One Airway, One Approach

The Role of NASONEX® & Singulair in Airway Disease

Date:2018/10/05王瀛標醫師

Disease

Efficacy and Safety of NASONEX®

for Allergic Rhinitis & Nasal Polyps

無酒精無酒精無酒精無酒精無香味無香味無香味無香味

22

NASONEX® (Mometasone Furoate INS)

• 中文名中文名中文名中文名 內舒拿水溶性鼻用噴液劑內舒拿水溶性鼻用噴液劑內舒拿水溶性鼻用噴液劑內舒拿水溶性鼻用噴液劑

• 適應症適應症適應症適應症 成人成人成人成人、、、、青少年及青少年及青少年及青少年及2歲歲歲歲以上兒童之以上兒童之以上兒童之以上兒童之季節性或常年性過季節性或常年性過季節性或常年性過季節性或常年性過

敏性鼻炎亦用於治敏性鼻炎亦用於治敏性鼻炎亦用於治敏性鼻炎亦用於治療療療療18歲歲歲歲及以上成年人輕度到及以上成年人輕度到及以上成年人輕度到及以上成年人輕度到中中中中

度鼻息肉之相關症狀度鼻息肉之相關症狀度鼻息肉之相關症狀度鼻息肉之相關症狀。。。。

3

• 用法用量用法用量用法用量用法用量

- 過敏性鼻炎過敏性鼻炎過敏性鼻炎過敏性鼻炎Allergic Rhinitis:≧≧≧≧ 12yrs: 200 mcg/day (2 sprays/each nostril QD)2-11 yrs: 100 mcg/day (1 spray /each nostril QD)

- 鼻息肉鼻息肉鼻息肉鼻息肉Nasal Polyps: ≧≧≧≧ 18yrs: 400 mcg/day (2 sprays/each nostril , BID)

ARIA Guidelines: Recommendations for Management of Allergic Rhinitis

Moderatesevere

intermittent

Mildpersistent

Moderatesevere

persistent

4

ARIA = Allergic Rhinitis and its Impact on Asthma.Bousquet et al. J Allergy Clin Immunol. 2001;108 (5 suppl):S147.

Mildintermittent

Immunotherapy

Allergen and irritant avoidance

Intranasal decongestant (<10 days) or oral decongestant

SecondSecond--generation generation nonsedatingnonsedating H1 antihistamineH1 antihistamineLeukotriene receptor antagonistsLeukotriene receptor antagonistsLocal chromone

IntraIntra--nasal nasal steroidssteroids

Allergic Rhinitis ARIA Guidelines: Recommendations for AR Symptom Relief

Congestion RhinorrheaItching/

Sneezing Duration

INS +++ +++ ++/+++ 12-48 h

““““Corticosteroids are the most effective pharmacological treatment for allergic rhinitis ””””

““““The effect of topical corticosteroids on nasal bloc kage and their anti-inflammatory properties favor them above other treatments. ””””

5

INS +++ +++ ++/+++ 12-48 h

Oral antihistamines + ++ +++/++ 12-24 h

Oral decongestants + - -/- 3-24 h

Intranasal cromones

+ + +/+ 2-6 h

Anticholinergics - ++ -/- 4-12 h

Antileukotrienes ++ + -/- Not reportedARIA = Allergic Rhinitis and its Impact on Asthma; INS = intranasal steroids.

Bousquet et al. Allergy. 2006;61:1086-96. Bousquet et al. Allergy. 2008;63(Suppl 86):8-160.

NASONEX® vs.. Fluticasone (FP) in PAR total nasal symptom

1

1.2

1.4

NASONEX 200 mcg qdFP 200 mcg qd

Placebo

* * *

†*

*

†*

*

†*

*

*P<0.05 vs.. placebo†P<0.05 vs.. FP

6Mandl M, et al. Ann Allergy Asthma Immunol. 1997;79:370

0

0.2

0.4

0.6

0.8

1

Day 8 Day 15 Day 29 Week 8 Week 12Endpoint Follow-up

* *

**

* * *

PAR = perennial allergic rhinitis.

TherapyLevel of

EvidenceGrade of

Recommendation RelevanceOral antibiotic <2 weeks No data D No

Oral antibiotic >12 weeks No data D Yes, for late relapse

Topical antibiotic No data D No

EP3OS Treatment Recommendations for Adults With Nasal Polyposis 1

~ Topical steroid is one of treatments以INS、口服類固醇、洗鼻三種方式治療鼻息肉和鼻竇炎相比，INS評分最高

7

EP3OS = 2007 European Position Paper on Rhinosinusitis and Nasal Polyposis.1. Fokkens W et al. Rhinol Suppl. 2007;20:1–136.

