FLUTICON-AZ
Each spray delivers:
Azelastine Hydrochloride IP 137 mcg
Fluticasone Propionate IP 50 mcg
COMPOSITION
Azelastine Hydrochloride IP 0.1% w/w
Fluticasone Propionate IP 0.0365% w/w
Benzalkonium Chloride Solution BP 0.02 % w/w (as preservative)
DESCRIPTION
A white to off-white colored homogenous re-dispersible suspension.
PHARMACODYNAMIC
Pharmacotherapeutic group: Decongestants and other nasal preparations for topical use, corticosteroids/ fluticasone, combinations.
ATC Code: R01AD58.
Mechanism of action and pharmacodynamic effects
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
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/Fluticasone Nasal Spray
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 rhinorrhea, 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 (Rhino conjunctivitis 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%.
PHARMACOKINETICS
Absorption
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.
Distribution
Fluticasone propionate has a large volume of distribution at steady-state (approximately 318 liter). Plasma protein binding is 91%.
The volume of distribution of azelastine is high indicating distribution predominantly into the peripheral tissue. 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.
THERAPEUTIC INDICATION
Relief of symptoms of moderate to severe seasonal and perennial allergic rhinitis if monotherapy with either intranasal antihistamine or glucocorticoid is not considered sufficient.
DOSAGE AND ADMINISTRATION
For full therapeutic benefit regular usage is essential.
Contact with the eyes should be avoided.
Adults and adolescents (12 years and older)
One actuation in each nostril twice daily (morning and evening).
Children below 12 years
Azelastine/Fluticasone 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/Fluticasone Nasal Spray is suitable for long-term use.
The duration of treatment should correspond to the period of allergenic exposure.
Method of administration
Azelastine/Fluticasone Nasal Spray is for nasal use only.
INSTRUCTION FOR USE
Apply FLUTICON-AZ Nasal Spray in the following way:
- Shake the bottle well before using the nasal spray.
- Blow your nose gently.
- Remove the dust cap of the bottle and keep its tip between your index finger and middle finger with thumb at the bottom.
- If you are using this nasal spray for the first time or have not used it for a week or more, then examine it by spraying it, away from you in the air, few times until a fine mist appears.
- To use the spray, tilt your head forward slightly while breathing out.
- Carefully insert the nozzle tip into one of the nostrils.
- Remember to point the nozzle tip towards the corner of your eye or ear and not towards the center of your nose.
- Press down with your fingers once to release a spray.
- Pull out the nozzle tip from the nostril.
- Close the other nostril with your finger and breathe slowly through your nose and exhale slowly through mouth.
- If you have been prescribed the second dose in the same nostril, wait a minute or two and repeat the process.
- Repeat STEPS 5 through 10 for the other nostril.
- After use, wipe the nozzle with a clean handkerchief or tissue and replace the dust cap.
- Do not blow your nose for few minutes after using the spray.
- Use the nasal spray as per your doctor’s recommendation and do not exceed the dose.
CONTRAINDICATION
FLUTICON-AZ aqueous nasal spray is contradicted in patients with a hypersensitivity to any of its ingredients.
OVERDOSE
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/Fluticasone 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.
WARNING AND PRECAUTIONS
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/Fluticasone 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/Fluticasone. 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/Fluticasone 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/Fluticasone 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/Fluticasone Nasal Spray.
Azelastine/Fluticasone Nasal Spray contains benzalkonium chloride. Long term use may cause oedema of the nasal mucosa.
DRUG INTERACTION
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.
PREGNANCY, LACTATION, FERTILITY AND ABILITY TO DRIVE OR USE MACHINE
Pregnancy
There are no or limited amount of data from the use of azelastine hydrochloride and fluticasone propionate in pregnant women. Therefore, Azelastine/Fluticasone 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/Fluticasone Nasal Spray should be used during lactation only if the potential benefit justifies the potential risk to the newborns/infant.
Fertility
There are only limited data with regard to fertility.
Effects on ability to Drive & Use Machine
Azelastine/Fluticasone Nasal Spray has minor influence on the ability to drive and use machines.
In isolated cases fatigue, weariness, exhaustion, dizziness or weakness that may also be caused by the disease itself, may occur when using Azelastine/Fluticasone Nasal Spray. In these cases, the ability to drive and use machines may be impaired. Alcohol may enhance this effect.
UNDESIRABLE EFFECTS
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 below by system organ class and frequency. Frequencies are defined as:
| System organ class | Frequency | Adverse reactions |
| Immune system disorders | Very Rare | Hypersensitivity including anaphylactic reactions, angioedema (oedema of the face or tongue and skin rash), bronchospasm |
| Immune system disorders | Common | Headache, Dysgeusia (unpleasant taste), unpleasant smell |
| Very Rare | Dizziness, somnolence (drowsiness, sleepiness) | |
| Eye disorders | Very Rare | Glaucoma, increased intraocular pressure, cataract |
| Not Known | Vision, blurred | |
| Respiratory, thoracic and mediastinal disorders
|
Very Common | Epistaxis |
| Uncommon | Nasal discomfort (including nasal irritation, stinging, itching), sneezing, nasal dryness, cough, dry throat, throat irritation | |
| Very Rare | Nasal septal perforation, mucosal erosion | |
| Not Known | Nasal ulcers | |
| Gastrointestinal disorders | Rare | Dry mouth |
| Very Rare | Nausea | |
| Skin and subcutaneous tissue disorders | Very rare | Rash, pruritus, urticaria |
| General disorders and administration site conditions | Very rare | Fatigue (weariness, exhaustion), weakness |
PRESENTATION
FLUTICON-AZ Nasal Sprays are supplied in 10 ml polypropylene translucent nasal spray bottles containing 70 metered doses.
STORAGE AND OTHER INFORMATION
Store at temperature below 30 °C. Keep this medicine out of the sight and reach of children. Do not touch the spray tip to any surface since this may contaminate the solution.
For further information, please contact
Magnus Pharma Pvt. Ltd.
Marketing office: Lekhnath Marg, Thamel, Kathmandu, Nepal
Phone No. 00977-1-5366878
Email: [email protected]