Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2023 Publisher: Mylan Products Ltd, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Pharmacotherapeutic group: Decongestants and other nasal preparations for topical use, corticosteroids/fluticasone, combinations
ATC code: R01AD58
Azelastine/Fluticasone Nasal Spray contains azelastine hydrochloride and fluticasone propionate, which have different modes of action and show synergistic effects in terms of improvement of allergic rhinitis and rhino-conjunctivitis symptoms.
Fluticasone propionate is a synthetic trifluorinated corticosteroid that possesses a very high affinity for the glucocorticoid receptor and has a potent anti-inflammatory action, e.g. 3-5 fold more potent than dexamethasone in cloned human glucocorticoid receptor binding and gene expression assays.
Azelastine, a phthalazinone derivative is classified as a potent long-acting anti-allergic compound with selective H1-antagonist, mast cell stabilizing and anti-inflammatory properties. Data from in vivo (preclinical) and in vitro studies show that azelastine inhibits the synthesis or release of the chemical mediators known to be involved in early and late stage allergic reactions, e.g. leukotrienes, histamine, platelet-activating factor (PAF) and serotonin.
A relief of nasal allergic symptoms is observed within 15 minutes after administration.
In 4 clinical studies in adults and adolescents with allergic rhinitis Azelastine/Fluticasone Nasal Spray one spray in each nostril twice daily significantly improved nasal symptoms (comprising rhinorrhoea, nasal congestion, sneezing and nasal itching) compared with placebo, azelastine hydrochloride alone and fluticasone propionate alone. It significantly improved ocular symptoms (comprising itching, tearing/watering and redness of the eyes) and the patients' disease-related quality of life (Rhinoconjunctivitis Quality of Life Questionnaire – RQLQ) in all 4 studies.
In comparison to a marketed fluticasone propionate nasal spray substantial symptom improvement (50% reduction in nasal symptoms severity) was achieved significantly earlier (3 days and more) with Azelastine/Fluticasone Nasal Spray. The superior effect of Azelastine/Fluticasone Nasal Spray to fluticasone propionate nasal spray was maintained throughout one-year study in patients with chronic persistent allergic rhinitis and nonallergic/vasomotor rhinitis.
In a ragweed pollen allergen exposure chamber study, first statistically significant relief of nasal symptoms was observed at 5 minutes after administration of Azelastine/Fluticasone Nasal Spray (compared to placebo). At 15 minutes after administration of Azelastine/Fluticasone Nasal Spray 60% of patients reported a clinically relevant reduction in symptom scores of at least 30%.
After intranasal administration of two sprays per nostril (548 mcg of azelastine hydrochloride and 200 mcg of fluticasone) of Azelastine/Fluticasone Nasal Spray, the mean (± standard deviation) peak plasma exposure (Cmax) was 194.5 ± 74.4 pg/mL for azelastine and 10.3 ± 3.9 pg/mL for fluticasone propionate and the mean total exposure (AUC) was 4217 ± 2618 pg/mL*hr for azelastine and 97.7 ± 43.1 pg/mL*hr for fluticasone. The median time to peak exposure (tmax) from a single dose was 0.5 hours for azelastine and 1.0 hours for fluticasone.
Fluticasone systemic exposure was ~50% increased comparing Azelastine/Fluticasone Nasal Spray with a marketed fluticasone nasal spray. Azelastine/Fluticasone Nasal Spray was equivalent to a marketed azelastine nasal spray with respect to azelastine systemic exposure. There was no evidence of pharmacokinetic interactions between azelastine hydrochloride and fluticasone propionate.
Fluticasone propionate has a large volume of distribution at steady-state (approximately 318 litre). Plasma protein binding is 91%.
The volume of distribution of azelastine is high indicating distribution predominantly into the peripheral tissue. The level of protein binding is 80-90%. Additionally, both drugs have broad therapeutic windows. Therefore, drug displacement reactions are unlikely.
Fluticasone propionate is cleared rapidly from the systemic circulation, principally by hepatic metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Swallowed fluticasone propionate is also subject to extensive first pass metabolism. Azelastine is metabolized to N-desmethylazelastine via various CYP isoenzymes, mainly CYP3A4, CYP2D6 and CYP2C19.
The elimination rate of intravenous administered fluticasone propionate is linear over the 250-1000 microgram dose range and are characterised by a high plasma clearance (CL=1.1 l/min). Peak plasma concentrations are reduced by approximately 98% within 3-4 hours and only low plasma concentrations were associated with the 7.8 h terminal half-life. The renal clearance of fluticasone propionate is negligible (<0.2%) and less than 5% as the carboxylic acid metabolite. The major route of elimination is the excretion of fluticasone propionate and its metabolites in the bile.
Plasma elimination half-lives after a single dose of azelastine are approximately 20-25 hours for azelastine and about 45 hours for the therapeutically active metabolite N-desmethylazelastine. Excretion occurs mainly via the faeces. The sustained excretion of small amounts of the dose in the faeces suggests that some enterohepatic circulation may take place.
Findings in general toxicology studies were similar to those observed with other glucocorticoids and are associated with exaggerated pharmacological activity. These findings are not likely to be relevant for humans given recommended nasal doses which results in minimal systemic exposure. No genotoxic effects of fluticasone propionate have been observed in conventional genotoxicity tests. Further, there were no treatment-related increases in the incidence of tumours in two year inhalation studies in rats and mice.
In animal studies glucocorticoids have been shown to induce malformations including cleft palate and intra-uterine growth retardation. Again this is not likely to be relevant for humans given recommended nasal doses which results in minimal systemic exposure (see section 5.2).
Azelastine hydrochloride displayed no sensitising potential in the guinea pig. Azelastine demonstrated no genotoxic potential in a battery of in vitro and in vivo tests, nor any carcinogenic potential in rats or mice. In male and female rats, azelastine at oral doses greater than 3 mg/kg/day caused a dose-related decrease in the fertility index; no substance-related alterations were found in the reproductive organs of males or females during chronic toxicity studies, however, embryotoxic and teratogenic effects in rats, mice and rabbits occurred only at maternal toxic doses (for example, skeletal malformations were observed in rats and mice at doses of 68.6 mg/kg/day).
Repeated dose intranasal toxicity studies in rats for a period up to 90 days and in dogs for 14 days with Azelastine/Fluticasone Nasal Spray revealed no new adverse effects in comparison to the individual components.
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