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Montelukast sodium, the active ingredient in SINGULAIR * , is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT 1 receptor.
Montelukast sodium is described chemically as [ R -( E )]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt.
The empirical formula is C 35 H 35 ClNNaO 3 S, and its molecular weight is 608.18. The structural formula is:
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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 SINGULAIR tablet contains 10.4 mg montelukast sodium, which is equivalent to 10 mg of montelukast, and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide, yellow ferric oxide, and carnauba wax.
Each 4-mg and 5-mg chewable SINGULAIR 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, hydroxypropyl cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate.
Each packet of SINGULAIR 4-mg oral granules contains 4.2 mg montelukast sodium, which is equivalent to 4 mg of montelukast. The oral granule formulation contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, and magnesium stearate.
*Registered trademark of MERCK & CO., Inc.The cysteinyl leukotrienes (LTC 4 , LTD 4 , LTE 4 ) 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 (CysLT 1 ) 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. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction. SINGULAIR has not been assessed in intranasal challenge studies. The clinical relevance of intranasal challenge studies is unknown.
Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT 1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or (beta)-adrenergic receptor). Montelukast inhibits physiologic actions of LTD 4 at the CysLT 1 receptor without any agonist activity.
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 ) is achieved in 3 to 4 hours (T max ). The mean oral bioavailability is 64%. The oral bioavailability and C max are not influenced by a standard meal in the morning.
For the 5-mg chewable tablet, the mean C max is achieved in 2 to 2.5 hours after administration to adults in the fasted state. The mean oral bioavailability is 73% in the fasted state versus 63% when administered with a standard meal in the morning.
For the 4-mg chewable tablet, the mean C max is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state.
The 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet when administered to adults in the fasted state. The co-administration of the oral granule formulation with applesauce did not have a clinically significant effect on the pharmacokinetics of montelukast. A high fat meal in the morning did not affect the AUC of montelukast oral granules; however, the meal decreased C max by 35% and prolonged T max from 2.3 ± 1.0 hours to 6.4 ± 2.9 hours.
The safety and efficacy of SINGULAIR 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 SINGULAIR 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 efficacy of SINGULAIR 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.
Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages 8 to 11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.
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 studies using human liver microsomes indicate that cytochromes P450 3A4 and 2C9 are involved in the metabolism of montelukast. Clinical studies investigating the effect of known inhibitors of cytochromes P450 3A4 (e.g., ketoconazole, erythromycin) or 2C9 (e.g., fluconazole) on montelukast pharmacokinetics have not been conducted. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6 (see Drug Interactions ). However, in vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8 (see Drug Interactions ).
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 2.7 to 5.5 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%).
Gender: The pharmacokinetics of montelukast are similar in males and females.
Elderly: 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.
Race: Pharmacokinetic differences due to race have not been studied.
Hepatic Insufficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% (90% Cl=7%, 85%) higher mean montelukast area under the plasma concentration curve (AUC) following a single 10-mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of SINGULAIR in patients with more severe hepatic impairment or with hepatitis have not been evaluated.
Renal Insufficiency: 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.
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 (4296 ng·hr/mL [range 1200 to 7153]) was 60% higher and the mean C max (667 ng/mL [range 201 to 1058]) was 89% higher than those observed in adults (mean AUC 2689 ng·hr/mL [range 1521 to 4595]) and mean C max (353 ng/mL [range 180 to 548]). The systemic exposure in children 12 to 23 months of age was less variable, but was still higher than that observed in adults. The mean AUC (3574 ng·hr/mL [range 2229 to 5408]) was 33% higher and the mean C max (562 ng/mL [range 296 to 814]) was 60% higher than those observed in adults. Safety and tolerability of montelukast in a single-dose pharmacokinetic study in 26 children 6 to 23 months of age were similar to that of patients two years and above (see ADVERSE REACTIONS ). The 4-mg oral granule formulation should be used for pediatric patients 12 to 23 months of age for the treatment of asthma, or for pediatric patients 6 to 23 months of age for the treatment of perennial allergic rhinitis. Since the 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet, it can also be used as an alternative formulation to the 4-mg chewable tablet in pediatric patients 2 to 5 years of age.
Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state:
Montelukast at doses of >/=100 mg daily dosed to pharmacokinetic steady state:
Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for SINGULAIR is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with SINGULAIR.
Montelukast is a potent inhibitor of P450 2C8, but no in vivo drug interaction studies have been conducted between montelukast and cytochrome P450 2C8 substrates. Caution should be exercised when concomitantly administering a cytochrome P450 2C8 substrate, such as paclitaxel, rosiglitazone, and repaglinide.
Montelukast causes inhibition of airway cysteinyl leuko-triene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD 4 in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD 4 -induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), SINGULAIR inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.
The effect of SINGULAIR on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received SINGULAIR, 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 SINGULAIR, 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 SINGULAIR. The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known (see CLINICAL PHARMACOLOGY , Clinical Studies ).
There have been no clinical trials in asthmatics 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. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion.
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. This was shown in two chronic asthma trials using doses up to 200 mg once daily and in one exercise challenge study using doses up to 50 mg, evaluated at the end of the once-daily dosing interval.
The efficacy of SINGULAIR 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 SINGULAIR, 530 treated with placebo, and 251 treated with active control). The patients studied were mild and moderate, non-smoking asthmatics 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 ) of 66% (approximate range, 40 to 90%). The co-primary endpoints in these trials were FEV 1 and daytime asthma symptoms. Secondary endpoints included morning and evening peak expiratory flow rates (AM PEFR, PM PEFR), rescue (beta)-agonist requirements, nocturnal awakening due to asthma, and other asthma-related outcomes. In both studies after 12 weeks, a random subset of patients receiving SINGULAIR 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, FEV 1 , expressed as mean percent change from baseline, are shown in FIGURE 1.
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The effect of SINGULAIR on other primary and secondary endpoints is shown in TABLE 1 as combined analyses of the U.S. and Multinational trials.
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In adult patients, SINGULAIR reduced "as-needed" (beta)-agonist use by 26.1% from baseline compared with 4.6% for placebo. In patients with nocturnal awakenings of at least 2 nights per week, SINGULAIR reduced the nocturnal awakenings by 34% from baseline, compared with 15% for placebo (combined analysis).
SINGULAIR, compared with placebo, significantly improved other protocol-defined, asthma-related outcome measurements (see TABLE 2).
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In one of these trials, a non-U.S. formulation of inhaled beclomethasone dipropionate dosed at 200 mcg (two puffs of 100 mcg ex-valve) twice daily with a spacer device was included as an active control. Over the 12-week treatment period, the mean percentage change in FEV 1 over baseline for SINGULAIR and beclomethasone were 7.49% vs 13.3% (p<0.001) respectively, see FIGURE 2; and the change in daytime symptom scores was -0.49 vs -0.70 on a 0 to 6 scale (p<0.001) for SINGULAIR and beclomethasone, respectively. The percentages of individual patients treated with SINGULAIR or beclomethasone achieving any given percentage change in FEV 1 from baseline are shown in FIGURE 3.
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In each placebo-controlled trial in adults, the treatment effect of SINGULAIR, 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 SINGULAIR in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma.
The efficacy of SINGULAIR 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 SINGULAIR 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 of 72% (approximate range, 45 to 90%) and a mean daily inhaled (beta)-agonist requirement of 3.4 puffs of albuterol. Approximately 36% of the patients were on inhaled corticosteroids.
Compared with placebo, treatment with one 5-mg SINGULAIR chewable tablet daily resulted in a significant improvement in mean morning FEV 1 percent change from baseline (8.7% in the group treated with SINGULAIR 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 (beta)-agonist use (11.7% decrease from baseline in the group treated with SINGULAIR 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.
