AVAMYS 27.5mcg/puf nasal spray, suspension medication leaflet

AVAMYS 27.5 micrograms/spray, nasal spray suspension

Each spray actuation delivers 27.5 micrograms of fluticasone furoate.

One actuation delivers 8.25 micrograms of benzalkonium chloride.

For the full list of excipients, see section 6.1.

Nasal spray, suspension.

White suspension.

Avamys is indicated in adults, adolescents and children (6 years and over)

Avamys is indicated for the treatment of the symptoms of allergic rhinitis.

Adults and adolescents (12 years and over)

The recommended starting dose is two spray actuations (27.5 micrograms of fluticasone furoate per sprayactuation) in each nostril once daily (total daily dose, 110 micrograms).

Once adequate control of symptoms is achieved, dose reduction to one spray actuation in each nostril(total daily dose 55 micrograms) may be effective for maintenance.

The dose should be titrated to the lowest dose at which effective control of symptoms is maintained.

Children (6 to 11 years of age)

The recommended starting dose is one spray actuation (27.5 micrograms of fluticasone furoate per sprayactuation) in each nostril once daily (total daily dose, 55 micrograms).

Patients not adequately responding to one spray actuation in each nostril once daily (total daily dose,55 micrograms) may use two spray actuations in each nostril once daily (total daily dose,110 micrograms).

Once adequate control of symptoms is achieved, dose reduction to one spray actuation in each nostril oncedaily (total daily dose, 55 micrograms) is recommended.

For full therapeutic benefit regular, scheduled usage is recommended. Onset of action has been observedas early as 8 hours after initial administration. However, it may take several days of treatment to achievemaximum benefit, and the patient should be informed that their symptoms will improve with continuousregular use (see section 5.1). The duration of treatment should be restricted to the period that correspondsto allergenic exposure.

Children under 6 years of age

The safety and efficacy of Avamys in children under the age of 6 years has not been established. Currentlyavailable data are described in section 5.1 and 5.2 but no recommendation on a posology can be made.

Elderly Patients

No dose adjustment is required in this population (see section 5.2).

Renal Impairment

No dose adjustment is required in this population (see section 5.2).

Hepatic Impairment

No dose adjustment is required in patients with hepatic impairment (see section 5.2).

Avamys nasal spray is for administration by the intranasal route only.

The intranasal device should be shaken before use. The device is primed by pressing the mist releasebutton for at least six spray actuations (until a fine mist is seen), whilst holding the device upright. Re-priming (approximately 6 sprays until a fine mist is seen) is only necessary if the cap is left off for 5 daysor the intranasal device has not been used for 30 days or more.

The device should be cleaned after each use and the cap replaced.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Systemic effects of nasal corticosteroid may occur, particularly at high doses prescribed for prolongedperiods. These effects are much less likely to occur than with oral corticosteroids and may vary inindividual patients and between different corticosteroid preparations. Potential systemic effects mayinclude Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children andadolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects includingpsychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

Treatment with higher than recommended doses of nasal corticosteroids may result in clinically significantadrenal suppression. If there is evidence for higher than recommended doses being used, then additionalsystemic corticosteroid cover should be considered during periods of stress or elective surgery.

Fluticasone furoate 110 micrograms once daily was not associated with hypothalamic-pituitary-adrenal(HPA) axis suppression in adult, adolescent or paediatric subjects. However the dose of intranasalfluticasone furoate should be reduced to the lowest dose at which effective control of the symptoms ofrhinitis is maintained. As with all intranasal corticosteroids, the total systemic burden of corticosteroidsshould be considered whenever other forms of corticosteroid treatment are prescribed concurrently.

If there is any reason to believe that adrenal function is impaired, care must be taken when transferringpatients from systemic steroid treatment to fluticasone furoate.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents withsymptoms such as blurred vision or other visual disturbances, the patient should be considered for referralto an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rarediseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemicand topical corticosteroids.

