ONBREZ BREEZHALER 150 MCG

עעבקנהזןולעטמרופ " ודילערשואוקדבנונכותותואירבהדרשמי לירפאב 2012 .

םיחקורהתונקתיפלןכרצלןולע ) םירישכת ( משתה " ו - 1986

אפורםשרמבתבייחוזהפורת

ארק / י תאןויעב שמתשתםרטבופוסדעןולעה / י הפורתב

ותרוצורישכתהםש :

הזירבזרבנוא רל

150 קמ " ג רלהזירבזרבנוא

300 קמ " ג

הפיאשלהקבאלשתוסומכ הפיאשלהקבאלשתוסומכ

בכרה :

לכ הסומכ הליכמ :

רלהזירבזרבנוא 150 קמ " ג :

Indacaterol maleate 194 mcg equivalentto150 mcgindacaterol.

רלהזירבזרבנוא 300 קמ " ג :

Indacaterol maleate 389mcg equivalentto300 mcgindacaterol.

םירמוח יתלב םיליעפ :

Lactosemonohydrate, gelatin.

רלייהזירבזרבנואלשהלוספקלכ 150 הליכמ 24.8 מ " טרדיהונומזוטקלג

רלייהזירבזרבנואלשהלוספקלכ 300 הליכמ 24.6 מ " טרדיהונומזוטקלג

תיטיופרתהצובק :

רוטפצרליביטקלסטסינוגא אטב 2 .

תה הפור ייש תכ תונופמיסיביחרמתארקנהתופורתתצובקל .

תיאופרתוליעפ :

רלהזירבזרבנוא שמשמ ת המישנהלעהלקהל םירגובמב תארקנהתואירתלחמבקעהמישניישקםע

תינורכתיתמיסחתואירתלחמ ) chronic obstructive pulmonary disease(COPD) .(

תבשמתשהלשי הפור םעקר הזיראלףרוצמהףאשמה . תאתוליכמהתוסומכוףאשמשיהזיראב

הפיאשלהקבאכהפורתה . הסומכהךותמהפורתהתפיאשתארשפאמףאשמה .

בםירירשהתאהפרמרלהזירבזרבנוא תונפד לש יכרד נטקהריוואה תו תואירב . תאחותפלרזוערבדה

יכרד ריוואה , ריוואהלעלקמו הצוחהתאצלוהמינפסנכיהל .

ךרובעהמשרנאיהעודמוארלהזירבזרבנואלשהלועפהןפואיבגלתולאשךלשיםא , תונפלשי

אפורל .

בשמתשהלןיאיתמ הפורת ?

הפורתבשמתשהלןיא םא יא - תיגרלאואהליגראלהבוגתךלהתיהםעפ לורטקדניאל ) ביכרמה

ליעפה ( , זוטקלל יביכרמראשל הטמםיטרופמההפורתה .

ךילאיטנבלררבדהםא , שי מאפורהתאעדייל רלהזירבזרבנואבשמתשהלילב .

בשוחךניהםא / יגרלאךניהיכת / ת , הנפ / אפורהמץועייתלבקלי .

הלילבמהפורתבשמתשהלןיא י לופיטהתלחתהינפלאפורבץעוו :

ואןוירהבתאםא ןוירהבתאשתבשוח , תאםאוא קינימ ה . שמתשהלהלוכיתאםאךלרמאיאפורה

רלהזירבזרבנואב .

המתסאךלשיםא ) ךירצךניאהזהרקמב / רלהזירבזרבנואםעלופיטלבקלה ( .

בלבתויעבךלשיםא .

לבוסךניהםא / היספליפאמת .

דיאוריתהתטולבבתויעבךלשיםא .

לבוסךניהםא / תרכוסמת .

לטונךניהםא / לתומודתופורתת בלופיט ךלשתואירהתלחמ ) האר / י ' תויתפורתןיבתובוגת ' .(

ךלשםויםויהייחלעהפורתהעיפשתךיא ?

יכריבסאל רלהזירבזרבנוא ת תונוכמבשמתשהלוגוהנלתלוכיהלעעיפש .

תורהזא :

הלשםימוטפמיסהםא - COPD ) המישנרצוק , המישנהןמזבםיפוצפצ , לועיש ( ואםירפתשמאל םא

לופיטהךלהמבםירימחמםה - הנפ / דימאפורלי .

יהשלכהפורתלואוהשלכןוזמלשיגרךניהםא , הפורתהתליטנינפלאפורלךכלעעידוהלךילע .

זוטקלהליכמהפורתה .

תויתפורתןיבתובוגת :

הםא י לטונךנ / תפסונהפורתת , םשרמאללתופורתללוכ , הפורתבלופיטהתעהזתרמגםאוא

תרחא , יאואםינוכיסעונמלידכלפטמהאפורלחוודלךילע - וליעי ןיבתובוגתמםיעבונהת - תויתפורת ,

דחוימב תואבהתוצובקהמתופורתיבגל :

ןואכידבלופיטלתושמשמהתופורת ) םיילקיצירטןואכידידגונןוגכ , מ ןימאונומיבכע

זאדיסקוא (

לופיטלתושמשמהרלהזירבזרבנואלתומודתופורת ךלשתואירהתלחמב ) יושעןהבשומיש

יאוולתועפותלןוכיסהתאתולעהל (

םדבןגלשאהתמרתאתודירומהתופורת . םינתשמתוללוכהלא ) לופיטלתושמשמהתופורת

דיזאיתורולכורדיהןוגכםדץחלרתיב ( , םיניטנסקליתמומכםירחאתונופמיסיביחרמ ) ןוגכ

ןיליפואת ( םידיאורטסוא ) נדרפןוגכ ןולוזי (

תורחאתויבבלתויעבואםדץחלרתיבלופיטלםישמשמהאטבימסוח ) פורפןוגכ ר א לולונ ( וא

המוקואלגבלופיטל ) לולומיטןוגכ .(

יאוולתועפות :

הפורתהלשהיוצרהתוליעפלףסונב , עיפוהלתולולעהבשומישהןמזב תועפות אוול י , אלןהךא

םלוכלצאתועיפומ .

חיכשיאוולתועפות דואמתו ) לכמדחאמרתוילעתועיפשמ 10 םילפוטמ :( ןורגבאכלשבוליש , תלזנ ,

םותסףא , תושטעתה , לועיש , כ שארבא םוחילבואםע .

תוחיכשיאוולתועפות ) עיפשהלתויושע לע לדחאןיב - 10 לכמ 100 םילפוטמ ( : שארבאכ ; תרוחרחס ;

לועיש ; םירירשתותיווע ; ןורגבאכ ; חצמבוםייחלבבאכואץחלתשגרה ) םיסוניסבתקלד ( ; באכ

םירירש ; םיידיהתופכבתוחיפנ , ב םיילוסרק ו ב התופכ םיילגר ; הזחבזעבאכ ) בלבתויעב ( ; בלתוקיפד

תוקזח ) תויצטיפלפ ( ; תלזנ ; באכ תומצעב םיקרפמבוא ; הזחבבאכ ; החירפ / דרג .

