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SingulairSingulair

montelukast sodium, MSD

 

I. THERAPEUTIC CLASS

SINGULAIR (montelukast sodium) is a selective and orally active leukotriene receptor antagonist that specifically inhibits the cysteinyl leukotriene CysLT1 receptor.

 

II. INDICATIONS

For the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older. SINGULAIR is indicated in adults and pediatric patients 2 years of age and older for the relief of daytime and nighttime symptoms of seasonal allergic rhinitis.

 

Mechanism of Action

The cysteinyl leukotrienes (LTC4, LTD4, LTE4), are potent inflammatory eicosanoids released from various cells including most cells and eosinophils. These important pro-asthmatic mediators 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 a number of airway actions, including bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. In allergic rhinitis, CysLT 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 CysLT has been shown to increase nasal airway resistance and symptoms of nasal obstruction. Montelukast is a potent, orally active compound that significantly improves parameters of asthmatic inflammation. Based on biochemical and pharmacological bioassays, it binds with high affinity and selectivity to the CysLT, receptor (in preference to other pharmacologically important airway receptors such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast potently inhibits physiologic actions of LTC4, LTD4, and LTE4 at the CysLT1, receptor without any agonist activity.

 

III. DOSAGE AND ADMINISTRATION

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.

Adults 15 Years of Age and Older with Asthma and/or Seasonal Allergic Rhinitis

The dosage for adults 15 years of age and older is one 10-mg tablet daily.

Pediatric Patients 6 to 14 Years of Age with Asthma and/or Seasonal Allergic Rhinitis

The dosage for pediatric patients 6 to 14 years of age is one 5-mg chewable tablet daily.

Pediatric Patients 2 to 5 Years of Age with Asthma and/or Seasonal Allergic Rhinitis

The dosage for pediatric patients 2 to 5 years of age is one 4-mg chewable tablet daily or one packet of 4-mg oral granules daily.

Pediatric Patients 12 months to 2 Years of Age with Asthma

The dosage for pediatric patients 12 months to 2 years of age is one packet of 4-mg oral granules daily.

 

Administration of oral granules:

SINGULAIR oral granules can be administered either directly in the mouth, or mixed with a spoonful of cold or room temperature soft food (e.g., applesauce) or dissolved in 1 teaspoonful (5 mL) of cold or room temperature baby formula or breast milk. The packet should not be opened until ready to use. After opening the packet, the full dose of SINGULAIR oral granules must be administered immediately (within 15 minutes). If mixed with food or dissolved in baby formula or breast milk, SINGULAIR oral granules must not be stored for future use. 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.

 

General Recommendations

The therapeutic effect of SINGULAIR on parameters of asthma control occurs within one day. SINGULAIR tablets, chewable tablets, and oral granules can be taken with or without food. Patients should be advised to continue taking SINGULAIR while their asthma is controlled, as well as during periods of worsening asthma.

 

No dosage adjustment is necessary for pediatric patients, for the elderly, for patients with renal insufficiency, or mild-to-moderate hepatic impairment, or for patients of either gender.

 

Montelukast is a long term-controller medication which should not be substituted for short acting β-agonists. It is effective alone or in combination with other prophylactic agent.

 

Montelukast is a preventive agent, which should be used in addition to other drugs for the management of asthma.

 

Therapy with SINGULAIR in Relation to Other Treatments for Asthma

SINGULAIR can be added to a patient's existing treatment regimen.

Reduction in Concomitant Therapy:

Bronchodilator Treatments: SINGULAIR can be added to the treatment regimen of patients who are not adequately controlled on bronchodilator alone. When a clinical response is evident (usually after the first dose), the patient's bronchodilator therapy can be reduced as tolerated.

 

Inhaled Corticosteroids: Treatment with SINGULAIR provides additional clinical benefit to patients treated with inhaled corticosteroids. A reduction in the corticosteroid dose can be made as tolerated. The dose should be reduced gradually with medical supervision. In some patients, the dose of inhaled corticosteroids can be tapered off completely. SINGULAIR should not be abruptly substituted for inhaled corticosteroids.

IV CLINICAL PHARMACOLOGY

IVa. Pharmacokinetics

IVa-1. Absorption

Montelukast is rapidly and nearly completely absorbed following oral administration. For the 10-mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal.

 

For the 5-mg chewable tablet, the Cmax is achieved 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73%. Food does not have a clinically important influence with chronic administration.

 

For the 4-mg chewable tablet, Cmax 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 coadministration of applesauce or a standard meal with the oral granule formulation did not have a clinically meaningful effect on the pharmacokinetics of montelukast as determined by AUC (1225.7 vs 1223.1 ng•hr/mL with and without applesauce, respectively and 1191.8 vs 1148.5 ng•hr/mL with and without a standard meal, respectively).

 

Safety and efficacy were demonstrated in clinical studies where the 4-mg chewable tablet, 5-mg chewable tablet, and 10-mg filmcoated tablet were administered without regard to the timing of food ingestion. The safety of SINGULAIR was also demonstrated in a clinical study in which the 4-mg oral granules were administered without regard to the timing of food ingestion.

 

IVa-2. 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 postdose were minimal in all other tissues.

 

IVa -3. Metabolism

Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients. In vitro studies using human liver microsomes indicate that cytochrome P450 3A4 and 2C9 are involved in the metabolism of montelukast. 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.

 

IVa-4. Elimination

The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates 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. No difference in pharmacokinetics was noted between dosing in the morning or in the evening. During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (~14%).

 

The comparative pharmacokinetics of montelukast when administered as two 5-mg chewable tablets versus one 10-mg film-coated tablet have not been evaluated. Therefore these two products should not be used interchangeably.

 

IVa -5. Characteristics in Patients

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. In clinical studies, there do not appear to be any differences in clinically important effects.

 

Hepatic Insufficiency

Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in approximately 41% higher mean montelukast area under the plasma concentration curve (AUC) following a single 10-mg dose. The elimination of montelukast is 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. There are no clinical data in patients with severe hepatic insufficiency (Child-Pugh score > 9).

 

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

The plasma concentration profile of montelukast following the 10-mg film-coated tablet is similar in adolescents z15 years old and young adults. The 10-mg film-coated tablet is recommended for use in patients ≥15 years old.

 

Pharmacokinetic studies show that the plasma profiles of the 4-mg oral granule formulation in pediatric patients 6 months to 2 years of age, the 4-mg chewable tablet in pediatric patients 2 to 5 years of age, and the 5-mg chewable tablet in pediatric patients 6 to 14 years of age were similar to the plasma profile of the 10-mg film-coated tablet in adults.

 

IVb. Pharmacodynamics

Montelukast causes potent inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatic patients. Doses as low as 5-mg cause substantial blockage of LTD4-induced bronchoconstriction.

Montelukast causes bronchodilation within 2 hours of oral administration; these effects were additive to the bronchodilation caused by a β-agonist.

Clinical studies in adults 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 studies 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.

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