Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihistamines – H1 antagonist, ATC code: R06A X13.
Pharmacotherapeutic group: Nasal decongestants for systemic use group, ATC code: R01BA52.
Mechanism of action
Loratadine is a tricyclic antihistamine with selective, peripheral H1-receptor activity.
Pseudoephedrine sulphate (d-isoephedrine sulphate) is a sympathomimetic agent with mostly α-mimetic activity in comparison with the β-activity. Pseudoephedrine sulphate provides a nasal decongestant effect after oral administration due to its vasoconstrictive action. It has an indirect sympathomimetic effect due primarily to the release of adrenergic mediators from the post-ganglionic nerve endings.

Pharmacodynamic effects
The pharmacodynamics of Clarinase Repetabs tablets are directly related to that of its components.
Loratadine has no clinically significant sedative or anticholinergic properties in the majority of the population and when used at the recommended dosage.
During long-term treatment there were no clinically significant changes in vital signs, laboratory test values, physical examinations or electrocardiograms.
Loratadine has no significant H2-receptor activity. It does not inhibit norepinephrine uptake and has practically no influence on cardiovascular function or on intrinsic cardiac pacemaker activity.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Loratadine
Absorption
Loratadine is rapidly and well-absorbed. Concomitant ingestion of food can delay slightly the absorption of loratadine but without influencing the clinical effect. The bioavailability of loratadine and of the active metabolite are dose proportional.
Increase in plasma concentrations of loratadine has been reported after concomitant use with ketoconazole, erythromycin, and cimetidine in controlled trials, but without clinically significant changes (including electrocardiographic).
Distribution
Loratadine is highly bound (97 % to 99 %) and its active major metabolite desloratadine (DL) moderately bound (73 % to 76 %) to plasma proteins.
In healthy subjects, plasma distribution half-lives of loratadine and its active metabolite are approximately 1 and 2 hours, respectively.

Biotransformation
After oral administration, loratadine undergoes an extensive first pass metabolism, mainly by CYP3A4 and CYP2D6. The major metabolite-desloratadine (DL) is pharmacologically active and responsible for a large part of the clinical effect. Loratadine and DL achieve maximum plasma concentrations (Tmax) between 1–1.5 hours and 1.5–3.7 hours after administration, respectively.

Elimination
Approximately 40 % of the dose is excreted in the urine and 42 % in the faeces over a 10 day period and that, mainly in the form of conjugated metabolites. Approximately 27 % of the dose is eliminated in the urine during the first 24 hours. Less than 1 % of the active substance is excreted unchanged in active form, as loratadine or DL.
The mean elimination half-lives are 8.4 hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92 hours) for the active metabolite.

Renal impairment
In patients with chronic renal impairment, both the area under the curve (AUC) and peak plasma levels (Cmax) increased for loratadine and its active metabolite as compared to the AUCs and peak plasma levels (Cmax) of patients with normal renal function. The mean elimination half-lives of loratadine and its active metabolite were not significantly different from those observed in normal subjects. Haemodialysis does not have an effect on the pharmacokinetics of loratadine or its active metabolite in subjects with chronic renal impairment.

Hepatic impairment
In patients with chronic alcoholic liver disease, the AUC and peak plasma levels (Cmax) of loratadine were double while the pharmacokinetic profile of the active metabolite was not significantly changed from that in patients with normal liver function. The elimination half-lives for loratadine and its metabolite were 24 hours and 37 hours, respectively, and increased with increasing severity of liver disease.

Elderly
The pharmacokinetic profile of loratadine and its metabolites is comparable in healthy adult volunteers and in healthy geriatric volunteers.

Pseudoephedrine sulphate
Absorption
After oral administration, pseudoephedrine sulphate is rapidly and completely absorbed. Onset of action occurs within 30 minutes and a dose of 60 mg has a decongestive action lasting for 4 to 6 hours.
Food may increase the amount of loratadine absorbed, but without clinically significant results. This is not observed with pseudoephedrine.

Distribution
Pseudoephedrine is presumed to cross the placenta and the haematoencephalic barrier.
The active substance is excreted in breast milk of lactating women.

Biotransformation
Pseudoephedrine sulphate undergoes incomplete hepatic metabolism by N-demethylation to an inactive metabolite.

Elimination
Its elimination half-life in humans, at an approximate urinary pH of 6, ranges from 5 to 8 hours. The active substance and its metabolite are excreted in urine, 55-75 % of the administered dose is excreted unchanged. The rate of excretion is accelerated and the duration of action decreased in acidic urine (pH5).
In case of alkalinisation of the urine, a partial resorption takes place.