Growth retardation

Growth retardation has been reported in children receiving nasal corticosteroids at licensed doses. Areduction in growth velocity has been observed in children treated with fluticasone furoate110 micrograms daily for one year (see section 4.8 and section 5.1). Therefore, children should bemaintained on the lowest possible efficacious dose which delivers adequate symptom control (see section4.2). It is recommended that the growth of children receiving prolonged treatment with nasalcorticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim ofreducing the dose of nasal corticosteroid if possible, to the lowest dose at which effective control ofsymptoms is maintained. In addition, consideration should be given to referring the patient to a paediatricspecialist (see section 5.1).

Patients on ritonavir

Concomitant administration with ritonavir is not recommended because of the risk of increased systemicexposure of fluticasone furoate (see section 4.5).

This medicinal product contains benzalkonium chloride. Long-term use may cause oedema of the nasalmucosa.

Interaction with CYP3A inhibitors

Fluticasone furoate is rapidly cleared by extensive first pass metabolism mediated by the cytochrome

P450 3A4.

Based on data with another glucocorticoid (fluticasone propionate), that is metabolised by CYP3A4,coadministration with ritonavir is not recommended because of the risk of increased systemic exposure offluticasone furoate.

Caution is recommended when co-administering fluticasone furoate with potent CYP3A inhibitorsincluding cobicistat-containing products as an increase in the risk of systemic side effects is expected. Co-administration should be avoided unless the benefit outweighs the increased risk of systemic corticosteroidside effects, in which case patients should be monitored for systemic corticosteroid side effects. In a druginteraction study of intranasal fluticasone furoate with the potent CYP3A4 inhibitor ketoconazole therewere more subjects with measurable fluticasone furoate concentrations in the ketoconazole group (6 of the20 subjects) compared to placebo (1 out of 20 subjects). This small increase in exposure did not result in astatistically significant difference in 24 hour serum cortisol levels between the two groups.

The enzyme induction and inhibition data suggest that there is no theoretical basis for anticipatingmetabolic interactions between fluticasone furoate and the cytochrome P450 mediated metabolism ofother compounds at clinically relevant intranasal doses. Therefore, no clinical studies have been conductedto investigate interactions of fluticasone furoate on other drugs.

There are no adequate data from the use of fluticasone furoate in pregnant women. In animal studiesglucocorticoids have been shown to induce malformations including cleft palate and intra-uterine growthretardation. This is not likely to be relevant for humans given recommended nasal doses which results inminimal systemic exposure (see section 5.2). Fluticasone furoate should be used in pregnancy only if thebenefits to the mother outweigh the potential risks to the foetus or child.

It is unknown whether nasal administered fluticasone furoate is excreted in human breast milk.

Administration of fluticasone furoate to women who are breast-feeding should only be considered if theexpected benefit to the mother is greater than any possible risk to the child.

There are no fertility data in humans.

Avamys has no or negligible influence on the ability to drive and use machines.

The most commonly reported adverse reactions during treatment with fluticasone furoate are epistaxis,nasal ulceration and headache. The most serious undesirable effects are rare reports of hypersensitivityreactions, including anaphylaxis (less than 1 case per 1000 patients).

There were over 2700 patients treated with fluticasone furoate in safety and efficacy studies for seasonaland perennial allergic rhinitis. Paediatric exposure to fluticasone furoate in safety and efficacy studies inseasonal and perennial allergic rhinitis included 243 patients 12 to <18 years, 790 patients 6 to <12 yearsand 241 patients 2 to <6 years.

Data from large clinical trials were used to determine the frequency of adverse reactions.

The following convention has been used for the classification of frequencies: Very common ≥1/10;

Common ≥1/100 to <1/10; Uncommon ≥1/1000 to <1/100; Rare ≥1/10,000 to <1/1000; Very rare<1/10,000; Not known (cannot be estimated from the available data).

Rare Hypersensitivity reactions including anaphylaxis, angioedema, rash, andurticaria.

Common Headache.

