Dymista

Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray contains two active substances: azelastine hydrochloride and fluticasone propionate.
Each g of suspension contains 1 mg azelastine hydrochloride and 365 mcg fluticasone propionate.
Each actuation (140 mg) delivers 137 micrograms azelastine hydrochloride (equivalent to 125 micrograms azelastine) and 50 micrograms fluticasone propionate.
Excipients/Inactive Ingredients: Disodium edetate, Glycerol, Microcrystalline cellulose, Carmellose sodium, Polysorbate 80, Benzalkonium chloride, Phenylethyl alcohol, Purified water.

Pharmacologic Category: Anti-allergic - Corticosteroid Combination.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Azelastine hydrochloride + Fluticasone propionate (Dymista) 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: 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 hydrochloride: 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.
Azelastine hydrochloride + fluticasone propionate (Dymista) Nasal Spray: In 4 clinical studies in adults and adolescents with allergic rhinitis, one spray of Azelastine hydrochloride + Fluticasone propionate (Dymista) 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 hydrochloride + Fluticasone propionate (Dymista) Nasal Spray. The superior effect of Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray to fluticasone propionate nasal spray was maintained throughout one-year study in patients with chronic persistent allergic rhinitis and nonallergic/vasomotor rhinitis.
Pharmacokinetics: Absorption: After intranasal administration of two sprays per nostril (548 mcg of azelastine hydrochloride and 200 mcg of fluticasone propionate) of Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray, the mean (± standard deviation) peak plasma exposure (C_max) 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.l pg/mL*hr for fluticasone propionate. The median time to peak exposure (t_max) from a single dose was 0.5 hours for azelastine and 1.0 hours for fluticasone propionate.
There was no evidence of pharmacokinetic interactions between azelastine hydrochloride and fluticasone propionate.
Distribution: 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.
Biotransformation: 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.
Elimination: 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.

Symptomatic treatment of moderate to severe allergic rhinitis and rhino-conjunctivitis in adults and children 12 years and older where use of a combination (intranasal antihistamine and glucocorticoid) is appropriate.
Target Population: Adults and adolescents (12 years and above).

Posology: For full therapeutic benefit regular usage is essential.
Contact with the eyes should be avoided.
Adults and children (12 years and above): One actuation in each nostril twice daily (morning and evening).
Children below 12 years: Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray is not recommended for use in children below 12 years of age as safety and efficacy has not been established in this age group.
Elderly: No dose adjustment is required in this population.
Renal and hepatic impairment: There are no data in patients with renal and hepatic impairment.
Duration of treatment: Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray is suitable for long-term use.
Method of administration: Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray is for nasal use only.
Instruction for use: Preparing the spray: The bottle should be shaken gently before use for about 5 seconds by tilting it upwards and downwards and the protective cap be removed afterwards. Prior to first use, Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray must be primed by pressing down and releasing the pump 6 times. If Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray has not been used for more than 7 days it must be reprimed once by pressing down and releasing the pump.
Using the spray: The bottle should be shaken gently before use for about 5 seconds by tilting it upwards and downwards and the protective cap be removed afterwards.
After blowing the nose, the suspension is to be sprayed once into each nostril keeping the head tilted downward. After use, the spray tip is to be wiped and the protective cap to be replaced.

With the nasal route of administration overdose reactions are not anticipated.
There are no data from patients available on the effects of acute or chronic overdosage with intranasal fluticasone propionate.
Intranasal administration of 2 milligrams fluticasone propionate (10 times the recommended daily dose) twice daily for seven days to healthy human volunteers has no effect on hypothalamo-pituitary-adrenal (HPA) axis function.
Administration of doses higher than those recommended over a long period of time may lead to temporary suppression of adrenal function. In these patients, treatment with Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray should be continued at a dose sufficient to control symptoms; the adrenal function will recover in a few days and can be verified by measuring plasma cortisol.
In the event of overdose after incidental oral uptake, disturbances of the central nervous system (including drowsiness, confusion, coma, tachycardia and hypotension) caused by azelastine hydrochloride are to be expected based on the results of animal experiments.
Treatment of these disorders must be symptomatic. Depending on the amount swallowed, gastric lavage is recommended. There is no known antidote.

Hypersensitivity to the active substances or to any of the excipients.

