AVAMYS

Israel - English - Ministry of Health

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Active ingredient:
FLUTICASONE FUROATE
Available from:
GLAXO SMITH KLINE (ISRAEL) LTD
ATC code:
R01AD12
Pharmaceutical form:
SPRAY
Composition:
FLUTICASONE FUROATE 27.5 MCG/DOSE
Administration route:
NASAL
Prescription type:
Required
Manufactured by:
GLAXO OPERATIONS (UK) LIMITED
Therapeutic group:
FLUTICASONE
Therapeutic area:
FLUTICASONE FUROATE
Therapeutic indications:
AVAMYS (fluticasone furoate) Nasal Spray is indicated for the treatment of the symptoms of seasonal and perennial allergic rhinitis in patients aged 2 years and older.
Authorization number:
141 80 31837 00
Authorization date:
2014-10-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Hebrew

17-08-2016

ראוני

2019

: ןודנה

Avamys

סימאבא /

Fluticasone Furoate 27.5 MCG/Dose

Nasal Spray

ה/דבכנ ה/אפור

,ה/דבכנ ת/חקור

תרבח

ג

ןיילקתימסוסקל

) מ"עב לארשי

GSK

ןולעה ןוכדע לע עידוהל תשקבמ (

לש אפורל

Avamys

.

רישכתל תומושרה תויוותהה

:לארשיב

AVAMYS (fluticasone furoate) Nasal Spray is indicated for the treatment of the symptoms

of seasonal and perennial allergic rhinitis in patients aged 2 years and older

םיאבה םיפיעסב ושענ םייתוהמ םינוכדע אפורל ןולעב

:

8

USE IN SPECIFIC POPULATIONS

8.6

Hepatic Impairment

Use AVAMYS Nasal Spray with caution in patients with

moderate or

severe hepatic impairment

[see

Clinical Pharmacology (12.3)].

: םינמוסמה םינוכדעל ארקמ

הרמחה תפסות

בתכ לוחכ

רקרמ בוהצב ןמוסמ

ןולעה

אפורל

חלשנ

םוסרפל

רגאמב

תופורתה

רתאבש

דרשמ

תואירבה

https://data.health.gov.il/drugs/index.html#/medDetails

ןתינו לבקל ספדומ ו

לע

לזב 'חר ןיילקתימסוסקלג תרבחל הינפ ידי

:ןופלטב הוקת חתפ

03-9297100

,הכרבב

ליהוס יוואלת

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The format of this leaflet was determined by the Ministry of Health and its content was checked and

approved in February 2014, and was updated according to the guidelines of the Ministry of Health in

December 2018

NAME OF THE MEDICINAL PRODUCT

AVAMYS

COMPOSITION

Each spray actuation delivers 27.5 micrograms of fluticasone furoate

PHARMACEUTICAL FORM

Nasal spray

1

THERAPEUTIC INDICATIONS

1.1

Treatment of Allergic Rhinitis

AVAMYS (fluticasone furoate) Nasal Spray is indicated for the treatment of

the symptoms of seasonal and perennial allergic rhinitis in patients aged 2 years and

older.

2

DOSAGE AND ADMINISTRATION

Administer AVAMYS Nasal Spray by the intranasal route only. Prime AVAMYS

Nasal Spray before using for the first time by shaking the contents well and releasing

6 sprays into the air away from the face. When AVAMYS Nasal Spray has not been

used for more than 30 days or if the cap has been left off the bottle for 5 days or

longer, prime the pump again until a fine mist appears. Shake AVAMYS Nasal Spray

well before each use.

Titrate an individual patient to the minimum effective dosage to reduce the possibility

of side effects.

2.1

Adults and Adolescents Aged 12 Years and Older

The recommended starting dosage is 110 mcg once daily administered as 2 sprays

(27.5 mcg/spray) in each nostril. When the maximum benefit has been achieved and

symptoms have been controlled, reducing the dosage to 55 mcg (1 spray in each

nostril) once daily may be effective in maintaining control of allergic rhinitis

symptoms.

2.2

Children Aged 2 to 11 Years

The recommended starting dosage in children is 55 mcg once daily administered as

1 spray (27.5 mcg/spray) in each nostril. Children not adequately responding to 55

mcg may use 110 mcg (2 sprays in each nostril) once daily. Once symptoms have

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been controlled, dosage reduction to 55 mcg once daily is recommended.

3

DOSAGE FORMS AND STRENGTHS

AVAMYS Nasal Spray is a nasal spray suspension. Each spray (50 microliters)

delivers 27.5 mcg of fluticasone furoate.

4

CONTRAINDICATIONS

AVAMYS Nasal Spray is contraindicated in patients with hypersensitivity to the

active substance or to any of its excipients listed in section 11

[see Warnings and

Precautions (5.3)]

5

WARNINGS AND PRECAUTIONS

5.1

Local Nasal Effects

Epistaxis and Nasal Ulceration

In clinical trials of 2 to 52 weeks’ duration, epistaxis and nasal ulcerations were

observed more frequently and some epistaxis events were more severe in patients

treated with AVAMYS Nasal Spray than those who received placebo

[see Adverse

Reactions (6.1)]

Candida Infection

Evidence of localized infections of the nose with

Candida albicans

was seen on nasal

exams in 7 of 2,745 patients treated with AVAMYS Nasal Spray during clinical trials

and was reported as an adverse event in 3 patients. When such an infection develops,

it may require treatment with appropriate local therapy and discontinuation of

AVAMYS Nasal Spray. Therefore, patients using AVAMYS Nasal Spray over

several months or longer should be examined periodically for evidence of

Candida

infection or other signs of adverse effects on the nasal mucosa.

Nasal Septal Perforation

Postmarketing cases of nasal septal perforation have been reported in patients

following the intranasal application of AVAMYS Nasal Spray

[see Adverse Reactions

(6.2)]

Impaired Wound Healing

Because of the inhibitory effect of corticosteroids on wound healing, patients who

have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use

AVAMYS Nasal Spray until healing has occurred.

5.2

Glaucoma and Cataracts

Nasal and inhaled corticosteroids 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 of increased intraocular pressure (IOP), glaucoma, and/or cataracts.