יאוולהתועפותמרתויואתחאםא רומחןפואבךילעהעיפשמ , הנפ / אפורלי .

םימעפלםילעתשמםישנאהמקלח רצקןמז הפורתהתפיאשרחאל . ילוחבחיכשםוטפמיסאוהלועיש

COPD . לעתשמךניהםא / ת רחאלרצקןמז תפיאש הפורתה , הגאדלא , הקירהסומכהדועלכ ,

האולמבהנמהתאתלביק . הקירהניאהסומכהםא , ףאש / י תוארוההיפלעבוש .

תיניצרלתכפוהיאוולהתועפותמרתויואתחאםא , ןיחבמךניהםאוא / ןניאשיאוולתועפותבה

הזןולעבתועיפומ , הנפ / אפורלי .

תועפות יאוול תדחוימתוסחייתהתובייחמה :

תוחיכשיאוולתועפות ) לדחאןיבלעעיפשהלתויושע - 10 לכמ 100 םילפוטמ :(

רבגומאמצ , ההובגןתשתקופת , לקשמןדבואםערבגומןובאת , תופייע , המר םדברכוסלשההובג

תרכוסהתלחמלשםינמיס ( - הנפ / דימאפורלי .

תוחיכשאליאוולתועפות ) לדחאןיבלעעיפשהלתויושע - 10 לכמ 1,000 םילפוטמ :(

הזחבץחל , לועיש , הפיאשרחאלדימהמישנרצוקואהמישנהןמזבםיפוצפצ ) תיוועלשםינמיס

תונופמיס ( - קספה / הנפולופיטהי / רלי דימאפו .

העילבואהמישניישק , ןושלהלשתוחפנתה , םינפהןםייתפשה , תדפרס , רועבהחירפ ) לשםינמיס

תיגרלאהבוגת ( – הנפ / דימאפורלי .

אלבלבצק רידס ; ריהמבלבצק ; םירירשבאכ ; השוחתרסוחואץוצקע .

העיפשמולאיאוולתועפותמרתויואתחאםא רומחןפואבךילע , הנפ / אפורלי דימ .

ןונימ :

דבלבאפורהתוארוהיפלןונימ . רובעלןיא לע תצלמומההנמה .

ןיא ליגלתחתמםירגבתמואםידלילרלהזירבזרבנואתתל 18 .

ינבםילפוטמ 65 םילוכיהלעמו בשמתשהל םירגובמםילפוטמומכןונימהותואברלהזירבזרבנוא

םירחא .

ןונימה אוהלבוקמה תחאהסומכלשהלוכתהתפיאש םויבםעפ , םוילכב , ףאשמהתועצמאב . שי

קרףואשל םויבםעפ תוכשמנרלהזירבזרבנואלשתועפשההורחאמ 24 תועש .

רלהזירבזרבנואלשהפיאש םויהךשמבםימוטפמיסהתאןיטקהלרוזעתםוילכבןמזהותואב

הלילהו . וטילרוכזלךלרוזעיםגרבדה הפורתהתאל .

ףאשמבקרשמתשהלשי ה ףרוצמ הזיראל . תוסומכהתאעולבלןיא .

הרוהאפורהשןמזהקרפךשמלרלהזירבזרבנואבלופיטהתאךישמהלשי .

COPD רלהזירבזרבנואבשמתשהלשיוחווטתכוראהלחמאיה םוילכ תויעבךלשישכקראלו

לשםירחאםימוטפמיסואהמישנ COPD .

רלהזירבזרבנואבלופיטהןמזךשמיבגלתולאשךלשיםא , הנפ / אפורלי .

ץלמומ ףואשל םוילכבןמזותואבהפורתהתא . תחכשםא ףואשל הנמ , שי התאףואשל הנמ האבה

תרחמלשםויבליגרהןמזב . ןיא ףואשל החכשנשהנמהלעתוצפלידכהלופכהנמ .

שומישהןפוא

ןתינ ל ףואש הזירבזרבנוא הייתשואהחוראירחאואינפלרל .

בשומישלתוארוה ףאשמ רלהזירבזרבנוא

ןולעהלשהזקלח ריבסמ דציכ רלהזירבזרבנואהףאשמתאקזחתלושמתשהל . ןויעבאורקלשי

רחאאלמלו תוארוהה . תולאשךלשיוהדימב , הנפ / חקורלואאפורלי .

הליכמרלהזירבזרבנואתזיראלכ :

זרבנואףאשמ דחארלהזירב

שגמ תוי ליכמה תו ףאשמהםעשומישלרלהזירבזרבנואתוסומכ

הפורתהלשהשדחהזיראתחיתפםע , וזהזיראבלולכהףאשמבשמתשהלשי , ףאשמהתאךילשהלו

תמדוקההזיראבהיהש .

רלהזירבזרבנואהתוסומכתאעולבלןיא : הפורתהתאףואשלךלרשפאמרלהזירבזרבנואהףאשמ

נש רלהזירבזרבנואהתסומכךותבתאצמ .

הזיראלףרוצמהרלהזירבזרבנואהףאשמבקרשמתשהלשי .

רחאףאשמלכםערלהזירבזרבנואתוסומכבשמתשהלןיא , זרבנואהףאשמבשמתשהלןיאו

תורחאתופורתלשתוסומכלוטילידכרלהזירב .

ףאשמבשומיש

הסכמהתאהלעמלךושמלשי .

ףאשמהתחיתפ :

תאתוטהלוףאשמהסיסבתאבטיהקיזחהלשי

ףאשמהתאחותפלידכהייפה .

הסומכהתנכה :

שומישהינפלדימ , תחאהסומכאיצוהלשי

תישגמה , תושביםיידיב .

הסומכהתסנכה :

הסומכהאתךותבהסומכהתאםישלשי .

ותבתורישיהסומכםישלןיא ך הייפה .

שמהתריגס ףא :

ףאשמהתאירמגלרוגסלשי . עומשלשי ' קילק '

תטלחומהותריגסםע .

הסומכהבוקינ :

יכנאבצמבףאשמהתאקיזחהלשי , הייפהרשאכ

הלעמיפלכתינפומ .

ץוחללשי ףוסהדע םירותפכהינשלע , תחאםעפ .

עומשלשי ' קילק ' הסומכהבוקינתעב .

םירותפכהלעץוחללןיא םיבקנמה רתוי םעפמ

תחא .

םירותפכהתאירמגלררחשלשי .

ףושנלשי :

הפלהייפהתסנכהינפל , הצוחהףושנלשי ןפואב

אלמ .

הייפהךותלףושנלןיא .

הפורתהתפיאש :

הפיאשהתחיקלינפל , הפהךותבהייפהםישלשי

רוגסלו בטיה הייפלביבסמםייתפשהתא .