Not known Transient ocular changes (see Clinical experience), vision blurred (see alsosection 4.4)

Very common *Epistaxis

Common Nasal ulceration, dyspnoea**

Uncommon Rhinalgia, nasal discomfort (including nasal burning, nasal irritation, andnasal soreness), nasal dryness.

Very rare Nasal septum perforation

Not known Bronchospasm

Musculoskeletal and connective tissue disorders (Children)

Not known ***Growth retardation (see Clinical experience).

Epistaxis

*Epistaxis was generally mild to moderate in intensity. In adults and adolescents, the incidence ofepistaxis was higher in longer-term use (more than 6 weeks) than in short-term use (up to 6 weeks).

Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses forprolonged periods (see section 4.4). Growth retardation has been reported in children receiving nasalcorticosteroids.

**Dyspnoea cases were reported in more than 1% of patients during clinical trials with fluticasonefuroate; similar rates were also observed in placebo groups.

The safety in children under 6 years has not been well established. Frequency, type and severity ofadverse reactions observed in the paediatric population are similar to those in the adult population.

Epistaxis

*In paediatric clinical studies of up to 12 weeks duration the incidence of epistaxis was similar betweenpatients receiving fluticasone furoate and patients receiving placebo.

Growth retardation

***In a one-year clinical study assessing growth in pre-pubescent children receiving 110 micrograms offluticasone furoate once daily, an average treatment difference of -0.27 cm per year in growth velocitywas observed compared to placebo (see Clinical efficacy and safety).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In a bioavailability study, intranasal doses of up to 2640 micrograms per day were administered over threedays with no adverse systemic reactions observed (see section 5.2).

Acute overdose is unlikely to require any therapy other than observation.

Pharmacotherapeutic group: Nasal preparations, corticosteroids. ATC code: R01AD12

Fluticasone furoate is a synthetic trifluorinated corticosteroid that possesses a very high affinity for theglucocorticoid receptor and has a potent anti-inflammatory action.

Seasonal Allergic Rhinitis in adults and adolescents

Compared with placebo, fluticasone furoate nasal spray 110 micrograms once daily significantly improvednasal symptoms (comprising rhinorrhoea, nasal congestion, sneezing and nasal itching) and ocularsymptoms (comprising itching/burning, tearing/watering and redness of the eyes) in all 4 studies. Efficacywas maintained over the full 24-hours dosing period with once daily administration.

Onset of therapeutic benefit was observed as early as 8 hours after initial administration, with furtherimprovement observed for several days afterwards.

Fluticasone furoate nasal spray significantly improved the patients’ perception of overall response totherapy, and the patients’ disease-related quality of life (Rhinoconjunctivitis Quality of Life Questionnaire- RQLQ), in all 4 studies.

Perennial Allergic Rhinitis in adults and adolescents

Fluticasone furoate nasal spray 110 micrograms once daily significantly improved nasal symptoms as wellas patients’ perception of overall response to therapy compared to placebo in three studies.

Fluticasone furoate nasal spray 110 micrograms once daily significantly improved ocular symptoms aswell as improving patients’ disease-related quality of life (RQLQ) compared to placebo in one study.

Efficacy was maintained over the full 24-hour dosing period with once daily administration.

In a two-year study designed to assess the ocular safety of fluticasone furoate (110 micrograms once dailyintranasal spray), adults and adolescents with perennial allergic rhinitis received either fluticasone furoate(n=367) or placebo (n=181). The primary outcomes [time to increase in posterior subcapsular opacity(0.3 from baseline in Lens Opacities Classification System, Version III (LOCS III grade)) and time toincrease in intraocular pressure (IOP; 7 mmHg from baseline)] were not statistically significant betweenthe two groups. Increases in posterior subcapsular opacity (0.3 from baseline) were more frequent insubjects treated with fluticasone furoate 110 micrograms [14 (4%)] versus placebo [4 (2%)] and weretransient in nature for ten subjects in the fluticasone furoate group and two subjects in the placebo group.

Increases in IOP (7 mmHg from baseline) were more frequent in subjects treated with fluticasone furoate110 micrograms: 7 (2%) for fluticasone furoate 110 micrograms once daily and 1 (<1%) for placebo.

