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Pharmacology: Mechanism of Action: Mometasone furoate is a corticosteroid demonstrating potent anti-inflammatory properties. The precise mechanism of corticosteroid action on allergic rhinitis is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation.
In two clinical studies utilizing nasal antigen challenge, Mometasone furoate Nasal Spray, 50 mcg decreased some markers of the early- and late-phase allergic response. These observations included decreases (vs. placebo) in histamine and eosinophil cationic protein levels, and reductions (vs. baseline) in eosinophils, neutrophils, and epithelial cell adhesion proteins. The clinical significance of these findings is not known.
The effect of Mometasone furoate Nasal Spray, 50 mcg on nasal mucosa following 12 months of treatment was examined in patients with allergic rhinitis. There was no evidence of atrophy and there was a marked reduction in intraepithelial eosinophilia and inflammatory cell infiltration (e.g., eosinophils, lymphocytes, monocytes, neutrophils, and plasma cells).
Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine Nasal Spray is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in-vitro studies. The major metabolite, desmethylazelastine, also possesses H1-receptor antagonist activity.
Pharmacokinetics: Absorption: Mometasone furoate administered as a nasal spray suspension has very low bioavailability (<1%) in plasma using a sensitive assay with a lower quantitation limit (LOQ) of 0.25 pcg/mL.
After intranasal administration of 2 sprays per nostril (548 mcg total dose) of Azelastine Nasal Spray, the mean azelastine peak plasma concentration (Cmax) is 200 pg/mL, the mean extent of systemic exposure (AUC) is 5122 pghr/mL and the median time to reach Cmax (tmax) is 3 hours. The systemic bioavailability of azelastine hydrochloride is approximately 40% after intranasal administration.
Distribution: The in vitro protein binding for mometasone furoate was reported to be 98% to 99% in concentration range of 5 to 500 ng/mL.
Based on intravenous and oral administration, the steady-state volume of distribution of azelastine is 14.5 L/kg. In vitro studies with human plasma indicate that the plasma protein binding of azelastine and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively.
Metabolism: Studies have shown that any portion of a mometasone furoate dose which is swallowed and absorbed undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. Upon in vitro incubation, one of the minor metabolites formed is 6β-hydroxymometasone furoate. In human liver microsomes, the formation of the metabolite is regulated by cytochrome P-450 3A4 (CYP3A4).
Azelastine is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified. After a single-dose, intranasal administration of Azelastine Nasal Spray (548 mcg total dose), the mean desmethylazelastine Cmax is 23 pg/mL, the AUC is 2131 pghr/mL and the median tmax is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations.
Elimination: Following intravenous administration, the effective plasma elimination half-life of mometasone furoate is 5.8 hours. Any absorbed drug is excreted as metabolites mostly via the bile, and to a limited extent, into the urine.
Following intranasal administration of Azelastine Nasal Spray, the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.
Special Populations: Hepatic impairment: Administration of a single inhaled dose of 400 mcg mometasone furoate to subjects with mild, moderate, and severe hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50 to 105 pcg/mL). The observed peak plasma concentrations appear to increase with severity of hepatic impairment, however, the numbers of detectable levels were few.
Following oral administration of azelastine, pharmacokinetic parameters were not influenced by hepatic impairment.
Renal impairment: The effects of renal impairment on mometasone furoate pharmacokinetics have not been adequately investigated. Based on oral, single-dose studies of azelastine, renal insufficiency (creatinine clearance <50 mL/min) resulted in a 70-75% higher Cmax and AUC compared to healthy subjects. Time to maximum concentration was unchanged.
Age: Mometasone furoate pharmacokinetics has not been investigated in the pediatric population.
Following oral administration of azelastine, pharmacokinetic parameters were not influenced by age.
Gender: The effects of gender on mometasone furoate pharmacokinetics have not been adequately investigated.
Following oral administration of azelastine, pharmacokinetic parameters were not influenced by gender.
Race: The effects of race on mometasone furoate pharmacokinetics have not been adequately investigated.
The effect of race on azelastine has not been evaluated.
Rationale for the Combination: Antihistamines are recommended as the first line of therapy for mild AR, and intranasal corticosteroids are first line for moderate and severe AR according to the recent guidelines. In accordance with these recommendations in clinical practice, antihistamines and topical corticosteroids are the most commonly used pharmacological agents for the treatment of AR. Antihistamines block neural and vascular H1 receptors and have a clinical effect on symptoms such as nasal itching, sneezing and rhinorrhea. They are rapidly absorbed and begin to reduce nasal symptoms (itching and sneezing) within 1 hr. On the other hand, efficacy of steroids depends upon their long term anti-inflammatory effect rather than upon direct receptor antagonism. Understanding both the efficacy and the pharmacologic properties of these commonly used drugs in the treatment of nasal allergic inflammation and its related nasal symptoms clearly shows that the combination of the two drugs would be better than either drug alone in patients with moderate to severe allergic rhinitis.