Topical antibiotic No data D NoTopical steroid Ib A YesOral steroid Ib A Yes

Nasal douche Ib, no data in single use A Yes, for

symptomatic relief

Oral/topical decongestant No data in single use D No

Mucolytics No data D No

Baseline score: 4.21

Study 1 (N=354) 1 Study 2 (N=310) 2

4.00 4.10 4.174.27 4.25

-0.6

-0.4

-0.2

0

Mean reduction in bilateral polyp grade score at 4 months a

NASONEX® in Patients With Nasal Polyposis: Efficacy Results – Polyp Grade

8

b

b b

-1.4

-1.2

-1.0

-0.8

-0.6

NASONEX200 µg once daily

Placebo

NASONEX 200 µg twice daily

aCoprimary endpoint.bP<0.05 vs. placebo.The mean change from baseline in polyp score at Mon th 1 in Study 1 was -0.61 for NASONEX 200 mg twice daily vs. -0.33 for placebo ( P<0.05).1. Small CB et al. J Allergy Clin Immunol. 2005;116:1275–1281.2. Stjärne P et al. Arch Otolaryngol Head Neck Surg. 2006;132:179–185.

Months MonthsStudy 1 (N=354) 1

-0.6

-0.4

-0.2

00 1 2 3 4

Study 2 (N=310) 2

-0.6

-0.4

-0.2

00 1 2 3 4

NASONEX® in Patients With Nasal Polyposis: Efficacy Results – Nasal Congestion ( 鼻塞鼻塞鼻塞鼻塞)

aa

9

-1.2

-1.0

-0.8

-0.6

a

a, b-1.2

-1.0

-0.8

-0.6

NASONEX 200 µg once daily

PlaceboNASONEX 200 µg twice daily

a, b

a, b

a, b a

a, ba, b

a, b

a

aa

a

Coprimaryendpoint

Coprimaryendpoint

Baseline nasal congestion was NASONEX once daily = 2.29, NASONEX twice daily = 2.35, and placebo = 2.28 in Study 1.Baseline nasal congestion was NASONEX once daily = 2.23, NASONEX twice daily = 2.20, and placebo = 2.18 in Study 2.aP<0.05 vs. placebo; bP<0.05 vs. NASONEX 200 µg once daily.1. Small CB et al. J Allergy Clin Immunol. 2005;116:1275–1281.2. Stjärne P et al. Arch Otolaryngol Head Neck Surg. 2006;132:179–185.

NASONEX Does Not Impair Long-Term Growth in 98 Children 3-9 Years After 1 Year of NASONEX

TreatmentM

ean

chan

ge in

hei

ght

from

bas

elin

e (c

m)

5

6

7

8 NASONEX 100 µg od (n=49)

Placebo (n=49)

10

Mea

n ch

ange

in h

eigh

t fr

om b

asel

ine

(cm

)

Months

0

1

2

3

4

Schenkel et al. Pediatrics. 2000;105:E22.

1 2 3 4 5 6 7 8 9 10 11 12

NASONEX : No influence on Serum Cortisolin Children 2–5 Years of Age Following 42 Days of

Treatment 1

Ser

um c

ortis

olR

IA)

10

12

14

16

Mean serum cortisol concentration-time profile on D ay 42 in children with AR

NASONEX 100 µgonce daily (n=26)

11

Ser

um c

ortis

ol(µ

g/dL

–R

IA)

0

2

4

6

8

Placebo once daily (n=26)

6:00 AM 10:00 AM 2:00 PM 6:00 PM 10:00 PM 2:00 AM 6:00 AM

NASONEX = mometasone furoate nasal spray; AR = allerg ic rhinitis; RIA = radioimmunoassay.1. Cutler DL et al. Pediatr Asthma Allergy Immunol. 2006;19:146–153.

Pla

sma

cort

isol

g/dL

)

NASONEX®: No Effect on Plasma Levels of Cortisol in Adults at 20 Times the Recommended Dose

Plasma Cortisol Profile FollowingIntranasal Administration of NASONEX

(NASONEX®)

4000 µg(4mg)

2000 µg1000 µg

NASONEX

15

20

12

Pla

sma

(µg/

N=24 men.NASONEX = mometasone furoate nasal spray.

Brannan et al. J Allergy Clin Immunol. 1996;97:198. Abstract 62.

1000 µgPlacebo

11 PM6 PM3 PM11 AM9 AM8 AM7 AM6 AM5 AMPre-Tx

0

5

10

NASONEX® Rapid Onset of Action:Significant Total Symptom Relief Within 5 Hours

of a Single Dose in Patients with SAR

13

* P<0.05 vs.. placebo. SAR =seasonal allergic rhinitis.Berkowitz et al. Allergy Asthma Proc. 1999;20:167.