Glaucoma and cataract formation was evaluated with intraocular pressure

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measurements and slit lamp examinations in 1 controlled 12-month trial in 806

adolescent and adult patients aged 12 years and older and in 1 controlled 12-week trial

in 558 children aged 2 to 11 years. The patients had perennial allergic rhinitis and

were treated with either AVAMYS Nasal Spray (110 mcg once daily in adult and

adolescent patients and 55 or 110 mcg once daily in pediatric patients) or placebo.

Intraocular pressure remained within the normal range (less than 21 mmHg) in greater

than or equal to 98% of the patients in any treatment group in both trials. However, in

the 12-month trial in adolescents and adults, 12 patients, all treated with AVAMYS

Nasal Spray 110 mcg once daily, had intraocular pressure measurements that

increased above normal levels (greater than or equal to 21 mmHg). In the same trial, 7

patients (6 treated with AVAMYS Nasal Spray 110 mcg once daily and 1 patient

treated with placebo) had cataracts identified during the trial that were not present at

baseline.

5.3

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria,

may occur after administration of AVAMYS Nasal Spray. Discontinue AVAMYS

Nasal Spray if such reactions occur

[see Contraindications (4)]

5.4

Immunosuppression

Persons who are using drugs that suppress the immune system are more susceptible to

infections than healthy individuals. Chickenpox and measles, for example, can have a

more serious or even fatal course in susceptible children or adults using

corticosteroids. In children or adults who have not had these diseases or have not been

properly immunized, particular care should be taken to avoid exposure. How the dose,

route, and duration of corticosteroid administration affect the risk of developing a

disseminated infection is not known. The contribution of the underlying disease

and/or prior corticosteroid treatment to the risk is also not known. If a patient is

exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG)

may be indicated. If a patient is exposed to measles, prophylaxis with pooled

intramuscular immunoglobulin (IG) may be indicated. (See the respective package

inserts for complete VZIG and IG prescribing information.) If chickenpox or measles

develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with caution, if at all, in patients with active or

quiescent tuberculous infections of the respiratory tract, untreated local or systemic

fungal or bacterial infections, systemic viral or parasitic infections, or ocular herpes

simplex because of the potential for worsening of these infections.

5.5

Hypothalamic-Pituitary-Adrenal Axis Effects

Hypercorticism and Adrenal Suppression

When intranasal steroids are used at higher-than-recommended dosages or in

susceptible individuals at recommended dosages, systemic corticosteroid effects such

as hypercorticism and adrenal suppression may appear. If such changes occur, the

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dosage of AVAMYS Nasal Spray should be discontinued slowly, consistent with

accepted procedures for discontinuing oral corticosteroid therapy.

The replacement of a systemic corticosteroid with a topical corticosteroid can be

accompanied by signs of adrenal insufficiency. In addition, some patients may

experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain,

lassitude, depression. Patients previously treated for prolonged periods with systemic

corticosteroids and transferred to topical corticosteroids should be carefully monitored

for acute adrenal insufficiency in response to stress. In those patients who have

asthma or other clinical conditions requiring long-term systemic corticosteroid

treatment, rapid decreases in systemic corticosteroid dosages may cause a severe

exacerbation of their symptoms.

5.6

Use of Cytochrome P450 3A4 Inhibitors

Coadministration with ritonavir is not recommended because of the risk of systemic

effects secondary to increased exposure to fluticasone furoate. Use caution with the

coadministration of AVAMYS Nasal Spray and other potent cytochrome P450 3A4

(CYP3A4) inhibitors, such as ketoconazole

[see Drug Interactions (7)]

5.7

Effect on Growth

Corticosteroids may cause a reduction in growth velocity when administered to

pediatric patients. Monitor the growth routinely of pediatric patients receiving

AVAMYS Nasal Spray. To minimize the systemic effects of intranasal

corticosteroids, including AVAMYS Nasal Spray, titrate each patient’s dose to the

lowest dosage that effectively controls his/her symptoms

[see Use in Specific

Populations (8.4)]

6

ADVERSE REACTIONS

Systemic and local corticosteroid use may result in the following:

Epistaxis, ulcerations,

Candida albicans

infection, impaired wound healing, and

nasal septal perforation

[see Warnings and Precautions (5.1)]

Cataracts and glaucoma

[see Warnings and Precautions (5.2)]

Immunosuppression

[see Warnings and Precautions (5.4)]

Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction

[see Warnings and Precautions (5.5), Use in Specific Populations (8.4)]

6.1

Clinical Trials Experience

The safety data described below reflect exposure to AVAMYS Nasal Spray in 1,563

patients with seasonal or perennial allergic rhinitis in 9 controlled clinical trials of 2 to

12 weeks’ duration. The data from adults and adolescents are based upon 6 clinical

trials in which 768 patients with seasonal or perennial allergic rhinitis (473 females

and 295 males aged 12 years and older) were treated with AVAMYS Nasal Spray 110

mcg once daily for 2 to 6 weeks. The racial distribution of adult and adolescent

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patients receiving AVAMYS Nasal Spray was 82% white, 5% black, and 13% other.

The data from pediatric patients are based upon 3 clinical trials in which 795 children

with seasonal or perennial rhinitis (352 females and 443 males aged 2 to 11 years)

were treated with AVAMYS Nasal Spray 55 or 110 mcg once daily for 2 to 12 weeks.

The racial distribution of pediatric patients receiving AVAMYS Nasal Spray was

75% white, 11% black, and 14% other.

Because clinical trials are conducted under widely varying conditions, adverse

reaction rates observed in the clinical trials of a drug cannot be directly compared

with rates in the clinical trials of another drug and may not reflect the rates observed

in practice.

Adults and Adolescents Aged 12 Years and Older

Overall adverse reactions were reported with approximately the same frequency by

patients treated with AVAMYS Nasal Spray and those receiving placebo. Less than

3% of patients in clinical trials discontinued treatment because of adverse reactions.

The rate of withdrawal among patients receiving AVAMYS Nasal Spray was similar

or lower than the rate among patients receiving placebo.

Table 1 displays the common adverse reactions (greater than 1% in any patient group

receiving AVAMYS Nasal Spray) that occurred more frequently in patients aged 12

years and older treated with AVAMYS Nasal Spray compared with placebo-treated

patients.

