MONTELUKAST SODIUM- montelukast sodium_tablet, chewable

The cysteinyl leukotrienes (LTC 4 4 4 1 Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT 1 4 1 Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD 4 4 The effect of montelukast sodium on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received montelukast sodium, a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received montelukast sodium, a mean increase of 0. 2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12. 5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12. 3% in favor of montelukast sodium. The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known [see Clinical Studies ( 14 Absorption Montelukast is rapidly absorbed following oral administration. After administration of the 10 mg film-coated tablet to fasted adults, the mean peak montelukast plasma concentration (C max max max For the 5 mg chewable tablet, the mean C max For the 4 mg chewable tablet, the mean C max The 4 mg oral granule formulation is bioequivalent to the 4 mg chewable tablet when administered to adults in the fasted state. The safety and effectiveness of montelukast sodium in patients with asthma were demonstrated in clinical trials in which the 10 mg film-coated tablet and 5 mg chewable tablet formulations were administered in the evening without regard to the time of food ingestion. The safety of montelukast sodium in patients with asthma was also demonstrated in clinical trials in which the 4 mg chewable tablet and 4 mg oral granule formulations were administered in the evening without regard to the time of food ingestion. The safety and effectiveness of montelukast sodium chewable tablets in patients with seasonal allergic rhinitis were demonstrated in clinical trials in which the 10 mg film-coated tablet was administered in the morning or evening without regard to the time of food ingestion. The comparative pharmacokinetics of montelukast when administered as two 5 mg chewable tablets versus one 10 mg film-coated tablet have not been evaluated. Distribution Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages 8 to 11 liters. Orally administered montelukast distributes into the brain in rats. Elimination The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5 day fecal collections and < 0. 2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile. In several studies, the mean plasma half-life of montelukast ranged from 2. 5 hours in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once-daily dosing with 10 mg montelukast, there is little accumulation of the parent drug in plasma (14%). Metabolism Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients. In vitro Specific Populations Patients with Hepatic Impairment Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% (90% CI=7%, 85%) higher mean montelukast AUC following a single 10 mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7. No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of montelukast sodium in patients with more severe hepatic impairment or with hepatitis have not been evaluated. Patients with Renal Impairment Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients. Male and Female Patients The pharmacokinetics of montelukast are similar in males and females. Racial Groups Pharmacokinetic differences due to race have not been studied. Adolescents and Pediatric Patients Pharmacokinetic studies evaluated the systemic exposure of the 4 mg oral granule formulation in pediatric patients 6 to 23 months of age, the 4 mg chewable tablets in pediatric patients 2 to 5 years of age, the 5 mg chewable tablets in pediatric patients 6 to 14 years of age, and the 10 mg film-coated tablets in young adults and adolescents >=15 years of age. The plasma concentration profile of montelukast following administration of the 10 mg film-coated tablet is similar in adolescents >=15 years of age and young adults. The 10 mg film-coated tablet is recommended for use in patients >=15 years of age. The mean systemic exposure of the 4 mg chewable tablet in pediatric patients 2 to 5 years of age and the 5 mg chewable tablets in pediatric patients 6 to 14 years of age is similar to the mean systemic exposure of the 10 mg film-coated tablet in adults. The 5 mg chewable tablet should be used in pediatric patients 6 to 14 years of age and the 4 mg chewable tablet should be used in pediatric patients 2 to 5 years of age. In children 6 to 11 months of age, the systemic exposure to montelukast and the variability of plasma montelukast concentrations were higher than those observed in adults. Based on population analyses, the mean AUC (4,296 nghr/mL [range 1,200 to 7,153]) was 60% higher and the mean C max max max [see Adverse Reactions ( 6. 1 Drug Interaction Studies Theophylline, Prednisone, and Prednisolone Montelukast sodium 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, and prednisolone. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state, did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline [predominantly a cytochrome P450 (CYP) 1A2 substrate]. Montelukast at doses of >= 100 mg daily dosed to pharmacokinetic steady state, did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Oral Contraceptives, fexofenadine, Digoxin, and Warfarin In drug interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), digoxin, and warfarin. Montelukast at doses of >= 100 mg daily dosed 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 mcg. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of fexofenadine did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP2C9, 3A4 and 1A2) or influence the effect of a single 30 mg oral dose of warfarin on prothrombin time or the International Normalized Ratio (INR). Thyroid Hormones, Sedative Hypnotics, Non-Steroidal Anti-Inflammatory Agents, Benzodiazepines, and Decongestants Although additional specific interaction studies were not performed, montelukast sodium 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. Cytochrome P450 (CYP) Enzyme Inducers Phenobarbital, which induces hepatic metabolism, decreased the area under the plasma concentration curve (AUC) of montelukast approximately 40% following a single 10 mg dose of montelukast. No dosage adjustment for montelukast sodium is recommended. It is reasonable to employ appropriate clinical monitoring when potent CYP enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast sodium. Effect of Montelukast on Cytochrome P450 (CYP) Enzymes Montelukast is a potent inhibitor of CYP2C8 in vitro. in vivo in vitro Cytochrome P450 (CYP) Enzyme Inhibitors In vitro [see Overdosage ( 10.

