Nasonex Mechanism of Action

Glucocorticoids.
Pharmacology: Pharmacodynamics: In studies utilizing nasal antigen challenge, mometasone furoate in Mometasone furoate (NASONEX) Aqueous Nasal Spray has shown anti-inflammatory activity in both the early- and late-phase allergic responses. This has been demonstrated by decreases (vs. placebo) in histamine and eosinophil activity and reductions (vs. baseline) in eosinophils, neutrophils, and epithelial cell adhesion proteins. Because of the low systemic availability of mometasone furoate after intranasal administration, any pharmacodynamic correlations have to be based upon sensitive indices of possible systemic exposure rather than measured MF levels. Systemic activity of exogenous corticosteroids is commonly expressed by evaluating the hypothalamic-pituitary-adrenal (HPA) axis activity.
In two trials with 1954 patients 12 years of age and older, Mometasone furoate (NASONEX) Aqueous Nasal Spray 200 mcg twice daily was effective in significantly improving symptoms of rhinosinusitis compared to placebo as evaluated by the Major Symptom Score (MSS) composite of symptoms (facial pain/pressure/tenderness, sinus headache, rhinorrhea, post nasal drip, and nasal congestion/stuffiness) during the 15 day treatment period (P02683 p <0.001; P02692 p=0.038). A 500 mg three times a day amoxicillin arm was not significantly different from placebo in reducing the symptoms of rhinosinusitis as evaluated by the MSS. Fewer subjects treated with Mometasone furoate (NASONEX) Aqueous Nasal Spray 200 mcg twice daily were considered by the treating physician to be treatment failures than those with placebo (p=0.0074). In addition, during the post-treatment follow-up period, the number of recurrences seen with Mometasone furoate (NASONEX) Aqueous Nasal Spray was low and comparable to the amoxicillin and placebo treatment groups. Treatment duration beyond 15 days was not evaluated in acute rhinosinusitis.
In clinical trials with nasal polyposis Mometasone furoate (NASONEX) Aqueous Nasal Spray showed significant improvement when compared to placebo in the clinically relevant endpoints of congestion, nasal polyp size and loss of smell.
Pharmacokinetics: Mometasone furoate monohydrate, administered as an aqueous nasal spray, has a systemic bioavailability of <1% in plasma, using a sensitive assay with a lower quantitation limit (LLOQ) of 0.25 pg/ml. Mometasone furoate suspension is very poorly absorbed from the gastrointestinal tract, and the small amount that may be swallowed and absorbed undergoes extensive first-pass hepatic metabolism prior to excretion in urine and bile.
Toxicology: Preclinical information: Pharmacodynamic properties: Mometasone furoate is a topical glucocorticosteroid with local anti-inflammatory properties at doses that are not systemically active.
The precise mechanism of action is unknown, but it is likely that much of the mechanism for the anti-allergic and anti-inflammatory effects of mometasone furoate lies in its ability to inhibit the release of mediators of allergic reactions. Mometasone furoate significantly inhibits the release of leukotrienes from leucocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency in inhibition of synthesis and release of IL-1, IL-5, IL-6, and TNFα; it is also a potent inhibitor of the production of the TH₂ cytokines, IL-4 and IL-5, from human CD4+ T-cells. In mixed leukocytes from atopic patients, mometasone furoate was a more potent inhibitor of leukotriene production than BDP.
In a preclinical model, mometasone furoate has been shown to reduce the accumulation of eosinophils markedly at the site of an allergic reaction. Additionally, mometasone furoate reduced the number of lymphocytes and the levels of messenger RNA for the proallergic cytokines IL-4 and IL-5.
Preclinical pharmacokinetics and metabolism: Several studies were conducted to investigate for mometasone furoate the absorption, distribution, metabolism and excretion following various routes of administration and in different species. Mometasone furoate and/or its metabolites are rapidly and extensively distributed in the rat. Mometasone furoate undergoes extensive first-pass metabolism and is excreted as metabolites mostly via the bile, and to a limited extent into the urine.
Preclinical safety data: No toxicologic effects unique to mometasone furoate exposure were demonstrated during the course of preclinical testing. All observed effects are typical of this class of compounds and are related to exaggerated pharmacologic effects of glucocorticoids.
Preclinical studies demonstrate that mometasone furoate is devoid of androgenic, anti-androgenic, estrogenic or anti-estrogenic activity but, like other glucocorticoids, it exhibits some anti-uterotrophic activity and delays vaginal opening in animal models at high oral doses of 56 mg/kg/day and 280 mg/kg/day.
Mometasone furoate was non-mutagenic in the mouse-lymphoma assay and the Salmonella/E. coli/mammalian microsome mutagenicity bioassay. At cytotoxic doses only, mometasone furoate produced an increase in chromosome aberrations in vitro in Chinese hamster ovary cell (CHO) cultures in the non-activation phase, but not in the presence of rat liver S9 fraction. However, mometasone furoate did not induce chromosomal aberrations in vitro in a Chinese hamster lung cell (CHL) chromosomal-aberrations assay or in vivo in the mouse bone-marrow erythrocyte-micronucleus assay, in the rat bone-marrow clastogenicity assay, and the mouse male germ-cell clastogenicity assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes. The finding of simple chromosomal aberrations in the non-activation phase of the CHO assay is considered to be related to cytotoxicity and is not considered to be of significance in the risk assessment of mometasone furoate because of the negative results in the S9 phase of this assay, the negative results in a second in vitro chromal aberrations assay (CHL assay), and the negative results in three in vivo chromosomal aberrations assays.
In studies of reproductive function, subcutaneous mometasone furoate was well tolerated at doses up to 7.5 μg/kg. At 15 μg/kg, mometasone furoate caused prolonged gestation and prolonged and difficult labor occurred with a reduction in offspring survival and body weight or body weight gain. There was no effect on fertility.
Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Teratology studies were conducted in rats, mice and rabbits by the oral, topical and/or subcutaneous routes. Effects noted were umbilical hernia in rats, cleft palate in mice, and gall bladder agenesis, umbilical hernia, and flexed front paws in rabbits. There were also reductions in maternal body weight gains, effects on fetal growth (lower fetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice.
In an oral teratology study in rabbits, at 700 μg/kg, increased incidences of resorption and malformations, including cleft palate and/or head malformations (hydrocephaly or domed head) were observed. Pregnancy failure was observed in most rabbits at 2800 μg/kg.
The carcinogenicity and toxicological potential of inhaled mometasone furoate (aerosol with CFC propellant and surfactant) at concentrations of 0.25 to 2.0 μg/l was investigated in studies in mice and rats of up to 24 months. Typical glucocorticoid-related effects, including several non-neoplastic lesions, were observed. No statistically significant dose-response relationship was detected for any of the tumor types.
While mometasone furoate has been shown to be a potent topical glucocorticoid, there is little systemic activity following intranasal administration. This is because of the low systemic bioavailability of the intranasal suspension, especially in man where systemic exposure is <1% at the clinical dose (200 μg/day).