AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE BIOGARAN 137 µg/50 µg nasal powder suspension Bottle/23g (120 sprays)

Azelastine hydrochloride......................................................................................................................................1 000 micrograms

Fluticasone propionate.................................................................................................................................365 micrograms

Per one mL of suspension.

One spray (0,14 g) delivers a dose containing 137 micrograms of azelastine hydrochloride (equivalent to 125 micrograms of azelastine) and 50 micrograms of fluticasone propionate.

Excipient with known effect: one spray (0,14 g) delivers 0,014 mg of benzalkonium chloride.

For the full list of excipients, see section Composition.

Symptomatic treatment of moderate to severe seasonal and perennial allergic rhinitis when monotherapy with an antihistamine or intranasal glucocorticoid is not considered sufficient.

Dosage

For optimal therapeutic effect, the treatment must be administered regularly.

Avoid any contact with the eyes.

Adults and adolescents (aged 12 years and over)

One spray in each nostril twice a day (morning and evening).

Children under 12 years

AZELASTINE HYDROCHLORIDE / FLUTICASONE PROPIONATE BIOGARAN is not recommended in children under 12 years of age, as safety and efficacy have not been established in this age group.

Elderly patients

No dose adjustment is necessary in elderly subjects.

Hepatic and renal impairment

No data are available in patients with renal and hepatic impairment.

Duration of treatment

The duration of treatment must correspond to the period of exposure to the allergen.

Method of administration

For nasal use only.

Directions for use

Spray preparation :

Before use, the bottle should be shaken gently for about 5 seconds, turning it upside down repeatedly; then the protective cap should be removed. Before first use, AZELASTINE CHLORHYDRATE / FLUTICASONE PROPIONATE BIOGARAN should be primed by actuating the pump 6 times.

If AZELASTINE CHLORHYDRATE / FLUTICASONE PROPIONATE BIOGARAN has not been used for more than 7 days, it will need to be primed again by actuating the pump once.

Use of the spray :

The bottle should be shaken gently before use for about 5 seconds, turning it upside down several times; then the protective cap should be removed. After blowing the nose, one spray of the suspension should be administered into each nostril while keeping the head tilted downward (see figure). After use, the spray nozzle should be wiped and the protective cap replaced.

Hypersensitivity to the active substances or to any of the excipients listed in section Composition.

Clinically significant drug interactions have been reported since marketing, between fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects, notably Cushing's syndrome and inhibition of adrenal function. Consequently, 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 (see section Interactions).

Systemic effects may occur with intranasal corticosteroids, particularly when prescribed at high doses for prolonged periods. The risk of these effects is lower than with oral corticosteroids, and the effects may vary between patients and between corticosteroids used. Potential systemic effects include Cushing's syndrome, a Cushingoid appearance, inhibition of adrenal function, growth retardation in children and adolescents, cataract, glaucoma and, more rarely, psychological or behavioural effects, including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

AZELASTINE CHLORHYDRATE / FLUTICASONE PROPIONATE BIOGARAN undergoes an extensive hepatic first-pass effect; consequently, systemic exposure to fluticasone propionate administered intranasally may increase in patients with severe hepatic impairment, which may result in a higher frequency of systemic adverse effects. Caution is required in cases of severe hepatic impairment.

Treatment at doses above the recommended dose of intranasal corticosteroids may result in clinically significant inhibition of adrenal function. When doses above the recommended doses are necessary, systemic corticosteroid supplementation should be considered during periods of stress or in cases of scheduled surgery.

In general, the dose of intranasal fluticasone should be reduced to the lowest dose allowing effective control of rhinitis symptoms. Doses above the recommended dose (see section Dosage and administration) have not been studied for AZELASTINE CHLORHYDRATE / FLUTICASONE PROPIONATE BIOGARAN. As with all nasal corticosteroids, the total systemic corticosteroid exposure should be taken into account when concomitant corticosteroid therapy in other forms is prescribed.

Growth retardation has been reported in children receiving intranasal corticosteroids at therapeutic doses. Regular monitoring of growth is recommended in adolescents receiving prolonged treatment with intranasal corticosteroids. If growth retardation occurs, treatment should be reviewed with a view to reducing the intranasal corticosteroid dose, if possible, to the minimum effective dose for symptom control.

Visual disturbances may occur with systemic or topical corticosteroid therapy. In case of blurred vision or any other visual symptoms occurring during corticosteroid therapy, an ophthalmic examination is required to look for cataract, glaucoma or rarer conditions such as central serous chorioretinopathy, as described with systemic or topical corticosteroid administration.

