Montelukast Sodium (Page 4 of 8)

10 OVERDOSAGE

No specific information is available on the treatment of overdosage with montelukast sodium. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.

11 DESCRIPTION

Montelukast sodium, the active ingredient in montelukast sodium tablets, 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:

image of chemical structure
(click image for full-size original)

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, USP contains 10.4 mg montelukast sodium, USP, which is equivalent to 10 mg of montelukast, and the following inactive ingredients: microcelac 100, croscarmellose sodium, low substituted hydroxypropyl cellulose, and magnesium stearate. The film coating consists of hypromellose, hydroxypropyl cellulose, titanium dioxide, polyethylene glycol 6000, iron oxide red and iron oxide yellow.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

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 β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD 4 at the CysLT 1 receptor without any agonist activity.

12.2 Pharmacodynamics

Montelukast causes inhibition of airway cysteinyl leukotriene 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), montelukast sodium inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.

The effect of montelukast sodium on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received montelukast sodium, a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received montelukast sodium, a mean increase of 0.2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12.5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12.3% in favor of montelukast sodium. The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known [see Clinical Studies (14)].

12.3 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.

The safety and effectiveness of montelukast sodium in patients with asthma were demonstrated in clinical trials in which the 10-mg film-coated tablet and 5-mg chewable tablet formulations were administered in the evening without regard to the time of food ingestion. The safety of montelukast sodium in patients with asthma was also demonstrated in clinical trials in which the 4 mg chewable tablet and 4 mg oral granule formulations were administered in the evening without regard to the time of food ingestion. The safety and effectiveness of montelukast sodium in patients with seasonal allergic rhinitis were demonstrated in clinical trials in which the 10-mg film-coated tablet was administered in the morning or evening without regard to the time of food ingestion.

The comparative pharmacokinetics of montelukast when administered as two 5 mg chewable tablets versus one 10 mg film-coated tablet have not been evaluated.

Distribution

Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages 8 to 11 liters. Orally administered montelukast distributes into the brain in rats.

Elimination

The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.

In several studies, the mean plasma half-life of montelukast ranged from 2.7 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%).

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 CYP3A4, 2C8 and 2C9 are involved in the metabolism of montelukast. At clinically relevant concentrations, 2C8 appears to play a major role in the metabolism of montelukast.

Specific Populations

Patients with Hepatic Impairment
Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% (90% CI=7%, 85%) higher mean montelukast AUC following a single 10-mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of montelukast sodium in patients with more severe hepatic impairment or with hepatitis have not been evaluated.

Patients with Renal Impairment
Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients.

Male and Female Patients
The pharmacokinetics of montelukast are similar in males and females.

Racial Groups
Pharmacokinetic differences due to race have not been studied.

Adolescents and Pediatric Patients
Pharmacokinetic studies evaluated the systemic exposure of the 4-mg oral granule formulation in pediatric patients 6 to 23 months of age, the 4 mg chewable tablets in pediatric patients 2 to 5 years of age, the 5 mg chewable tablets in pediatric patients 6 to 14 years of age, and the 10-mg film-coated tablets in young adults and adolescents ≥15 years of age.

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

Drug Interaction Studies

Theophylline, Prednisone, and Prednisolone
Montelukast sodium has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, and prednisolone.

Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state, did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline [predominantly a cytochrome P450 (CYP) 1A2 substrate]. Montelukast at doses of ≥100 mg daily dosed to pharmacokinetic steady state, did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone.

Oral Contraceptives, fexofenadine, Digoxin, and Warfarin
In drug interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), digoxin, and warfarin. Montelukast at doses of ≥100 mg daily dosed to pharmacokinetic steady state did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of fexofenadine, did not change did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP2C9, 3A4 and 1A2) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the International Normalized Ratio (INR).

Thyroid Hormones, Sedative Hypnotics, Non-Steroidal Anti-Inflammatory Agents, Benzodiazepines, and Decongestants
Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants.

Cytochrome P450 (CYP) Enzyme Inducers
Phenobarbital, which induces hepatic metabolism, decreased the area under the plasma concentration curve (AUC) of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast sodium is recommended. It is reasonable to employ appropriate clinical monitoring when potent CYP enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast sodium.

Effect of Montelukast on Cytochrome P450 (CYP) Enzymes
Montelukast is a potent inhibitor of CYP2C8 in vitro. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative 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). Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit CYP 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.

Cytochrome P450 (CYP) Enzyme Inhibitors In vitro studies have shown that montelukast is a substrate of CYP 2C8, 2C9, and 3A4. Co-administration of montelukast with itraconazole, a strong CYP 3A4 inhibitor, resulted in no significant increase in the systemic exposure of montelukast. Data from a clinical clinical drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8, and 2C9) demonstrated that gemfibrozil, at a therapeutic dose, increased the systemic exposure of montelukast by 4.4-fold. Co-administration of itraconazole, gemfibrozil, and montelukast did not further increase the systemic exposure of montelukast. Based on available clinical experience, no dosage adjustment of montelukast is required upon co-administration with gemfibrozil [see Overdosage (10)]

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