Table 1. Adverse Reactions with >1% Incidence in Controlled Clinical

Trials of 2 to 6 Weeks’ Duration with AVAMYS Nasal Spray in Adult

and Adolescent Patients with Seasonal or Perennial Allergic Rhinitis

Adverse Event

Adult and Adolescent Patients

Aged 12 Years and Older

Vehicle Placebo

(n = 774)

AVAMYS Nasal Spray

110 mcg Once Daily

(n = 768)

Headache

54 (7%)

72 (9%)

Epistaxis

32 (4%)

45 (6%)

Pharyngolaryngeal pain

8 (1%)

15 (2%)

Nasal ulceration

3 (<1%)

11 (1%)

Back pain

7 (<1%)

9 (1%)

There were no differences in the incidence of adverse reactions based on gender or

race. Clinical trials did not include sufficient numbers of patients aged 65 years and

older to determine whether they respond differently from younger subjects.

Pediatric Patients Aged 2 to 11 Years

In the 3 clinical trials in pediatric patients aged 2 to younger than 12 years, overall

adverse reactions were reported with approximately the same frequency by patients

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treated with AVAMYS Nasal Spray and those receiving placebo. Table 2 displays the

common adverse reactions (greater than 3% in any patient group receiving AVAMYS

Nasal Spray), that occurred more frequently in patients aged 2 to 11 years treated with

AVAMYS Nasal Spray compared with placebo-treated patients.

Table 2. Adverse Reactions with >3% Incidence in Controlled Clinical Trials of 2

to 12 Weeks’ Duration with AVAMYS Nasal Spray in Pediatric Patients with

Seasonal or Perennial Allergic Rhinitis

Adverse Event

Pediatric Patients Aged 2 to Younger than 12 Years

Vehicle Placebo

(n = 429)

AVAMYS

Nasal Spray

55 mcg Once Daily

(n = 369)

AVAMYS

Nasal Spray

110 mcg Once Daily

(n = 426)

Headache

31 (7%)

28 (8%)

33 (8%)

Nasopharyngitis

21 (5%)

20 (5%)

21 (5%)

Epistaxis

19 (4%)

17 (5%)

17 (4%)

Pyrexia

7 (2%)

17 (5%)

19 (4%)

Pharyngolaryngeal pain

14 (3%)

16 (4%)

12 (3%)

Cough

12 (3%)

12 (3%)

16 (4%)

There were no differences in the incidence of adverse reactions based on gender or race. Pyrexia

occurred more frequently in children aged 2 to younger than 6 years compared with children aged 6 to

younger than12 years.

Long-term (52-Week) Safety Trial

In a 52-week, placebo-controlled, long-term safety trial, 605 patients (307 females

and 298 males aged 12 years and older) with perennial allergic rhinitis were treated

with AVAMYS Nasal Spray 110 mcg once daily for 12 months and 201 were treated

with placebo nasal spray. While most adverse reactions were similar in type and rate

between the treatment groups, epistaxis occurred more frequently in patients who

received AVAMYS Nasal Spray (123/605, 20%) than in patients who received

placebo (17/201, 8%). Epistaxis tended to be more severe in patients treated with

AVAMYS Nasal Spray. All 17 reports of epistaxis that occurred in patients who

received placebo were of mild intensity, while 83, 39, and 1 of the total 123 epistaxis

events in patients treated with AVAMYS Nasal Spray were of mild, moderate, and

severe intensity, respectively. No patient experienced a nasal septal perforation during

this trial.

6.2

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse

reactions have been identified during postmarketing use of AVAMYS Nasal Spray.

Because these reactions are reported voluntarily from a population of uncertain size, it

is not always possible to reliably estimate their frequency or establish a causal

relationship to drug exposure. These events have been chosen for inclusion due to

either their seriousness, frequency of reporting, or causal connection to fluticasone

furoate or a combination of these factors.

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Immune System Disorders

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.

Respiratory, Thoracic, and Mediastinal Disorders

Rhinalgia, nasal discomfort (including nasal burning, nasal irritation, and nasal

soreness), nasal dryness, and nasal septal perforation.

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.

Any suspected adverse events should be reported to the Ministry of Health according

to the National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffect

Medic@moh.gov.il

Additionally, you should also report to GSK Israel (il.safety@gsk.com).

7

DRUG INTERACTIONS

Fluticasone furoate is cleared by extensive first-pass metabolism mediated by

CYP3A4. In a drug interaction trial of intranasal fluticasone furoate and the CYP3A4

inhibitor ketoconazole given as a 200-mg once-daily dose for 7 days, 6 of 20 subjects

receiving fluticasone furoate and ketoconazole had measurable but low levels of

fluticasone furoate compared with 1 of 20 receiving fluticasone furoate and placebo.

Based on this trial and the low systemic exposure, there was a 5% reduction in 24-

hour serum cortisol levels with ketoconazole compared with placebo. The data from

this trial should be carefully interpreted because the trial was conducted with

ketoconazole 200 mg once daily rather than 400 mg, which is the maximum

recommended dosage. Therefore, caution is required with the coadministration of

AVAMYS Nasal Spray and ketoconazole or other potent CYP3A4 inhibitors.

Based on data with another glucocorticoid, fluticasone propionate, metabolized by

CYP3A4, coadministration of AVAMYS Nasal Spray with the potent CYP3A4

inhibitor ritonavir is not recommended because of the risk of systemic effects

secondary to increased exposure to fluticasone furoate. High exposure to

corticosteroids increases the potential for systemic side effects, such as cortisol

suppression.

Enzyme induction and inhibition data suggest that fluticasone furoate is unlikely to

significantly alter the cytochrome P450-mediated metabolism of other compounds at

clinically relevant intranasal dosages.

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8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Teratogenic Effects

Pregnancy Category C. Corticosteroids have been shown to be teratogenic in

laboratory animals when administered systemically at relatively low dosage levels.

There were no teratogenic effects in rats and rabbits at inhaled fluticasone furoate

dosages of up to 91 and 8 mcg/kg/day, respectively (approximately 7 and 1 times,

respectively, the maximum recommended daily intranasal dose in adults on a mcg/m

basis). There was also no effect on pre- or post-natal development in rats treated with

up to 27 mcg/kg/day by inhalation during gestation and lactation (approximately 2

times the maximum recommended daily intranasal dose in adults on a mcg/m

basis).

There are no adequate and well-controlled studies in pregnant women. AVAMYS

Nasal Spray should be used during pregnancy only if the potential benefit justifies the

potential risk to the fetus.

Nonteratogenic Effects

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids

during pregnancy. Such infants should be carefully monitored.

8.3

Nursing Mothers

It is not known whether fluticasone furoate is excreted in human breast milk.

