9628411 SINGULAIR®
(MONTELUKAST SODIUM)
TABLETS, CHEWABLE TABLETS, AND ORAL GRANULES
DESCRIPTION
Montelukast sodium, the active ingredient in SINGULAIR*, is a lective 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 empirical formula is C35H35ClNNaO3S, and its molecular weight is 608.18. The structural formula
is:
N Cl S C OO
-
Na+
HO
H3C
H3
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 cellulo, lacto monohydrate, croscarmello sodium, hydroxypropyl cellulo, and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulo, hydroxypropyl cellulo, 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 cellulo, hydroxypropyl cellulo, red ferric oxide, croscarmello 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 cellulo, and magnesium stearate.
CLINICAL PHARMACOLOGY
Mechanism of Action
The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are relead from various cells, including mast cells and eosinophils. The 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 correlat
ed 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 relead from the nasal mucosa after allergen exposure during both early- and late-pha reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increa nasal airway resistance and symptoms of nasal obstruction. * Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1998-2007 MERCK & CO., Inc.
All rights rerved
SINGULAIR has not been assd 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 lectivity 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.
Pharmacokinetics
Absorption
Montelukast is rapidly absorbed following oral administration. After administration of the 10-mg film-coated tablet to fasted adults, the mean peak montelukast plasma concentration (C max) 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 decread 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 asonal 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.
markup是什么意思The comparative pharmacokinetics of montelukast when administered as two 5-mg chewable tablets versus one 10-mg film-coated tablet have not been evaluated.
Distribution
Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages 8 to 11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdo were minimal in all other tissues.
银箔
Metabolism
Montelukast is extensively metabolized. In studies with therapeutic dos, 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. Bad 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 (e Drug Interactions). In vitro studies have shown that montelukast is a potent inhibitor of cytochrome P450 2C8; however, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate reprentative of drugs primarily metabolized by CYP2C8) demonstrated that montelukast does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e Drug Interactions).
Elimination
The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral do 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 veral 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 dos up to 50 mg. During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (14%). Special Populations
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 do 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.las
简奥斯丁的遗憾
Hepatic Insufficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decread metabolism of montelukast resulting in 41% (90% CI=7%, 85%) higher mean montelukast area under the plasma concentration curve (AUC) following a single 10-mg do. 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 vere 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 the 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 ta
timezoneblet is similar in adolescents ≥15 years of age and young adults. The 10-mg film-coated tablet is recommended for u in patients ≥15 years of age.species
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 ud in pediatric patients 6 to 14 years of age and the 4-mg chewable tablet should be ud 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 tho obrved in adults. Bad on population analys, 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 tho obrved 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 obrved 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 tho obrved in adults. Safety and tolerability of montelukast in a single-do pharmacokinetic study in 26 children 6 to 23 months
of age were similar to that of patients two years and above (e ADVERSE REACTIONS). The 4-mg oral granule formulation should be ud 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 ud as an alternative formulation to the 4-mg chewable tablet in pediatric patients 2 to 5 years of age.
Drug Interactions
Montelukast at a do of 10 mg once daily dod to pharmacokinetic steady state:
• did not cau clinically significant changes in the kinetics of a single intravenous do of theophylline (predominantly a cytochrome P450 1A2 substrate).
• did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP 2C9, 3A4 and 1A2) or influence the effect of a single 30-mg oral do of warfarin on prothrombin time or the INR (International Normalized Ratio).
• did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin.
• did not change the plasma concentration profile of terfenadine (a substrate of CYP 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following coadministration with terfenadine 60 mg twice daily.照例
Montelukast at dos of ≥100 mg daily dod to pharmacokinetic steady state:
• did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg.
• did not cau any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone.
Phenobarbital, which induces hepatic metabolism, decread the AUC of montelukast approximately 40% following a single 10-mg do 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 in vitro. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate reprentative of drugs
primarily metabolized by CYP2C8) in 12 healthy individuals demonstrated that the pharmacokinetics of rosiglitazone are not altered when the drugs are coadministered, indicating that montelukast does not inhibit CYP2C8 in vivo. Therefore, montelukast is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide.)
Pharmacodynamics
Montelukast caus inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics. Dos as low as 5 mg cau substantial blockage of LTD4-induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), SINGULAIR inhibited early- and late-pha 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 decrea 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 asonal allergic rhinitis aged 15 years and older who received SINGULAIR, a mean increa of 0.2% in peripheral blood eosinophil counts was noted,
compared with a mean increa 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 the obrvations and the clinical benefits of montelukast noted in the clinical trials is not known (e CLINICAL PHARMACOLOGY, Clinical Studies).
Clinical Studies
GENERAL
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 dod 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 asonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. Clinical Studies – Asthmabrow
ADULTS AND ADOLESCENTS 15 YEARS OF AGE AND OLDER
Clinical trials in adults and adolescents 15 years of age and older demonstrated there is no additiona
l clinical benefit to montelukast dos above 10 mg once daily. This was shown in two chronic asthma trials using dos up to 200 mg once daily and in one exerci challenge study using dos 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 β-agonist per day on an “asneeded” basis. The patients had a mean baline percent of predicted forced expiratory volume in 1 cond (FEV1) of 66% (approximate range, 40 to 90%). The co-primary endpoints in the trials were
SINGULAIR Placebo FEV 1 and daytime asthma symptoms. Secondary endpoints included morning and evening peak expiratory flow rates (AM PEFR, PM PEFR), rescue β-agonist requirements, nocturnal awakening due to asthma, and other asthma-related outcomes. In both studies after 12 weeks, a random subt 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. tri
al on the primary endpoint, FEV 1, expresd as mean percent change from baline, are shown in FIGURE 1. FIGURE 1 FEV 1 Mean Percent Change from Baline
(U.S. Trial) The effect of SINGULAIR on other primary and condary endpoints is shown in TABLE 1 as combined analys of the U.S. and Multinational trials. TABLE 1
aisiaEffect of SINGULAIR on Primary and Secondary Endpoints
in Placebo-controlled Trials
(Combined Analys - U.S. and Multinational Trials) SINGULAIR Placebo
Endpoint Baline Mean Change from Baline Baline Mean Change from Baline Daytime Asthma Symptoms (0 to 6 scale) 2.43 -0.45* 2.45 -0.22 β-agonist (puffs per day) 5.38 -1.56* 5.55 -0.41 AM PEFR (L/min) 361.3 24.5* 364.9 3.3 PM PEFR (L/min) 385.2 17.9* 389.3 2.0 Nocturnal Awakenings (#/week) 5.37 -1.84* 5.44 -0.79 * p<0.001, compared with placebo
In adult patients, SINGULAIR reduced “as-needed” β-agonist u by 26.1% from baline 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 baline, compared with 15% for placebo (combined analysis).预约报名
SINGULAIR, compared with placebo, significantly improved other protocol-defined, asthma-related outcome measurements (e TABLE 2). TABLE 2 Effect of SINGULAIR on Asthma-Related Outcome Measurements (Combined Analys - U.S. and Multinational Trials)
