Generic Name: MONTELUKAST SODIUM
Brand Name: Montelukast Sodium
- Substance Name(s):
- MONTELUKAST SODIUM
DRUG INTERACTIONS
7 No dose adjustment is needed when montelukast sodium is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, 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)].
OVERDOSAGE
10 No specific information is available on the treatment of overdosage with montelukast sodium. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks and, in short-term studies, up to 900 mg/day to patients for approximately a week without clinically important adverse experiences. 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. There have been reports of acute overdosage in post-marketing experience and clinical studies with montelukast sodium. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and pediatric patients. There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of montelukast sodium and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.
DESCRIPTION
11 Montelukast sodium, the active ingredient in montelukast sodium tablets and montelukast sodium chewable tablets, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 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 molecular formula is C35H35CINNaO3S, 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 contains 10.4 mg montelukast sodium, which is equivalent to 10 mg of montelukast, and the following inactive ingredients:anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide, and yellow ferric oxide. Each 4 mg and 5 mg chewable montelukast sodium tablet 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: mannitol, microcrystalline cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate. image-2
CLINICAL STUDIES
14 14.1 Asthma 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.S. and Multinational) similarly designed, randomized, 12-week, double-blind, placebo-controlled trials in 1576 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 3.5% Black. Patients had mild or moderate asthma and were non-smokers who required approximately 5 puffs of inhaled β-agonist per day on an “as-needed” basis. The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV1) of 66% (approximate range, 40 to 90%). The co-primary endpoints in these trials were FEV1 and daytime asthma symptoms. In both studies after 12 weeks, a random subset of patients receiving montelukast sodium was switched to placebo for an additional 3 weeks of double-blind treatment to evaluate for possible rebound effects. The results of the U.S. trial on the primary endpoint, morning FEV1, expressed as mean percent change from baseline averaged over the 12-week treatment period, are shown in FIGURE 2. Compared with placebo, treatment with one montelukast sodium 10 mg tablet daily in the evening resulted in a statistically significant increase in FEV1 percent change from baseline (13.0%-change in the group treated with montelukast sodium vs. 4.2%-change in the placebo group, p<0.001); the change from baseline in FEV1 for montelukast sodium was 0.32 liters compared with 0.10 liters for placebo, corresponding to a between-group difference of 0.22 liters (p<0.001, 95% CI 0.17 liters, 0.27 liters). The results of the Multinational trial on FEV1 were similar. FIGURE 2: FEV1 Mean Percent Change from Baseline (U.S. Trial: 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 2. Results on these endpoints were similar in the US study. TABLE 2 Effect of Montelukast Sodium on 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 2.35 -0.49p<0.001, compared with placebo 245 2.40 -0.26 β-agonist (puffs per day) 371 5.35 -1.65 241 5.78 -0.42 AM PEFR (L/min) 372 339.57 25.03 244 335.24 1.83 PM PEFR (L/min) 372 355.23 20.13 244 354.02 -0.49 Nocturnal Awakenings (#/week) 285 5.46 -2.03 195 5.57 -0.78 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 (27.3%, p < 0.001). In the US study, 7.8% 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 = 0.334). 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 (25.7%, p < 0.001). In the US study, 6.9% 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 = 0.196). image3 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” β-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 β-agonist on an “as-needed” basis. The patients had a mean baseline percent predicted FEV1 of 72% (approximate range, 45 to 90%) and a mean daily inhaled β-agonist requirement of 3.4 puffs of albuterol. Approximately 36% of the patients were on inhaled corticosteroids. The median age was 11 years (range 6 to 15); 35.4% were females and 64.6% were males. The ethnic/racial distribution in this study was 80.1% Caucasian, 12.8% Black, 4.5% Hispanic, and 2.7% other origins. Compared with placebo, treatment with one 5 mg montelukast sodium chewable tablet daily resulted in a significant improvement in mean morning FEV1 percent change from baseline (8.7% in the group treated with montelukast sodium vs. 4.2% change from baseline in the placebo group, p<0.001). There was a significant decrease in the mean percentage change in daily “as-needed” inhaled β-agonist use (11.7% decrease from baseline in the group treated with montelukast sodium vs. 8.2% increase from baseline in the placebo group, p<0.05). This effect represents a mean decrease from baseline of 0.56 and 0.23 puffs per day for the montelukast and placebo groups, respectively. Subgroup analyses indicated that younger pediatric patients aged 6 to 11 had efficacy results comparable to those of the older pediatric patients aged 12 to 14. 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 8.3% Black. 