Montelukast sodium chewable tablets are a leukotriene receptor antagonist indicated for: Prophylaxis and chronic treatment of asthma in patients 2 years 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 2 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 Montelukast sodium chewable tablets are indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 2 years of age and older. Montelukast sodium chewable tablets are indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 6 years of age and older. Montelukast sodium chewable tablets are indicated for the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 2 years of age and older. Because the benefits of montelukast sodium chewable tablets may not outweigh the risk of neuropsychiatric symptoms in patients with allergic rhinitis [see Warnings and Precautions ( 5. 1 Montelukast sodium chewable tablets are not indicated for the treatment of an acute asthma attack.

Administration (by indications): Asthma: Once daily in the evening for patients 2 years 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 2 years and older ( 2. 3 Dosage (by age): 6 to 14 years: one 5 mg chewable tablet ( 2 2 to 5 years: one 4 mg chewable tablet ( 2 Patients with both asthma and allergic rhinitis should take only one dose daily in the evening ( 2. 4 For asthma, administer montelukast sodium chewable tablets 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 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 Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time. For prevention of EIB, administer a single dose of montelukast sodium chewable tablets orally at least 2 hours, before exercise. The following doses are recommended: Table 2: Recommended Dosage in Exercise-Induced Bronchoconstriction (EIB) * Safety and effectiveness in patients younger than 6 years of age have not been established. Age Dose Pediatric patients 6 to 14 years of age* one 5 mg chewable tablet An additional dose of montelukast sodium chewable tablets should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium chewable 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 beta-agonist. Daily administration of montelukast sodium chewable tablets for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. For allergic rhinitis, administer montelukast sodium chewable 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 of seasonal allergic rhinitis are recommended: Table 3: Recommended Dosage in Seasonal Allergic Rhinitis * Safety and effectiveness in patients younger than 2 years of age with seasonal allergic rhinitis have not been established. Age Dose 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 The following doses for the treatment of symptoms of perennial allergic rhinitis are recommended: Table 4: Recommended Dosage in Perennial Allergic Rhinitis Age Dose 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 Patients who miss a dose should take the next dose at their regular time and should not take 2 doses at the same time. For patients with both asthma and allergic rhinitis, administer only one montelukast sodium chewable 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.

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 Graviti Pharmaceuticals Inc. , at 1-855-298-4506 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 Montelukast Sodium 10 mg/day Placebo Body As A Whole Pain, abdominal 2. 5 Asthenia/fatigue 1. 8 Digestive System Disorders Dyspepsia 2. 1 Pain, dental 1. 0 Gastroenteritis, infectious 1. 5 Nervous System/Psychiatric Headache 18. 1 Dizziness 1. 4 Respiratory System Disorders Influenza 4. 4 Congestion, nasal 1. 3 Skin/Skin Appendages Disorder Rash 1. 2 Laboratory Adverse Reactions Number of patients tested (montelukast sodium and placebo, respectively): ALT and AST, 1935, 1170; pyuria, 1924, 1159. ALT increased 2. 0 AST increased 1. 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. 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. 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 reactions 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. 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 2 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. 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.