During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects.
Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Potential systemic effects may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).
Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray undergoes extensive first-pass metabolism, therefore the systemic exposure of intranasal fluticasone propionate in patients with severe liver disease is likely to be increased. This may result in a higher frequency of systemic adverse events. Caution is advised when treating these patients. Treatment with higher than recommended doses of nasal corticosteroids may result in clinically significant adrenal suppression. If there is evidence for higher than recommended doses being used, then additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.
In general, the dose of intranasal fluticasone formulations should be reduced to the lowest dose at which effective control of the symptoms of rhinitis is maintained. Higher doses than the recommended one have not been tested for Azelastine hydrochloride + Fluticasone propionate (Dymista). As with all intranasal corticosteroids, the total systemic burden of corticosteroids should be considered whenever other forms of corticosteroid treatment are prescribed concurrently.
Growth retardation has been reported in children receiving nasal corticosteroids at licensed doses. Since growing up is also given in adolescents, it is recommended that the growth of adolescents receiving prolonged treatment with nasal corticosteroids is regularly monitored, too. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of nasal corticosteroid if possible, to the lowest dose at which effective control of symptoms is maintained.
Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Close monitoring is warranted in patients with a change in vision or with a history of increased ocular pressure, glaucoma and/or cataracts.
If there is any reason to believe that adrenal function is impaired, care must be taken when transferring patients from systemic steroid treatment to Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray.
In patients who have tuberculosis, any type of untreated infection, or have had a recent surgical operation or injury to the nose or mouth, the possible benefits of the treatment with Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray should be weighed against possible risk.
Infections of the nasal airways should be treated with antibacterial or antimycotical therapy, but do not constitute a specific contraindication to treatment with Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray.
Azelastine hydrochloride+ Fluticasone propionate (Dymista) contains benzalkonium chloride. Long term use may cause oedema of the nasal mucosa.

Pregnancy: There are no or limited amount of data from the use of azelastine hydrochloride and fluticasone propionate in pregnant women. Therefore, Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Lactation: It is unknown whether nasally administered azelastine hydrochloride/metabolites or fluticasone propionate/metabolites are excreted in human breast milk. Azelastine hydrochloride + Fluticasone propionate (Dymista) Nasal Spray should be used during lactation only if the potential benefit justifies the potential risk to the newborns/infant.

Commonly, dysgeusia, a substance-specific unpleasant taste, may be experienced after administration (often due to incorrect method of application, namely tilting the head too far backwards during administration).
Adverse reactions are listed as follows by system organ class and frequency. Frequencies are defined as: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1000), Very rare (<1/10,000), Not known (cannot be estimated from the available data). (See table.)

Click on icon to see table/diagram/image

Systemic effects of some nasal corticosteroids may occur, particularly when administered at high doses for prolonged periods.
Growth retardation has been reported in children receiving nasal corticosteroids. Growth retardation may be possible in adolescents, too.
In rare cases osteoporosis was observed if nasal glucocorticoids were administered long-term.

Fluticasone propionate: Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after intranasal dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely.
A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects. Co-treatment with other CYP 3A4 inhibitors, including cobicistat-containing products is also expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.
Studies have shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. Nevertheless, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole), as there is potential for increased systemic exposure to fluticasone propionate.
Azelastine hydrochloride: No specific interaction studies with azelastine hydrochloride nasal spray have been performed. Interaction studies at high oral doses have been performed. However, they bear no relevance to azelastine nasal spray as given recommended nasal doses result in much lower systemic exposure. Nevertheless, care should be taken when administering azelastine hydrochloride in patients taking concurrent sedative or central nervous medications because sedative effect may be enhanced. Alcohol may also enhance this effect.

Do not refrigerate or freeze.
Store at temperatures not exceeding 30°C.
Shelf-life: Bottle with 23 g suspension in 25 ml bottles: 24 months.
In-use shelf life (after first use): 3 months.

Instruction for Use: Preparing the spray: 1. Shake the bottle gently for 5 seconds by tilting it upwards and downwards and then remove the protective cap.
2. The first time the nasal spray is used, the patient must prime the pump by quirting it into the air.
3. Prime the pump by putting two fingers on either side of the spray pump and place the thumb on the bottom of the bottle.
4. Press down and release the pump 6 times until a fine mist appears.
5. Now the pump is primed and ready to use.
6. If the nasal spray has not been used for more than 7 days, the patient will need to re-prime the pump once by pressing down and releasing the pump.
Using the spray: 1. Shake the bottle gently for 5 seconds by tilting it upwards and downwards and then remove the protective cap.
2. Blow the nose to clear the nostrils.
3. Keep the head tilted downwards towards the toes. Do not tilt head backwards.
4. Hold the bottle upright and carefully insert the spray tip into one nostril.
5. Close other nostril with a finger, rapidly press down once and sniff gently at the same time.
6. Breathe out through the mouth.
7. Repeat in the other nostril.
8. 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.
9. After each use, wipe the spray tip with a clean tissue or cloth and then replace the protective cap.
10. Do not prick the nozzle in case spray is not obtained. Clean the actuator with water.

Antihistamines & Antiallergics / Nasal Decongestants & Other Nasal Preparations

R01AD58 - fluticasone, combinations ; Belongs to the class of topical corticosteroids used for prophylaxis and treatment of allergic rhinitis.

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