The Therapeutic Index (TIX) indicated NASONEX® as an INS with high efficacy and low potential of adverse events

14Therapeutic index for intranasal corticosteroids in allergic rhinitisReference: Rhinology 49: 272-280, 2011

根據Therapeutic index (TIX)評分結果，Nasonex具有以下特點:

15Therapeutic index for intranasal corticosteroids in allergic rhinitisReference: Rhinology 49: 272-280, 2011

97%97%97%97%

98%98%98%98%

Patients Report NASONEX® Easy to Use

The NASONEX® Nasal Spray is easy to use

The NASONEX® Nasal Spray applicator fits comfortably in the nostril

(方便使用方便使用方便使用方便使用)

(置入鼻孔內相當舒服置入鼻孔內相當舒服置入鼻孔內相當舒服置入鼻孔內相當舒服)

16

94%94%94%94%

96%96%96%96%

Synovate Market Research, December 2006; n=1,500 NASONEX usersSynovate Market Research, December 2006; n=1,500 NASONEX users

The NASONEX® Nasal Spray is easy to pump/press

The NASONEX® Nasal Spray is comfortable to hold while administering a dose (or mist in the nose)

50% 100%

(置入鼻孔內相當舒服置入鼻孔內相當舒服置入鼻孔內相當舒服置入鼻孔內相當舒服)

(操作起來相當簡單操作起來相當簡單操作起來相當簡單操作起來相當簡單)

(藥劑噴霧在鼻孔內感覺相當舒服藥劑噴霧在鼻孔內感覺相當舒服藥劑噴霧在鼻孔內感覺相當舒服藥劑噴霧在鼻孔內感覺相當舒服)

塑膠瓶設計不易摔破塑膠瓶設計不易摔破塑膠瓶設計不易摔破塑膠瓶設計不易摔破，，，，噴霧較細緻易附著在鼻黏膜上等噴霧較細緻易附著在鼻黏膜上等噴霧較細緻易附著在鼻黏膜上等噴霧較細緻易附著在鼻黏膜上等。。。。

17

One Airway, One Approach

Asthma and Allergic Rhinitis: 2 Related Conditions Linked by 1 Common Airway

• Frequently overlapping conditions

• Involvement of similar tissues

• Common inflammatory processes

18

- Common inflammatory cells

- Common inflammatory mediators

Adapted from Phillip G et al. Curr Med Res Opin. 2004;20:1549–1558.

Epidemiologic Links between Allergic Rhinitis and Asthma

8 out of 10 Asthma patients Have Allergic Rhinitis

Up to 80%of all asthmatic patients have allergic rhinitis

Adapted from Bousquet J et al J Allergy Clin Immunol 2001;108(suppl 5):S147–S334; Sibbald B, Rink E Thorax 1991;46:895–901; Leynaert B et al J Allergy Clin Immunol 1999;104:301–304; Brydon MJ Asthma J 1996:29–32.

All asthmatic patients

Need for Changes in Asthma ManagementA Real Life Issue

• Many asthma patients remain uncontrolled: – 94.7% did not meet all GINA

criteria for asthma controla

(AIRE Study)1

– 51% did not meet criteria for

• In patients with comorbidasthma/allergic rhinitis 3–7:

Health careresourceutilization Quality

of

Slide 20

asthma control despite the use of an ICS or an ICS + LABA (INSPIRE study)2

Office visitsHospitalizationsMedication costs

oflife

aAt the time of this study, GINA criteria for asthma control included the following: minimal chronic symptoms, minimal exacerbations, no emergency visits, minimal need for as-needed β agonists, no limitations in daily activities, and normal or near-normal lung function.

GINA=Global Initiative for Asthma; AIRE=Asthma Insights and Reality in Europe; ICS=inhaled corticosteroids; LABA=long-acting β-agonists;INSPIRE=International Asthma Patient Insight Research.

1. Rabe KF et al. Eur Respir J. 2000;16:802–807. 2. Partridge MR et al. BMC Pulm Med. 2006;6:13. doi:10.1186/1147–2466-6-13. 3. Thomas M et al. Pediatrics. 2005;115(1):129–134. 4. Kang H-Y et al. Yonsei Med J. 2008;49(4):521–529. 5. Price D et al. Clin Exp Allergy. 2005;35:282–287. 6. LaForest L et al. Int Arch Allergy Immunol. 2005;136:281–286. 7. Valovirta E et al. BMC Pulm Med. 2006;6(suppl 1):S3.

