AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE TEVA 137 µg/50 µg Nasal spray suspension Fl/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 older)

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

Children elderly under 12 years

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

Persons elderlyes

No dose adjustment is necessary in this population.

Hepatic and renal impairment

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

Duration of treatment

AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE TEVA is suitable for long-term use.

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

Method of administration

AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE TEVA must be used exclusively by the nasal route.

Directions for use

Spray preparation :

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

If AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE TEVA has not been used for more than 7 days, it must be primed again. The bottle must be shaken gently before use for about 5 seconds, by turning it upside down repeatedly, the protective cap must be removed and the pump must be pressed and released once.

Use of the spray :

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 tip must be wiped and the protective cap replaced.

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

Since marketing, clinically significant drug interactions have been reported 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 (see section Interactions).

Systemic effects may occur with nasally administered 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, cushingoid appearance, adrenal suppression, 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 HYDROCHLORIDE/FLUTICASONE PROPIONATE TEVA undergoes a significant hepatic first-pass effect; therefore, systemic exposure to intranasally administered fluticasone propionate may increase in patients with severe hepatic impairment, which may lead to a higher frequency of systemic adverse events.

Caution is advised when treating these patients.

Treatment at doses above the recommended doses of nasal corticosteroids may result in clinically significant adrenal suppression. When doses above the recommended doses are necessary, systemic corticosteroid supplementation should be considered during periods of stress or in case 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 HYDROCHLORIDE/FLUTICASONE PROPIONATE TEVA. As with all nasal corticosteroids, the total systemic corticosteroid exposure must be taken into account when concomitantly prescribing other forms of corticosteroid therapy.

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

Visual disturbances may be reported during systemic or topical corticosteroid therapy. If a patient presents with symptoms such as blurred vision or other visual disturbances, referral to an ophthalmologist should be considered to evaluate possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR), which have been reported after the use of systemic or topical corticosteroids.

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

If impairment of adrenal function is suspected, caution is required when switching from systemic corticosteroid treatment to AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE TEVA.

In patients with tuberculosis, an untreated type of infection, or in case of recent injuries or surgical procedures involving the nose or mouth, the potential benefits of treatment with AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE TEVA must be weighed against the risks.

Nasal airway infections must be treated with antibacterial or antifungal therapy, but do not constitute a specific contraindication to treatment with AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE TEVA.

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

Fluticasone propionate

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 clinically significant drug interactions related to fluticasone propionate is low.

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

Studies have shown that other cytochrome P450 3A4 inhibitors led to negligible (erythromycins) or small (ketoconazole) increases in systemic exposure to fluticasone propionate without a notable decrease in serum 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. Interaction studies at high oral doses have been performed. However, these are not relevant to azelastine nasal spray because the recommended nasal doses result in much lower systemic exposure. oral high doses have been performed. However, these are not relevant to azelastine nasal spray because the recommended nasal doses result in much lower systemic exposure. Nevertheless, caution is advised when azelastine hydrochloride is co-administered with sedatives or medicinal products acting on the central nervous system, due to the risk of increased sedative effect. Alcohol may also potentiate 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 TEVA should only be used during pregnancy if the potential benefit outweighs the 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 breast milk has not been studied. AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE TEVA should only be used during breastfeeding if the expected benefit for the mother outweighs the potential risk to the newborn/infant.

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

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

Dysgeusia, perception of an unpleasant taste specific to the substance, is frequently felt after administration (often due to tilting the head too far back during administration).

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

Very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1 000, < 1/100), rare (≥ 1/10 000, < 1/1 000), very rare (< 1/10 000), frequency not known (cannot be estimated from the available data).

* 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.

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

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

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

Reporting of suspected adverse reactions

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 data are available on the effects of acute or chronic overdose of intranasal fluticasone propionate.

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

Administration of doses higher than the recommended doses over the long term may lead to temporary inhibition of adrenal function.

In these patients, treatment with AZELASTINE HYDROCHLORIDE/FLUTICASONE PROPIONATE TEVA should be continued at a dose sufficient to control symptoms; 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 animal studies.