However, other corticosteroids have been detected in human milk. Since there are no

data from controlled trials on the use of intranasal fluticasone furoate by nursing

mothers, caution should be exercised when AVAMYS Nasal Spray is administered to

a nursing woman.

8.4

Pediatric Use

Controlled clinical trials with AVAMYS Nasal Spray included 1,224 patients aged 2

to 11 years and 344 adolescent patients aged 12 to 17 years

[see Clinical Studies

(14.1)]

. The safety and effectiveness of AVAMYS Nasal Spray in children younger

than 2 years have not been established.

Controlled clinical trials have shown that intranasal corticosteroids may cause a

reduction in growth velocity in pediatric patients. This effect has been observed in the

absence of laboratory evidence of HPA axis suppression, suggesting that growth

velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric

patients than some commonly used tests of HPA axis function. The long-term effects

of reduction in growth velocity associated with intranasal corticosteroids, including

the impact on final adult height, are unknown. The potential for “catch-up” growth

following discontinuation of treatment with intranasal corticosteroids has not been

adequately studied. The growth of pediatric patients receiving intranasal

corticosteroids, including AVAMYS Nasal Spray, should be monitored routinely

(e.g., via stadiometry). The potential growth effects of prolonged treatment should be

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weighed against the clinical benefits obtained and the risks/benefits of treatment

alternatives. To minimize the systemic effects of intranasal corticosteroids, including

AVAMYS Nasal Spray, each patient’s dose should be titrated to the lowest dosage

that effectively controls his/her symptoms.

A randomized, double-blind, parallel-group, multicenter, 1-year placebo-controlled

clinical growth trial evaluated the effect of 110 mcg of AVAMYS Nasal Spray once

daily on growth velocity in 474 prepubescent children (girls aged 5 to 7.5 years and

boys aged 5 to 8.5 years) with stadiometry. Mean growth velocity over the 52-week

treatment period was lower in the patients receiving AVAMYS Nasal Spray

(5.19 cm/year compared with placebo (5.46 cm/year). The mean treatment difference

was -0.27 cm/year [95% CI: -0.48 to -0.06]

[see Warnings and Precautions (5.7)]

8.5

Geriatric Use

Clinical studies of AVAMYS Nasal Spray did not include sufficient numbers of

subjects aged 65 years and older to determine whether they respond differently from

younger subjects. Other reported clinical experience has not identified differences in

responses between the elderly and younger patients. In general, dose selection for an

elderly patient should be cautious, usually starting at the low end of the dosing range,

reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of

concomitant disease or other drug therapy.

8.6

Hepatic Impairment

Use AVAMYS Nasal Spray with caution in patients with moderate or severe hepatic

impairment

[see Clinical Pharmacology (12.3)].

8.7

Renal Impairment

No dosage adjustment is required in patients with renal impairment

[see Clinical

Pharmacology (12.3)]

10

OVERDOSAGE

Chronic overdosage may result in signs/symptoms of hypercorticism

[see Warnings

and Precautions (5.5)]

. There are no data on the effects of acute or chronic

overdosage with AVAMYS Nasal Spray. Because of low systemic bioavailability and

an absence of acute drug-related systemic findings in clinical trials (with dosages of

up to 440 mcg/day for 2 weeks [4 times the maximum recommended daily dose]),

overdose is unlikely to require any therapy other than observation.

Intranasal administration of up to 2,640 mcg/day (24 times the recommended adult

dose) of fluticasone furoate was administered to healthy human volunteers for 3 days.

Single- and repeat-dose trials with orally inhaled fluticasone furoate doses of 50 to

4,000 mcg have shown decreased mean serum cortisol at doses of 500 mcg or higher.

The oral median lethal dose in mice and rats was greater than

2,000 mg/kg

(approximately 74,000 and 147,000 times, respectively, the maximum recommended

daily intranasal dose in adults and 52,000 and 105,000 times, respectively, the

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maximum recommended daily intranasal dose in children, on a mcg/m

basis).

Acute overdosage with the intranasal dosage form is unlikely since 1 bottle of

AVAMYS Nasal Spray contains approximately 3 mg of fluticasone furoate, and the

bioavailability of fluticasone furoate is less than 1% for 2.64 mg/day given

intranasally and 1% for 2 mg/day given as an oral solution.

11

DESCRIPTION

Fluticasone furoate, the active component of AVAMYS Nasal Spray, is a synthetic

fluorinated corticosteroid having the chemical name (6

)-6,9-difluoro-

17-{[(fluoro-methyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-

17-yl 2-furancarboxylate and the following chemical structure:

Fluticasone furoate is a white powder with a molecular weight of 538.6, and the

empirical formula is C

S. It is practically insoluble in water.

AVAMYS Nasal Spray is an aqueous suspension of micronized fluticasone furoate

for topical administration to the nasal mucosa by means of a metering (50

microliters), atomizing spray pump. After initial priming

[see Dosage and

Administration (2)]

, each actuation delivers 27.5 mcg of fluticasone furoate in a

volume of 50 microliters of nasal spray suspension. AVAMYS Nasal Spray also

contains Glucose anhydrous, Dispersible cellulose, Benzalkonium chloride solution,

Polysorbate 80, Disodium edentate and purified water

12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent

anti-inflammatory activity. The precise mechanism through which fluticasone furoate

affects rhinitis symptoms is not known. Corticosteroids have been shown to have a

wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils,

macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes,

cytokines) involved in inflammation. Specific effects of fluticasone furoate

demonstrated in in vitro and in vivo models included activation of the glucocorticoid

response element, inhibition of pro-inflammatory transcription factors such as NFkB,

and inhibition of antigen-induced lung eosinophilia in sensitized rats.

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Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human

glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and

1.7 times that of fluticasone propionate. The clinical relevance of these findings is

unknown.

12.2

Pharmacodynamics

Adrenal Function

The effects of AVAMYS Nasal Spray on adrenal function have been evaluated in 4

controlled clinical trials in patients with perennial allergic rhinitis. Two 6-week

clinical trials were designed specifically to assess the effect of AVAMYS Nasal Spray

on the HPA axis with assessments of both 24-hour urinary cortisol excretion and

serum cortisol levels in domiciled patients. In addition, one 52-week safety trial and

one 12-week safety and efficacy trial included assessments of 24-hour urinary cortisol

excretion. Details of the trials and results are described below. In all 4 trials, since

serum fluticasone determinations were generally below the limit of quantification,

compliance was assured by efficacy assessments.

