 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 reactions 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 ( 5.5 )]

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 )] .