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

Pharmacotherapeutic class: Decongestants and other nasal preparations for topical use, corticosteroids/fluticasone, in combination, ATC code: R01AD58.

Mechanism of action and effects pharmacodynamic

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

Fluticasone propionate

Fluticasone propionate is a synthetic trifluorinated corticosteroid with very high affinity for the glucocorticoid receptor and it has a potent anti-inflammatory action, approximately 3 to 5 times more potent than that of dexamethasone observed 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 H antagonist receptor1, 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 known to be 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 administration.

Nasal spray of azelastine hydrochloride and pluticasone propionate

In 4 clinical studies including adults and adolescents with allergic rhinitis, one spray of azelastine hydrochloride and fluticasone propionate nasal spray 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 eye redness) were significantly improved, as was patients' quality of life (RQLQ, Rhinoconjunctivitis Quality of Life Rhinoconjunctivitis Quality of Life) in the 4 studies.

Improvement in symptoms (50% reduction in the severity of nasal symptoms) was obtained significantly earlier (3 days or more) with azelastine hydrochloride and fluticasone propionate nasal spray compared with a commercial fluticasone propionate nasal spray. The statistically significant effect obtained with azelastine hydrochloride and fluticasone propionate nasal spray, compared with a fluticasone propionate nasal spray, was maintained in a one-year study in patients with persistent allergic rhinitis or non-allergic/vasomotor rhinitis.

In a chamber study exposed to ragweed pollen allergens, the first statistically significant relief of nasal symptoms was observed within 5 minutes following administration of azelastine hydrochloride and fluticasone propionate nasal spray (compared with placebo). A clinically relevant reduction in symptom scores of at least 30% was reported within 15 minutes following administration of azelastine hydrochloride and fluticasone propionate nasal spray by 60% of patients.

Absorption

After intranasal administration of two sprays per nostril (548 micrograms of azelastine hydrochloride and 200 micrograms of fluticasone propionate) of azelastine hydrochloride and fluticasone propionate nasal spray, 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 elapsed to reach maximum concentration (tmax) after a single dose was 0,5 hour for azelastine and 1,0 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 commercial fluticasone propionate nasal spray. Systemic exposure to azelastine with azelastine hydrochloride and fluticasone propionate nasal spray was equivalent to that obtained with commercial azelastine nasal spray. 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, making 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 rate of fluticasone propionate administered intravenously 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 % within 3 to 4 hours, and only low plasma concentrations have been 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 following administration of a single dose 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 quantities of the dose in the faeces appears to indicate that an enterohepatic cycle may be involved.

Fluticasone propionate

The results of general toxicology studies were similar to those observed with other glucocorticoids and correspond to exaggerated pharmacodynamic effects. These results are unlikely to be relevant to humans, given the recommended intranasal doses, which result in low systemic exposure. No genotoxic effect was observed with fluticasone propionate in standard genotoxicity tests. Two-year inhalation studies conducted in rats and mice did not demonstrate any significant treatment-related increase in tumour incidence.

Malformations, including cleft palate and intrauterine growth retardation, were observed in animal studies with glucocorticoids. Again, this is unlikely to be relevant to humans, given the recommended intranasal doses, which result in low systemic exposure (see section Pharmacokinetics).

Azelastine hydrochloride

Azelastine hydrochloride showed no sensitising potential in guinea pigs. No genotoxic potential of azelastine was demonstrated in the tests performed in vitro and in vivo, and no carcinogenic potential was demonstrated in rats or mice. In male and female rats, azelastine at oral doses above 3 mg/kg/day caused a dose-dependent decrease in the fertility index; no substance-related alterations were detected in the reproductive organs of males or females during chronic toxicity studies; however, embryotoxic and teratogenic effects were observed in rats, mice and rabbits at maternotoxic doses (for example, skeletal malformations observed in rats and mice at doses of 68,6 mg/kg/day).

Nasal spray of azelastine hydrochloride and pluticasone propionate

Repeated-dose intranasal toxicity studies conducted in rats for up to 90 days and in dogs for 14 days with the azelastine hydrochloride and fluticasone propionate nasal spray revealed no new adverse effects compared with the individual active substances.

3 years.

Shelf life after first opening of the container: 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)