נופםירותפכהשכףאשמהתאקיזחהלשי םי

הלאמשוהנימי ) הטמלוהלעמלאלו .(

תוריהמבהמינפםושנלשי ךא עובקבצקב , קומע

רשפאשהמכדע . םירותפכהלעץוחללןיא

םיבקנמה .

בלםישלשי :

ףאשמהךרדהמישנהךלהמב , הסומכה

אתבתבבותסמ , לילצעומשלךילעו שורשרלש .

תואירלעיגתהפורתהרשאכ , שוחת / םעטבי

קותמ .

עמושךניאם / שורשרלשלילצת , יכןכתי

הסומכהללחבהעוקתהסומכה . הזהרקמב , שי

תאתוריהזבררחשלוףאשמהתאחותפל

לעהסומכה - הסיסבלעהחיפטידי רישכמ . ןיא

תאררחשלידכםיבקנמהםירותפכהלעץוחלל

הסומכה . םיבלשלערוזחלשי 8 ו – 9 תדימב

ךרוצה .

המישנהתריצע :

י המישנהתאקיזחהלךישמהלש ךשמלתוחפל

5-10 ןתינשהמכדעואתוינש תאצוהןמזב

הפהמףאשמה . ףושנלשיזא .

ףאשמהתאחותפלשי ידכ הראשנםאתוארל

הסומכבהקבא . הסומכבהקבאהראשנםא , שי

םיבלשלערוזחלוףאשמהתארוגסל 8 דע 11 .

הסומכהתאןקורלםילוכיםישנאהתיברמ

יאשב םייתשואתחאהפ .

םימעפלםילעתשמםישנאהמקלח רצקןמז

הפורתהתפיאשרחאל . לעתשמךניהםא / ת , לא

הגאד , הקירהסומכהדועלכןכש , תאתלביק

האולמבהנמה .

הסומכהתאצוה :

םויסרחאל תפיאש זרבנואלשתימויההנמה

רלהזירב , הייפהתאבושחותפלשי , תאאיצוהל

הקירההסומכה התואקורזלו . תארוגסלשי

הסכמהתאריזחהלוףאשמה .

זרבנואהףאשמךותבתוסומכהתאןסחאלןיא

רלהזירב .

ימויןונימבקעמןומיס :

לשבקעמתלבטשיהזיראהלשימינפהקלחב

ימויהןונימה . םאיטנבלרהםויבןמסלןתינ

האבההנמלןמזהיתמרוכזלךלרזוערבדה .

רוכזלשי :

רלהזירבזרבנואהתוסומכתאעולבלןיא .

הזיראלףרוצמהרלהזירבזרבנואהףאשמבקרשמתשהלשי .

תישגמהךותברלהזירבזרבנואהתוסומכתאןסחאלשידימת , שומישהינפלדימןאיצוהלו .

רלהזירבזרבנואהףאשמלשהייפהךותבתורישירלהזירבזרבנואהתוסומכתאםישלןיא .

ץוחללןיא תחאםעפמרתויםיבקנמהםירותפכהלע .

רלהזירבזרבנואהףאשמלשהייפהךותלףושנלןיא .

הפיאשהינפלםירותפכהתאררחשלשידימת .

םימםערלהזירבזרבנואהףאשמתאףוטשלןיא . שביותוארומשלשי . האר / י ' תוקנלךיא

ףאשמהתא ' .

רלהזירבזרבנואהףאשמתאקרפלןיא .

הלשידימת זרבנואהתפורתלשהשדחההזיראהםעעיגמהרלהזירבזרבנואהףאשמבשמתש

רלהזירב .

רלהזירבזרבנואהףאשמךותברלהזירבזרבנואהתוסומכתאןסחאלןיא .

שביםוקמברלהזירבזרבנואהתוסומכוףאשמתארומשלשידימת .

ףסונעדימ :

םיתיעל , בעלתויושעהסומכהלשדואמתונטקתוסיפ ךיפלסנכיהלוןנסמהתארו . הרוקרבדהםא ,

יושעךניה / ה ןושלהלעהלאתוסיפבשוחל . קזנלתמרוגהניאולאתוסיפלשהפיאשואהעילב .

תחאםעפמרתויתבקונמהסומכהםאתולעלםייושעהסומכהתריבשלםייוכיסה ) בלש 6 .(

ףאשמהתאתוקנלךיא :

עובשבםעפףאשמהתאתוקנלשי . נלשי לידכשביויקנדבםעץוחבמוםינפבמהייפהתאבג ריסה

הקבאתויראש . םימםעףאשמהתאףוטשלןיא . שביורמושלשי . ףאשמהתאקרפלןיא .

ענמ / י הלערה !

וםידלילשםדיגשיהלץוחמרוגסםוקמברומשלשיתרחאהפורתלכווזהפורת / ידילעותוקוניתוא

ענמתךכ / י הלערה .

םא תפאש רלהזירבזרבנואידמרתוי םאוא והשימ / רחאי / ףאשת / ה תועטב תא הפורתה , הנפ / י דימ

ואאפורל םילוחתיבלשןוימרדחל , ךתאהפורתהתזיראאבהו . יאופרלופיטבךרוצהיהייכןכתי .

ךתלחמבלופיטלהמשרנוזהפורת , רחאהלוחב / ת , קיזהלהלולעאיה . ךיבורקלוזהפורתןתתלא ,

ינכש ךירכמואך .

ךשוחבתופורתלוטילןיא ! נמהותיוותהקודב ה םעפלכב לטונךניהש / ת הפורת . בכרה / י םייפקשמ

הםא י קוקזךנ / םהלה .

הנסחא :

תירוקמההזיראבןסחאלשי לתחתמו - C 30 0 . תוחלוםוחמןגהלושביםוקמברומשלשי .

הזיראהיאנתיפלםג / ה םיצלמומההנסחא , תורמשנתופורת דבלבתלבגומהפוקתל . בלםישלאנ

רישכתהלשהגופתהךיראתל ! קפסלשהרקמלכב , הפורתהתאךלקפיסשחקורבץעוויהלךילע .

הזיראהתואבתונושתופורתןסחאלןיא . המוגפהזיראהםאשמתשהלןיא .

סמ ' הפורתהםושיר :

רלהזירבזרבנוא 150 קמ " ג : 144 76 33112 00

להזירבזרבנוא ר 300 קמ " ג : 144 75 33111 00

ןרצי : גייאןייטשהמראפסיטרבונ ' י , גייאהמראפסיטרבונרובעץיווש ' י , לזב , ץיווש .

םושירהלעב : גייאססיורסהמראפסיטרבונ ' י , חר ' םחש 36 , חתפ - הווקת

עעבקנהזןולעטמרופ " ודילערשואוקדבנונכותותואירבהדרשמי לירפאב 2012 .