These events were transient in nature for six subjects in the fluticasone furoate group and one placebosubject. At weeks 52 and 104, 95% of subjects in both treatment groups had posterior subcapsular opacityvalues within ± 0.1 of baseline values for each eye and, at week 104, ≤1% of subjects in both treatmentgroups had 0.3 increase from baseline in posterior subcapsular opacity. At weeks 52 and 104, themajority of subjects (>95%) had IOP values of within ± 5 mmHg of the baseline value. Increases inposterior subcapsular opacity or IOP were not accompanied by any adverse events of cataracts orglaucoma.

Seasonal and perennial allergic rhinitis in children

The paediatric posology is based on assessment of the efficacy data across the allergic rhinitis populationin children.

In seasonal allergic rhinitis, fluticasone furoate nasal spray 110 micrograms once daily was effective butno significant differences were observed between fluticasone furoate nasal spray 55 micrograms oncedaily and placebo on any endpoint.

In perennial allergic rhinitis, fluticasone furoate nasal spray 55 micrograms once daily exhibited a moreconsistent efficacy profile than fluticasone furoate nasal spray 110 micrograms once daily over 4 weeks’treatment. Post-hoc analysis over 6 and 12 weeks in the same study, as well as 6-week HPA axis safetystudy, supported the efficacy of fluticasone furoate nasal spray 110 micrograms once daily.

A 6-week study that assessed the effect of fluticasone furoate nasal spray 110 micrograms once daily onadrenal function in children aged 2 to 11 years showed that there was no significant effect on 24-hourserum cortisol profiles, compared with placebo.

A randomised, double-blind, parallel-group, multicenter, one-year placebo-controlled clinical growthstudy evaluated the effect of fluticasone furoate nasal spray 110 micrograms daily on growth velocity in474 prepubescent children (5 to 7.5 years of age for girls and 5 to 8.5 years of age for boys) withstadiometry. Mean growth velocity over the 52-week treatment period was lower in the patients receivingfluticasone furoate (5.19 cm/year) compared to placebo (5.46 cm/year). The mean treatment differencewas -0.27 cm per year [95% CI -0.48 to -0.06].

Seasonal and perennial allergic rhinitis in children (under 6 years)

Safety and efficacy studies were performed in a total of 271 patients from 2 to 5 years of age in bothseasonal and perennial allergic rhinitis, of whom 176 were exposed to fluticasone furoate.

Safety and efficacy in this group has not been well established.

Fluticasone furoate undergoes incomplete absorption and extensive first-pass metabolism in the liver andgut resulting in negligible systemic exposure. The intranasal dosing of 110 micrograms once daily doesnot typically result in measurable plasma concentrations (<10 pg/mL). The absolute bioavailability forintranasal fluticasone furoate is 0.50 %, such that less than 1 microgram of fluticasone furoate would besystemically available after administration of 110 micrograms (see section 4.9).

The plasma protein binding of fluticasone furoate is greater than 99 %. Fluticasone furoate is widelydistributed with volume of distribution at steady-state of, on average, 608 L.

Fluticasone furoate is rapidly cleared (total plasma clearance of 58.7 L/h) from systemic circulationprincipally by hepatic metabolism to an inactive 17β-carboxylic metabolite (GW694301X), by thecytochrome P450 enzyme CYP3A4. The principal route of metabolism was hydrolysis of the S-fluoromethyl carbothioate function to form the 17β-carboxylic acid metabolite. In vivo studies haverevealed no evidence of cleavage of the furoate moiety to form fluticasone.

Elimination was primarily via the faecal route following oral and intravenous administration indicative ofexcretion of fluticasone furoate and its metabolites via the bile. Following intravenous administration, theelimination phase half-life averaged 15.1 hours. Urinary excretion accounted for approximately 1 % and 2% of the orally and intravenously administered dose, respectively.