SINGULAIR, one 5-mg chewable tablet daily at bedtime, significantly decreased the percent of days asthma exacerbations occurred (SINGULAIR 20.6% vs placebo 25.7%, p</=0.05). (See TABLE 2 for definition of asthma exacerbation.) Parents' global asthma evaluations (parental evaluations of the patients' asthma, see TABLE 2 for definition of score) were significantly better with SINGULAIR compared with placebo (SINGULAIR 1.34 vs placebo 1.69, p</=0.05).
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.
The efficacy of SINGULAIR 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 SINGULAIR. While the primary objective was to determine the safety and tolerability of SINGULAIR 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 SINGULAIR is efficacious in the maintenance treatment of asthma in patients 2 to 5 years of age.
Separate trials in adults evaluated the ability of SINGULAIR 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 stable asthmatic adults with a mean FEV 1 of approximately 84% of predicted who were previously maintained on various inhaled corticosteroids (delivered by metered-dose aerosol or dry powder inhalers). 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 SINGULAIR 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). Approximately 40% of the montelukast-treated patients and 29% of the placebo-treated patients could be tapered off inhaled corticosteroids and remained off inhaled corticosteroids at the conclusion of the study (p=NS). It is not known whether the results of this study can be generalized to asthmatics 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 SINGULAIR to beclomethasone resulted in statistically significant improvements in FEV 1 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 SINGULAIR alone or placebo alone as indicated by FEV 1 , daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and "as-needed" (beta)-agonist requirements.
In adult asthmatic patients 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 SINGULAIR, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of SINGULAIR in aspirin-sensitive patients was similar to the effect observed in the general population of asthmatic patients studied. The effect of SINGULAIR on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated (see PRECAUTIONS , General ).
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 percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with SINGULAIR, 10 mg, once daily in the evening, resulted in a statistically significant reduction in mean maximal percent fall in FEV 1 and mean time to recovery to within 5% of the pre-exercise FEV 1 . 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. SINGULAIR did not, however, prevent clinically significant deterioration in maximal percent fall in FEV 1 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 SINGULAIR.
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).
SINGULAIR should not be used as monotherapy for the treatment and management of exercise-induced bronchospasm. Patients who have exacerbations of asthma after exercise should continue to use their usual regimen of inhaled (beta)-agonists as prophylaxis and have available for rescue a short-acting inhaled (beta)-agonist (see PRECAUTIONS , General and Information for Patients ).
The efficacy of SINGULAIR 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 SINGULAIR 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 SINGULAIR 10-mg tablets compared with placebo. The efficacy results of one trial are shown below; the remaining three trials that demonstrated efficacy showed similar results. The mean changes from baseline in daytime nasal symptoms score in the treatment groups that received SINGULAIR tablets, loratadine and placebo are shown in TABLE 3.
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The efficacy of SINGULAIR 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 SINGULAIR 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, SINGULAIR 10-mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6-week treatment period (TABLE 4); 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).
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The other 6-week study evaluated SINGULAIR 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 SINGULAIR vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between SINGULAIR and the active-control. The primary outcome variable included nasal itching in addition to nasal congestion, rhinorrhea, and sneezing. The estimated difference between SINGULAIR 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).
SINGULAIR is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older.
SINGULAIR is indicated for the relief of symptoms of allergic rhinitis (seasonal allergic rhinitis in adults and pediatric patients 2 years of age and older, and perennial allergic rhinitis in adults and pediatric patients 6 months of age and older).
Hypersensitivity to any component of this product.
SINGULAIR is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus.
Patients should be advised to have appropriate rescue medication available. Therapy with SINGULAIR can be continued during acute exacerbations of asthma.
While the dose of inhaled corticosteroid may be re-duced gradually under medical supervision, SINGULAIR should not be abruptly substituted for inhaled or oral corticosteroids.
SINGULAIR should not be used as monotherapy for the treatment and management of exercise-induced bronchospasm. Patients who have exacerbations of asthma after exercise should continue to use their usual regimen of inhaled (beta)-agonists as prophylaxis and have available for rescue a short-acting inhaled (beta)-agonist.
Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking SINGULAIR. Although SINGULAIR 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 PHARMACOLOGY , Clinical Studies ).
In rare cases, patients with asthma on therapy with SINGULAIR 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 SINGULAIR and these underlying conditions has not been established (see ADVERSE REACTIONS ).
SINGULAIR 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, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin.
Although additional specific interaction studies were not performed, SINGULAIR 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.
Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for SINGULAIR is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with SINGULAIR.
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 area under the plasma concentration versus time curve (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 mouse bone marrow chromosomal aberration assay.
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).
No teratogenicity was observed in rats at oral doses up to 400 mg/kg/day (estimated exposure was approximately 100 times the AUC for adults at the maximum recommended daily oral dose) and in rabbits at oral doses up to 300 mg/kg/day (estimated exposure was approximately 110 times the AUC for adults at the maximum recommended daily oral dose). Montelukast crosses the placenta following oral dosing in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, SINGULAIR should be used during pregnancy only if clearly needed.
Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women exposed to SINGULAIR while pregnant. Healthcare providers are encouraged to report any prenatal exposure to SINGULAIR by calling the Pregnancy Registry at (800) 986-8999.
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 SINGULAIR is given to a nursing mother.
Safety and efficacy of SINGULAIR 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 Clinical Studies and ADVERSE REACTIONS .)
The efficacy of SINGULAIR 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 6 months 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 SINGULAIR 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 ). Efficacy of SINGULAIR 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 SINGULAIR 4-mg oral granules in pediatric patients 12 to 23 months of age with asthma has been demonstrated in an analysis of 172 pediatric patients, 124 of whom were treated with SINGULAIR, in a 6-week, double-blind, placebo-controlled study (see ADVERSE REACTIONS ). Efficacy of SINGULAIR in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma based on similar mean systemic exposure (AUC), and that the disease course, pathophysiology and the drug's effect are substantially similar among these populations, supported by efficacy data from a safety trial in which efficacy was an exploratory assessment.
The safety of SINGULAIR 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 ). The safety of SINGULAIR 4-mg oral granules in pediatric patients as young as 6 months of age with perennial allergic rhinitis is supported by extrapolation from safety data obtained from studies conducted in pediatric patients 6 months to 23 months of age with asthma and from pharmacokinetic data comparing systemic exposures in patients 6 months to 23 months of age to systemic exposures in adults.
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. Long-term trials evaluating the effect of chronic administration of SINGULAIR on linear growth in pediatric patients have not been conducted.
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.
SINGULAIR has been evaluated for safety in approximately 2600 adult and adolescent patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with SINGULAIR occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo, regardless of causality assessment:
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The frequency of less common adverse events was comparable between SINGULAIR and placebo.
Cumulatively, 569 patients were treated with SINGULAIR for at least 6 months, 480 for one year, and 49 for two years in clinical trials. With prolonged treatment, the adverse experience profile did not significantly change.
SINGULAIR has been evaluated for safety in 321 pediatric patients 6 to 14 years of age. Cumulatively, 169 pediatric patients were treated with SINGULAIR for at least 6 months, and 121 for one year or longer in clinical trials. The safety profile of SINGULAIR in the 8-week, double-blind, pediatric efficacy trial was generally similar to the adult safety profile. In pediatric patients 6 to 14 years of age receiving SINGULAIR, the following events occurred with a frequency >/=2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: pharyngitis, influenza, fever, sinusitis, nausea, diarrhea, dyspepsia, otitis, viral infection, and laryngitis. The frequency of less common adverse events was comparable between SINGULAIR and placebo. With prolonged treatment, the adverse experience profile did not significantly change.
SINGULAIR 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 SINGULAIR for at least 3 months, 230 for 6 months or longer, and 63 patients for one year or longer in clinical trials. SINGULAIR 4 mg administered once daily at bedtime was generally well tolerated in clinical trials. In pediatric patients 2 to 5 years of age receiving SINGULAIR, the following events occurred with a frequency >/=2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis.