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, β-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 FEV1 of approximately 84% of predicted who were previously maintained on various inhaled corticosteroids (delivered by metered-dose aerosol or dry powder inhalers). The median age was 41.5 years (range 16 to 70); 52.2% were females and 47.8% were males. The ethnic/racial distribution in this study was 92.0% Caucasian, 3.5% Black, 2.2% Hispanic, and 2.2% Asian. The types of inhaled corticosteroids and their mean baseline requirements included beclomethasone dipropionate (mean dose, 1203 mcg/day), triamcinolone acetonide (mean dose, 2004 mcg/day), flunisolide (mean dose, 1971 mcg/day), fluticasone propionate (mean dose, 1083 mcg/day), or budesonide (mean dose, 1192 mcg/day). Some of these inhaled corticosteroids were non-U.S.-approved formulations, and doses expressed may not be ex-actuator. The pre-study inhaled corticosteroid requirements were reduced by approximately 37% during a 5- to 7-week placebo run-in period designed to titrate patients toward their lowest effective inhaled corticosteroid dose. Treatment with montelukast sodium resulted in a further 47% reduction in mean inhaled corticosteroid dose compared with a mean reduction of 30% in the placebo group over the 12-week active treatment period (p≤0.05). It is not known whether the results of this study can be generalized to patients with asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids. 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 FEV1 compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with montelukast or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to montelukast sodium alone or placebo alone as indicated by FEV1, daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-needed” β-agonist requirements. 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 (5.3)]. 14.2 Exercise-Induced Bronchoconstriction (EIB) Exercise-Induced Bronchoconstriction (Adults and Adolescents 15 years of age and older) The efficacy of montelukast, 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. 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 10 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV1 following the 2 hours post-dose exercise challenge in all three studies (Study A, Study B, and Study C). In Study A, a single dose of montelukast sodium 10 mg demonstrated a statistically significant protective benefit against EIB when taken 2 hours prior to exercise. Some patients were protected from EIB at 8.5 and 24 hours after administration; however, some patients were not. The results for the mean maximum percent fall at each timepoint in Study A are shown in TABLE 3 and are representative of the results from the other two studies. TABLE 3: Mean Maximum Percent Fall in FEV1 Following Exercise Challenge in Study A (N=47) ANOVA Model Time of exercise challenge following medication administration Mean Maximum percent fall in FEV1 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) Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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 FEV1 percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with montelukast sodium, 10 mg, once daily in the evening, resulted in a statistically significant reduction in mean maximal percent fall in FEV1 and mean time to recovery to within 5% of the pre-exercise FEV1. Exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose). This effect was maintained throughout the 12-week treatment period indicating that tolerance did not occur. Montelukast sodium did not, however, prevent clinically significant deterioration in maximal percent fall in FEV1 after exercise (i.e., ≥20% decrease from pre-exercise baseline) in 52% of patients studied. In a separate crossover study in adults, a similar effect was observed after two once-daily 10 mg doses of montelukast sodium. 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.e., 20 to 24 hours after the preceding dose). 14.3 Allergic Rhinitis (Seasonal and Perennial) 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 5029 patients, of whom 1799 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 0-3 categorical scale. Four of the five trials showed a significant reduction in daytime nasal symptoms scores with montelukast sodium 10 mg tablets 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 4. The remaining three trials that demonstrated efficacy showed similar results. TABLE 4: Effects of Montelukast Sodium on Daytime Nasal Symptoms ScoreAverage of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing as assessed by patients on a 0 to 3 categorical scale. in a Placebo- and Active-controlled Trial in Patients with Seasonal Allergic Rhinitis (ANCOVA Model) Treatment Group (N) Baseline Mean Score Mean Change from Baseline Difference Between Treatment and Placebo (95% CI) Least-Squares Mean Montelukast 10 mg (344) 2.09 -0.39 -0.13Statistically different from placebo (p≤0.001). (-0.21, -0.06) Placebo (351) 2.10 -0.26 N.A. Active ControlThe study was not designed for statistical comparison between montelukast sodium and the active control (loratadine). (Loratadine 10 mg) (599) 2.06 -0.46 -0.24 (-0.31, -0.17) 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 3357 patients, of whom 1632 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. The ethnic/racial distribution in this study was 83.2% 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 5); 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 5: Effects of Montelukast Sodium on Daytime Nasal Symptoms Score Average of individual scores of nasal congestion, rhinorrhea, sneezing as assessed by patients on a 0 to 3 categorical scale. in a Placebo-controlled Trial in Patients with Perennial Allergic Rhinitis (ANCOVA Model) Treatment Group (N) Baseline Mean Score Mean Change from Baseline Difference Between Treatment and Placebo (95% CI) Least-Squares Mean Montelukast 10 mg (1000) 2.09 -0.42 -0.08Statistically different from placebo (p≤0.001). (-0.12, -0.04) Placebo (980) 2.10 -0.35 N.A. 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 (-0.09, 0.01). The estimated difference between the active-control and placebo was -0.10 with a 95% CI of (-0.19, -0.01).