ONBREZ ® BREEZHALER ®

(Indacaterol maleate)

150 microgram and 300 micrograminhalation powder hard capsules

Prescribing Information

1 Trade names

150 microgram inhalation powder hard capsules

ONBREZ ® BREEZHALER ® 150 microgram, inhalation powder, hard capsules

300 microgram inhalation powder hard capsules

ONBREZ ® BREEZHALER ® 300 microgram, inhalationpowder, hard capsules

2 Description and composition

Pharmaceutical form

Inhalation powder, hard capsules.

150 microgram: Black product code “IDL 150”printed above and black company logo

printed under black bar on natural transparent uncolored capsule.

300 microgram: Blue product code “IDL 300” printed above and blue company logo printed

under blue bar on natural transparent uncolored capsule.

Active substance

150 microgram inhalation powder hard capsules

Each capsule contains 194 microgram indacaterol maleate equivalentto 150 microgram

indacaterol.

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ONB ASPI APR12 CL V2 REF CDS 270112

The delivered dose (the dose that leaves the mouthpiece of the ONBREZ BREEZHALER

inhaler) is equivalentto120microgramindacaterol.

300 microgram inhalation powder hard capsules

Each capsule contains 389 microgram indacaterol maleate equivalentto 300 microgram

indacaterol.

The delivered dose (the dose that leaves the mouthpiece of the ONBREZ BREEZHALER

inhaler) is equivalentto240microgramindacaterol.

Active moiety

Indacaterol

Excipients

Lactose monohydrate and gelatine

Onbrez Breezhaler 300 : Each capsule contains 24.6 mg lactose.

Onbrez Breezhaler 150 : Each capsule contains 24.8 mg lactose .

3 Indications

Maintenance of bronchodilator treatment of airflow obstruction in adult patients with chronic

obstructive pulmonary disease (COPD).

4 Dosage and administration

Adults

The recommended dosage of ONBREZ BREEZHALERis the once-dailyinhalation of the

content of one 150 microgramcapsule using the ONBREZBREEZHALER inhaler. The

dosage should only be increased on medical advice.

Once-daily inhalation of the content of one300 microgramcapsule, using the ONBREZ

BREEZHALER inhaler, has been shown to provide additional clinical benefit to some

patients, e.g. with regard tobreathlessness, particularly for patients with severe COPD. The

maximum dose is 300 microgramonce-daily.

Dosing in special populations

No dosage adjustment is required for geriatric patients, patients with mild and moderate

hepatic impairment, or renally impaired patients.No data is available for subjects with severe

hepatic impairment (see section 11 Clinical Pharmacology).

ONBREZ BREEZHALER should notbe used in patients under 18 years of age.

Method of administration

ONBREZ BREEZHALER capsules mustbe administered only by the oral inhalation route

and only using the ONBREZ BREEZHALERinhaler. ONBREZ BREEZHALER capsules

must not be swallowed.

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ONB ASPI APR12 CL V2 REF CDS 270112

ONBREZ BREEZHALER should be administered atthe sametimeof the day each day. If a

dose is missed, the next dose should betaken at the usual time the next day.

ONBREZ BREEZHALER capsules mustalways be stored in the blister, and only removed

IMMEDIATELY BEFORE USE.

5 Contraindications

ONBREZ BREEZHALER is contraindicated in patients with hypersensitivity to indacaterol, to

lactose or to anyof the other excipients.

6 Warnings and precautions

Asthma

ONBREZ BREEZHALER should not beused in asthmadue tothe absence of long-term

outcomedata in asthmawith ONBREZ BREEZHALER.

Hypersensitivity

Immediate hypersensitivity reactions have been reported after administration of ONBREZ

BREEZHALER. If signs suggestingallergic reactions (in particular, difficulties in breathing

or swallowing, swellingof tongue, lips andface, urticaria, skin rash) occur, ONBREZ

BREEZHALER should be discontinued immediately and alternative therapy instituted.

Paradoxical bronchospasm

As with other inhalation therapy, administration of ONBREZ BREEZHALER may result in

paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs,

ONBREZ BREEZHALER should be discontinuedimmediately and alternative therapy

instituted.

Deterioration of disease

ONBREZ BREEZHALER is not indicated for theinitial treatment of acute episodes of

bronchospasm,i.e.,as a rescue therapy. In case ofdeterioration ofCOPD whilst on treatment

with ONBREZ BREEZHALER, a re-evaluation ofthe patient and the COPD treatment

regimen should be undertaken. An increasein the daily dose ofONBREZ BREEZHALER

beyond the maximum dose of 300 microgram is not appropriate.

Systemic effects

Although no clinically relevant effect on the cardiovascular systemis usually seen after the

administration of ONBREZ BREEZHALER at the recommended doses, as with other beta

adrenergic agonists, indacaterolshould be used with cautionin patients with cardiovascular

disorders (coronary artery disease, acutemyocardial infarction, cardiac arrhythmias,

hypertension), in patients with convulsive disorders or thyrotoxicosis, and in patients who are

unusually responsive to beta

-adrenergic agonists.

As with other inhaled beta

-adrenergic drugs, ONBREZ BREEZHALER should not be used

more often or at higher doses than recommended.

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ONB ASPI APR12 CL V2 REF CDS 270112

ONBREZ BREEZHALER should notbe used in conjunctionwith other long-acting beta

adrenergic agonists or medications containing long-acting beta

-adrenergic agonists.

Cardiovascular effects

Like other beta

-adrenergic agonists, indacaterol may produce a clinically significant

cardiovascular effect in somepatients as measured by increases in pulse rate, blood pressure,

and/or symptoms. In case such effects occur,the drug may need tobe discontinued. In

addition, beta-adrenergic agonists have been reported to produce ECG changes, such as

flattening of the T wave and ST segment depression, although the clinical significance of

these findings is unknown.

Clinically relevant effects onprolongation of the QTc-intervalhave not been observed in

clinical studies ofONBREZ BREEZHALER at recommended therapeutic doses (see section

11 Clinical pharmacology).

Hypokalemia

Beta

-adrenergic agonists may produce significant hypokalemia in somepatients, which has

the potential to produce adverse cardiovascular effects. The decrease in serumpotassiumis

usually transient, not requiring supplementation. In patientswith severe COPD, hypokalaemia

may be potentiated by hypoxia and concomitant treatment (see section 8 Interactions) which

may increase the susceptibilityto cardiac arrhythmias.

Hyperglycemia

Inhalation of high doses of beta

-adrenergic agonists may produce increases in plasma

glucose. Upon initiation of treatment withONBREZ BREEZHALER plasmaglucose should

be monitored more closely in diabetic patients.

During clinical studies, clinically notable changes in bloodglucose were generally more

frequent by 1-2% on ONBREZBREEZHALER at the recommended doses than on placebo.

ONBREZ BREEZHALER has not been investigatedin patients with not well controlled

diabetes mellitus.

7 Adverse drug reactions

Summaryof safetyprofile

The safety experience with ONBREZ BREEZHALERcomprises exposure of up to one year

at doses two- to four-fold the recommended therapeutic doses .