Clinical Trials Specifically Designed to Assess Hypothalamic-Pituitary-Adrenal

Axis Effect:

In a 6-week randomized, double-blind, parallel-group trial in adult and

adolescent patients aged 12 years and older with perennial allergic rhinitis, AVAMYS

Nasal Spray 110 mcg was compared with both placebo nasal spray and prednisone as

a positive-control group that received prednisone 10 mg orally once daily for the final

7 days of the treatment period. Adrenal function was assessed by 24-hour urinary

cortisol excretion before and after 6 weeks of treatment and by serial serum cortisol

levels. Patients were domiciled for collection of 24-hour urinary cortisol. After 6

weeks of treatment, there was a change from baseline in the mean 24-hour urinary

cortisol excretion in the group treated with AVAMYS Nasal Spray (n = 43) of -1.16

mcg/day compared with -3.48 mcg/day in the placebo group (n = 42). The difference

from placebo in the group treated with AVAMYS Nasal Spray was 2.32 mcg/day

(95% CI: -6.76, 11.39). Urinary cortisol data were not available for the

positive-control (prednisone) treatment group. For serum cortisol levels, after 6 weeks

of treatment there was a change from baseline in the mean (0 to 24 hours) of -0.38 and

0.08 mcg/dL for the group treated with AVAMYS Nasal Spray (n = 43) and the

placebo group (n = 44), respectively, with a difference between the group treated with

AVAMYS Nasal Spray and the placebo group of -0.47 mcg/dL (95% CI: -1.31, 0.37).

For comparison, in the positive-control (prednisone, n = 12) treatment group, there

was a change in mean serum cortisol (0-24 hours) from baseline of -4.49 mcg/dL with

a difference between the prednisone and placebo group of -4.57 mcg/dL (95% CI:

-5.83, -3.31).

The second 6-week trial conducted in children aged 2 to 11 years was of similar

design to the adult trial, including adrenal function assessments, but did not include a

prednisone positive-control arm. Patients were treated once daily with AVAMYS

Nasal Spray 110 mcg or placebo nasal spray. After 6 weeks of treatment, there was a

Page

12

21

change in the mean 24-hour urinary cortisol excretion in the group treated with

AVAMYS Nasal Spray (n = 43) of 0.49 mcg/day compared with 1.92 mcg/day in the

placebo group (n = 41), with a difference between the group treated with Avamys

Nasal Spray and the placebo group of -1.43 mcg/day (95% CI: -5.21, 2.35). For

serum cortisol levels, after 6 weeks, there was a change from baseline in mean (0 to

24 hours) of -0.34 and -0.23 mcg/dL for the group treated with AVAMYS Nasal

Spray (n = 48) and for the placebo group (n = 47), respectively, with a difference

between the group treated with AVAMYS Nasal Spray and the placebo group of

-0.11 mcg/dL (95% CI: -0.88, 0.66).

Additional Hypothalamic-Pituitary-Adrenal Axis Assessments

In the 52-week safety trial in adolescents and adults aged 12 years and older with

perennial allergic rhinitis, AVAMYS Nasal Spray 110 mcg (n = 605) was compared

with placebo nasal spray (n = 201). Adrenal function was assessed by 24-hour urinary

cortisol excretion in a subset of patients who received AVAMYS Nasal Spray (n =

370) or placebo (n = 120) before and after 52 weeks of treatment. After 52 weeks of

treatment, the mean change from baseline 24-hour urinary cortisol excretion was 5.84

mcg/day in the group treated with AVAMYS Nasal Spray and 3.34 mcg/day in the

placebo group. The difference from placebo in mean change from baseline 24-hour

urinary cortisol excretion was 2.50 mcg/day (95% CI: -5.49, 10.49).

In the 12-week safety and efficacy trial in children aged 2 to 11 years with perennial

allergic rhinitis, AVAMYS Nasal Spray 55 mcg (n = 185) and AVAMYS Nasal

Spray 110 mcg (n = 185) were compared with placebo nasal spray (n = 188). Adrenal

function was assessed by measurement of 24-hour urinary free cortisol in a subset of

patients who were aged 6 to 11 years (103 to 109 patients per group) before and after

12 weeks of treatment. After 12 weeks of treatment, there was a decrease in mean 24-

hour urinary cortisol excretion from baseline in the group treated with AVAMYS

Nasal Spray 55 mcg (n = 109) of -2.93 mcg/day and in the group treated with

AVAMYS Nasal Spray 110 mcg (n = 103) of -2.07 mcg/day compared with an

increase in the placebo group (n = 107) of 0.08 mcg/day. The difference from placebo

in mean change from baseline in 24-hour urinary cortisol excretion for the group

treated with AVAMYS Nasal Spray 55 mcg was -3.01 mcg/day (95% CI: -6.16, 0.13)

and -2.14 mcg/day (95% CI: -5.33, 1.04) for the group treated with AVAMYS Nasal

Spray 110 mcg.

When the results of the HPA axis assessments described above are taken as a whole,

an effect of intranasal fluticasone furoate on adrenal function cannot be ruled out,

especially in pediatric patients.

Cardiac Effects

A QT/QTc trial did not demonstrate an effect of fluticasone furoate administration on

the QTc interval. The effect of a single dose of 4,000 mcg of orally inhaled

fluticasone furoate on the QTc interval was evaluated over 24 hours in 40 healthy

male and female subjects in a placebo- and positive-controlled (a single dose of 400

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13

21

mg oral moxifloxacin) cross-over trial. The QTcF maximal mean change from

baseline following fluticasone furoate was similar to that observed with placebo with

a treatment difference of 0.788 msec (90% CI: -1.802, 3.378). In contrast,

moxifloxacin given as a 400-mg tablet resulted in prolongation of the QTcF maximal

mean change from baseline compared with placebo with a treatment difference of

9.929 msec (90% CI: 7.339, 12.520). While a single dose of fluticasone furoate had

no effect on the QTc interval, the effects of fluticasone furoate may not be at steady

state following single dose. The effect of fluticasone furoate on the QTc interval

following multiple-dose administration is unknown.

