Alisade - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each spray actuation delivers 27.5 micrograms of fluticasone furoate.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Nasal spray, suspension.

White suspension.

4.1

Adults, adolescents (12 years and over) and children (6 – 11 y

Alisade is indicated for the treatment of:

• • the symptoms of allergic rhinitis

4.2 Posology and method of administration

Fluticasone furoate nasal spray is for ad

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

Adults and Adolescents (12 years and over)

The recommended starting dose is two spray actuations (27.5 micrograms of fluticasone furoate per spray actuation) 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 spray actuation) 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 once daily (total daily dose, 55 micrograms) is recommended.

Children under 6 years of age: The experience in children under the age of 6 years is limited (see section 5.1 and 5.2). Safety and efficacy in this group has not been well established.

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

Renal Impaired Patients: No dose adjustment is required in this population (see section 5.2).

Hepatic Impaired Patients: No dose adjustment is required in mild to moderate hepatic impairment. There are no data in patients with severe hepatic impairment (see section 4.4 and 5.2).

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

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

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients of Alisade.

4.4 Special warnings and precautions for use

Fluticasone furoate undergoes extensive first-pass metabolism, therefore the systemic exposure of intranasal fluticasone furoate in patients with severe liver disease is likely to be increased. This may result in a higher frequency of systemic adverse events (see section 4.2 and 5.2). Caution is advised when treating these patients.

Ritonavir

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

Systemic effects of nasal corticosteroid may occur, particularly at high doses prescribed for prolonged periods. These effects vary between patients and different corticosteroids (see section 5.2).

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 coosteroid cover should be considered during periods of stress or elective surgery. Fluticasone fur10 micrograms once daily was not associated with hypothalamic-pituitary-adrenal (H is suppression in adult, adolescent or paediatric subjects. However the dose of intranasal flutic furoate should be reduced to the lowest dose at which effective control of the symptoms of rhinitis is maintained. 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 some nasal corticosteroids at licensed doses. It is recommended that the height of children receiving prolonged treatment with nasal corticosteroids is regularly monitored. 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. In addition, consideration should be given to referring the patient to a paediatric specialist (see section 5.1).

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

Nasal and inhaled corticosteriods may result in the development of glaucoma and/or cataracts. Therefore close monitoring is warranted in patients with a change in vision or with a history if increased pressure, glaucoma and/or cataracts.

Alisade contains benzalkonium chloride. It may cause irritation of the nasal mucosa.

4.5 Interaction with other medicinal products and other forms of interaction

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, co-administration with ritonavir is not recommended because of the risk of increased systemic exposure of fluticasone furoate.

Caution is recommended when co-administering fluticasone furoate with potent CYP3A4 inhibitors as an increase in systemic exposure cannot be ruled out. In a drug interaction study of intranasal fluticasone furoate with the potent CYP3A4 inhibitor ketoconazole there were more subjects with measurable fluticasone furoate concentrations in the ketoconazole group (6 of the 20 subjects) compared to placebo (1 out of 20 subjects). This small increase in exposure did not result in a statistically significant difference in 24 hour serum cortisol levels between the two groups (see section 4.4).

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

• 4.6 Pregnancy and lactation

There are no adequate data from the use of fluticasone furoate in pregnant women. In animal studies glucocorticoids have been shown to induce malformations including cleft palate and intra-uterine growth retardation. This is not likely to be relevant for humans given recommended nasal doses which results in minimal systemic exposure (see section 5.2). Fluticasone furoate should be used in pregnancy only if the benefits 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 breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed as fluticasone furoate is not expected to affect this ability.

4.8 Undesirable effects

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.

*Epistaxis was generally mild to moderate in intensity. In adults and adolescents, the incidence of epistaxis was higher in longer-term use (more than 6 weeks) than in short-term use (up to 6 weeks). In paediatric clinical studies of up to 12 weeks duration the incidence of epistaxis was similar between patients receiving fluticasone furoate and patients receiving placebo.

Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods.

4.9 Overdose

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

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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Corticosteroids. ATC code: R01AD12

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

Clinical experience:

Seasonal Allergic Rhinitis in adults and adolescents

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

Perennial Allergic Rhinitis in adults and adolescents:

Fluticasone furoate nasal spray 110 micrograms once daily significantly improved nasal symptoms as well as 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 as well 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.