The most common adverse drug reactions at the recommended doses were nasopharyngitis,

upper respiratorytract infection, cough, headache and muscle spasms. These were in the vast

majority mild or moderate and became less frequent when treatment was continued.

At the recommended doses, the adverse drugreaction profile of ONBREZ BREEZHALER in

patients with COPD shows clinicallyinsignificant systemic effects ofbeta

-adrenergic

stimulation. Mean heart rate changes were less than one beat per min, and tachycardia was

infrequent and reported at a similar rate as under placebo treatment. Relevant prolongations of

F were not detectable in comparisonto placebo. The frequency of notable QT

F intervals

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ONB ASPI APR12 CL V2 REF CDS 270112

[i.e., >450 ms(males) and >470 ms(females)] and reports of hypokalaemia were similar to

placebo. The mean of the maximum changesin blood glucose were similar on ONBREZ

BREEZHALER and on placebo.

Description of population

The ONBREZ BREEZHALER Phase III clinical development programconsisted of 16 key

studies and enrolled 9,000 patients with a clinical diagnosisof moderate to severe COPD.

Safety data from11 of these studies with treatment durations of 12 weeks or longer were

pooled from 4,746 patients exposed to indacaterol up to 600 microgramonce-daily, of which

2,611 were on treatment with 150 microgramonce-daily and 1,157 on treatment with 300

microgramonce-daily. Approximately 41% of patients had severe COPD. The mean age of

patients was 64 years, with 48% of patients aged65 years or older, and the majority (80%)

was Caucasian.

Tabulated summaryof adverse drug reactions from clinical trials

Adverse drug reactions in Table 7-1 are fromthis pooledCOPD safety database, listed

according toMedDRA systemorgan class andsorted in descending order of frequency on

indacaterol 150 microgramonce-daily. Within eachsystemorgan class, the adverse reactions

are ranked byfrequency,with the most frequent reactions first. In addition, the corresponding

frequency category using the following convention (CIOMS III) is also provided for each

adverse reaction: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000,

<1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports.

Table 7-1 Adverse drug reactions in pooled COPD safetydatabase

Adverse DrugReactions Indacaterol

150μg o.d.

N=2,611

n(%) Indacaterol

300μg o.d.

N=1,157

n(%) Placebo

N=2,012

n(%) Frequency

category

Infections and infestations

-Nasopharyngitis

- Upper respiratory tract infection

- Sinusitis

167 (6.4)

175 (6.7)

52 (2.0)

165 (14.3)

164 (14.2)

37 (3.2)

169 (8.4)

206 (10.2)

42 (2.1)

Very

common

Very

common

Common

Immune System Disorders

- Hypersensitivity 1

11 (0.4)

4 (0.4)

7 (0.4)

Uncommon

Metabolism and nutritiondisorders

- Diabetes andhyperglycemia*

18 (0.7)

19 (1.6)

18 (0.9)

Common

Nervous system disorders

- - headache

-Dizziness

- Paraesthesia

93 (3.6)

37 (1.4)

9 (0.3)

43 (3.7)

29 (2.5)

3 (0.3)

61 (3.0)

40 (2.0)

3 (0.2)

Common

Common

Uncommon

Cardiac disorders

- Ischaemicheart disease*

- Palpitations

22 (0.8)

13 (0.5)

12 (0.5)

19 (1.6)

14 (1.2)

8 (0.7)

8(0.4)

23 (1.1)

Common

Common

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ONB ASPI APR12 CL V2 REF CDS 270112

- Atrial fibrillation

-Tachycardia 5 (0.2) 7 (0.6) 11 (0.5)

8 (0.4) Uncommon

Uncommon

Respiratory,thoracicand

mediastinal disorders

-Cough

- Oropharyngeal pain incl. throat

irritation

- Rhinorrhoea

129 (4.9)

50 (1.9)

40 (1.5)

5 (0.2)

95 (8.2)

37(3.2)

37 (3.2)

8 (0.7)

104 (5.2)

33 (1.6)

22 (1.1)

13 (0.7)

Common

Common

Common

Uncommon

Skin and subcutaneoustissue

disorders

Pruritus/rash

22 (0.8)

17 (1.5)

19 (0.9)

Common

Musculoskeletal and connective

tissue disorders

- Musclespasm

- Musculoskeletal pain

Myalgia

46 (1.8)

16 (0.6)

23 (0.9)

40 (3.5)

26 (2.3)

8 (0.7)

21 (1.0)

23 (1.1)

12 (0.6)

Common

Common

Uncommon

General disorders and

administration site conditions

- Peripheral edema

-Chest pain

28 (1.1)

33 (1.3)

16 (1.4)

19 (1.6)

13 (0.7)

24 (1.2)

Common

Common

Adverse drug reactions (ADRs) selected based on pooled COPD safetydatabase; frequencies based on

percentage of patientswithrespective ADR intheCOPD safetypopulation; frequency category based on150

microgram or300 microgramdose,whichever had higher rate. 1

Reports of hypersensitivityhave beenreceived

from post-approval marketingexperience in associationwiththe use of ONBREZBREEZHALER, because these

were reports voluntarily froma population ofuncertainsize,it is not alwayspossible to reliably estimate the

frequencyor establish a causal relationship to drugexposure.Therefore the frequencywas calculated from

clinical trialexperience. Terms markedwith *are StandardMedDRA Query terms.

At a higher, non-recommended dose,i.e., 600 microgram once-daily,the safety

profile of ONBREZBREEZHALER was overall similar to that of recommended

doses. An additional adverse drug reaction was tremor. Nasopharyngitis,

muscle spasm, headache and peripheral edema occurred more frequentlythan

at the recommended doses.Selected adverse drug reactions

In Phase III clinical studies, health care providers observed duringclinic visits that on average

17-20% of patients experienced a sporadic cough that occurred usually within 15 seconds

following inhalation and typically lasted for 5 seconds (about10 seconds in current smokers).

It was observed with a higher frequency in female thanin male patients and in current smokers than in

ex-smokers.

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ONB ASPI APR12 CL V2 REF CDS 270112

This cough experienced post inhalation was generally well tolerated and did not lead to any

patient discontinuing from the studies at the recommended doses (cough is a symptom of

COPD and up to 8.2% of patients reported cough as an adverse event). There is no evidence

that cough experienced post inhalation is associated withbronchospasm, exacerbations,

deteriorations of disease or loss of efficacy.

8 Interactions

Drugs known to prolong QTc interval

ONBREZ BREEZHALER, as other beta

-adrenergic agonists, should be administered with

caution to patients being treatedwith monoamine oxidaseinhibitors, tricyclic antidepressants,

or drugs known to prolong the QT interval, asanyeffect of these on the QTinterval may be

potentiated. Drugs known to prolong the QT-interval may increase the risk of ventricular

arrhythmia (see section 6Warnings and precautions).

Sympathomimetic agents

Concomitant administration of other sympathomimetic agents (alone or as part of

combination therapy) may potentiate theundesirable effects ofONBREZ BREEZHALER

(see section 6 Warnings and precautions).