12.3

Pharmacokinetics

Absorption

Following intranasal administration of fluticasone furoate, most of the dose is

eventually swallowed and undergoes incomplete absorption and extensive first-pass

metabolism in the liver and gut, resulting in negligible systemic exposure. At the

highest recommended intranasal dosage of 110 mcg once daily for up to 12 months in

adults and up to 12 weeks in children, plasma concentrations of fluticasone furoate are

typically not quantifiable despite the use of a sensitive HPLC-MS/MS assay with a

lower limit of quantification (LOQ) of 10 pg/mL. However, in a few isolated cases (

less than0.3%) fluticasone furoate was detected in high concentrations above 500

pg/mL, and in a single case the concentration was as high as 1,430 pg/mL in the 52-

week trial. There was no relationship between these concentrations and cortisol levels

in these subjects. The reasons for these high concentrations are unknown.

Absolute bioavailability was evaluated in 16 male and female subjects following

supratherapeutic dosages of fluticasone furoate (880 mcg given intranasally at 8-hour

intervals for 10 doses, or 2,640 mcg/day). The average absolute bioavailability was

0.50% (90% CI: 0.34%, 0.74%).

Due to the low bioavailability by the intranasal route, the majority of the

pharmacokinetic data was obtained via other routes of administration. Trials using

oral solution and intravenous dosing of radiolabeled drug have demonstrated that at

least 30% of fluticasone furoate is absorbed and then rapidly cleared from plasma.

Oral bioavailability is on average 1.26%, and the majority of the circulating

radioactivity is due to inactive metabolites.

Distribution

Following intravenous administration, the mean volume of distribution at steady state

is 608 L.

Binding of fluticasone furoate to human plasma proteins is greater than 99%.

Metabolism

In vivo studies have revealed no evidence of cleavage of the furoate moiety to form

fluticasone. Fluticasone furoate is cleared (total plasma clearance of 58.7 L/h) from

systemic circulation principally by hepatic metabolism via CYP3A4. The principal

Page

14

21

route of metabolism is hydrolysis of the S-fluoromethyl carbothioate function to form

the inactive 17

-carboxylic acid metabolite.

Elimination

Fluticasone furoate and its metabolites are eliminated primarily in the feces,

accounting for approximately 101% and 90% of the orally and intravenously

administered dose, respectively. Urinary excretion accounted for approximately 1%

and 2% of the orally and intravenously administered dose, respectively. The

elimination phase half-life averaged 15.1 hours following intravenous administration.

Population Pharmacokinetics

Fluticasone furoate is typically not quantifiable in plasma following intranasal dosing

of 110 mcg once daily with the exception of isolated cases of very high plasma levels

(see Absorption). Overall, quantifiable levels (greater than 10 pg/mL) were observed

in less than31% of patients aged 12 years and older and in less than16% of children

(aged 2 to 11 years) following intranasal dosing of 110 mcg once daily and in less

than7% of children following intranasal dosing of 55 mcg once daily. There was no

evidence to suggest that the presence or absence of detectable levels of fluticasone

furoate was related to gender, age, or race.

Hepatic Impairment

The pharmacokinetics of fluticasone furoate following intranasal administration in

subjects with hepatic impairment have not been evaluated. Data available with orally

inhaled fluticasone furoate/vilanterol are applicable to intranasal dosing of fluticasone

furoate. Following repeat dosing of orally inhaled fluticasone furoate/vilanterol 200

mcg/25 mcg (100 mcg/12.5 mcg in the severe impairment group) for 7 days,

fluticasone furoate systemic exposure (AUC) increased 34%, 83%, and 75% in

subjects with mild, moderate, and severe hepatic impairment, respectively, compared

with healthy subjects.

In subjects with moderate hepatic impairment receiving fluticasone furoate/vilanterol

200 mcg/25 mcg, mean serum cortisol (0 to 24 hours) was reduced by 34% (90% CI:

11%, 51%) compared with healthy subjects. In subjects with severe hepatic

impairment receiving fluticasone furoate/vilanterol 100 mcg/12.5 mcg, mean serum

cortisol (0 to 24 hours) was increased by 14% (90% CI: -16%, 55%) compared with

healthy subjects

[see Use in Specific Populations (8.6)]

Renal Impairment

Fluticasone furoate is not detectable in urine from healthy subjects following

intranasal dosing. Less than 1% of dose-related material is excreted in urine [see Use

in Specific Populations (8.7)].13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Fluticasone furoate produced no treatment-related increases in the incidence of tumors

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15

21

in 2-year inhalation studies in rats and mice at doses of up to 9 and 19 mcg/kg/day,

respectively (less than the maximum recommended daily intranasal dose in adults and

children on a mcg/m

basis).

Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage

in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There

was also no evidence of genotoxicity in the in vivo micronucleus test in rats.

No evidence of impairment of fertility was observed in reproductive studies

conducted in male and female rats at inhaled fluticasone furoate doses of up to 24 and

91 mcg/kg/day, respectively (approximately 2 and 7 times, respectively, the

maximum recommended daily intranasal dose in adults on a mcg/m

basis).

14

CLINICAL STUDIES

14.1

Seasonal and Perennial Allergic Rhinitis

Adult and Adolescent Patients Aged 12 Years and Older

The efficacy and safety of AVAMYS Nasal Spray was evaluated in 5 randomized,

double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 4

weeks’ duration in adult and adolescent patients aged 12 years and older with

symptoms of seasonal or perennial allergic rhinitis. The 5 clinical trials included one

2-week dose-ranging trial in patients with seasonal allergic rhinitis, three 2-week

confirmatory efficacy trials in patients with seasonal allergic rhinitis, and one 4-week

efficacy trial in patients with perennial allergic rhinitis. These trials included 1,829

patients (697 males and 1,132 females). About 75% of patients were Caucasian, and

the mean age was 36 years. Of these patients, 722 received AVAMYS Nasal Spray

110 mcg once daily administered as 2 sprays in each nostril.

Assessment of efficacy was based on total nasal symptom score (TNSS). TNSS is

calculated as the sum of the patients’ scoring of the 4 individual nasal symptoms

(rhinorrhea, nasal congestion, sneezing, and nasal itching) on a 0 to 3 categorical

severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective (rTNSS)

or instantaneous (iTNSS). rTNSS required the patients to record symptom severity

over the previous 12 hours; iTNSS required patients to record symptom severity at the

time immediately prior to the next dose. Morning and evening rTNSS scores were

averaged over the treatment period and the difference from placebo in the change

from baseline rTNSS was the primary efficacy endpoint. The morning iTNSS (AM

iTNSS) reflects the TNSS at the end of the 24-hour dosing interval and is an

indication of whether the effect was maintained over the 24-hour dosing interval.

