Azelastine hydrochloride, fluticasone propionate.
One actuation (0.14 g) delivers azelastine hydrochloride 137 micrograms and fluticasone propionate 50 micrograms.
Azelastine hydrochloride is a white, odorless, crystalline powder with a bitter taste. It has a molecular weight of 418.37. It is sparingly soluble in water, methanol, and propylene glycol and slightly soluble in ethanol, octanol, and glycerin. It has a melting point of 225°C and the pH of 5.2. Its chemical name is (±)-1-(2H)-phthalazinone,4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-,monohydrochloride.
Its molecular formula = C22H24ClN3O·HCl.
Fluticasone propionate is a synthetic corticosteroid, a white powder with a melting point of 273°C, a molecular weight of 500.6. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. Fluticasone propionate having the chemical name S-(fluoromethyl)-6alpha,9-difluoro-11 Beta,-17-dihydroxy-16alpha-methyl-3-oxoandrosta-1,4-diene-17 Beta-carbothioate, 17-propionate, the molecular formula = C25H31F3O5S.
Excipients/Inactive ingredients: Disodium edetate, glycerol, microcrystalline cellulose, carmellose sodium, polysorbate 80, benzalkonium chloride, phenylethyl alcohol and purified water.
ATC Code: R01AD58.
Pharmacology: Pharmacodynamics: Azelastine hydrochloride, a phthalazinone derivative, inhibits histamine H1 receptor activity in blood vessels and respiratory tract providing hyper-reactivity of airway reduction, bronchial epithelial cilia motility increase and mucociliary transport improvement. The onset of action will be achieved within 30 minutes to 1 hour and reached the maximum effect in 3 hours. The inhibition is lasting for 12 hours.
Fluticasone propionate: It is a synthetic trifluorinated corticosteroid. The precise mechanism for allergic rhinitis symptoms is not known but corticosteroids have been shown a wide range of effects on mediator cells (e.g., basophils, eosinophils, T-helper cells, mast cells, neutrophils) in nasal mucosa, nasal reactivity for allergens, and release of inflammatory mediators and proteolytic enzymes. Additionally, fluticasone propionate may decrease histamine and tryptase releasing from nasal mucosa. The maximum effect of fluticasone propionate may take several days after regular use.
Pharmacokinetics: Absorption: After intranasal administration of two sprays per nostril (548 mcg of azelastine hydrochloride and 200 mcg of fluticasone propionate) of Dymista Nasal Spray, the mean (± standard deviation) peak plasma exposure (Cmax) was 194.5 ± 74.4 pg/mL for azelastine hydrochloride and 10.3±3.9 pg/mL for fluticasone propionate and the AUC was 4217 ± 2618 pg/mL*hr for azelastine hydrochloride and 97.7 ± 43.1 pg/mL*hr for fluticasone propionate. The median time to peak exposure (tmax) from a single dose was 0.5 hours for azelastine hydrochloride and 1.0 hours for fluticasone propionate.
Bioavailability of azelastine from Dymista Nasal Spray following intranasal administration was comparable with monotherapy azelastine hydrochloride (Astelin) nasal spray (i.e., approximately 40%).
Bioavailability of fluticasone from Dymista Nasal Spray following intranasal administration was 44-61% higher than monotherapy fluticasone propionate (bioavailability for monotherapy fluticasone nasal spray was less than 2%). Due to the low intranasal bioavailability, pharmacokinetic data for fluticasone propionate were obtained via other routes of administration. Studies using oral dosing of radiolabeled fluticasone propionate showed negligible oral bioavailability and high extraction from plasma. The majority of the circulating radioactivity was due to an inactive metabolite.
Distribution: Based on intravenous and oral administration, the steady-state volume of distribution of azelastine hydrochloride is 14.5 L/kg. In vitro, indicate that the plasma protein binding of azelastine hydrochloride and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively.
Following intravenous administration, the volume of distribution averaged 4.2L/kg. The percentage of fluticasone propionate bound to human plasma proteins averaged 91%.
Metabolism: Azelastine hydrochloride is oxidatively metabolized to the principal active metabolite, desmethyl-azelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified. The total clearance of azelastine is approximately 0.50 L/kg/hr.
For fluticasone propionate, the only circulating metabolite detected in man is the 17-Beta carboxylic acid derivative, which is formed through the CYP3A4 pathway. This inactive metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol (In vitro). Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. The average total clearance of fluticasone propionate is relatively high (approximately 66 L/hr).
Elimination: Following intranasal administration of Dymista Nasal Spray, the elimination half-life of azelastine hydrochloride is approximately 25 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.
Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.
Toxicology: Preclinical safety data: Dymista Nasal Spray: No studies of carcinogenicity, mutagenicity, or fertility were conducted with Dymista Nasal Spray; however, studies are available for the individual active components, azelastine hydrochloride and fluticasone propionate, as described as follows.
Azelastine hydrochloride: the carcinogenicity studies in rats and mice, azelastine hydrochloride did not show evidence of carcinogenicity at oral doses up to 30 mg/kg and 25 mg/kg, respectively. These doses were approximately 240 and 100 times of the maximum recommended human daily intranasal dose on a mg/m2 basis.
Additionally, there were no genotoxic effects in the Ames test, DNA repair test, mouse lymphoma forward mutation assay, mouse micronucleus test, or chromosomal aberration test in rat bone marrow.
Fertility studies in rats showed no effects on male or female fertility at oral doses up to 30 mg/kg (approximately 240 times of the maximum recommended human daily intranasal dose on a mg/m2 basis). At 68.6 mg/kg (approximately 550 times of the maximum recommended human daily intranasal dose on a mg/m2 basis), the duration of estrous cycles was prolonged and copulatory activity and the number of pregnancies were decreased. The numbers of corpora lutea and implantations were decreased; however, implantation ratio was not affected.
Fluticasone propionate: no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 20 times the maximum recommended daily (MRD) intranasal dose in adults and approximately 10 times the maximum recommended daily intranasal dose in children) for 78 weeks or in rats at inhaled doses up to 57 mcg/kg (approximately 2 times the MRD in adults and equal to MRD intranasal dose in children) for 104 weeks. Moreover, fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells In vitro. No evidence of fertility impairment in male and female rats received subcutaneous doses up to 50 mcg/kg (approximately 2 times the MRD intranasal dose in adults on a mcg/m2 basis).
Dymista Nasal Spray uses for relief of symptoms of moderate to severe: Seasonal allergic rhinitis in adult and children over 6 years old; Perennial allergic rhinitis in adult and children over 12 years old if the use of either intranasal antihistamine or corticosteroid alone is not considered sufficient.
Posology: Children under 6 years: This medicine is not recommended for children under 6 years.
Adults and adolescents (children 6 years and above): one spray into each nostril in the morning and evening.
Special populations: Renal and hepatic impairment: There are no data in patients with renal and hepatic impairment.
Method of administration: For nasal use only. Read the following instructions carefully and use only as directed.
Preparing the spray: Shake the bottle gently for 5 seconds by tilting it upwards and downwards and then remove the protective cap.
The first time the nasal spray is used, the pump must be primed by squirting it into the air.
Prime the pump by putting two fingers on either side of the spray pump and place the thumb on the bottom of the bottle.
Press down and release the pump 6 times until a fine mist appears.
Now the pump is primed and ready to use.
If the nasal spray has not been used for more than 7 days, the pump needs to be re-primed once by pressing down and releasing the pump.
Using the spray: Shake the bottle gently for 5 seconds by tilting it upwards and downwards and then remove the protective cap.
Blow the nose to clear nostrils.
Keep the head tilted downwards towards the toes. Do not tilt head backwards.
Hold the bottle upright and carefully insert the spray tip into one nostril.
Close other nostril with a finger, rapidly press down once and sniff gently at the same time.
Breathe out through the mouth.
Repeat in other nostril.
Breathe in gently, and do not tilt the head back after dosing. This will stop the medicine going into the throat and causing an unpleasant taste.
After each use wipe the spray tip with a clean tissue or cloth and then replace the protective cap.
Do not prick the nozzle in case spray is not obtained. Clean the actuator with water.
Azelastine hydrochloride: There have been no reported of azelastine hydrochloride overdosage. Acute azelastine hydrochloride overdosage is increased somnolence. Since one bottle contains approximately 17 mg of azelastine hydrochloride and single dose of the oral formulation of azelastine hydrochloride (up to 16 mg) have not resulted in increased incidence of serious adverse events.
In mice given oral azelastine hydrochloride > 120 mg/kg body weight (480 times of the maximum recommended human daily nasal dose based on mg/m2) caused significant mortality, preceded by tremor, convulsion, decreased muscle tone and salivation. In dogs, 10 mg/kg or 270 times of the maximum recommended human daily nasal dose (mg/m2 basis) as a single dose did not reveal any overdosage signs or symptoms but 20 mg/kg dosing caused lethal.
General supportive measures should be employed if overdosage occurs because there is no specific antidote for azelastine hydrochloride.
Fluticasone propionate: Intranasal administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily for 7 days to healthy human volunteers was well tolerated. Single oral fluticasone propionate doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. In contrast, oral doses 40 mg to 80 mg daily for 10 days caused hypothalamus-Pituitary-Adrenal axis suppression.