Close monitoring is recommended in patients with visual disturbances or a history of elevated intraocular pressure, glaucoma and/or cataracts.

In case of suspected impairment of adrenal function, caution is required when transferring a patient from systemic corticosteroid treatment to treatment with AZELASTINE CHLORHYDRATE / FLUTICASONE PROPIONATE BIOGARAN.

In patients with tuberculosis, untreated infection, or recent injuries or surgical procedures on the nose or mouth, the expected benefit of corticosteroid therapy should be weighed against the risks incurred.

Nasal infections should be treated with antibacterial or antifungal therapy, but do not constitute a specific contraindication to treatment with AZELASTINE CHLORHYDRATE / FLUTICASONE PROPIONATE BIOGARAN.

AZELASTINE CHLORHYDRATE / FLUTICASONE PROPIONATE BIOGARAN contains benzalkonium chloride. Long-term use may cause oedema of the nasal mucosa.

Fluticasone propionateuticasone

Under normal conditions of use, plasma concentrations of fluticasone propionate after intranasal administration are low, due to a significant hepatic first-pass effect and high systemic clearance via cytochrome P450 3A4 in the intestine and liver. The risk of a clinically significant drug interaction related to the presence of fluticasone propionate is low.

A drug interaction study conducted in healthy volunteers showed that ritonavir (a very potent inhibitor of cytochrome P450 3A4) can markedly increase plasma concentrations of fluticasone propionate, leading to a marked reduction in plasma cortisol concentrations. Clinically significant drug interactions have been reported in patients using fluticasone propionate products by intranasal or inhaled routes with ritonavir, resulting in systemic corticosteroid effects. Concomitant administration of CYP3A4 inhibitors, including products containing cobicistat, is expected to increase the risk of systemic side effects. The combination should be avoided, unless the benefits outweigh the increased risk of systemic corticosteroid side effects; in that case, patients should be monitored for possible systemic corticosteroid side effects.

Studies have shown that other cytochrome P450 3A4 inhibitors result in negligible (erythromycins) or small (ketoconazole) increases in systemic exposure to fluticasone propionate without notable decreases in plasma cortisol concentrations. However, caution is required with concomitant administration of potent cytochrome P450 3A4 inhibitors (for example: ketoconazole), due to the risk of increased systemic exposure to fluticasone propionate.

Azelastine hydrochloride

No specific interaction study has been conducted with azelastine hydrochloride nasal spray. Existing interaction studies were conducted orally at high doses and therefore do not reflect the low systemic exposures obtained with the lower doses used nasally. Nevertheless, caution is required when azelastine hydrochloride is administered concomitantly with sedatives or medicines acting on the central nervous system because of the risk of increasing their sedative effect. Alcohol may also enhance this effect (see section Driving and using machines).

Fertility

Data on the effect on fertility are limited (see section Preclinical safety).

Pregnancy

Data on the use of azelastine hydrochloride and fluticasone propionate in pregnant women are limited or non-existent. Therefore AZELASTINE HYDROCHLORIDE / FLUTICASONE PROPIONATE BIOGARAN should be used during pregnancy only if the expected benefit for the mother outweighs the potential risks to the foetus (see section Preclinical safety).

Breast-feeding

The passage of azelastine hydrochloride and its metabolites or of fluticasone propionate and its metabolites into human milk has not been studied. AZELASTINE HYDROCHLORIDE / FLUTICASONE PROPIONATE BIOGARAN should be used during breast-feeding only if the expected benefit for the mother outweighs the potential risks to the newborn or infant.

AZELASTINE HYDROCHLORIDE / FLUTICASONE PROPIONATE BIOGARAN has a minor influence on the ability to drive and use machines.

In isolated cases, a feeling of tiredness, lassitude, exhaustion, weakness or dizziness, which may also be caused by the condition itself, may occur during use of AZELASTINE HYDROCHLORIDE / FLUTICASONE PROPIONATE BIOGARAN. In these cases, the ability to drive and use machines may be impaired. This effect may be potentiated by alcohol consumption.

Dysgeusia with perception of an unpleasant taste specific to the product is frequently felt after administration (often due to excessive backward tilting of the head during administration).

