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Pharmacology: Montelukast: The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important mediators bind to cysteinyl leukotriene receptors. Cysteinyl leukotriene have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene mediated effects include bronchoconstriction, mucous secretion, vascular permeability and eosinophil recruitment. In allergic rhinitis, cysteinyl leukotrienes are released from nasal mucosa after allergen exposure during both early-and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with cysteinyl leukotrienes has been shown to increase nasal airway resistance and symptoms of nasal obstruction. Montelukast is an orally active compound which binds with high affinity and selectively to the cysteinyl leukotriene type 1 receptor thereby preventing cysteinyl leukotriene from exerting their effects.
Levocetirizine: Levocetirizine, the active enantiomer of cetirizine, is an antihistamine. Its principal effects are mediated via selective inhibition of H1 receptors. The antihistamine activity of Levocetirizine has been documented in a variety of animal and human models.
Pharmacokinetics: Montelukast: Absorption: Montelukast is rapidly absorbed following oral administration. Mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration of a 10 mg dose in adults in the fasted state. The mean oral bioavailability is 64%. The oral; bioavailability and (Cmax) are not influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10 mg film-coated was administered without regard to the timing of food ingestion. Cmax is achieved in 2 hours after administration of the 5 mg chewable tablet in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.
Distribution: Montelukast is more than 99% bound to plasma proteins. Steady-state volume of distribution of Montelukast averages 8-11 liters. Studies in rats with radio labeled Montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radio labeled material at 24 hours post dose were minimal in all other tissues.
Metabolism: Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of Montelukast are undetected at steady state in adults and children. In vitro studies using human liver microsomes indicate that cytochrome P450 3A4, 2A6 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, 2C10 or 2D6. The contribution of metabolites to the therapeutic effect of Montelukast is minimal.
Elimination: The plasma clearance of Montelukast averages 45 mL/min in healthy adults. Following an oral dose of radio labeled 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.
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. Due to the Levocetirizine component of Montelukast plus Levocetirizine however, dosage adjustment may be required in elderly patients (See Elderly under Dosage & Administration).
Patients with Renal Impairment: Since Montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of Montelukast was not evaluated in patients with renal insufficiency. Due to the Levocetirizine component of MONTELUKAST PLUS LEVOCETIRIZINE however, dosage adjustment is required in patients with renal impairment (See Patients with Renal Impairment under Dosage & Administration).
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% 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 Montelukast in patients with more severe hepatic impairment or with hepatitis has not been evaluated.
Levocetirizine: Absorption: Levocetirizine is rapidly and extensively absorbed following oral administration. Peak plasma concentrations are achieved 0.9 h after dosing. Steady state is achieved after two days. Peak concentrations are 270 ng/mL and 308 ng/mL following a single and repeated 5 mg dose once daily, respectively. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.
Distribution: No tissue distribution data are available in humans, neither concerning the passage of Levocetirizine through the blood-brain barrier. In rats and dogs, the highest tissue levels are found in liver and kidneys, the lowest in CNS compartment. Levocetirizine is 90% bound to plasma proteins. The distribution of Levocetirizine is restrictive, as the volume of distribution is 0.4 l/kg.
Metabolism: The extent of metabolism of Levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible.
Metabolic pathways include aromatic oxidation, N- and O-dealkylation and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose. Due to its low metabolism and absence of metabolic inhibition potential, the interaction of Levocetirizine with other substances, or vice-versa, is unlikely.
Elimination: The plasma half-life in adults is 7.9 ± 1.9 hours. The mean apparent total body clearance is 0.63 mL/min/kg. The major route of excretion of Levocetirizine and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.
Elderly: Limited pharmacokinetic data is available in elderly subjects. Following once daily repeated oral administration of 30 mg Levocetirizine for 6 days in 9 elderly subjects (74 - 75 years of age), the total body clearance was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine has been shown to be dependent on renal function rather than age. Therefore, the dosage of Levocetirizine should be adjusted in accordance with renal function in elderly patients.
Patients with Renal Impairment: The apparent body clearance of Levocetirizine is correlated to the creatinine clearance. It is therefore recommended to adjust the dosage and frequency of dosage of Levocetirizine, based on creatinine clearance in patients with moderate and severe renal impairment (See Dosage & Administration).
Patients with Hepatic Impairment: Levocetirizine has not been studied in patients with hepatic impairment. The non-renal clearance (indicative of hepatic contribution) was found to constitute about 28% of the total body clearance in healthy adult subjects after oral administration. As Levocetirizine is mainly excreted unchanged by the kidney, it is unlikely that the clearance of Levocetirizine is significantly decreased in patients solely with hepatic impairment.