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

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] [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. 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). Risk Summary A published clinical lactation study reports the presence of montelukast in human milk. Data available on the effects of the drug on infants, either directly [see Use in Specific Populations ( 8. 4 Safety and effectiveness of montelukast sodium for asthma have been established in pediatric patients 6 to 14 years of age. Use of montelukast sodium for this indication is supported by evidence from well-controlled studies. Safety and efficacy data in this age group are similar to those seen in adults [see Adverse Reactions ( 6. 2 The effectiveness of montelukast sodium 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 2 to 14 years of age have been established and is supported by extrapolation from the demonstrated effectiveness 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 montelukast sodium 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 ( 6. 1 The safety of montelukast sodium 4 mg and 5 mg chewable tablets in pediatric patient 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 ( 6. 1 The safety and effectiveness in pediatric patients below the age of 12 months with asthma, 6 months with perennial allergic rhinitis, and 6 years with exercise-induced bronchoconstriction have not been established. Growth Rate in Pediatric Patients A 56-week, multi-center, double-blind, randomized, active- and placebo-controlled parallel group study was conducted to assess the effect of montelukast sodium on growth rate in 360 patients with mild asthma, aged 6 to 8 years. Treatment groups included montelukast sodium 5 mg once daily, placebo, and beclomethasone dipropionate administered as 168 mcg twice daily with a spacer device. For each subject, a growth rate was defined as the slope of a linear regression line fit to the height measurements over 56 weeks. The primary comparison was the difference in growth rates between montelukast sodium and placebo groups. Growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for the montelukast sodium, placebo, and beclomethasone treatment groups were 5. 08), respectively. The differences in growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for montelukast sodium minus placebo, beclomethasone minus placebo, and montelukast sodium minus beclomethasone treatment groups were 0. 09), respectively. Growth rate (expressed as mean change in height over time) for each treatment group is shown in FIGURE 1. Figure 1: Change in Height (cm) from Randomization Visit by Scheduled Week (Treatment Group Mean +/- Standard Error of the Mean) 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. The pharmacokinetic profile and the oral bioavailability of a single 10 mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required. No dosage adjustment is recommended in patients with mild-to-moderate hepatic insufficiency [see Clinical Pharmacology ( 12. 3 No dosage adjustment is recommended in patients with renal insufficiency [see Clinical Pharmacology ( 12.

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

MEDICATION GUIDE
Montelukast Sodium Chewable Tablets, USP (mon te loo ′ kast soe ′ dee um) What is the most important information I should know about montelukast sodium chewable tablets? Serious mental health problems have happened in people taking montelukast sodium chewable tablets agitation, including aggressive behavior or hostility hallucinations (seeing or hearing things that are not really there) suicidal thoughts and actions (including suicide) attention problems memory problems tremor bad or vivid dreams obsessive-compulsive symptoms trouble sleeping depression restlessness uncontrolled muscle movements disorientation (confusion) sleep walking feeling anxious stuttering irritability What are montelukast sodium chewable tablets? 1. Do not take montelukast sodium chewable tablets if you need relief right away for a sudden asthma attack 2. 3. and Do not Before taking montelukast sodium chewable tablets, tell your healthcare provider about all your medical conditions, including if you: How should I take montelukast sodium chewable tablets? anyone when to take it If you or your child misses a dose of montelukast sodium chewable tablets, just take the next dose at your regular time. For adults and children 2 years of age and older with asthma: For people 6 years of age and older for the prevention of exercise-induced asthma: do not Do not take 2 doses of montelukast sodium chewable tablets within 24 hours (1 day). For anyone 2 years of age and older with seasonal allergic rhinitis, or for anyone 6 months of age and older with perennial allergic rhinitis: What should I avoid while taking montelukast sodium chewable tablets? What are the possible side effects of montelukast sodium chewable tablets? Montelukast sodium chewable tablets may cause serious side effects, including: "What is the most important information I should know about montelukast sodium chewable tablets?" Increase in certain white blood cells (eosinophils) and possible inflamed blood vessels throughout the body (systemic vasculitis). Tell your healthcare provider right away if you get one or more of these symptoms: ◦ a feeling of pins and needles or numbness of arms or legs ◦ rash ◦ a flu-like illness ◦ severe inflammation (pain and swelling) of the sinuses (sinusitis) The most common side effect of montelukast sodium chewable tablets include: upper respiratory infection cough flu fever stomach pain runny nose headache diarrhea sinus infection sore throat earache or ear infection These are not all the possible side effects of montelukast sodium chewable tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store montelukast sodium chewable tablets? Keep montelukast sodium chewable tablets and all medicines out of reach of children. General information about the safe and effective use of montelukast sodium chewable tablets. What are the ingredients in montelukast sodium chewable tablets? Active ingredient: Inactive ingredients: 4 mg and 5 mg chewable tablets: Distributed by: This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 02/2024">OVERDOSAGE
No specific information is available on the treatment of overdosage with montelukast sodium. 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. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.
NONCLINICAL TOXICOLOGY
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 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 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).
