Aerius Mechanism of Action

Desloratadine is a non-sedating, long-acting histamine antagonist with potent, selective peripheral H₁-receptor antagonist activity. Desloratadine has demonstrated antiallergic and antihistaminic properties.
Pharmacology: Pharmacodynamics: After oral administration, desloratadine selectively blocks peripheral histamine H₁-receptors because the drug is effectively excluded from entry to the central nervous system (CNS).
In addition to antihistaminic activity, desloratadine has demonstrated antiallergic activity from numerous in vitro and in vivo studies. These include inhibiting the release of proinflammatory cytokines such as IL-4, IL-6, IL-8 and IL-13 from human mast cells/basophils, as well as inhibition of the expression of the adhesion molecule P-selectin on endothelial cells. The clinical relevance of these observations remains to be confirmed.
In a multiple-dose clinical trial, in which up to 20mg of desloratadine was administered daily for 14 days, no statistically or clinically relevant cardiovascular effect was observed. In a clinical pharmacologic trial, in which desloratadine was administered at a dose of 45mg daily (nine times the clinical dose) for ten days, no prolongation of the QTc interval was seen.
Desloratadine does not readily penetrate the central nervous system. At the recommended dose of 5mg daily, there was no excess incidence of somnolence as compared to placebo. AERIUS Tablets even at a dose of 7.5mg daily did not affect psychomotor performance in clinical trials. A single dose of desloratadine 5mg did not affect standard measures of flight performance including exacerbation of subjective sleepiness or tasks related to flying.
No clinically relevant changes in desloratadine plasma concentrations were observed in multiple-dose ketoconazole, erythromycin, azithromycin, fluoxetine and cimetidine interaction trials.
In clinical pharmacologic trials, co-administration of alcohol did not increase the alcohol-induced impairment in performance or increase in sleepiness. No significant differences were found in the psychomotor test results between desloratadine and placebo groups, whether administered alone or with alcohol.
In patient with allergic rhinitis (AR), AERIUS was effective in relieving symptoms such as sneezing, nasal discharge and itching, as well as ocular itching, tearing and redness, and itching of palate. AERIUS effectively controlled symptoms for 24 hours.
In addition to the established classifications of seasonal and perennial, allergic rhinitis can alternatively be classified as intermittent allergic rhinitis and persistent allergic rhinitis according to the duration of symptoms. Intermittent allergic rhinitis is defined as the presence of symptoms for less than 4 days per week or for less than 4 weeks. Persistent allergic rhinitis is defined as the presence of symptoms for 4 days or more per week and for more than 4 weeks.
In two 4-week trials in patients with seasonal allergic rhinitis (SAR) and concurrent asthma, desloratadine was effective in reducing the symptoms of both SAR (rhinorrhea, nasal congestion, nasal itching and sneezing, itching/burning eyes, tearing/watering eyes, redness of eyes, and itching of ears or palate) and asthma (coughing, wheezing, difficulty breathing), and decreasing beta-agonist use. FEV₁ was not altered in the desloratadine or placebo treatment groups. The improvement in symptoms, with no decrease in pulmonary function, supports the safety of administering desloratadine to patients with SAR and concomitant mild-to-moderate asthma.
In trials conducted in patients with chronic idiopathic urticaria (CIU), AERIUS Tablets were effective in relieving pruritus and decreasing the size and number of hives as early as 1 day after initiation of treatment. In each trial, the effects were sustained over the 24 hour dosing interval. Treatment with AERIUS Tablets also improved sleep and daytime function, as measured by reduced interference with sleep and routine daily activities.
AERIUS was effective in alleviating the burden of seasonal allergic rhinitis as shown by the total score of the rhino-conjunctivitis quality of life questionnaire. The greatest amelioration was seen in the domains of practical problems and daily activities limited by symptoms.
Tablet: Chronic idiopathic urticaria was studied as a clinical model for urticarial conditions, since the underlying pathophysiology is similar, regardless of etiology, and because chronic patients can be more easily recruited prospectively. Since histamine release is a casual factor in all urticarial diseases, desloratadine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria, as advised in clinical guidelines.
Syrup: Safety of AERIUS Syrup was demonstrated in three pediatric trials. Children ages 6 months-11 years who were candidates for antihistamine therapy received a daily dose of 1mg (6 through 11 months of age), 1.25mg (1 through 5 years of age) or 2.5mg (6 through 11 years of age). Treatment was well tolerated as documented by clinical laboratory tests, vital signs, and ECG interval data, including QTc. When given at the recommended doses, the pharmacokinetic activity of desloratadine (see Pharmacokinetics as follows) was comparable in the pediatric and adult populations. Thus, since the course of seasonal allergic rhinitis (SAR) / chronic idiopathic urticarial (CIU) and the profile of desloratadine are similar in adults and pediatric patients, desloratadine efficacy data in adults can be extrapolated to the pediatric population.
Pharmacokinetics: Desloratadine plasma concentrations can be detected within 30 minutes of desloratadine administration. Desloratadine is well absorbed with maximum concentration achieved after approximately 3 hours; the terminal phase half-life is approximately 27 hours. The degree of accumulation of desloratadine was consistent with its half-life (approximately 27 hours) and a once daily dosing frequency. The bioavailability of desloratadine was dose proportional over the range of 5mg to 20mg.
Desloratadine is moderately bound (83% - 87%) to plasma proteins. There is no evidence of clinically relevant drug accumulation following once daily dosing of desloratadine (5mg to 20mg) for 14 days.
The enzyme responsible for the metabolism of desloratadine has not been identified yet, and therefore some interactions with other drugs cannot be fully excluded. In vivo studies with specific inhibitors of CYP3A4 and CYP2D6 have shown that these enzymes are not important in the metabolism of desloratadine. Desloratadine does not inhibit CYP3A4 or CYP2D6 and is neither a substrate nor an inhibitor of P-glycoprotein.
In a single dose trial using a 7.5mg dose of desloratadine, there was no effect of food (high-fat, high caloric breakfast) on the disposition of desloratadine. In another study, grapefruit juice had no effect on the disposition of desloratadine.
Syrup: In a single dose, crossover trial of desloratadine, the Tablet and Syrup formulations were bioequivalent and not affected by the presence of food (high-fat, high caloric breakfast).
In separate single dose studies, at the recommended doses, pediatric patients have comparable AUC and C_max values of desloratadine to those in adults who received a 5mg dose of desloratadine Syrup.
Toxicology: Preclinical toxicology: Desloratadine is the primary active metabolite of loratadine. Pre-clinical studies conducted with desloratadine and loratadine demonstrated that there are no qualitative or quantitative differences in the toxicity profile of desloratadine and loratadine at comparable levels of exposure to desloratadine.
Pre-clinical data with desloratadine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction. The lack of carcinogenic potential was demonstrated in studies conducted with loratadine.