There was considerable variability in the pharmacokinetic data in all studies of loratadine, probably due to the extensive first-pass metabolism. Individual histograms of area under the curve, clearance, and volume of distribution showed a log normal distribution with a 25-fold range in distribution in healthy subjects.

Loratadine is about 97% bound to plasma proteins at the expected plasma concentrations (2.5 to 100 ng/ml) after a therapeutic dose. Loratadine does not affect the plasma protein binding of warfarin and digoxin. The metabolite descarboethoxyloratadine is 73% to 77% bound to plasma proteins (at 0.5 to 100 ng/ml).

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 nor 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.

In a study in which loratadine alone was administered at four times the clinical dose for 90 days, no clinically significant increase in the QT_c was seen on ECGs.

In a single-rising dose study of loratadine alone in which doses up to 160 mg (16 times the clinical dose) were administered, no clinically significnt changes on the QT_c interval in the ECGs were observed.

Pseudoephedrine sulfate (d-isoephedrine sulfate) is an orally active sympathomimetic amine which exerts a decongestant action on the nasal mucosa. It is recognized as an effective agent for the relief of nasal congestion due to allergic rhinitis. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory side effects.

The bioavailability of loratadine; pseudoephedrine sulfate from loratadine; pseudoephedrine sulfate 24 hour extended release tablets is similar to that achieved with separate administration of the components. Coadministration of loratadine and pseudoephedrine does not significantly affect the bioavailability of either component.

In a single-dose study, food increased the AUC of loratadine by approximately 125% and C_max by approximately 80%. However, food did not significantly affect the pharmacokinetics of pseudoephedrine sulfate or descarboethoxyloratadine.

Loratadine; Pseudoephedrine Sulfate 12 hour Extended Release Tablets Only: The pseudoephedrine component of loratadine; pseudoephedrine sulfate 12 hour extended release tablets was absorbed at a similar rate and was equally available from the combination tablet as from a pseudoephedrine sulfate repetabs 120 mg tablet. Mean (%CV) steady-state peak plasma concentration of 464 ng/mL (22) was attained at 3.9 hours (50). The terminal half-life of pseudoephedrine from the combination tablet administered twice daily was 6.3 hours (23). The ingestion of food was found not to affect the absorption of pseudoephedrine from loratadine; pseudoephedrine sulfate 12 hour extended release tablets. Loratadine and pseudoephedrine sulfate do not influence the pharmacokinetics of each other when administered concomitantly.

CLINICAL STUDIES

12 Hour Extended Release Tablets

Clinical trials of loratadine; pseudoephedrine sulfate 12 hour extended release tablets in seasonal allergic rhinitis involved approximately 3700 patients who received either the combination product, a comparative treatment, or placebo, in double-blind, randomized controlled studies. Four of the largest studies involved approximately 1600 patients in comparisons of the combination product, loratadine (5 mg bid), pseudoephedrine sulfate (120 mg bid), and placebo. Improvement in symptoms of seasonal allergic rhinitis for patients receiving loratadine; pseudoephedrine sulfate 12 hour extended release tablets was significantly greater than the improvement in those patients who received the individual components or placebo. The combination reduced the intensity of sneezing, rhinorrhea, nasal pruritus, and eye tearing more than pseudoephedrine and reduced the intensity of nasal congestion more than loratadine, demonstrating a contribution of each of the components. The onset of antihistamine and nasal decongestant actions occurred after the first dose of loratadine; pseudoephedrine sulfate 12 hour extended release tablets. Loratadine; pseudoephedrine sulfate 12 hour extended release tablets were well tolerated, with a frequency of sedation similar to that seen with placebo, and an adverse event profile clinically similar to that of pseudoephedrine.

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