CLINICAL STUDIES
Adults and Adolescents 15 Years of Age and Older with Asthma Clinical trials in adults and adolescents 15 years of age and older demonstrated there is no additional clinical benefit to montelukast doses above 10 mg once daily. The efficacy of montelukast sodium for the chronic treatment of asthma in adults and adolescents 15 years of age and older was demonstrated in two (U. and Multinational) similarly designed, randomized, 12-week, double-blind, placebo-controlled trials in 1,576 patients (795 treated with montelukast sodium, 530 treated with placebo, and 251 treated with active control). The median age was 33 years (range 15 to 85); 56. 8% were females and 43. 2% were males. The ethnic/racial distribution in these studies was 71. 6% Caucasian, 17. 7% Hispanic, 7. 2% other origins and 3. Patients had mild or moderate asthma and were non-smokers who required approximately 5 puffs of inhaled beta-agonist per day on an "as-needed" basis. The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV 1 1 The results of the U. trial on the primary endpoint, morning FEV 1 1 1 1 Figure 2: FEV 1 Montelukast Sodium N=406; Placebo N=270) (ANOVA Model) The effect of montelukast sodium on other primary and secondary endpoints, represented by the Multinational study is shown in TABLE 6. Results on these endpoints were similar in the U. Table 6: Effect of Montelukast Sodiumon Primary and Secondary Endpoints in a Multinational Placebo-controlled Trial (ANOVA Model) Montelukast Sodium Placebo Endpoint N Baseline Mean Change from Baseline N Baseline Mean Change from Baseline Daytime Asthma Symptoms (0 to 6 scale) 372 2. 001, compared with placebo 245 2. 26 beta-agonist (puffs per day) 371 5. 42 AM PEFR (L/min) 372 339. 83 PM PEFR (L/min) 372 355. 49 Nocturnal Awakenings (#/week) 285 5. 78 Both studies evaluated the effect of montelukast sodium on secondary outcomes, including asthma attack (utilization of health-care resources such as an unscheduled visit to a doctor''s office, emergency room, or hospital; or treatment with oral, intravenous, or intramuscular corticosteroid), and use of oral corticosteroids for asthma rescue. In the Multinational study, significantly fewer patients (15. 6% of patients) on montelukast sodium experienced asthma attacks compared with patients on placebo (27. 8% of patients on montelukast sodium and 10. 3% of patients on placebo experienced asthma attacks, but the difference between the two treatment groups was not significant (p=0. In the Multinational study, significantly fewer patients (14. 8% of patients) on montelukast sodium were prescribed oral corticosteroids for asthma rescue compared with patients on placebo (25. 9% of patients on montelukast sodium and 9. 9% of patients on placebo were prescribed oral corticosteroids for asthma rescue, but the difference between the two treatment groups was not significant (p=0. Onset of Action and Maintenance of Effects In each placebo-controlled trial in adults, the treatment effect of montelukast sodium, measured by daily diary card parameters, including symptom scores, "as-needed" beta-agonist use, and PEFR measurements, was achieved after the first dose and was maintained throughout the dosing interval (24 hours). No significant change in treatment effect was observed during continuous once-daily evening administration in non-placebo-controlled extension trials for up to one year. Withdrawal of montelukast sodium in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma. Pediatric Patients 6 to 14 Years of Age with Asthma The efficacy of montelukast sodium in pediatric patients 6 to 14 years of age was demonstrated in one 8-week, double-blind, placebo-controlled trial in 336 patients (201 treated with montelukast sodium and 135 treated with placebo) using an inhaled beta-agonist on an "as-needed" basis. The patients had a mean baseline percent predicted FEV 1 Compared with placebo, treatment with one 5 mg montelukast sodium chewable tablet daily resulted in a significant improvement in mean morning FEV 1 Similar to the adult studies, no significant change in the treatment effect was observed during continuous once-daily administration in one open-label extension trial without a concurrent placebo group for up to 6 months. Pediatric Patients 2 to 5 Years of Age with Asthma The efficacy of montelukast sodium for the chronic treatment of asthma in pediatric patients 2 to 5 years of age was explored in a 12-week, placebo-controlled safety and tolerability study in 689 patients, 461 of whom were treated with montelukast sodium. The median age was 4 years (range 2 to 6); 41. 5% were females and 58. 5% were males. The ethnic/racial distribution in this study was 56. 5% Caucasian, 20. 9% Hispanic, 14. 