Hypokalemia

Concomitant treatment with methylxanthine derivatives, steroids, or non-potassium-sparing

diuretics may potentiate the possible hypokalaemic effect of beta

-adrenergic agonists (see

section 6 Warnings and precautions).

Beta-adrenergic blockers

Beta-adrenergic blockers may weakenor antagonise the effect of beta

-adrenergic agonists.

Therefore ONBREZ BREEZHALER should not begiven together with beta-adrenergic

blockers (including eye drops)unless there are compelling reasons for their use. Where

required, cardioselective beta-adrenergic blockers should be preferred, although they should

be administered with caution.

Metabolic and transporter based drug interaction

Inhibition ofthe key contributors of indacaterol clearance, CYP3A4 and P-gp, has noimpact

on safety of therapeutic doses of ONBREZBREEZHALER. Drug interaction studies were

carried out using potent and specificinhibitors of CYP3A4 and P-gp (i.e., ketoconazole,

erythromycin, verapamil and ritonavir). Verapamil was used as the prototypic inhibitor of P-

gp and resulted in 1.4- to two-fold increase in AUC and 1.5-fold increase in C

. Co-

administration of erythromycin with ONBREZBREEZHALER resulted in an increase of 1.4-

to 1.6-fold for AUC and 1.2 fold for C

. Combined inhibition ofP-gp and CYP3A4 by the

very strong dual inhibitor ketoconazole caused a 2-fold and 1.4-fold increase in AUC and

, respectively. Concomitant treatment with ritonavir, another dualinhibitor of CYP3A4

and P-gp, resulted in a 1.6- to 1.8-fold increase in AUC whereas C

was unaffected.Taken

together, the data suggest that systemic clearance is influenced bymodulation of both P-gp

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ONB ASPI APR12 CL V2 REF CDS 270112

and CYP3A4 activities and that the 2-foldAUC increase caused by the strong dual inhibitor

ketoconazole reflects the impact of maximalcombined inhibition. The magnitude of exposure

increases due to drug interactions does notraise any safety concerns given the safety

experience oftreatment with ONBREZ BREEZHALERin clinical trials of up to one year at

doses two- to four-fold therecommended therapeutic doses .

ONBREZ BREEZHALER has not been shown tocause drug interactions with co-

medications.In vitroinvestigationshave indicatedthat indacaterol has negligible potential to

cause metabolic interactions with medicationsat the systemic exposure levels achieved in

clinical practice.

9 Women of child-bearing potential, pregnancy,breast-

feeding and fertility

Pregnancy

No clinical data on exposed pregnancies in COPD patients are available. Studies inanimals

have shown reproductive toxicity associated with an increased incidence of one skeletal

variation in rabbits (see section13 Non-clinical safety data). The potential risk for humans is

unknown. Because there are no adequate and well-controlled studies in pregnant women,

indacaterol should be used during pregnancy only ifthe expected benefit justifies the potential

risk to the fetus.

Labour and delivery

Like other beta

-adrenergic agonists, ONBREZ BREEZHALER may inhibit labor due to a

relaxant effect on uterine smooth muscle.

Breast-feeding

It is not known whether indacaterol passes into human breastmilk. The substance has been

detected in the milk of lactating rats. Because many drugs are excreted in human milk, as with

other inhaled beta

-adrenergic drugs, the use of ONBREZ BREEZHALER by breast-feeding

women should only be consideredif the expected benefit tothe woman is greater than any

possible risk to the infant.

Fertility

A decreasedpregnancyrate has been observed in rats. Nevertheless, it is considered unlikelythat

indacaterol will affect reproductive or fertilityperformance in humans following inhalationof

themaximumrecommendeddose.

10 Effects onabilityto drive and use machines

Onbrez Breezhaler has no or negligible influence on the abilitytodrive and use machines.

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ONB ASPI APR12 CL V2 REF CDS 270112

11 Overdosage

In COPD patients single doses of 10 times the maximum recommended therapeutic dose were

associated with a moderate increase in pulserate, systolic blood pressure increase and QT

interval.

An overdose of indacaterol is likely to lead to exaggerated effects typical of beta

-adrenergic

stimulantsi.e., tachycardia, tremor, palpitations,headache, nausea, vomiting, drowsiness,

ventricular arrhythmias, metabolic acidosis, hypokalaemia and hyperglycemia.

Supportive and symptomatic treatment is indicated. In serious cases, patients should be

hospitalized. Use of cardioselective beta-blockers may beconsidered, but only under the

supervision of a physician and with extreme caution since the useof beta-adrenergic blockers

may provoke bronchospasm.

12 Clinical pharmacology

Mechanism of Action(MoA)

Indacaterol is an ‘ultra’ long-acting beta

-adrenergic agonist for once-daily administration.

The pharmacological effects of beta

-adrenoceptor agonists, including indacaterol, are at least

in part attributable to stimulation of intracellular adenyl cyclase,the enzymethat catalyzes the

conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic

monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle.

In vitrostudies have shown that indacaterol has more than 24-fold greater agonist activity at

beta

-receptors compared to beta

-receptors and 20-fold greater agonist activity compared to

beta

-receptors. This selectivity profile is similarto formoterol.

When inhaled, indacaterol acts locally in the lungas a bronchodilator. Indacaterol is a nearly

full agonist at the human beta

-adrenergic receptor with nanomolar potency. In isolated

human bronchus, indacaterol hasa rapid onset of action anda long duration of action.

Although beta

-receptorsare the predominant adrenergic receptors in bronchial smooth

muscle and beta

-receptors are the predominant receptorsin the human heart, there are also

beta

-adrenergic receptors in the human heart comprising 10% to 50% ofthe total adrenergic

receptors. The precise function of beta

-adrenergic receptors in the heart is not known, but

their presence raises the possibilitythat even highly selective beta

-adrenergic agonists may

have cardiac effects.

Pharmacodynamics (PD)

PrimaryPharmacodynamic Effects

ONBREZ BREEZHALER provided consistently significant improvementin lung function (as

measured by the forced expiratory volumein one second, FEV

) over 24 hours in a number of

clinical pharmacodynamic and efficacy trials. There was a rapid onset of action within 5

minutes after inhalation of ONBREZ BREEZHALER, comparable tothe effect of the fast-

acting beta

-agonist salbutamol and a peak effectoccurring between 2-4 hours following the

dose. There was no evidence for tachyphylaxis tothe bronchodilator effect after repeated

dosing for up to 52 weeks . The bronchodilator effect didnot depend on the time of dosing

(morning or evening).

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ONB ASPI APR12 CL V2 REF CDS 270112

ONBREZ BREEZHALER reduced both dynamic and resting hyperinflation in patients with

moderate to severe COPD. Inspiratory capacity during constant, sub-maximal exercise

increased by317 mLcompared to placebo after administration of 300 microgramonce-daily

over 14 days. A statistically significant increase in resting inspiratory capacity, exercise

endurance and FEV

were also demonstrated as well as a significant improvement in

measures of dyspnoea.

