Aerius Mechanism of Action





Zuellig Pharma
Full Prescribing Info
Pharmacology: Desloratadine is a non-sedating long-acting histamine antagonist with potent, selective peripheral H1-receptor antagonist activity. Desloratadine has demonstrated antiallergic, antihistaminic, and anti-inflammatory activity.
Pharmacodynamics: Desloratadine, the active ingredient in Desloratadine oral solution is an antihistamine with selective peripheral H1-receptor antagonist activity.
In addition to antihistaminic activity, desloratadine has demonstrated antiallergic and anti-inflammatory activity from numerous in vitro (mainly conducted on cells of human origin) and in vivo studies. These studies have shown that desloratadine inhibits the broad cascade of events that initiate and propagate allergic inflammation, including: The release of proinflammatory cytokines including IL-4, IL-6, IL-8, IL-13 from human mast cells/basophils; the release of important proinflammatory chemokines such as RANTES (Regulated upon Activation, Normal T-cell Expressed and Secreted); superoxide anion production by activated polymorphonuclear neutrophils; eosinophil adhesion and chemotaxis; the expression of the adhesion molecules such as P-selectin; IgE-dependent release of histamine, prostaglandin (PGD2) and leukotriene (LTC4); the acute allergic bronchoconstrictor response and allergic cough in animal models.
Desloratadine does not penetrate the central nervous system. At the recommended dose of 5 mg daily, there was no excess incidence of somnolence as compared to placebo.
No clinically relevant changes in desloratadine plasma concentration were observed in multiple-dose ketoconazole, erythromycin, azithromycin, fluoxetine and cimetidine interaction trials.
Tablet/Syrup: 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 a multiple dose clinical trial, in which up to 20 mg 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 45 mg daily (nine times the clinical dose) for ten days, no prolongation of the QTc interval was seen.
AERIUS tablets even at a dose of 7.5 mg daily did not affect psychomotor performance in clinical trials. In a single dose study, desloratadine 5 mg did not affect standard measures of flight performance including exacerbation of subjective sleepiness or tasks related to flying.
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 adults and adolescent patients with allergic rhinitis (AR), AERIUS tablets were effective in relieving symptoms such as sneezing, nasal discharge and itching, congestion/stuffiness, as well as ocular itching, tearing and redness, and itching of palate. AERIUS tablets 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 and asthma, and decreasing beta-agonist use with no adverse effect on FEV1. 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.
Chronic idiopathic urticaria was studied as a clinical model for urticaria 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 causal 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.
In trials conducted in adults and adolescents 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 tablets were 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.
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 1 mg (6 through 11 months of age), 1.25 mg (1 through 5 years of age) or 2.5 mg (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 plasma concentration of desloratadine (see text as previously mentioned) was comparable in the pediatric and adult populations. Thus, since the course of SAR/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.
Oral solution: In a study in which desloratadine was administered at a dose of 45 mg daily (nine times the clinical dose) for ten days, no prolongation of the QTc interval was seen.
Desloratadine given at a single daily dose of 7.5 mg to adults and adolescents did not affect psychomotor performance in clinical studies, nor did a single daily dose of 5 mg to adults affect standard measures of flight performance under simulated flight conditions. Desloratadine has no or negligible influence on the ability to drive and use machines.
Pharmacokinetics: 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 5 mg to 20 mg.
Desloratadine is moderately bound (83%-87%) to plasma proteins. There is no evidence of clinically relevant drug accumulation following once daily dosing of desloratadine (5 mg to 20 mg) 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.
Tablet/Syrup: Desloratadine plasma concentration can be detected within 30 minutes of desloratadine administration.
In a single dose trial using a 7.5 mg 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 had comparable AUC and Cmax values of desloratadine to those in adults who received a 5 mg dose of desloratadine syrup.
Oral solution: Desloratadine is extensively metabolized to 3-hydroxy desloratadine, an active metabolite, which is subsequently glucuronidated. A human mass balance study documented a recovery of approximately 87% of the 14C-desloratadine dose, which was equally distributed in urine and feces as metabolic products.
The pharmacokinetic profile of desloratadine is comparable in healthy adult volunteers and in healthy geriatric volunteers and no dosage adjustment is required.
In single dose trials of oral solution (5 mg), there was no effect of food on the disposition of desloratadine. In another study, grapefruit juice had no effect on the disposition of desloratadine.
Toxicology: PRECLINICAL TOXICOLOGY: Desloratadine is the primary active metabolite of loratadine.
The lack of carcinogenic potential was demonstrated in studies conducted with loratadine.
Tablet/Syrup: Non-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.
Non-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.
Oral solution: Preclinical data with desloratadine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction.
In a clinical program, desloratadine was demonstrated to be safe and efficacious in the treatment of symptoms associated with allergic rhinitis. In addition, the safety and efficacy of desloratadine was demonstrated in the treatment of the symptoms of chronic idiopathic urticaria and other dermatologic disorders.
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