4% other origins, and 8. While the primary objective was to determine the safety and tolerability of montelukast sodium in this age group, the study included exploratory efficacy evaluations, including daytime and overnight asthma symptom scores, beta-agonist use, oral corticosteroid rescue, and the physician''s global evaluation. The findings of these exploratory efficacy evaluations, along with pharmacokinetics and extrapolation of efficacy data from older patients, support the overall conclusion that montelukast sodium is efficacious in the maintenance treatment of asthma in patients 2 to 5 years of age. Effects in Patients on Concomitant Inhaled Corticosteroids Separate trials in adults evaluated the ability of montelukast sodium to add to the clinical effect of inhaled corticosteroids and to allow inhaled corticosteroid tapering when used concomitantly. One randomized, placebo-controlled, parallel-group trial (n=226) enrolled adults with stable asthma with a mean FEV 1 In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of montelukast sodium to beclomethasone resulted in statistically significant improvements in FEV 1 1 In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) demonstrated that montelukast sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of montelukast sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of montelukast sodium on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated [see Warnings and Precautions ( 5. 4 Exercise-Induced Bronchoconstriction (Adults, Adolescents, and Pediatric Patients 6 years of age and older) The efficacy of montelukast sodium 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U. and Multinational), randomized, double-blind, placebo-controlled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8. 5 or 12 hours, and 24 hours following administration of a single dose of study drug (montelukast sodium 10 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV 1 Table 7: Mean Maximum Percent Fall in FEV 1 Time of exercise challenge following medication administration Mean Maximum percent fall in FEV 1 Least squares-mean Treatment difference % for Montelukast Sodium versus Placebo (95% CI) Montelukast Sodium Placebo 2 hours 13 22 -9 (-12, -5) 8. 5 hours 12 17 -5 (-9, -2) 24 hours 10 14 -4 (-7, -1) The efficacy of montelukast sodium chewable tablets, 5 mg, when given as a single dose 2 hours before exercise for the prevention of EIB, was investigated in one multinational, randomized, double-blind, placebo-controlled crossover study that included a total of 64 pediatric patients 6 to 14 years of age with EIB. Exercise challenge testing was conducted at 2 hours and 24 hours following administration of a single dose of study drug (montelukast sodium 5 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV 1 Table 8: Mean Maximum Percent Fall in FEV 1 time of exercise challenge following medication administration Mean Maximum percent fall in FEV 1 Least squares-mean Treatment difference % for Montelukast Sodium versus Placebo Montelukast Sodium Placebo 2 hours 15 20 -5 (-9, -1) 24 hours 13 17 -4 (-7, -1) The efficacy of montelukast sodium for prevention of EIB in patients below 6 years of age has not been established. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. In a 12-week, randomized, double-blind, parallel group study of 110 adult and adolescent asthmatics 15 years of age and older, with a mean baseline FEV 1 1 1 1 In pediatric patients 6 to 14 years of age, using the 5 mg chewable tablet, a 2-day crossover study demonstrated effects similar to those observed in adults when exercise challenge was conducted at the end of the dosing interval (i. , 20 to 24 hours after the preceding dose). Seasonal Allergic Rhinitis The efficacy of montelukast sodium tablets for the treatment of seasonal allergic rhinitis was investigated in 5 similarly designed, randomized, double-blind, parallel-group, placebo- and active-controlled (loratadine) trials conducted in North America. The 5 trials enrolled a total of 5,029 patients, of whom 1,799 were treated with montelukast sodium tablets. Patients were 15 to 82 years of age with a history of seasonal allergic rhinitis, a positive skin test to at least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at study entry. The period of randomized treatment was 2 weeks in 4 trials and 4 weeks in one trial. The primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing) as assessed by patients on a 0 to 3 categorical scale. Four of the five trials showed a significant reduction in daytime nasal symptoms scores with montelukast sodium tablets, 10 mg compared with placebo. The results of one trial are shown below. The median age in this trial was 35. 0 years (range 15 to 81); 65. 4% were females and 34. 6% were males. The ethnic/racial distribution in this study was 83. 1% Caucasian, 6. 4% other origins, 5. 8% Black, and 4. 8% Hispanic. The mean changes from baseline in daytime nasal symptoms score in the treatment groups that received montelukast sodium tablets, loratadine, and placebo are shown in TABLE 9. The remaining three trials that demonstrated efficacy showed similar results. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening. Table 9: Effects of Montelukast Sodium on Daytime Nasal Symptoms Score Average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing as assessed by patients on a 0 to 3 categorical scale. Treatment Group (N) Baseline Mean Score Mean Change from Baseline Difference Between Treatment and Placebo (95% CI) Least-Squares Mean Montelukast 10 mg (344) 2. 