Safety and effectiveness in pediatric patients younger than 12 months of age with asthma have not been established.
SINGULAIR has been evaluated for safety in 175 pediatric patients 6 to 23 months of age. The safety profile of SINGULAIR in a 6-week, double-blind, placebo-controlled clinical study was generally similar to the safety profile in adults and pediatric patients 2 to 14 years of age. SINGULAIR administered once daily at bedtime was generally well tolerated. In pediatric patients 6 to 23 months of age receiving SINGULAIR, the following events occurred with a frequency >/=2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: upper respiratory infection, wheezing; otitis media; pharyngitis, tonsillitis, cough; and rhinitis. The frequency of less common adverse events was comparable between SINGULAIR and placebo.
SINGULAIR has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. SINGULAIR administered once daily in the morning or in the evening was generally well tolerated with a safety profile similar to that of placebo. In placebo-controlled clinical trials, the following event was reported with SINGULAIR with a frequency >/=1% and at an incidence greater than placebo, regardless of causality assessment: upper respiratory infection, 1.9% of patients receiving SINGULAIR vs. 1.5% of patients receiving placebo. In a 4-week, placebo-controlled clinical study, the safety profile was consistent with that observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies.
SINGULAIR 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. SINGULAIR administered once daily in the evening was generally well tolerated with a safety profile similar to that of placebo. In this study, the following events occurred with a frequency >/=2% and at an incidence greater than placebo, regardless of causality assessment: headache, otitis media, pharyngitis, and upper respiratory infection.
SINGULAIR has been evaluated for safety in 3357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1632 received SINGULAIR in two, 6-week, clinical studies. SINGULAIR administered once daily was generally well tolerated, with 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 events were reported with SINGULAIR with a frequency >/=1% and at an incidence greater than placebo, regardless of causality assessment: sinusitis, upper respiratory infection, sinus headache, cough, epistaxis, and increased ALT. The incidence of somnolence was similar to that of placebo.
The safety in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the established 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 additional adverse reactions have been reported in post-marketing use: hypersensitivity reactions (including anaphylaxis, angioedema, pruritus, urticaria, and very rarely, hepatic eosinophilic infiltration); dream abnormalities and hallucinations, drowsiness, irritability, agitation including aggressive behavior, restlessness, insomnia, paraesthesia/hypoesthesia, and very rarely seizures; arthralgia, myalgia including muscle cramps; increased bleeding tendency, bruising; palpitations; edema; nausea, vomiting, dyspepsia, diarrhea, and very rarely pancreatitis. Rare cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with SINGULAIR. Most of these occurred in combination with other confounding factors, such as use of other medications, or when SINGULAIR was administered to patients who had underlying potential for liver disease such as alcohol use or other forms of hepatitis.
In rare cases, patients with asthma on therapy with SINGULAIR 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 SINGULAIR and these underlying conditions has not been established (see PRECAUTIONS , Eosinophilic Conditions ).
No mortality occurred following single oral doses of montelukast up to 5000 mg/kg in mice (estimated exposure was approximately 335 and 210 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose) and rats (estimated exposure was approximately 230 and 145 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose).
No specific information is available on the treatment of overdosage with SINGULAIR. 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 pediatric patients in post-marketing experience and clinical studies of up to at least 150 mg/day with SINGULAIR. The clinical and laboratory findings observed were consistent with the safety profile in adults and older pediatric patients. There were no adverse experiences reported in the majority of overdosage reports. The most frequent adverse experiences observed were thirst, somnolence, mydriasis, hyperkinesia, and abdominal pain.
It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.
SINGULAIR should be taken once daily. For asthma, the dose should be taken in the evening. For allergic rhinitis, the time of administration may be individualized to suit patient needs.
Patients with both asthma and allergic rhinitis should take only one tablet daily in the evening.
The dosage for adults and adolescents 15 years of age and older is one 10-mg tablet daily.