Secondary Pharmacodynamic Effects

The characteristic adverse effects of inhaled beta

-adrenergic agonists occur as a result of

activation ofsystemic beta-adrenergic receptors. The most common adverse effects include

skeletal muscle tremor and cramps, insomnia,tachycardia, decreases in serumpotassiumand

increases in plasmaglucose.

Effects on cardiac electrophysiology

The effect of ONBREZBREEZHALER on the QT intervalwas evaluated in a double-blind,

placebo-and active (moxifloxacin)-controlled study following multiple doses of indacaterol

150 microgram, 300 microgramor 600 microgramonce-daily for 2 weeks in 404 healthy

volunteers. Fridericia’s method forheart rate correction was employed to derive the corrected

QT interval(QT

F). Maximum meanprolongation of QT

F intervals were <5 ms, and the

upper limit of the 90% confidence intervalwas below 10 msfor all time-matched

comparisons versus placebo. This shows thatthere is no concern for a pro-arrhythmic

potential related to QT-interval prolongations at recommended therapeutic doses. There was

no evidence of a concentration-delta QTc relationship in the rangeof doses evaluated.

Electrocardiographic monitoringin patients with COPD

The effect of ONBREZ BREEZHALER on heart rate and rhythmwas assessed using

continuous 24-hour ECG recording (Holter monitoring) in a subset of 605 patients with

COPD froma 26-week,double-blind,placebo-controlled Phase III study (see section 12

Clinicalstudies). Holter monitoring occurred once at baselineand up to 3 times during the 26-

week treatment period (at weeks 2, 12 and 26).

A comparison of the mean heart rate over 24 hours showed no increase frombaseline for both

doses evaluated, 150 microgramonce-daily and300 microgram once-daily. The hourly heart

rate analysis was similar for both doses compared to placebo and tiotropium. The pattern of

diurnal variation over 24 hours was maintained and was similar to placebo.

No difference fromplacebo or tiotropiumwas seen in the rates ofatrial fibrillation, time spent

in atrial fibrillation and also the maximumventricular rate of atrial fibrillation.

No clear patterns in the rates ofsingle ectopic beats, couplets or runs wereseen across visits.

Because the summary data on rates ofventricular ectopic beats can be difficult to interpret,

specific pro-arrhythmic criteria were analyzed. In this analysis, baseline occurrence of

ventricular ectopic beats was compared to changefrombaseline, setting certain parameters for

the change to describe the pro-arrhythmicresponse. The number of patients with a

documented pro-arrhythmic response was very similar across both indacaterol doses

compared to placebo and tiotropium.

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ONB ASPI APR12 CL V2 REF CDS 270112

Overall, there was no clinically relevant difference in the development of arrhythmic events in

patients receiving indacaterol treatment over those patients who received placebo or treatment

with tiotropium.

Effects on serum potassiumand plasma glucose

Changes in serumpotassiumand plasmaglucose were evaluated in a 26-week, double-blind,

placebo-controlled Phase III study (see section 12Clinical studies). At 1 hour post-dose at

week 12, mean changes compared to placeboin serumpotassiumranging from0.03 to 0.05

mmol/L and in mean plasmaglucose ranging from 0.25 to 0.31 mmol/L were observed.

Pharmacokinetics (PK)

Absorption

The median time to reach peak serum concentrations of indacaterol was approximately 15 min

after single or repeated inhaled doses. Systemic exposure toindacaterol increased with

increasing dose (150 microgramto 600 microgram) in a dose proportional manner. Absolute

bioavailability of indacaterol after an inhaled dose was on average 43-45%.Systemic

exposure results froma composite of pulmonary and intestinal absorption.

Indacaterol serumconcentrations increased with repeatedonce-daily administration. Steady-

state was achieved within 12 to 15 days. The mean accumulation ratio of indacaterol,i.e.,

AUC over the 24-h dosing interval on Day 14 or Day 15 compared to Day 1, was in the range

of 2.9 to 3.8 for once-daily inhaled dosesbetween 75 microgramand 600 microgram.

Distribution

After intravenous infusion the volume of distribution (V

) of indacaterol was 2,361 L to 2,557

L indicating an extensive distribution. Thein vitrohuman serum and plasma protein binding

was 94.1 to 95.3% and 95.1 to 96.2%, respectively.

Biotransformation/Metabolism

After oral administration ofradiolabelled indacaterolin a human ADME (absorption,

distribution, metabolism,excretion) study, unchanged indacaterolwas the main component in

serum,accounting for about one third of total drug-related AUC over 24 h. A hydroxylated

derivative was the most prominent metabolite in serum.A phenolic O-glucuronide of

indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer

of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated

products were furthermetabolites identified.

In vitroinvestigations indicatedthat UGT1A1 is the only UGT isoformthat metabolized

indacaterol to the phenolic O-glucuronide.The oxidative metabolites were found in

incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be

the predominant isoenzyme responsiblefor hydroxylation of indacaterol.In vitro

investigations further indicated thatindacaterolis a low affinity substrate for the efflux pump

P-gp.

Elimination

In clinical studies which included urine collection, the amount of indacaterol excreted

unchangedviaurine was generally lowerthan 2% of the dose. Renal clearance of indacaterol

was, on average, between 0.46 and 1.20 L/h. Whencompared with the serumclearance of

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ONB ASPI APR12 CL V2 REF CDS 270112

indacaterol of 18.8 to 23.3L/h, it is evident that renal clearance plays a minor role (about 2 to

6% of systemic clearance) in the elimination of systemicallyavailable indacaterol.

In a human ADME study where indacaterol was given orally, the fecal route of excretion was

dominant over the urinary route. Indacaterol was excreted into human feces primarily as

unchanged parent drug (54% of the dose) and,to a lesser extent, hydroxylated indacaterol

metabolites (23% ofthe dose). Massbalance was complete with≥90% of the dose recovered

in the excreta.

Indacaterol serumconcentrations declined ina multi-phasicmanner with an averageterminal

half-life ranging from45.5 to 126 hours. Theeffective half-life,calculated fromthe

accumulation of indacaterol after repeated dosing ranged from40 to 56 hours which is

consistent with the observed time-to-steady state of approximately 12 to 15 days.

Special Populations

A population analysis of the effect of age, gender and weight on systemic exposure in COPD

patients after inhalation indicated that ONBREZBREEZHALER can be used safely in all age

and weight groups and regardlessof gender. It did not suggestany difference between ethnic

subgroups in this population. Limited treatment experience is available for the black

population.

The pharmacokinetics ofindacaterol was investigated in two different UGT1A1 genotypes –

the fully functional [(TA)

, (TA)

] genotype and the low activity [(TA)

, (TA)

] genotype

(Gilbert’s syndrome genotype).The study demonstrated that steady-state AUC and C

of

indacaterol were 1.2-fold higher in the [(TA)

, (TA)

] genotype, indicating that systemic

exposure to indacaterol is onlyinsignificantly affected by this UGT1A1 genotypic variation.

