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Pharmacology: Loratadine is a potent long acting tricyclic antihistamine with selective peripheral H1-receptor antagonistic activity.
Human histamine skin wheal studies following single and repeated 10 mg oral doses of Loratadine have shown that the drug exhibits an antihistaminic effect beginning within 1 to 3 hours, reaching a maximum at 8 to 12 hours, and lasting in excess of 24 hours. There was no evidence of tolerance to this effect after 28 days of dosing with Loratadine.
Whole body autoradiographic studies in rats and monkeys, radiolabeled tissue distribution studies in mice and rats, and in vivo radioligand studies in mice have shown that neither Loratadine or its metabolites readily cross the blood-brain barrier. Radioligand binding studies with guinea pig pulmonary and brain H1-receptors indicate that there was preferential binding to peripheral versus central nervous system H1-receptors.
Repeated application of Loratadine rapidly disintegrating tablets to the hamster cheek pouch did not cause local irritation.
Pharmacokinetics: Loratadine was rapidly absorbed following oral administration of 10 mg tablets, once daily for 10 days to healthy adult volunteers with times to maximum concentration (Tmax) of 1.3 hours for Loratadine and 2.5 hours for its major active metabolite, descarboethoxyloratadine. Based on a cross-study comparison of single doses of Loratadine syrup and tablets given to healthy adult volunteers, the plasma concentration profile of descarboethoxyloratadine for the two formulations is comparable. The pharmacokinetics of Loratadine and descarboethoxyloratadine are independent of dose over the dose range of 10 to 40 mg and are not altered by the duration of treatment. In a single dose study, food increased the systemic bioavailability (AUC) of Loratadine and descarboethoxyloratadine by approximately 40% and 15%, respectively. The time to peak plasma concentration (Tmax) of Loratadine and descarboethoxyloratadine was delayed by 1 hour.
Peak plasma concentrations (Cmax) were not affected by food.
Pharmacokinetic studies showed that Loratadine rapidly disintegrating tablets provide plasma concentrations of Loratadine descarboethoxyloratadine similar to those achieved with Loratadine tablets. Following oral administration of 10 mg Loratadine once daily for 10 days with each dosage forms in a randomized crossover comparison in 24 normal adult subjects, similar mean exposures (AUC) and peak plasma concentrations (Cmax) of Loratadine were observed Loratadine rapidly disintegrating tablets mean AUC and Cmax were 11% and 6% greater than that of the Loratadine tablet values, respectively. Descarboethoxyloratadine bioequivalence was demonstrated between the two formulations. After 10 days of dosing, mean peak plasma concentrations were attained at 1.3 hours and 2.3 hours (Tmax) for parent and metabolite, respectively.
In a single dose study with Loratadine rapidly disintegrating tablets, food increased the AUC of Loratadine by approximately 48% and did not appreciably affect the AUC of descarboethoxyloratadine. The times to peak plasma concentration (Tmax) of Loratadine and descarboethoxyloratadine were delayed approximately 2.4 and 3.7 hours, respectively, when food was consumed prior to Loratadine rapidly disintegrating tablets administration. Parent and metabolite peak concentrations (Cmax) were not affected by food.
In a single-dose study with Loratadine rapidly disintegrating tablets in 24 subjects, the AUC of Loratadine was increased by 26% when administered without water compared to administration with water, while Cmax was not substantially affected. The bioavailability of descarboethoxyloratadine was not different when administered without water.
Approximately 80% of the total Loratadine dose administered can be found equally distributed between urine and feces in the form of metabolic products within 10 days. In nearly all patients, exposure (AUC) to the metabolite is greater than to the parent Loratadine. The mean elimination half-life in normal adult subjects (n = 54) were 8.4 hours (range = 3 to 20 hours) for Loratadine and 28 hours (range = 8.8 to 92 hours) for descarboethoxyloratadine. Loratadine and descarboethoxyloratadine reached steady state in most patients by approximately the fifth dosing day. There was considerable variability in the pharmacokinetic data in all studies of Loratadine tablets and syrup, probably due to the extensive first-pass metabolism.
In vitro studies with human liver microsomes indicate that Loratadine is metabolized to descarboethoxyloratadine predominantly to cytochrome P450 3A4 (CYP3A4) and, to a lesser extent, by cytochrome P450 2D6 (CYP2D6). In the presence of CYP3A4 inhibitor ketoconazole, Loratadine is metabolized to descarboethoxyloratadine predominantly by CYP2D6. Concurrent administration of Loratadine with either Ketoconazole, Erythromycin (both CYP3A4 inhibitors), or Cimetidine (CYP2D6 and CYP3A4 inhibitor) to healthy volunteers was associated with substantially increased plasma concentrations of Loratadine.
The pharmacokinetic profile of Loratadine in children in the 6 to 12 year age group is similar to that of adults. In a single dose pharmacokinetic study of 13 pediatric volunteers (aged 8 - 12 years) given 10 ml of Loratadine syrup containing 10 mg of Loratadine, the ranges of individual subject values of pharmacokinetic parameters (AUC and Cmax) were comparable to those following administration of a 10 mg tablet or syrup to adult volunteers.