In animal studies, given high-dose fluticasone propionate via subcutaneous, oral and inhalation shown reversible thymus gland depletion and gastric ulcer.
If chronic overdose symptoms occur, fluticasone propionate should be gradually discontinued.
Do not use Dymista Nasal Spray if allergic to azelastine hydrochloride or fluticasone propionate or any of the other ingredients of this medicine (listed under Description).
Use with caution in patient with/untreated tuberculosis or the infection of bacteria, fungal, virus, history of increased ocular pressure, glaucoma and/or cataracts.
Contact with the eyes should be avoided.
This medicine contains benzalkonium chloride. It may cause irritation of the nasal mucosa and bronchospasm.
Effects on ability to drive and use machines: Dymista Nasal Spray has minor influence on the ability to drive or use machines due to azelastine hydrochloride might cause somnolence. Very rarely, the patient may experience dizziness or drowsiness due to the disease itself or using Dymista Nasal Spray. In these cases, do not drive or operate machinery. Please be aware that alcohol drinking or other central nervous system depressants may enhance these effects.
Use in Children: Taking nasal glucocorticoids (such as Dymista) for a long time cause children and adolescents to grow more slowly. The doctor will check the child's height regularly and make sure he or she is taking the lowest possible effective dose.
Not recommended for children under 6 years.
Pregnancy: Pregnancy Category C.
Azelastine hydrochloride: Although the adequate and well-controlled studies in human have not been done but studies in animals have shown teratogenic effects and classified as pregnancy category C. In mice received oral azelastine hydrochloride 68.6 mg/kg/day (280 times of the maximum recommended human daily nasal dose which based on mg/m2) shown external and skeletal abnormalities, embryotoxic, fetotoxic and teratogenic. It is similar to abortion and fetotoxic effects in rats receiving oral azelastine hydrochloride 68.6 mg/kg/day (550 times of the maximum recommended human daily nasal dose which based on mg/m2). In rats given oral azelastine hydrochloride 30 mg/kg/day (240 times of the maximum recommended human daily nasal dose which based on mg/m2) caused delayed ossification (undeveloped metacarpus) and increased incidence of 14th rib.
Fluticasone propionate: Fluticasone propionate classifies as pregnancy category C and corticosteroids have been shown the teratogenicity in animals. Subcutaneous fluticasone propionate was given in the mouse and rats at the dosing equivalent to 4 times of the MRD in adult humans based on a mcg/m2 (45 and 100 mcg/kg, respectively), revealed fetal toxicity including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification. The fetal weight reduction and cleft palate also observed in rabbits receiving subcutaneous fluticasone propionate at 4 mcg/kg dosing (less than the MRD in adult humans on a mcg/m2 basis) but there was no teratogenic reports in rabbits given the oral dose 300 mcg/kg which is 25 times the MRD in adult humans on a mcg/m2 basis. Fluticasone propionate crossed the placenta following the 1,000 mcg/kg oral administration in rats and the 300 mcg/kg oral dosing in rabbits (approximately 4 and 25 times the MRD intranasal dose for adult humans on a mcg/m2 basis, respectively).
Lactation: It is not known whether Dymista Nasal Spray is excreted in human breast milk.
Azelastine hydrochloride: It is not known if azelastine hydrochloride is excreted in human milk.
Fluticasone propionate: Thought, it is not known whether fluticasone propionate is excreted in human milk but it should be considered because the systemic corticosteroids distribute into breast milk.
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Nasal fluticasone propionate affects to the normal production of hormones in the body, particularly if using high doses for a long time. Blurred vision, bone fracture, excess hair growth in female, rounding of face/neck/ trunk, hypertension, increased thirst and urination, impotence in male, lack of menstruation, muscle wasting or weakness might occur. Moreover, the prolonged treatment in children and adolescents might cause them grow more slowly than others.
The drug-interaction studies have not been performed with Dymista Nasal Spray. The coadministration with strong cytochrome P-450 (CYP) 3A4 inhibitors (e.g., ritonavir, ketoconazole) should be concerned because they affect to plasma concentration of fluticasone propionate.
Incompatibilities: Not applicable.
Store upright with the dust cap in place at controlled room temperature 30°C.
Protect from light. Do not store in the freezer or refrigerator.
Do not throw away any medicines via wastewater or household waste.
Shelf-life: Shelf life after first opening: Dispose of any unused medicine 6 months after first opening the nasal spray.
R01AD58 - fluticasone, combinations ; Belongs to the class of topical corticosteroids used for prophylaxis and treatment of allergic rhinitis.
Dymista nasal spray
25 mL x 1's
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