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Claritin (Loratadine) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Claritin (Loratadine) is a white to off-white powder not soluble in water, but very soluble in acetone, alcohol, and chloroform. It has a molecular weight of 382.89, and empirical formula of C22H23ClN2O2; its chemical name is ethyl4-(8-chloro-5,6-dihydro-11 H- benzo[5,6]cyclohepta[1,2- b ]pyridin-11-ylidene)-1- piperidinecarboxylate and has the following structural formula:

Loratadine

CLARITIN tablets contain 10 mg micronized loratadine, an antihistamine, to be administered orally. They also contain the following inactive ingredients: Corn starch, lactose, and magnesium stearate.

CLARITIN syrup contains 1 mg/ml micronized loratadine, an antihistamine, to be administered orally. It also contains the following inactive ingredients: Citric acid, artificial flavor, glycerin, propylene glycol, sodium benzoate, sugar, and water. The pH is between 2.5 and 3.1.

CLARITIN Reditabs (rapidly-disintegrating tablets) contain 10 mg micronized loratadine, an antihistamine, to be administered orally. It disintegrates in the mouth within seconds after placement on the tongue, allowing its contents to be subsequently swallowed with or without water. Claritin Reditabs also contain the following inactive ingredients: Citric acid, gelatin, mannitol, and mint flavor.

CLINICAL PHARMACOLOGY

CLARITIN (Loratadine) is a long-acting tricyclic antihistamine with selective peripheral histamine 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 CLARITIN.

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.

Repeated application of CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) to the hamster cheek pouch did not cause local irritation.

PHARMACOKINETICS

Absorption:

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 and descarboethoxyloratadine similar to those achieved with loratadine tablets. Following administration of 10 mg loratadine once daily for 10 days with each dosage form 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 by 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.

Metabolism:

In vitro studies with human liver microsomes indicate that loratadine is metabolized to descarboethoxyloratadine predominantly by cytochrome P450 3A4 (CYP3A4) and, to a lesser extent, by cytochrome P450 2D6 (CYP2D6). In the presence of a 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 (see DRUG INTERACTIONS section).

Elimination:

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-lives 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 CLARITIN Tablets and Syrup, probably due to the extensive first-pass metabolism.

Special Populations:

Pediatric: 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 to 12 years) given 10 mL of CLARITIN Syrup containing 10 mg 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.

The pharmacokinetic profile of loratadine in children in the 2 to 5-year age group (n = 18) is similar to that of adults. In a single-dose pharmacokinetic study of pediatric subjects (age 2 to 5 years) given 5 mL of CLARITIN Syrup containing 5 mg loratadine, the range 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 or children eight years of age and older.

Geriatric:

In a study involving 12 healthy geriatric subjects (66 to 78 years old), the AUC and peak plasma levels (Cmax) of both loratadine and descarboethoxyloratadine were approximately 50% greater than those observed in studies of younger subjects. The mean elimination half-lives for the geriatric subjects were 18.2 hours (range = 6.7 to 37 hours) for loratadine and 17.5 hours (range = 11 to 38 hours) for descarboethoxyloratadine.

Renal Impairment:

In a study involving 12 subjects with chronic renal impairment (creatinine clearance ≤ 30 mL/min) both AUC and Cmax increased by approximately 73% for loratadine and by 120% for descarboethoxyloratadine, as compared to six subjects with normal renal function (creatinine clearance ≥ 80 mL/min). The mean elimination half-lives of loratadine (7.6 hours) and descarboethoxyloratadine (23.9 hours) were not substantially different from that observed in normal subjects. Hemodialysis does not have an effect on the pharmacokinetics of loratadine or descarboethoxyloratadine in subjects with chronic renal impairment.

Hepatic Impairment:

In seven patients with chronic alcoholic liver disease, the AUC and Cmax of loratadine were double while the pharmacokinetic profile of descarboethoxyloratadine was not substantially different from that observed in other trials enrolling normal subjects. The elimination half-lives for loratadine and descarboethoxyloratadine were 24 hours and 37 hours, respectively, and increased with increasing severity of liver disease.

Clinical Trials:

Clinical trials of CLARITIN Tablets involved over 10,700 patients, 12 years of age and older, who received either CLARITIN Tablets or another antihistamine and/or placebo in double-blind randomized controlled studies. In placebo-controlled trials, 10 mg once daily of CLARITIN Tablets was superior to placebo and similar to clemastine (1 mg BID) or terfenadine (60 mg BID) in effects on nasal and non-nasal symptoms of allergic rhinitis. In these studies, somnolence occurred less frequently with CLARITIN Tablets than with clemastine and at about the same frequency as terfenadine or placebo. In studies with CLARITIN Tablets at doses two to four times higher than the recommended dose of 10 mg, a dose-related increase in the incidence of somnolence was observed. Therefore, some patients, particularly those with hepatic or renal impairment and the elderly, or those on medications that impair clearance of loratadine and its metabolites, may experience somnolence. In addition, three placebo-controlled, double-blind, 2-week trials in 188 pediatric patients with seasonal allergic rhinitis aged 6 to 12 years, were conducted at doses of CLARITIN Syrup up to 10 mg once daily. In a double-blind, placebo-controlled study, the safety of 5 mg loratadine, administered in 5 mL of CLARITIN Syrup, was evaluated in 60 pediatric patients between 2 and 5 years of age. No unexpected adverse events were observed.

Clinical trials of CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) involved over 1300 patients who received either CLARITIN REDITABS (loratadine rapidly-disintegrating tablets), CLARITIN Tablets, or placebo. In placebocontrolled trials, one CLARITIN REDITABS (loratadine rapidly-disintegrating tablets) once daily was superior to placebo and similar to CLARITIN Tablets in effects on nasal and non-nasal symptoms of seasonal allergic rhinitis.

Among those patients involved in double-blind, randomized, controlled studies of loratadine tablets, approximately 1000 patients (age 12 and older), were enrolled in studies of chronic idiopathic urticaria. In placebo-controlled clinical trials, loratadine tablets 10 mg once daily were superior to placebo in the management of chronic idiopathic urticaria, as demonstrated by reduction of associated itching, erythema, and hives. In these studies, the incidence of somnolence seen with loratadine tablets was similar to that seen with placebo.

In a study in which CLARITIN tablets were administered to adults at 4 times the clinical dose for 90 days, no clinically significant increase in the QTc was seen on ECGs.

In a single-rising dose study in which doses up to 160 mg (16 times the clinical dose) were studied, loratadine did not cause any clinically significant changes on the QTc interval in the ECGs.

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