Seasonal and perennial allergic rhinitis in children:

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

In seasonal allergic rhinitis, fluticasone furoate nasal spray 110 micrograms once daily was effective but no significant differences were observed between fluticasone furoate nasal spray 55 micrograms once daily and placebo on any endpoint.

In perennial allergic rhinitis, fluticasone furoate nasal spray 55 micrograms once daily exhibited a more consistent 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 safety study, 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 on adrenal function in children aged 2 to 11 years showed that there was no significant effect on 24-hour serum cortisol profiles, compared with placebo.

Results from a placebo-controlled knemometry study of fluticasone furoate nasal spray

110 micrograms once daily revealed no clinically relevant effects on short-term lower leg growth rate in children (6 to 11 years).

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 both seasonal and perennial allergic rhinitis, of whom 176 were exposed to fluticasone furoate.

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

5.2 Pharmacokinetic properties

Absorption: Fluticasone furoate undergoes incomplete absorption and extensive first-pass metabolism in the liver and gut resulting in negligible systemic exposure. The intranasal dosing of 110 micrograms once daily does not typically result in measurable plasma concentrations (<10 pg/ml). The absolute bioavailability for intranasal fluticasone furoate is 0.50 %, such that less than 1 microgram of fluticasone furoate would be systemically available after administration of 110 micrograms (see section 4.9).

Distribution: The plasma protein binding of fluticasone furoate is greater than 99 %. Fluticasone furoate is widely distributed with volume of distribution at steady-state of, on average, 608 l.

Metabolism: Fluticasone furoate is rapidly cleared (total plasma clearance of 58.7 l/h) from systemic circulation principally by hepatic metabolism to an inactive 17p-carboxylic metabolite (GW694301X), by the cytochrome P450 enzyme CYP3A4. The principal route of metabolism was hydrolysis of the S-fluoromethyl carbothioate function to form the 17p-carboxylic acid metabolite. In vivo studies have

revealed no evidence of cleavage of the furoate

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

Children:             Xjv

In the majority of patients fluticasone furoate is not quantifiable (< 10 pg/ml) following intranasal dosing of 110 micrograms once daily. Quantifiable levels were observed in 15.1 % of paediatric patients following intranasal dosing of 110 micrograms once daily and only 6.8 % of paediatric patients following 55 micrograms once daily. There was no evidence for higher quantifiable levels of fluticasone furoate in younger children (less than 6 years of age). Median fluticasone furoate concentrations in those subjects with 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 and 14.4 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/ml at 55 micrograms and 110 micrograms, respectively.

Elderly:

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 furoate concentrations in the elderly, when compared with the younger patients.

Renal Impairment:

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 to affect the pharmacokinetics of fluticasone furoate.

Hepatic Impairment:

There are no data with intranasal fluticasone furoate in patients with hepatic impairment. A study of a single 400 microgram dose of orally inhaled fluticasone furoate in patients with moderate hepatic impairment resulted in increased Cmax (42 %) and AUC(O-x) (172 %) and a modest (on average 23 %) decrease in cortisol levels in patients compared to healthy subjects. From this study the average predicted exposure of 110 micrograms of intranasal fluticasone furoate in patients with moderate hepatic impairment would not be expected to result in suppression of cortisol. Therefore moderate hepatic impairment is not predicted to result in a clinically relevant effect for the normal adult dose. There are no data in patients with severe hepatic impairment. The exposure of fluticasone furoate is likely to be further increased in such patients.

5.3 Preclinical safety data

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

6.1 List of excipients

Glucose anhydrous

Dispersible cellulose

Polysorbate 80

Benzalkonium chloride

Disodium edetate

Purified water

6.2 Incompatibilities

KV

Not applicable.

6.3 Shelf life

• 3 years

In-use shelf life: 2 months

6.4 Special precautions for storage

Do not refrigerate or freeze.

6.5 Nature and contents of container

Alisade nasal spray is a predominantly off-white plastic device with a dose indicator window, light blue side actuated lever and lid which contains a stopper. The plastic device contains the nasal spray suspension within a Type I amber bottle (glass) fitted with a metering spray pump.

The medicinal product is available in three pack sizes: 30, 60 and 120 sprays.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Glaxo Group Ltd

Greenford, Middlesex, UB6 0NN

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/474/001

EU/1/08/474/002

EU/1/08/474/003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF T