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Extended-Release, Non-sedating Antihistamine/Decongestant Tablets.
Pharmacology: Loratadine is a potent long-acting antihistamine with selective peripheral H1-receptor antagonistic activity.
Pseudoephedrine sulfate, one of the naturally occurring alkaloids of Ephedra and an orally administered vasoconstrictor, produces a gradual but sustained decongestant effect facilitating shrinkage of congested mucosa in upper respiratory areas. The mucous membrane of the respiratory tract is decongested through the action on the sympathetic nerves.
The combination of loratadine and pseudoephedrine sulfate controls histamine mediated symptoms and relieves the nasal congestion associated with allergic rhinitis and the common cold.
Pharmacodynamics: During studies of its effects on the CNS, loratadine has exhibited no depressant activity and no acute anticholinergic activity.
Loratadine has exhibited a very low affinity for membrane receptors from the cerebral cortex and does not readily penetrate into the CNS. 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.
The sedation profile of loratadine, 10 mg daily, is comparable to that of placebo and, during long term treatment, there were no clinically significant changes in vital signs, laboratory test values, physical examinations or electrocardiograms. In studies with loratadine 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.
Loratadine has no significant H2-receptor activity, does not inhibit norepinephrine uptake and has practically no influence on cardiovascular function or on intrinsic cardiac pacemaker activity. In a study in which loratadine tablets were administered at four times the clinical dose for 90 days, no clinically significant increase in the QTc was seen on ECGs.
Pseudoephedrine acts directly on both α- and to a lesser degree, β-adrenergic receptors. It is believed that α- adrenergic effects result from the inhibition of the production of cyclic adenosine-3', 5'-monophosphate (AMP) by inhibition of the enzyme adenyl cyclase, whereas β-adrenergic effects result from stimulation of adenyl cyclase activity. Like ephedrine, pseudoephedrine also has an indirect effect by releasing norepinephrine from its storage sites.
Pseudoephedrine acts directly on α-adrenergic receptors in the mucosa of respiratory tract producing vasoconstriction which results in shrinkage of swollen nasal mucous membranes, reduction of tissue hyperemia, edema and nasal congestion, and in an increase in nasal airway patency. Drainage of sinus secretions is increased and obstructed eustachian ostia may be opened.
Pseudoephedrine may relax bronchial smooth muscle by stimulation of β2-adrenergic receptors; however, substantial bronchodilation has not been demonstrated consistently following oral administration of the drug.
Oral administration of usual doses of pseudoephedrine to normotensive patients usually produces negligible effect on blood pressure. Pseudoephedrine may increase the irritability of the heart muscle and may alter the rhythmic function of the ventricles, especially in large doses or after administration to patients such as those with cardiac disease who are hypersensitive to the myocardial effects of sympathomimetic drugs. Tachycardia, palpitation, and/or multifocal premature ventricular contractions may occur.
Pseudoephedrine may cause mild CNS stimulation, especially in patients who are sensitive to the effects of sympathomimetic drugs.
Pharmacokinetics: Loratadine: After oral administration, loratadine is rapidly and well absorbed and undergoes an extensive first pass metabolism. In normal subjects, plasma distribution half-lives of loratadine and its active metabolite are approximately 1 and 2 hours, respectively. Initial data in normal subjects demonstrated a mean elimination half-life of 12.4 hours for loratadine and 19.6 hours for the active metabolite.
Subsequent data in normal adult subjects demonstrated mean elimination half-lives of 8.4 hours (range=3 to 20 hours) for loratadine and 28 hours (range=8.8 to 92 hours) for the major active metabolite. In nearly all patients, exposure (AUC) to the metabolite was greater than exposure to the parent compound.
Loratadine is highly bound (97% to 99%) and its active metabolite moderately bound (73% to 76%) to plasma proteins.
The bioavailability parameters of loratadine and of the active metabolite are dose proportional.
Approximately 40% of the dose is excreted in the urine and 42% in the feces 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. Traces of unchanged loratadine and of its active metabolite were found in the urine.
The pharmacokinetic profile of loratadine and its metabolites is comparable in healthy adult volunteers and in healthy geriatric volunteers.
In patients with chronic renal impairment, both the AUCs and peak plasma levels (Cmax) increased for loratadine and its 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 metabolite were not significantly different from that observed in normal subjects. Hemodialysis does not have an effect on the pharmacokinetics of loratadine or its active metabolite in subjects with chronic renal 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 of loratadine and its metabolite were 24 hours and 37 hours, respectively, and increased with increasing severity of liver disease.
Loratadine and its active metabolite are excreted in the breast milk of lactating women. Forty-eight hours after dosing, only 0.029% of the loratadine dose is detected in the milk as unchanged loratadine and its active metabolite.
Pseudoephedrine: Absorption: After oral administration of 60 mg of pseudoephedrine hydrochloride as tablets or oral solution, nasal decongestion occurs within 30 minutes and persists for 4-6 hours. Nasal decongestion may persist for 8 hours following oral administration of 60 mg and up to 12 hours following 120 mg of the drug in extended-release preparations.
Distribution: Although specific information is lacking, pseudoephedrine is presumed to cross the placenta and to enter CSF. The drug may also be distributed into milk.
Elimination: Pseudoephedrine is incompletely metabolized in the liver by N-demethylation to an inactive metabolite. The drug and its metabolite are excreted in urine; 55-75% of a dose is excreted unchanged. The rate of urinary excretion of pseudoephedrine is accelerated when urine is acidified to a pH of about 5 by prior administration of ammonium chloride. When the urine is alkalinized to a pH of about 8 by prior administration of sodium bicarbonate, some of the drug is reabsorbed in the kidney tubule and the rate of urinary excretion is slowed.