Additional secondary efficacy variables were assessed, including the total ocular

symptom score (TOSS) and the Rhinoconjunctivitis Quality of Life Questionnaire

(RQLQ). TOSS is calculated as the sum of the patients’ scoring of the 3 individual

ocular symptoms (itching/burning, tearing/watering, and redness) on a 0 to 3

categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective

(rTOSS) or instantaneous scores (iTOSS). To assess efficacy, rTOSS and AM iTOSS

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16

21

were evaluated as described above for the TNSS. Patients’ perceptions of

disease-specific quality of life were evaluated through use of the RQLQ, which

assesses the impact of allergic rhinitis treatment through 28 items in 7 domains

(activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye

symptoms, and emotional) on a 7-point scale where 0 = no impairment and 6 =

maximum impairment. An overall RQLQ score is calculated from the mean of all

items in the instrument. An absolute difference of greater than or equal to0.5 in mean

change from baseline over placebo is considered the minimally important difference

(MID) for the RQLQ.

Dose-ranging Trial: The dose-ranging trial was a 2-week trial that evaluated the

efficacy of 4 doses of fluticasone furoate nasal spray (440, 220, 110, and 55 mcg) in

patients with seasonal allergic rhinitis. In this trial, each of the 4 doses of fluticasone

furoate nasal spray demonstrated greater decreases in the rTNSS than placebo, and the

difference was statistically significant (Table 3).

Table 3. Mean Change from Baseline in Reflective Total Nasal Symptom Score

over 2 Weeks in Patients with Seasonal Allergic Rhinitis

Treatment

n

Baseline

(AM +

PM)

Change

from

Baseline

Difference from Placebo

LS Mean

95% CI

P Value

Fluticasone furoate 440 mcg

-4.02

-2.19

-2.75, -1.62

<0.001

Fluticasone furoate 220 mcg

-3.19

-1.36

-1.93, -0.79

<0.001

Fluticasone furoate 110 mcg

-3.84

-2.01

-2.58, -1.44

<0.001

Fluticasone furoate 55 mcg

-3.50

-1.68

-2.25, -1.10

<0.001

Placebo

-1.83

Each of the 4 doses of fluticasone furoate nasal spray also demonstrated greater

decreases in the AM iTNSS than placebo, and the difference between each of the 4

fluticasone furoate treatment groups and placebo was statistically significant,

indicating that the effect was maintained over the 24-hour dosing interval.

Seasonal Allergic Rhinitis Trials:

Three clinical trials were designed to evaluate the

efficacy of AVAMYS Nasal Spray 110 mcg once daily compared with placebo in

patients with seasonal allergic rhinitis over a 2-week treatment period. In all 3 trials,

AVAMYS Nasal Spray 110 mcg demonstrated a greater decrease from baseline in the

rTNSS and AM iTNSS than placebo, and the difference from placebo was statistically

significant. In terms of ocular symptoms, in all 3 seasonal allergic rhinitis trials,

AVAMYS Nasal Spray 110 mcg demonstrated a greater decrease from baseline in the

rTOSS than placebo and the difference from placebo was statistically significant. For

the RQLQ in all 3 seasonal allergic rhinitis trials, AVAMYS Nasal Spray 110 mcg

demonstrated greater decrease from baseline in the overall RQLQ than placebo, and

the difference from placebo was statistically significant. The difference in the overall

RQLQ score mean change from baseline between the groups treated with AVAMYS

Nasal Spray and placebo ranged from -0.60 to -0.70 in the 3 trials, meeting the

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21

minimally important difference criterion. Table 4 displays the efficacy results from a

representative trial in patients with seasonal allergic rhinitis.

Perennial Allergic Rhinitis Trials:

One clinical trial was designed to evaluate the

efficacy of AVAMYS Nasal Spray 110 mcg once daily compared with placebo in

patients with perennial allergic rhinitis over a 4-week treatment period. AVAMYS

Nasal Spray 110 mcg demonstrated a greater decrease from baseline in the rTNSS and

AM iTNSS than placebo, and the difference from placebo was statistically significant.

Similar to patients with seasonal allergic rhinitis, the improvement of nasal symptoms

with AVAMYS Nasal Spray in patients with perennial allergic rhinitis persisted for a

full 24 hours, as evaluated by AM iTNSS immediately prior to the next dose.

However, unlike the trials in patients with seasonal allergic rhinitis, patients with

perennial allergic rhinitis who were treated with AVAMYS Nasal Spray 110 mcg did

not demonstrate statistically significant improvement from baseline in rTOSS or in

disease-specific quality of life as measured by the RQLQ compared with placebo. In

addition, the overall RQLQ score mean change from baseline difference between the

group treated with AVAMYS Nasal Spray and the placebo group was -0.23, which

did not meet the minimally important difference of greater than or equal to 0.5. Table

4 displays the efficacy results from the clinical trial in patients with perennial allergic

rhinitis.

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21

Table 4. Mean Changes in Efficacy Variables in Adult and Adolescent Patients

with Seasonal or Perennial Allergic Rhinitis

Treatment

n

Baseline

Change from

Baseline –

LS Mean

Difference from Placebo

LS Mean

95% CI

P Value

Reflective Total Nasal Symptom Scores

Seasonal allergic

rhinitis trial

Fluticasone

furoate 110 mcg

-3.55

-1.47

-2.01, -0.94

<0.001

Placebo

-2.07

Perennial allergic

rhinitis trial

Fluticasone

furoate 110 mcg

-2.78

-0.71

-1.20, -0.21

0.005

Placebo

-2.08

Instantaneous Total Nasal Symptom Scores

Seasonal allergic

rhinitis trial

Fluticasone

furoate 110 mcg

-2.90

-1.38

-1.90, -0.85

<0.001

Placebo

-1.53

Perennial allergic

rhinitis trial

Fluticasone

furoate 110 mcg

-2.45

-0.71

-1.20, -0.21

0.006

Placebo

-1.75

Reflective Total Ocular Symptom Scores

Seasonal allergic

rhinitis trial

Fluticasone

furoate 110 mcg

-2.23

-0.60

-1.01, -0.19

0.004

Placebo

-1.63

Perennial allergic

rhinitis trial

Fluticasone

furoate 110 mcg

-1.39

-0.15

-0.52, 0.22

0.428

Placebo

-1.24

Rhinoconjunctivitis Quality of Life Questionnaire

Seasonal allergic

rhinitis trial

Fluticasone

furoate 110 mcg

-1.77

-0.60

-0.93, -0.28

<0.001

Page

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21

Placebo

-1.16

Perennial allergic

rhinitis trial

Fluticasone

furoate 110 mcg

-1.41

-0.23

-0.59, 0.13

0.214

Placebo

-1.18

Onset of action was evaluated by frequent instantaneous TNSS assessments after the