13 Statistically different from placebo (p<=0. Placebo (351) 2. Active Control The study was not designed for statistical comparison between montelukast sodium and the active control (loratadine). 24 Perennial Allergic Rhinitis The efficacy of montelukast sodium tablets for the treatment of perennial allergic rhinitis was investigated in 2 randomized, double-blind, placebo-controlled studies conducted in North America and Europe. The two studies enrolled a total of 3,357 patients, of whom 1,632 received montelukast sodium 10 mg tablets. Patients 15 to 82 years of age with perennial allergic rhinitis as confirmed by history and a positive skin test to at least one relevant perennial allergen (dust mites, animal dander, and/or mold spores), who had active symptoms at the time of study entry, were enrolled. In the study in which efficacy was demonstrated, the median age was 35 years (range 15 to 81); 64. 1% were females and 35. 9% were males. 2% Caucasian, 8. 1% Black, 5. 4% Hispanic, 2. 3% Asian, and 1. 0% other origins. Montelukast sodium 10 mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6-week treatment period (TABLE 10); in this study the primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, and sneezing). Table 10: Effects of Montelukast Sodium on Daytime Nasal Symptoms Score Treatment Group (N) Baseline Mean Change from Baseline Difference Between Treatment Montelukast 10 mg (1,000) 2. 08 Statistically different from placebo (p<=0. Placebo (980) 2. The other 6-week study evaluated montelukast 10 mg (n = 626), placebo (n = 609), and an active-control (cetirizine 10 mg; n = 120). The primary analysis compared the mean change from baseline in daytime nasal symptoms score for montelukast sodium vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between montelukast sodium and the active-control. The primary outcome variable included nasal itching in addition to nasal congestion, rhinorrhea, and sneezing. The estimated difference between montelukast sodium and placebo was -0. 04 with a 95% CI of (-0. The estimated difference between the active-control and placebo was -0. 10 with a 95% CI of (-0.
MEDICATION GUIDE
Montelukast Sodium Chewable Tablets, USP (mon te loo ′ kast soe ′ dee um) What is the most important information I should know about montelukast sodium chewable tablets? Serious mental health problems have happened in people taking montelukast sodium chewable tablets agitation, including aggressive behavior or hostility hallucinations (seeing or hearing things that are not really there) suicidal thoughts and actions (including suicide) attention problems memory problems tremor bad or vivid dreams obsessive-compulsive symptoms trouble sleeping depression restlessness uncontrolled muscle movements disorientation (confusion) sleep walking feeling anxious stuttering irritability What are montelukast sodium chewable tablets? 1. Do not take montelukast sodium chewable tablets if you need relief right away for a sudden asthma attack 2. 3. and Do not Before taking montelukast sodium chewable tablets, tell your healthcare provider about all your medical conditions, including if you: How should I take montelukast sodium chewable tablets? anyone when to take it If you or your child misses a dose of montelukast sodium chewable tablets, just take the next dose at your regular time. For adults and children 2 years of age and older with asthma: For people 6 years of age and older for the prevention of exercise-induced asthma: do not Do not take 2 doses of montelukast sodium chewable tablets within 24 hours (1 day). For anyone 2 years of age and older with seasonal allergic rhinitis, or for anyone 6 months of age and older with perennial allergic rhinitis: What should I avoid while taking montelukast sodium chewable tablets? What are the possible side effects of montelukast sodium chewable tablets? Montelukast sodium chewable tablets may cause serious side effects, including: "What is the most important information I should know about montelukast sodium chewable tablets?" Increase in certain white blood cells (eosinophils) and possible inflamed blood vessels throughout the body (systemic vasculitis). Tell your healthcare provider right away if you get one or more of these symptoms: ◦ a feeling of pins and needles or numbness of arms or legs ◦ rash ◦ a flu-like illness ◦ severe inflammation (pain and swelling) of the sinuses (sinusitis) The most common side effect of montelukast sodium chewable tablets include: upper respiratory infection cough flu fever stomach pain runny nose headache diarrhea sinus infection sore throat earache or ear infection These are not all the possible side effects of montelukast sodium chewable tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store montelukast sodium chewable tablets? Keep montelukast sodium chewable tablets and all medicines out of reach of children. General information about the safe and effective use of montelukast sodium chewable tablets. What are the ingredients in montelukast sodium chewable tablets? Active ingredient: Inactive ingredients: 4 mg and 5 mg chewable tablets: Distributed by: This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 02/2024

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