Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, UK
Pharmacotherapeutic group: Other Antiasthmatics, Inhalants, - Glucocorticoids
ATC code: R03BA07
Mometasone furoate is a topical glucocorticoid with local anti-inflammatory properties.
It is likely that much of the mechanism for the effects of mometasone furoate lies in its ability to inhibit the release of mediators of the inflammatory cascade.In vitro, mometasone furoate inhibits the release of leukotrienes from leukocytes 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 TNF-alpha; it is also a potent inhibitor of LT production and in addition it is an extremely potent inhibitor of the production of the Th2 cytokines, IL-4 and IL-5, from human CD4+ T-cells.
Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone.
In a clinical trial, inhaled mometasone furoate has been shown to reduce airway reactivity to adenosine monophosphate in hyperreactive patients. In another trial, pretreatment using the Asmanex Twisthaler for five days significantly attenuated the early and late phase reactions following inhaled allergen challenge and also reduced allergen-induced hyperresponsiveness to methacholine.
Inhaled mometasone furoate treatment was also shown to attenuate the increase in inflammatory cells (total and activated eosinophils) in induced sputum following allergen and methacholine challenge. The clinical significance of these findings is not known.
In asthmatic patients, repeated administration of inhaled mometasone furoate for 4 weeks at doses of 200 micrograms twice daily to 1200 micrograms once daily showed no evidence of clinically relevant HPA-axis suppression at any dose level and was associated with detectable systemic activity only at a dose of 1600 micrograms per day.
In long-term clinical trials using doses up to 800 micrograms per day, there was no evidence of HPA axis suppression, as assessed by reductions in morning plasma cortisol levels or abnormal responses to cosyntropin.
In a 28 day clinical trial involving 60 asthmatic patients, administration of Asmanex Twisthaler at doses of 400 micrograms, 800 micrograms or 1200 micrograms once daily, or 200 micrograms twice daily, did not result in a statistically significant decrease in 24-hour plasma cortisol AUC.
The potential systemic effect of twice daily dosing of mometasone furoate was evaluated in an active and placebo controlled trial that compared 24-hour plasma cortisol AUC in 64 adult asthmatic patients treated for 28 days with mometasone furoate 400 micrograms twice daily, 800 micrograms twice daily, or prednisone 10 mg once daily. Mometasone furoate 400 micrograms twice daily treatment reduced plasma cortisol AUC(0-24) values from placebo values by 10-25%. Mometasone furoate 800 micrograms twice daily reduced plasma cortisol AUC(0-24) from placebo values by 21-40%. Reduction in cortisol was significantly greater after prednisone 10 mg once daily than with placebo or either of the mometasone treatment groups.
Double-blind placebo-controlled trials of 12-weeks duration have shown that treatment with Asmanex Twisthaler at delivered doses within the range of 200 micrograms (once-daily in the evening) - 800 micrograms per day resulted in improved lung function as measured by FEV1 and peak expiratory flow, improved asthma symptom control, and decreased need for inhaled beta2--agonist. Improved lung function was observed within 24 hours of the start of treatment in some patients, although maximum benefit was not achieved before 1 to 2 weeks or longer. Improved lung function was maintained for the duration of treatment.
The systemic bioavailability of mometasone furoate following oral inhalation in healthy volunteers is low, due to poor absorption from the lungs and the gut and extensive pre-systemic metabolism. Plasma concentrations of mometasone following inhalation at the recommended doses of 200 micrograms to 400 micrograms per day were generally near or below the limit of quantification (50 pg/ml) of the analytical assay and were highly variable.
After intravenous bolus administration, the Vd is 332 l. The in vitro protein binding for mometasone furoate is high, 98% to 99% in concentration range of 5 to 500 ng/ml.
The portion of an inhaled mometasone furoate dose that is swallowed and absorbed in the gastrointestinal tract undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. In human liver microsomes, mometasone is metabolised by cytochrome P-450 3A4 (CYP3A4).
After intravenous bolus administration, mometasone furoate has a terminal elimination T1/2 of approximately 4.5 hours. A radiolabelled, orally inhaled dose is excreted mainly in the feces (74%) and to a lesser extent in the urine (8%).
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows.
All toxicological effects observed are typical of this class of compounds and are related to exaggerated pharmacological effects of glucocorticoids.
Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. 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 studies of reproductive function, subcutaneous mometasone furoate, at 15 micrograms/kg prolonged gestation and prolonged and difficult labour occurred with a reduction in offspring survival and body weight or body weight gain. There was no effect on fertility.
Mometasone furoate is excreted in low doses in the milk of suckling rats.
In long-term carcinogenicity studies in mice and rats, inhaled mometasone furoate demonstrated no statistically significant increase in the incidence of tumours.
Mometasone furoate showed no genotoxic activity in a standard battery of in vitro and in vivo tests.
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