The dosage for pediatric patients 6 to 14 years of age is one 5-mg chewable tablet daily. No dosage adjustment within this age group is necessary.
The dosage for pediatric patients 2 to 5 years of age is one 4-mg chewable tablet or one packet of 4-mg oral granules daily.
The dosage for pediatric patients 12 to 23 months of age is one packet of 4-mg oral granules daily to be taken in the evening.
The dosage for pediatric patients 6 to 23 months of age is one packet of 4-mg oral granules daily.
Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis and in patients less than 12 months of age with asthma have not been established.
SINGULAIR 4-mg oral granules can be administered either directly in the mouth, dissolved in 1 teaspoonful (5 mL) of cold or room temperature baby formula or breast milk, or mixed with a spoonful of cold or room temperature soft foods; based on stability studies, only applesauce, carrots, rice, or ice cream should be used. The packet should not be opened until ready to use. After opening the packet, the full dose (with or without mixing with baby formula, breast milk, or food) must be administered within 15 minutes. If mixed with baby formula, breast milk, or food, SINGULAIR oral granules must not be stored for future use. Discard any unused portion. SINGULAIR oral granules are not intended to be dissolved in any liquid other than baby formula or breast milk for administration. However, liquids may be taken subsequent to administration. SINGULAIR oral granules can be administered without regard to the time of meals.
No. 3841--SINGULAIR Oral Granules, 4 mg, are white granules with 500 mg net weight, packed in a child-resistant foil packet. They are supplied as follows:
NDC 0006-3841-30 unit of use carton with 30 packets.
No. 3796--SINGULAIR Tablets, 4 mg, are pink, oval, bi-convex-shaped chewable tablets, with code MRK 711 on one side and SINGULAIR on the other. They are supplied as follows:
NDC 0006-0711-31 unit of use high-density polyethylene (HDPE) bottles of 30 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant
NDC 0006-0711-54 unit of use high-density polyethylene (HDPE) bottles of 90 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant
NDC 0006-0711-28 unit dose paper and aluminum foil-backed aluminum foil peelable blister packs of 100.
No. 3760--SINGULAIR Tablets, 5 mg, are pink, round, bi-convex-shaped chewable tablets, with code MRK 275 on one side and SINGULAIR on the other. They are supplied as follows:
NDC 0006-0275-31 unit of use high-density polyethylene (HDPE) bottles of 30 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant
NDC 0006-0275-54 unit of use high-density polyethylene (HDPE) bottles of 90 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant
NDC 0006-0275-28 unit dose paper and aluminum foil-backed aluminum foil peelable blister packs of 100.
No. 3761--SINGULAIR Tablets, 10 mg, are beige, rounded square-shaped, film-coated tablets, with code MRK 117 on one side and SINGULAIR on the other. They are supplied as follows:
NDC 0006-0117-31 unit of use high-density polyethylene (HDPE) bottles of 30 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant
NDC 0006-0117-54 unit of use high-density polyethylene (HDPE) bottles of 90 with a polypropylene child-resistant cap, an aluminum foil induction seal, and silica gel desiccant
NDC 0006-0117-28 unit dose paper and aluminum foil-backed aluminum foil peelable blister pack of 100
NDC 0006-0117-80 bulk packaging high-density polyethylene (HDPE) bottles of 8000 with a non-child-resistant white plastic closure with a wax paper/pulp liner, an aluminum foil induction seal, and silica gel desiccant.
Store SINGULAIR 4-mg oral granules, 4-mg chewable tablets, 5-mg chewable tablets and 10-mg film-coated tablets at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. Store in original package.
Store bottle of 8000 SINGULAIR 10-mg film-coated tablets at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. Store in original container. When product container is subdivided, repackage into a well-closed, light-resistant container.