HOW SUPPLIED
16 /STORAGE AND HANDLING Montelukast Sodium Chewable Tablets, 4 mg, are pink, oval, biconvex-shaped chewable tablets, engraved with “APO” on one side and “M4” on the other side. They are supplied as follows: Unit dose packages of 30 (3 x 10) NDC 68084-638-21 Montelukast Sodium Chewable Tablets, 5 mg, are pink, round, biconvex-shaped chewable tablets, engraved with “APO” on one side and “M5” on the other side. They are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-619-01 Montelukast Sodium Film-Coated Tablets, 10 mg, are beige, rounded square-shaped, biconvex film-coated tablets, engraved with “APO” on one side and “M10” on the other side. They are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-620-01 Storage Store montelukast 4 mg chewable tablets, 5 mg chewable tablets and 10 mg film-coated tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture and light.
RECENT MAJOR CHANGES
Warnings and Precautions Neuropsychiatric Events (5.4) 11/2012
GERIATRIC USE
8.5 Geriatric Use 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.
DOSAGE FORMS AND STRENGTHS
3 •Montelukast Sodium Film-Coated Tablets, 10 mg, are beige, rounded square-shaped, biconvex film-coated tablets, engraved with “APO” on one side and “M10” on the other side. •Montelukast Sodium Chewable Tablets, 5 mg, are pink, round, biconvex-shaped tablets, engraved with “APO” on one side and “M5” on the other side. •Montelukast Sodium Chewable Tablets, 4 mg, are pink, oval, biconvex-shaped tablets, engraved with “APO” on one side and “M4” on the other side. 1.Montelukast Sodium Film-Coated Tablets, 10 mg 2.Montelukast Sodium Chewable Tablets, 5 mg and 4 mg
MECHANISM OF ACTION
12.1 Mechanism of Action The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.
INDICATIONS AND USAGE
1 Montelukast sodium tablets are a leukotriene receptor antagonist indicated for: 1.Prophylaxis and chronic treatment of asthma in patients 2 years of age and older (1.1). 2.Acute prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older (1.2). 3.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 (1.3). 1.1 Asthma Montelukast sodium is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 2 years of age and older. 1.2 Exercise-Induced Bronchoconstriction (EIB) Montelukast sodium is indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older. Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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 2 years of age and older.
PEDIATRIC USE
8.4 Pediatric Use Safety and efficacy of montelukast sodium have been established in adequate and well-controlled studies in pediatric patients with asthma 6 to 14 years of age. Safety and efficacy profiles in this age group are similar to those seen in adults [see Adverse Reactions (6.1), Clinical Pharmacology, Special Populations (12.3), and Clinical Studies (14.1, 14.2)]. The efficacy 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 years to 14 years of age is supported by extrapolation from the demonstrated efficacy 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)]. Efficacy of montelukast sodium in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma and is based on similar pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations. Efficacy in this age group is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients 2 to 5 years of age. The safety of montelukast sodium 4 mg and 5 mg chewable tablets in pediatric patients aged 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 and 6 months with perennial allergic rhinitis have not been established. The safety and effectiveness in pediatric patients below the age of 6 years with exercise-induced bronchoconstriction have not been established. Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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 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 5.67 (5.46, 5.88), 5.64 (5.42, 5.86), and 4.86 (4.64, 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 0.03 (-0.26, 0.31), -0.78 (-1.06, -0.49); and 0.81 (0.53, 1.09), 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) image-1
PREGNANCY
8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, montelukast sodium should be used during pregnancy only if clearly needed. Teratogenic Effect No teratogenicity was observed in rats and rabbits at doses approximately 100 and 110 times, respectively, the maximum recommended daily oral dose in adults based on AUCs [see Nonclinical Toxicology (13.2)]. During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women being treated with montelukast sodium during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and montelukast sodium has not been established.
NUSRING MOTHERS
8.3 Nursing Mothers Studies in rats have shown that montelukast is excreted in milk. It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when montelukast sodium is given to a nursing mother.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS 1.Do not prescribe montelukast sodium to treat an acute asthma attack (5.1). 2.Advise patients to have appropriate rescue medication available (5.1). 3.Inhaled corticosteroid may be reduced gradually. Do not abruptly substitute montelukast sodium for inhaled or oral corticosteroids (5.2). 4.Patients with known aspirin sensitivity should continue to avoid aspirin or non-steroidal anti-inflammatory agents while taking montelukast sodium (5.3). 5.Neuropsychiatric events have been reported with montelukast sodium. Instruct patients to be alert for neuropsychiatric events. Evaluate the risks and benefits of continuing treatment with montelukast sodium if such events occur (5.4 and 6.2). 6.Systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, has been reported. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy (5.5 and 6.2). 7.Inform patients with phenylketonuria that the 4 mg and 5 mg chewable tablets contain phenylalanine (5.6). 5.1 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. 5.2 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. 5.3 Aspirin Sensitivity Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast sodium. Although montelukast sodium is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients [see Clinical Studies (14.1)]. 5.4 Neuropsychiatric Events Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking montelukast sodium. Post-marketing reports with montelukast sodium use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving montelukast sodium appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with montelukast sodium if such events occur [see Adverse Reactions (6.2)]. 5.5 Eosinophilic Conditions 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 events usually, but not always, have been 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. A causal association between montelukast sodium and these underlying conditions has not been established [see Adverse Reactions (6.2)]. 5.6 Phenylketonuria Phenylketonuric patients should be informed that the 4 mg and 5 mg chewable tablets contain phenylalanine (a component of aspartame), 1.344 and 1.68 mg per 4 mg and 5 mg chewable tablet, respectively.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information) 17.1 Information for Patients 1.Patients should be advised to take montelukast sodium daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, and to contact their physicians if their asthma is not well controlled. 2.Patients should be advised that oral montelukast sodium is not for the treatment of acute asthma attacks. They should have appropriate short-acting inhaled β-agonist medication available to treat asthma exacerbations. Patients who have exacerbations of asthma after exercise should be instructed to have available for rescue a short-acting inhaled β-agonist. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. 3.Patients should be advised that, while using montelukast sodium medical attention should be sought if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed. 4.Patients receiving montelukast sodium should be instructed not to decrease the dose or stop taking any other anti-asthma medications unless instructed by a physician. 5.Patients should be instructed to notify their physician if neuropsychiatric events occur while using montelukast sodium. 6.Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast sodium. 7.Phenylketonuric patients should be informed that the 4-mg and 5-mg chewable tablets contain phenylalanine (a component of aspartame). MONTELUKAST SODIUM TABLETS 10 mg MONTELUKAST SODIUM CHEWABLE TABLETS 4 mg and 5 mg PACKAGING INFORMATION American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Apotex Corp. as follows: (4 mg / 30 UD) NDC 68084-638-21 packaged from NDC 60505-3573 (5 mg / 100 UD) NDC 68084-619-01 packaged from NDC 60505-3574 (10 mg / 100 UD) NDC 68084-620-01 packaged from NDC 60505-3562 Packaged and Distributed by: American Health Packaging Columbus, OH 43217 8261901/1213 17.2 FDA-Approved Patient Labeling 8261901/1213 Patient Information Montelukast Sodium Tablets Montelukast Chewable Tablets Read the Patient Information Leaflet that comes with montelukast sodium tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is montelukast sodium? •Montelukast sodium is a prescription medicine that blocks substances in the body called leukotrienes. This may help to improve symptoms of asthma and allergic rhinitis. Montelukast sodium tablet does not contain a steroid. Montelukast sodium tablet is used to: 1.Prevent asthma attacks and for the long-term treatment of asthma in adults and children ages 2 years and older. Do not take montelukast sodium tablet if you need relief right away for a sudden asthma attack. If you get an asthma attack, you should follow the instructions your healthcare provider gave you for treating asthma attacks. 