SINGULAIR Basic Profile :The unique ORAL asthma controller

• Easy to administer

• 4-mg and 5 -mg

Children 6 months to 2 years of age

One 4-mg oral granulepackage mixed with

food taken once dailyin the evening

Children 2 to 5 years of age

One 4-mg cherry-flavored chewable

tablet in the evening

Children 6 to 14 years of age

One 5-mg cherry-flavored chewable

tablet in the evening

Patients 15 years of age and olderOne 10-mg tablet

in the evening

E.1

• 4-mg and 5 -mg chewable tablets

21產品圖樣因放大比例與色差，和實體略有不同，僅供參考，請以實物為準。

Four Dosages

•10 mg 膜衣錠 15歲以上

• 5 mg 咀嚼錠 6~14歲

• 4 mg 咀嚼錠 2~5歲

• 4 mg 顆粒劑 0.5~5歲

SINGULAIR® with a Steroid Targets Dual Pathways of Inflammation

block steroid-sensitivemediators

blocks the effects of cysteinylleukotrienes

Inhaled steroidsMontelukast

mediatorsleukotrienes

Complementary Effect

• Singulair ® blocks the cysteinyl leukotriene pathway of asthmatic inflammation

• Steroids do NOT inhibit the formation of cysteinyl leukotrienesin the airways of patients with asthma

The slide represents an artistic rendition.

Adapted from Diamant Z, Sampson AP. Clin Exp Allergy. 1999;29:1449–1453; Barnes PJ. Am J Respir Crit Care Med. 1996;154:S21–S27; Claesson H-E, Dahlén S-E. J Intern Med. 1999;245:205–227; Price DB et al. Thorax. 2003;58:211–216.

Airway Inflammation Persisted Despite Corticosteroid Use

20,00010,000

1,000Eosinophil× 103/g

p<0.01

p<0.001

p<0.001

p<0.01

In a clinical study of 74 patients

ICS=inhaled corticosteroids; OCS ± ICS=received oral corticosteroids with or without ICS

Adapted from Louis R et al Am J Respir Crit Care Med 2000;161:9-16.

100

10

1

× 103/gsputum

Controlgroup

Mild to moderate

ICSlow-dose(n=10)

ICShigh-dose

(n=15)

OCS(n=10)

OCS ± ICS(n=7)

Severe asthma

Leukotrienes in Asthma

Actions of Cysteinyl Leukotrienes in the Asthmatic Airway

Decreased mucustransport

Airwayepithelium

Increasedmucus secretion

Cationic proteins(epithelial cell damage)

Increased releaseof tachykinins

白三烯素有關的發炎反應:

包括水腫,痰液分泌增加,

呼吸道上皮細胞的受損,

甚至導致支氣管收縮,進而嚴重影響患者的肺功能.

Adapted from Hay DWP et al Trends Pharmacol Sci 1995;16:304–309.

of tachykinins

Sensory Cfibers

Smooth muscle

Contraction and proliferation—bronchoconstriction

Inflammatory cells(e.g., mast cells, eosinophils)

Bloodvessel

Edema

Cysteinyl leukotrienes

Eosinophilrecruitment

25

SINGULAIR® Significantly Reduced the Rate of Exacerbations 1

2.34

1.602

3

Exa

cerb

atio

n E

piso

deY

ear

32%

P≤0.001

Prevention of Viral-Induced Asthma (PREVIA):

Slide 26

1.60

0

1

Singulair ® 4 mg (n=265)

Placebo (n=257)

Exa

cerb

atio

n E

piso

deR

ate/

Yea

r

1. Bisgaard H et al. Am J Respir Crit Care Med. 2005;171:315–322.

SINGULAIR® with Fluticasone Produced Superior Reduction in Blood Eosinophils

Mean (SE) change

from baseline in blood

eosinophilcount

(x103/ µL)

Singulair ®

+ fluticasone (n=747)*Salmeterol LABA)

+ fluticasone (n=743)**

-0.01 (0.01)

-0.02

-0.01

0

(x10 / µL) over

48 weeks

*Montelukast 10 mg + fluticasone 200 µg, **salmeterol 100 µg + fluticasone 200 µg. Values are least squares mean change from baseline. P-value is for between-group difference. Baseline value = 0.3 x 10 3/µL in both treatment groups.

-0.04 (0.01)

-0.05

-0.04

-0.03

-0.02

p=0.011

Bjermer L et al BMJ 2003;327:891-895.

