No toxicological effects unique to mometasone furoate exposure were demonstrated. 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, antiandrogenic, estrogenic or antiestrogenic activity but, like other glucocorticoids, it exhibits some antiuterotrophic activity and delays vaginal opening in animal models at high oral doses of 56 mg/kg/day and 280 mg/kg/day.
Like other glucocorticoids, mometasone furoate showed a clastogenic potential in-vitro at high concentrations. However, no mutagenic effects can be expected at therapeutically relevant doses.
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.
Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Effects noted were umbilical hernia in rats, cleft palate in mice and gallbladder agenesis, umbilical hernia, and flexed front paws in rabbits. There were also reductions in maternal body weight gains, effects on foetal growth (lower foetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice.
The carcinogenicity potential of inhaled mometasone furoate (aerosol with CFC propellant and surfactant) at concentrations of 0.25 to 2.0 micrograms/l was investigated in 24-month studies in mice and rats. Typical glucocorticoid-related effects, including several non-neoplastic lesions, were observed. No statistically significant dose-response relationship was detected for any of the tumour types.
Pharmacotherapeutic group: Other Antiasthmatics, Inhalants, - Glucocorticoids, ATC code R03B A07
Mechanism of action
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.
Pharmacodynamic effects
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 Elomet 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.
Clinical efficacy and safety
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 Elomet 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 Elomet 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.
Elomet furoate exhibits marked anti-inflammatory activity and marked anti-psoriatic activity in standard animal predictive models.
In the croton oil assay in mice, Elomet was equipotent to betamethasone valerate after single application and about 8 times as potent after five applications.
In guinea pigs, Elomet was approximately twice as potent as betamethasone valerate in reducing m.ovalis-induced epidermal acanthosis (i.e. anti-psoriatic activity) after 14 applications.
Pharmacotherapeutic group: Decongestants and Other Nasal Preparations for Topical Use-Corticosteroids, ATC code: R01A D09
Mechanism of action
Mometasone furoate is a topical glucocorticosteroid with local anti-inflammatory properties at doses that are not systemically active.
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 leukotriene production. 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.
Pharmacodynamic effects
In studies utilising nasal antigen challenge, Elomet 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.
In 28% of the patients with seasonal allergic rhinitis, Elomet Nasal Spray demonstrated a clinically significant onset of action within 12 hours after the first dose. The median (50%) onset time of relief was 35.9 hours.
Paediatric population
In a placebo-controlled clinical trial in which paediatric patients (n=49/group) were administered Elomet Nasal Spray 100 micrograms daily for one year, no reduction in growth velocity was observed.
There are limited data available on the safety and efficacy of Elomet Nasal Spray in the paediatric population aged 3 to 5 years, and an appropriate dosage range cannot be established. In a study involving 48 children aged 3 to 5 years treated with intranasal mometasone furoate 50, 100 or 200 μg/day for 14 days, there was no significant differences from placebo in the mean change in plasma cortisol level in response to the tetracosactrin stimulation test.
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Elomet exhibits marked anti-inflammatory activity and marked anti-psoriatic activity in standard animal predictive models.
In the croton oil assay in mice, mometasone was equipotent to betamethasone valerate after single application and about 8 times as potent after five applications.
In guinea pigs, mometasone was approximately twice as potent as betamethasone valerate in reducing m.ovalis-induced epidermal acanthosis (i.e. anti-psoriatic activity) after 14 applications.
Absorption
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.
Distribution
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.
Biotransformation
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).
Elimination
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 %).
Pharmacokinetic studies have indicated that systemic absorption following topical application of Elomet furoate cream 1mg/g is minimal, approximately 0.4% of the applied dose in man, the majority of which is excreted within 72 hours following application. Characterisation of metabolites was not feasible owing to the small amounts present in plasma and excreta.
Absorption
Mometasone furoate, administered as an aqueous nasal spray, has a systemic bioavailability of <1% in plasma, using a sensitive assay with a lower quantitation limit of 0.25 pg/ml.
Distribution
Not applicable as mometasone is poorly absorbed via the nasal route.
Biotransformation
The small amount that may be swallowed and absorbed undergoes extensive first-pass hepatic metabolism.
Elimination
Absorbed mometasone furoate is extensively metabolized and the metabolites are excreted in urine and bile.
Pharmacokinetic studies have indicated that systemic absorption following topical application of Elomet cream 1mg/g is minimal, approximately 0.4% of the applied dose in man, the majority of which is excreted within 72 hours following application. Characterisation of metabolites was not feasible owing to the small amounts present in plasma and excreta.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