first dose in the clinical trials in patients with seasonal allergic rhinitis and perennial

allergic rhinitis. Onset of action was generally observed within 24 hours in patients

with seasonal allergic rhinitis. In patients with perennial rhinitis, onset of action was

observed after 4 days of treatment. Continued improvement in symptoms was

observed over approximately 1 and 3 weeks in patients with seasonal or perennial

allergic rhinitis, respectively.

Pediatric Patients Aged 2 to 11 Years

The efficacy and safety of AVAMYS Nasal Spray were evaluated in 1,112 children

(633 boys and 479 girls), mean age of 8 years with seasonal or perennial allergic

rhinitis in 2 controlled clinical trials. The pediatric patients were treated with

AVAMYS Nasal Spray 55 or 110 mcg once daily for 2 to 12 weeks (n = 369 for each

dose). The trials were similar in design to the trials conducted in adolescents and

adults; however, the efficacy determination was made from patient- or

parent/guardian-reported TNSS for children aged 6 to

younger than 12 years. Children treated with AVAMYS Nasal Spray generally

exhibited greater decreases in nasal symptoms than placebo-treated patients. In

seasonal allergic rhinitis, the difference in rTNSS was statistically significant only for

the 110-mcg dose. In perennial allergic rhinitis, the difference in rTNSS was

statistically significant only for the 55-mcg dose. Changes in rTOSS in the seasonal

allergic rhinitis trial were not statistically significant compared with placebo for either

dose. rTOSS was not assessed in the perennial allergic rhinitis trial. Table 5 displays

the efficacy results from the clinical trials in patients with perennial allergic rhinitis

and seasonal allergic rhinitis in children aged 6 to younger than 12 years. Efficacy in

children aged 2 to younger than 6 years was supported by a numerical decrease in the

rTNSS.

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21

Table 5. Mean Changes in Efficacy Variables in Pediatric Patients Aged 6 to

Younger than 12 Years with Seasonal or Perennial Allergic Rhinitis

Treatment

n

Baseline

Change from

Baseline –

LS Mean

Difference from Placebo

LS Mean

95% CI

P Value

Reflective Total Nasal Symptom Scores

Seasonal allergic

rhinitis trial

Fluticasone

furoate 55 mcg

-2.71

-0.16

-0.69, 0.37

0.553

Fluticasone

furoate 110 mcg

-3.16

-0.62

-1.15, -0.08

0.025

Placebo

-2.54

Perennial allergic

rhinitis trial

Fluticasone

furoate 55 mcg

-4.16

-0.75

-1.24, -0.27

0.003

Fluticasone

furoate 110 mcg

-3.86

-0.45

-0.95, 0.04

0.073

Placebo

-3.41

Instantaneous Total Nasal Symptom Scores

Seasonal allergic

rhinitis trial

Fluticasone

furoate 55 mcg

-2.37

-0.23

-0.77, 0.30

0.389

Fluticasone

furoate 110 mcg

-2.80

-0.67

-1.21, -0.13

0.015

Placebo

-2.13

Perennial allergic

rhinitis trial

Fluticasone

furoate 55 mcg

-3.62

-0.75

-1.24, -0.27

0.002

Fluticasone

furoate 110 mcg

-3.52

-0.65

-1.14, -0.16

0.009

Placebo

-2.87

Reflective Total Ocular Symptom Scores

Seasonal allergic

rhinitis trial

Fluticasone

furoate 55 mcg

-1.26

0.04

-0.33, 0.41

0.826

Fluticasone

furoate 110 mcg

-1.45

-0.15

-0.52, 0.22

0.426

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21

Placebo

-1.30

16

HOW SUPPLIED/STORAGE AND HANDLING

16.1

Shelf life

The expiry date of the product is indicated on the label and packaging materials.

In-use shelf life: 2 months.

16.2 Nature and contents of

container

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.

16.3 Special precautions for storage

Do not refrigerate

or freeze.

Immediately after use put the cap back on firmly.

Store the device in the upright position with the cap in place.

17.

Manufacturer

Glaxo Operation (UK) Limited, Barnard Castle, UK.

18. License Holder and Importer

GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach Tikva.

19. License Number

141-80-31837

Avam DR v5

ןכרצל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכרצל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

21.7.2013

םושירה רפסמו תילגנאב רישכת םש

Avamys 141-80-31837

םושירה לעב םש

GlaxoSmithKline (Israel) Ltd.,

25 Basel St., Petach Tikva

! דבלב תורמחהה טורפל דעוימ הז ספוט תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט :יאוול תועפות

-

.הילכה תרתוי תקיפס יא תרתוי תקיפס יא הילכה תרתוי תוטולב ובש בצמ הניה הילכה .םידיאורטס םינומרוה קיפסמ תורציימ ןניא םייושע הילכה תרתוי תקיפס יא לש םינימסת :לולכל

תופייע

השלוח

תרוחרחס

הליחב

האקה לש היוצרה תוליעפל ףסונב הב שומישה ןמזב ,הפורתה יאוול תועפות עיפוהל תולולע וא יוריג ...ףאהמ םומיד :ןוגכ לש ימינפה קלחב תוחונ רסוח .ףאב םיביכ בקע ןכתי ףאה :תוללוכ רתויב תוחיכשה יאוולה תועפות

ינב םירגבתמו םירגובמב

12

הלעמו

שאר יבאכ

ףאהמ םימומיד

ןורג באכ

ףאב םיעצפ

בג באכ

ינב םידליב

2

דע

12

שאר יבאכ

ןורג באכ

ףאהמ םימומיד

םוח

לועיש תושקובמה תורמחהה תונמוסמ ובש ,ןולעה ב"צמ בוהצ עקר לע

( ונמוס תורמחה רדגב םניאש םייוניש ןולעב ו עקר אללב ) קוריב

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