2.Prevent exercise-induced asthma in people 15 years of age and older. 3.Help control the symptoms of allergic rhinitis (sneezing, stuffy nose, runny nose, itching of the nose). Montelukast sodium tablet is used to treat: •outdoor allergies that happen part of the year (seasonal allergic rhinitis) in adults and children ages 2 years and older, and •indoor allergies that happen all year (perennial allergic rhinitis) in adults and children ages 2 years and older. Who should not take montelukast sodium tablet? Do not take montelukast sodium tablet if you are allergic to any of its ingredients. See the end of this leaflet for a complete list of the ingredients in montelukast sodium tablet. What should I tell my healthcare provider before taking montelukast sodium tablet? Before taking montelukast sodium tablet, tell your healthcare provider if you: •are allergic to aspirin •have phenylketonuria. Montelukast sodium chewable tablets contain aspartame, a source of phenylalanine •have any other medical conditions •are pregnant or plan to become pregnant. Talk to your doctor if you are pregnant or plan to become pregnant, as montelukast sodium tablet may not be right for you. •are breast-feeding or plan to breast-feed. It is not known if montelukast sodium passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking montelukast sodium tablet. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how montelukast sodium tablet works, or montelukast sodium tablet may affect how your other medicines work. How should I take montelukast sodium tablets? For anyone who takes montelukast sodium tablets: •Take montelukast sodium tablet exactly as prescribed by your healthcare provider. Your healthcare provider will tell you how much montelukast sodium tablet to take, and when to take it. •Do not stop taking montelukast sodium tablet or change when you take it without talking with your healthcare provider. •You can take montelukast sodium tablet with food or without food. • If you or your child misses a dose of montelukast sodium tablet, just take the next dose at your regular time. Do not take 2 doses at the same time. •If you take too much montelukast sodium tablets, call your healthcare provider or a Poison Control Center right away. For adults and children 2 years of age and older with asthma: •Take montelukast sodium tablet 1 time each day, in the evening. Continue to take montelukast sodium tablet every day for as long as your healthcare provider prescribes it, even if you have no asthma symptoms. •Tell your healthcare provider right away if your asthma symptoms get worse, or if you need to use your rescue inhaler medicine more often for asthma attacks. • Do not take montelukast sodium tablet if you need relief right away from a sudden asthma attack. If you get an asthma attack, you should follow the instructions your healthcare provider gave you for treating asthma attacks. •Always have your rescue inhaler medicine with you for asthma attacks. •Do not stop taking or lower the dose of your other asthma medicines unless your healthcare provider tells you to. For patients 15 years of age and older for the prevention of exercise-induced asthma: •Take montelukast sodium tablet at least 2 hours before exercise. •Always have your rescue inhaler medicine with you for asthma attacks. •If you take montelukast sodium tablet every day for chronic asthma or allergic rhinitis, do not take another dose to prevent exercise-induced asthma. Talk to your healthcare provider about your treatment for exercise-induced asthma. • Do not take 2 doses of montelukast sodium tablet within 24 hours (1 day). For adults and children 2 years of age and older with seasonal allergic rhinitis, or for adults and children 2 years of age and older with perennial allergic rhinitis: •Take montelukast sodium tablet 1 time each day, at about the same time each day. What is the dose of montelukast sodium tablet? The dose of montelukast sodium tablet prescribed for your or your child’s condition is based on age: •2 to 5 years: one 4 mg chewable tablet •6 to 14 years: one 5 mg chewable tablet. •15 years and older: one 10 mg tablet. What should I avoid while taking montelukast sodium tablet? If you have asthma and aspirin makes your asthma symptoms worse, continue to avoid taking aspirin or other medicines called non‑-steroidal anti-inflammatory drugs (NSAIDs) while taking montelukast sodium tablet. What are the possible side effects of montelukast sodium tablet? Montelukast sodium tablet may cause serious side effects. • Behavior and mood-related changes. Tell your healthcare provider right away if you or your child have any of these symptoms while taking montelukast sodium tablet: •agitation including aggressive behavior or hostility •attention problems •bad or vivid dreams •depression •disorientation (confusion) •feeling anxious •hallucinations (seeing or hearing things that are not really there) •irritability •memory problems •restlessness •sleep walking •suicidal thoughts and actions (including suicide) •tremor •trouble sleeping 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 •a flu-like illness •rash •severe inflammation (pain and swelling) of the sinuses (sinusitis) The most common side effects with montelukast sodium tablet include: •upper respiratory infection •fever •headache •sore throat •cough •stomach pain •diarrhea •earache or ear infection •flu •runny nose •sinus infection Other side effects with montelukast sodium tablet include: •increased bleeding tendency, low blood platelet count •allergic reactions [including swelling of the face, lips, tongue, and/or throat (which may cause trouble breathing or swallowing), hives and itching] •dizziness, drowsiness, pins and needles/numbness, seizures (convulsions or fits) •palpitations •nose bleed, stuffy nose •heartburn, indigestion, inflammation of the pancreas, nausea, stomach or intestinal upset, vomiting •hepatitis •bruising, rash, severe skin reactions (erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis) that may occur without warning •joint pain, muscle aches and muscle cramps •tiredness, swelling Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of montelukast sodium tablet. For more information ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store montelukast sodium tablets? •Store montelukast sodium tablets at 59°F to 86°F (15° to 30°C). •Keep montelukast sodium tablets in a dry place and away from light. General Information about the safe and effective use of montelukast sodium tablets Medicines are sometimes prescribed for purposes other than those mentioned in Patient Information Leaflets. Do not use montelukast sodium tablet for a condition for which it was not prescribed. Do not give montelukast sodium tablet to other people even if they have the same symptoms you have. It may harm them. Keep montelukast sodium tablets and all medicines out of the reach of children. This leaflet summarizes information about montelukast sodium tablets. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about montelukast sodium tablets that is written for health professionals. What are the ingredients in montelukast sodium tablets? Active ingredient: montelukast sodium Inactive ingredients: • 4 mg and 5 mg chewable tablets: mannitol, microcrystalline cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate. •People with Phenylketonuria: montelukast sodium 4 mg chewable tablets contain 1.344 mg of phenylalanine, and montelukast sodium 5 mg chewable tablets contain 1.68 mg of phenylalanine. • 10 mg tablet: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide, and yellow ferric oxide. Pediatric use information for patients ages 6 to 14 years of age for prevention of exercise-induced asthma is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. MONTELUKAST SODIUM TABLETS 10 mg MONTELUKAST SODIUM CHEWABLE TABLETS 4 mg and 5 mg Packaged and Distributed by: American Health Packaging Columbus, OH 43217 8261901/1213
DOSAGE AND ADMINISTRATION
2 Administration (by indications): 1.Asthma (2.1): Once daily in the evening for patients 2 years and older. 2.Acute prevention of EIB (2.2): 10 mg tablet at least 2 hours before exercise for patients 15 years of age and older. 3.Seasonal allergic rhinitis (2.3): Once daily for patients 2 years and older. 4.Perennial allergic rhinitis (2.3): Once daily for patients 2 years and older. Dosage (by age) (2): 1.15 years and older: one 10 mg tablet. 2.6 to 14 years: one 5 mg chewable tablet. 3.2 to 5 years: one 4 mg chewable tablet. Patients with both asthma and allergic rhinitis should take only one dose daily in the evening (2.4). 2.1 Asthma Montelukast sodium should be taken once daily in the evening. The following doses are recommended: For adults and adolescents 15 years of age and older: one 10 mg tablet. For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet. For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet. Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established. There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion. 2.2 Exercise-Induced Bronchoconstriction (EIB) in Patients 15 Years of Age and Older For prevention of EIB, a single 10 mg dose of montelukast should be taken at least 2 hours before exercise. An additional dose of montelukast 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. Safety and efficacy in patients younger than 15 years of age have not been established. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights; this drug product is not labeled with that pediatric information. 2.3 Allergic Rhinitis For allergic rhinitis, montelukast sodium should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs. The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10 mg tablet. For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet. For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet. 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: For adults and adolescents 15 years of age and older: one 10 mg tablet. For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet. For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established. 2.4 Asthma and Allergic Rhinitis Patients with both asthma and allergic rhinitis should take only one montelukast sodium dose daily in the evening.