In the majority of patients fluticasone furoate is not quantifiable (< 10 pg/mL) following intranasal dosingof 110 micrograms once daily. Quantifiable levels were observed in 15.1 % of paediatric patientsfollowing intranasal dosing of 110 micrograms once daily and only 6.8 % of paediatric patients following55 micrograms once daily. There was no evidence for higher quantifiable levels of fluticasone furoate inyounger children (less than 6 years of age). Median fluticasone furoate concentrations in those subjectswith quantifiable levels at 55 micrograms were 18.4 pg/mL and 18.9 pg/mL for 2-5 yrs and 6-11 yrs,respectively.

At 110 micrograms, median concentrations in those subjects with quantifiable levels were 14.3 pg/mL and14.4 pg/mL for 2-5 yrs and 6-11 yrs, respectively. The values are similar to those seen in adults (12+)where median concentrations in those subjects with quantifiable levels were 15.4 pg/mL and 21.8 pg/mLat 55 micrograms and 110 micrograms, respectively.

Only a small number of elderly patients (≥ 65 years, n=23/872; 2.6 %) provided pharmacokinetic data.

There was no evidence for a higher incidence of patients with quantifiable fluticasone furoateconcentrations in the elderly, when compared with the younger patients.

Fluticasone furoate is not detectable in urine from healthy volunteers after intranasal dosing. Less than 1% of dose-related material is excreted in urine and therefore renal impairment would not be expected toaffect the pharmacokinetics of fluticasone furoate.

There are no data with intranasal fluticasone furoate in patients with hepatic impairment. Data areavailable following inhaled administration of fluticasone furoate (as fluticasone furoate or fluticasonefuroate/vilanterol) to subjects with hepatic impairment that are also applicable for intranasal dosing. Astudy of a single 400 microgram dose of orally inhaled fluticasone furoate in patients with moderatehepatic impairment (Child-Pugh B) resulted in increased Cmax (42 %) and AUC(0-∞) (172 %) and amodest (on average 23 %) decrease in cortisol levels in patients compared to healthy subjects. Followingrepeat dosing of orally inhaled fluticasone furoate/vilanterol for 7 days, there was an increase influticasone furoate systemic exposure (on average two-fold as measured by AUC(0-24)) in subjects withmoderate or severe hepatic impairment (Child-Pugh B or C) compared with healthy subjects. The increasein fluticasone furoate systemic exposure in subjects with moderate hepatic impairment (fluticasonefuroate/vilanterol 200/25 micrograms) was associated with an average 34% reduction in serum cortisolcompared with healthy subjects. There was no effect on serum cortisol in subjects with severe hepaticimpairment (fluticasone furoate/vilanterol 100/12.5 micrograms). Based on these findings the averagepredicted exposure of 110 micrograms of intranasal fluticasone furoate in this patient population wouldnot be expected to result in suppression of cortisol.

Findings in general toxicology studies were similar to those observed with other glucocorticoids and areassociated with exaggerated pharmacological activity. These findings are not likely to be relevant forhumans given recommended nasal doses which results in minimal systemic exposure. No genotoxiceffects of fluticasone furoate have been observed in conventional genotoxicity tests. Further, there were notreatment-related increases in the incidence of tumours in two year inhalation studies in rats and mice.

Glucose anhydrous

Dispersible cellulose

Polysorbate 80

Disodium edetate

Purified water

Not applicable.

3 years

In-use shelf life: 2 months

Do not refrigerate or freeze.

Store upright.

Always keep the cap on.

14.2 mL Type I or Type III amber bottle (glass) fitted with a metering spray pump.

The medicinal product is available in three pack sizes: 1 bottle of 30, 60 or 120 sprays.

Not all pack sizes may be marketed.

No special requirements for disposal.

GlaxoSmithKline (Ireland) Limited12 Riverwalk, Citywest Business Campus

Dublin 24, Ireland

EU/1/07/434/001

EU/1/07/434/002

EU/1/07/434/003

Date of first authorisation: 11 January 2008

Date of latest renewal: 17 December 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency: http://www.ema.europa.eu