Adverse reactions are listed below by system organ class and by frequency of occurrence. Frequencies are defined as follows:

Very common: (≥ 1/10)

Common:  (≥ 1/100 to <1/10)

Uncommon: (≥ 1/1 000 to < 1/100)

Rare:   (≥ 1/10 000 to < 1/1 000)

Very rare: (< 1/10 000)

Unknown: (the available data do not allow the frequency of occurrence to be estimated).

* A very small number of spontaneous reports have been identified after prolonged treatment with intranasal fluticasone propionate.

** Perforation of the nasal septum has been reported after the use of intranasal corticosteroids.

Intranasal corticosteroids may have systemic effects, particularly when administered at high doses for prolonged periods (see section Warnings and precautions).

Growth retardation has been observed in children receiving intranasal corticosteroids. Growth retardation is also possible in adolescents (see section Warnings and precautions).

In rare cases, osteoporosis has been observed after prolonged use of intranasal glucocorticoids.

Reporting of suspected adverse effects.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/.

No overdose reaction is expected after intranasal administration.

No clinical data are available concerning the effects of acute or chronic overdose of fluticasone propionate.

No effect on the function of the hypothalamic-pituitary-adrenal (HPA) axis was observed with intranasal administration of 2 mg of fluticasone propionate (10 times the recommended daily dose) twice daily for seven days in healthy volunteers.

Administration of doses higher than the recommended long-term doses may cause a temporary inhibition of adrenal function. In this case, treatment with AZELASTINE HYDROCHLORIDE / FLUTICASONE PROPIONATE BIOGARAN must be continued at the minimum effective dose; adrenal function may recover within a few days and can be verified by measuring plasma cortisol.

In case of overdose following accidental ingestion, disturbances of the central nervous system (including drowsiness, confusion, coma, tachycardia and hypotension) caused by azelastine hydrochloride are expected, given the results of studies conducted in animals.

Treatment of these disorders will be symptomatic. Depending on the amount ingested, gastric lavage may be performed. There is no known antidote.

Pharmacotherapeutic class: nasal decongestants and other nasal preparations for topical use, corticosteroids/fluticasone, combinations, ATC code: R01AD58.

Mechanism of action and pharmacodynamic effects.

AZELASTINE HYDROCHLORIDE / FLUTICASONE PROPIONATE BIOGARAN contains azelastine hydrochloride and fluticasone propionate, which have different modes of action and exert synergistic effects on improving the symptoms of allergic rhinitis and allergic rhinoconjunctivitis.

Fluticasone propionate

Fluticasone propionate is a synthetic trifluorinated corticosteroid with a very high affinity for the glucocorticoid receptor and possesses a potent anti-inflammatory action, approximately 3 to 5 times more potent than that of dexamethasone in human glucocorticoid receptor binding tests and gene expression tests.

Azelastine hydrochloride

Azelastine, a phthalazinone derivative, is described as a long-acting anti-allergic selective H1, mast cell stabiliser and exerting anti-inflammatory properties. Data from (preclinical) studies in vivo (preclinical) and in vitro demonstrated an inhibitory effect of azelastine on the synthesis or release of mediators involved in immediate and delayed allergic reactions such as leukotrienes, histamine, platelet-activating factor (PAF) and serotonin.

Relief of nasal allergy symptoms is observed within 15 minutes following intranasal administration.

Azelastine hydrochloride and fluticasone propionate nasal spray

In 4 clinical studies including adults and adolescents with allergic rhinitis, a spray of azelastine hydrochloride and fluticasone propionate in each nostril twice daily significantly relieved nasal symptoms (including rhinorrhea, nasal congestion, sneezing and nasal itching) compared with placebo, azelastine hydrochloride alone and fluticasone propionate alone. Ocular symptoms (including itching, watering/moistening and redness of the eyes) were significantly improved, as was patients' quality of life (RQLQ, Rhinoconjunctivitis Quality of Life questionnaires). in the 4 studies.

An improvement in symptoms (reduction of 50 % in the severity of nasal symptoms) was obtained significantly earlier (3 days and more) with azelastine hydrochloride and fluticasone propionate compared with administration of nasal fluticasone alone. The superiority of the effect obtained with azelastine hydrochloride and fluticasone propionate over a fluticasone propionate-based product was maintained in a one-year study conducted in patients with persistent allergic rhinitis or non-allergic/vasomotor rhinitis.