9088824 Issued July 2005
COPYRIGHT © MERCK & CO., INC., 1998-2005
All rights reserved
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SINGULAIR® (SING-u-lair) Tablets, Chewable Tablets, and Oral Granules
Generic name: montelukast (mon-te-LOO-kast) sodium
Read this information before you start taking SINGULAIR®. Also, read the leaflet you get each time you refill SINGULAIR, since there may be new information in the leaflet since the last time you saw it. This leaflet does not take the place of talking with your doctor about your medical condition and/or your treatment.
SINGULAIR is prescribed for the treatment of asthma and allergic rhinitis:
Do not take SINGULAIR if you are allergic to SINGULAIR or any of its ingredients.
The active ingredient in SINGULAIR is montelukast sodium.
See the end of this leaflet for a list of all the ingredients in SINGULAIR.
Tell your doctor about:
For adults and children 12 months of age and older with asthma:
For adults and children 2 years of age and older with seasonal allergic rhinitis, or for adults and children 6 months of age and older with perennial allergic rhinitis:
Do not open the packet until ready to use.
SINGULAIR 4-mg oral granules can be given:
Be sure that the entire dose is mixed with the food, baby formula, or breast milk and that the child is given the entire spoonful of the food, baby formula, or breast milk mixture right away (within 15 minutes).
IMPORTANT: Never store any oral granules mixed with food, baby formula, or breast milk for use at a later time. Throw away any unused portion.
Do not put SINGULAIR oral granules in any liquid drink other than baby formula or breast milk. However, your child may drink liquids after swallowing the SINGULAIR oral granules.
If you have asthma and if your asthma is made worse by aspirin, continue to avoid aspirin or other medicines called non-steroidal anti-inflammatory drugs while taking SINGULAIR.
The side effects of SINGULAIR are usually mild, and generally did not cause patients to stop taking their medicine. The side effects in patients treated with SINGULAIR were similar in type and frequency to side effects in patients who were given a placebo (a pill containing no medicine).
The most common side effects with SINGULAIR include:
Less common side effects that have happened with SINGULAIR include (listed alphabetically):
agitation including aggressive behavior, allergic reactions (including swelling of the face, lips, tongue, and/or throat, which may cause trouble breathing or swallowing), hives, and itching, bad/vivid dreams, increased bleeding tendency, bruising, diarrhea, drowsiness, hallucinations (seeing things that are not there), hepatitis, indigestion, inflammation of the pancreas, irritability, joint pain, muscle aches and muscle cramps, nausea, palpitations, pins and needles/numbness, restlessness, seizures (convulsions or fits), swelling, trouble sleeping, and vomiting.
Rarely, asthmatic patients taking SINGULAIR have experienced a condition that includes certain symptoms that do not go away or that get worse. These occur usually, but not always, in patients who were taking steroid pills by mouth for asthma and those steroids were being slowly lowered or stopped. Although SINGULAIR has not been shown to cause this condition, you must tell your doctor right away if you get one or more of these symptoms:
These are not all the possible side effects of SINGULAIR. For more information ask your doctor or pharmacist.
Talk to your doctor if you think you have side effects from taking SINGULAIR.
General Information about the safe and effective use of SINGULAIR
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use SINGULAIR for a condition for which it was not prescribed. Do not give SINGULAIR to other people even if they have the same symptoms you have. It may harm them. Keep SINGULAIR and all medicines out of the reach of children.
Store SINGULAIR at 25°C (77°F). Protect from moisture and light. Store in original package.
This leaflet summarizes information about SINGULAIR. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about SINGULAIR that is written for health professionals.
Active ingredient: montelukast sodium
SINGULAIR chewable tablets contain aspartame, a source of phenylalanine.
Phenylketonurics: SINGULAIR 4-mg and 5-mg chewable tablets contain 0.674 and 0.842 mg phenylalanine, respectively.
Inactive ingredients:
Asthma is a continuing (chronic) inflammation of the bronchial passageways which are the tubes that carry air from outside the body to the lungs.
Rx only
9094218 Issued July 2005
COPYRIGHT © MERCK & CO., INC., 1998-2005
All rights reserved