420

SINGULAIR ® + Budesonide Had a Faster Onset of Action

AM PEF 400

410

Singulair ® + budesonide 800 µg(n=433)

Budesonide 1600 µg(n=425)

SINGULAIR + ICS效果 > ICS劑量加倍

PEF (L/min)

Days relative to start of trialRun-in

390

400

-14 -7 0 7 143

P=0.001between groups

Price DB, Hernandez D, Magyar P et al. Thorax 2003;58:211-216

• 結果顯示，使用Singulair的小

兒氣喘患者，比使用LABA的

患者有更好改善效果

Salmeterol: 使立穩優氟吸入劑 (GSK)SABA: short-acting β-agonist 短效型乙型拮抗劑LABA: long-acting β-agonist 吸入型乙型交感神經興奮劑FEV1 forced expiratory volume in 1 second 第㆒秒用力㈺出量

PRAACTICAL Study in Asthma Patients with AR on ICS Therapy

Adding SINGULAIR ® Reduced the Incidence of Asthma Attacks

Reduction from1:3 patients to1:10 patients

p=0.001

% of patients

per year with 20

35 31.8%

25

30

68%

N=701Asthma attack: worsening of asthma requiring hospitalization, emergency visit, or oral corticosteroids use.Adapted from Borderias L et al. Presented at the 15th Annual Congress of the European Respiratory Society, Copenhagen, Denmark, September 17–21, 2005. Poster 3692.

per year with

asthma

attacks

0

5

10

15

20

Prior to Singulair ®

10.1%

Post Singulair ®

2011 Japanese Guideline for Childhood Asthma(<2 years old)

Reference: Allergology International. 2011; 60: 147~169

< 2歲的asthma 小朋友,也同樣建

議LTRA (Singulair ®) 為需要basic

treatment的首選藥物(step2) 同時

也是其他step的重要治療選擇

2011 Japanese Guideline for Childhood Asthma(2~5 years old)

Reference: Allergology International. 2011; 60: 147~169

2~5歲的asthma 小朋友,也同樣建議LTRA

(Singulair ®) 為需要basic treatment的首選藥

物(step2) 同時也是其他step的重要治療選擇

2011 Japanese Guideline for Childhood Asthma(6~15 years old)

Reference: Allergology International. 2011; 60: 147~169

6~15歲.,

同樣建議LTRA (Singulair ®) 作為第一線

治療的選擇,同時也可以合併ICS或是其他

治療藥物

Treating asthma kids > 2 years old

DATCATDiagnosis and Treatment Guidelines for Childhood As thma in

Taiwan 台灣兒童氣喘診療指引台灣兒童氣喘診療指引台灣兒童氣喘診療指引台灣兒童氣喘診療指引

※ ICS Inhaled CorticoSteroid吸入型類固醇

Singulair ®

Singulair ®

台灣兒童氣喘診療指引學術研討會 DATCAT P31

入型類固醇

※ LABA long-acting β-agonist 吸入型乙型交感神經興奮劑

※※※※ LTRA leukotriene receptor antagonist (MontelukastSodium) 白三烯受體拮抗劑白三烯受體拮抗劑白三烯受體拮抗劑白三烯受體拮抗劑

Singulair ®

健保給付規範6.2.4. Montelukast sodium (如Singulair Coated Tab 5mg & 10mg : )：(90/7/1)1.限用於六歲以上之小兒及成人「輕度至中度持續性支氣管哮喘」疾患。2.病歷上應詳細記載上個月發作次數、頻率及PEFR值之變化。3.每月最大量限三十粒。4.本品項不得與cromoglycate或ketotifen併用。※「輕度持續支氣管哮喘 (mild persistent asthma)」之定義：(1)氣喘發作次數每週多於一次，但並非每天發作。(2)發作時會影響日常生活及睡眠。(3)夜晚發作次數每月多於二次。(4)尖峰呼氣流速 (Peak Expiratory Flow Rate；PEFR) 或第一秒呼氣量大於80%預測值；每日變異值為20-(4)尖峰呼氣流速 (Peak Expiratory Flow Rate；PEFR) 或第一秒呼氣量大於80%預測值；每日變異值為20-30%。

6.2.5.Montelukast sodium 4mg(如Singulair Chewable Tab. 4mg、Singulair oral granules 4mg)：(92/1/1、100/7/1)須符合下列各項條件：1.限用於「輕度至中度持續支氣管哮喘病患」。2.Chewable Tab. 4mg限用於二歲~五歲嬰幼兒、oral granules 4mg限用於6個月~五歲嬰幼兒。3.病歷上應詳細記載上個月發作次數、頻率。4.每月最大量限三十粒(包)。5.本品項不得與cromoglycate或ketotifen併用

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