In an allergen exposure chamber study using ragweed pollen, the first significant relief of nasal symptoms was observed at 5 minutes after administration of azelastine hydrochloride and fluticasone propionate (compared with placebo). A clinically relevant reduction in symptom scores of at least 30 % was reported at 15 minutes after administration of azelastine hydrochloride and fluticasone propionate by 60 % of patients.

Absorption

After intranasal administration of two sprays per nostril (548 µg of azelastine hydrochloride and 200 µg of fluticasone propionate) of azelastine hydrochloride and fluticasone propionate, the mean maximum plasma concentration (± standard deviation) (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 4 217 ± 2 618 pg/mL*h for azelastine and 97,7 ± 43,1 pg/mL*h for fluticasone propionate. The median time to reach maximum concentration (tmax) after a single dose was 0,5 hour for azelastine and one hour for fluticasone propionate.

Systemic exposure to fluticasone propionate was increased by approximately 50 % with azelastine hydrochloride and fluticasone propionate nasal spray compared with a commercially available fluticasone propionate nasal spray. Systemic exposure to azelastine with azelastine hydrochloride and fluticasone propionate nasal spray was equivalent to that obtained with azelastine nasal spray alone. No evidence of pharmacokinetic interactions between azelastine hydrochloride and fluticasone propionate was found.

Distribution

The volume of distribution of fluticasone propionate at steady state is large (approximately 318 litres). Plasma protein binding is 91%.

The volume of distribution of azelastine is high, distributing mainly into peripheral tissues. The protein binding rate is 80-90%. The therapeutic margin of each active ingredient is wide, which makes the risk of significant receptor-level interactions unlikely.

Biotransformation

Fluticasone propionate is rapidly cleared from the systemic circulation, mainly by hepatic metabolism to an inactive carboxylic acid metabolite, by the enzyme CYP3A4 of cytochrome P450. Swallowed fluticasone propionate is also subject to a significant hepatic first-pass effect. Azelastine is metabolised to N-desmethylazelastine by various CYP isoenzymes, mainly CYP3A4, CYP2D6 and CYP2C19.

Elimination

The elimination of intravenously administered fluticasone propionate is linear for doses ranging from 250 to 1 000 micrograms and is characterised by a high plasma clearance (Cl=1,1 L/min). Maximum plasma concentrations decrease by approximately 98% over 3 to 4 hours, and only low plasma concentrations were associated with the terminal half-life of 7,8 h.

Renal clearance of fluticasone propionate is negligible (< 0,2%) and less than 5% is eliminated as the carboxylic acid metabolite. Elimination of fluticasone propionate and its metabolites occurs via biliary secretion.

Plasma elimination half-lives after single-dose administration of azelastine are approximately 20-25 hours for azelastine and approximately 45 hours for its therapeutically active metabolite N-desmethylazelastine. Excretion occurs mainly via the faeces. Prolonged excretion of small amounts of the dose in the faeces suggests that an enterohepatic cycle may take place.

Fluticasone propionate

General toxicology studies found results similar to those of other glucocorticoids, corresponding to exaggerated pharmacodynamic effects. The risk of such observations in humans receiving the recommended therapeutic doses by the nasal route is unlikely given the lower systemic exposures. No genotoxic effects were observed with fluticasone propionate in standard genotoxicity tests. Studies conducted by inhalation for 2 years in rats and mice did not reveal any significant treatment-related increase in the incidence of tumours.

Malformations, including cleft palate and intrauterine growth retardation, were observed in animal studies with fluticasone. These findings are of little predictive value for a risk in humans receiving the treatment at therapeutic doses by the nasal route, given the low systemic exposures (see section Pharmacokinetics).

Azelastine hydrochloride

Azelastine hydrochloride showed no sensitizing potential in guinea pigs. No genotoxic potential of azelastine was observed in 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-dependent decrease in the fertility index; no substance-related alteration was detected in the reproductive organs of males or females during the chronic toxicity studies, but embryotoxic and teratogenic effects were observed in rats, mice and rabbits at maternally toxic doses (for example, skeletal malformations observed in rats and mice at doses of 68,6 mg/kg/day).

Azelastine hydrochloride and fluticasone propionate nasal spray

Intranasal repeated-dose toxicity studies conducted in rats for up to 90 days and in dogs for 14 days with azelastine hydrochloride and fluticasone propionate revealed no new adverse effects compared with each of the active substances individually.

3 years.

Shelf life after first opening (in use): 6 months.

Do not refrigerate. Do not freeze.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

• Allergic rhinitis, second-intention treatment (of the)