Patients with mild and moderate hepatic impairment showedno relevant changes in C

or

AUC of indacaterol, nor didprotein binding differ betweenmild and moderate hepatic

impaired subjects and their healthy controls. Studies in subjects with severe hepatic

impairment were not performed.

Due to the very low contribution of the urinary pathway to total body elimination, a study in

renally impaired subjects was not performed.

13 Clinical studies

The ONBREZ BREEZHALER Phase III clinical development programconsisted of 16 key

studies and enrolled over 9,000 patients with aclinical diagnosis of moderate to severe

COPD, who were 40 years old or older, had a smoking history of at least 20 pack years, had a

post-bronchodilator FEV

<80% and≥30% of the predicted normal value and a post-

bronchodilator FEV

/FVC ratio ofless than 70%.

In these studies, indacaterol, administeredonce-daily at doses of 150 microgramand 300

microgram, showed clinically meaningful improvements in lung function (as measured by the

forced expiratory volume in one second, FEV

) over 24 hours. At the 12-week primary

endpoint (24-hour trough FEV

), the 150 microgramdose resulted in a 0.13-0.18 L increase

compared to placebo (p<0.001) and a 0.06 L increase compared to salmeterol 50 microgram

twice a day (p<0.001). The 300 microgramdose resulted in a 0.17-0.18 L increase compared

to placebo (p<0.001) and a 0.1 L increase compared to formoterol 12 microgramtwice a day

Page 13

ONB ASPI APR12 CL V2 REF CDS 270112

(p<0.001). Both doses resulted in an increase of 0.04-0.05 L over open-label tiotropium 18

microgramonce-daily (150 microgram, p=0.004; 300 microgram, p=0.01).

Indacaterol administered once-dailyat the sametime each day, either in the morning or

evening, had a rapid onset of action within 5minutes similar to that of salbutamol 200

microgramand statistically significantly fastercompared to salmeterol/fluticasone 50/500

microgram, and mean peak improvements in FEV

relative to baseline of 0.25-0.33 L at

steady-state occurring between2-4 hours following the dose. The 24-hour bronchodilator

effect of ONBREZ BREEZHALERwas maintained fromthe first dose throughout a one-year

period with no evidence of lossof efficacy (tachyphylaxis).

In a 26-week, placebo-and active (open labeltiotropium)-controlled study in 2,059 patients,

the mean improvement relative to baseline in FEV

at 5 minutes was 0.12 L and 0.13 L for

ONBREZ BREEZHALER 150 microgramand 300microgram once-daily, respectively, and

the mean peak improvement, relative to baseline, after the first dose (Day 1) was 0.19 L and

0.24 L, respectively, and improved to0.23 L and 0.26 L, respectively, when

pharmacodynamic steady-state was reached (Day14) . At the primary end point (Week 12),

both ONBREZ BREEZHALER 150 microgramand 300 microgramonce-daily treatment

groups showed a significantly higher trough FEV

value compared to placebo (both 0.18 L,

p<0.001) and to tiotropium(0.05 L, p=0.004, and 0.04 L, p=0.01, respectively).

In this study, 12-hour serial spirometric measurements were performed in a subset of patients

throughout daytime hours (12 hours). Serial FEV

values over 12 hours at Day 1 and trough

values at Day 2 are shown in Figure 12-1, and at Day 182/183 in Figure 12-2,

respectively. Improvement of lung function was maintained for 24 hours after the first dose

and consistently maintained over the 26-week treatment period with no evidence of tolerance.

Figure12-1Serial least square mean FEV

1 over 12 h at Day 1 and trough FEV

1 at

Day 2 (ITT subset with 12 hour serial spirometry)

1.15 1.20 1.25 1.30 1.35 1.40 1.45 1.50 1.55

Time(h) FEV 1 (L )

Indacaterol150µgo.d. Indacaterol300µgo.d. Tiotropium18µgo.d. Placebo I I I I I I I

1.15 1.20 1.25 1.30 1.35 1.40 1.45 1.50 1.55

Time(h) FEV 1 (L )

Indacaterol150µgo.d. Indacaterol300µgo.d. Tiotropium18µgo.d. Placebo I I I I I I I

1.15 1.20 1.25 1.30 1.35 1.40 1.45 1.50 1.55

Time(h) FEV 1 (L )

Indacaterol150µgo.d. Indacaterol300µgo.d. Tiotropium18µgo.d. Placebo I I I I I I I

Figure12-2Serial least square mean FEV

1 over 12 hat Day 182 and trough FEV

1 at

Day 183 (ITT subset with 12hour serial spirometry)

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ONB ASPI APR12 CL V2 REF CDS 270112

1.15 1.20 1.25 1.30 1.35 1.40 1.45 1.50 1.55

Time(h) FE V 1 (L )

Indacaterol150 µgo.d. Indacaterol300 µgo.d. Tiotropium18µgo.d. Placebo I I I I I I I

1.15 1.20 1.25 1.30 1.35 1.40 1.45 1.50 1.55

Time(h) FE V 1 (L )

Indacaterol150 µgo.d. Indacaterol300 µgo.d. Tiotropium18µgo.d. Placebo I I I I I I I

1.15 1.20 1.25 1.30 1.35 1.40 1.45 1.50 1.55

Time(h) FE V 1 (L )

Indacaterol150 µgo.d. Indacaterol300 µgo.d. Tiotropium18µgo.d. Placebo I I I I I I I

In a 26-week, placebo-controlled safety extension to this study in 414 patients, efficacy was

not a primary endpoint, however at the secondary end point (Week 52) of trough FEV

,

treatment with both ONBREZ BREEZHALER 150microgramand 300 microgramonce-daily

resulted in a significantly higher trough FEV

value compared to placebo (0.17 L, p<0.001

and 0.18L, p<0.001, respectively).

Results of a 12-week, placebo-controlled study in 416 patients which evaluated the 150

microgramonce-daily dose, were similar to theresults for this dose in the 26-week study. The

mean peak improvementin FEV

, relative to baseline, was 0.23 L after 1 day of once-daily

treatment At the primary end point (Week12), treatment withONBREZ BREEZHALER 150

microgramonce-daily resulted ina significantlyhigher trough FEV

value compared to

placebo (0.13 L, p<0.001).

In a 26-week, placebo-and active (blind salmeterol)-controlled study in 1,002 patients which

evaluated the ONBREZ BREEZHALER 150 microgramonce-daily dose, the mean

improvement in FEV

, relative to baseline, at 5 minuteswas 0.11 L with a peak improvement

of 0.25 L relative to baseline after the first dose (Day 1). At the primary end point (Week 12),

treatment with ONBREZ BREEZHALER 150 microgramonce-daily showed a significantly

higher trough FEV

value compared to both placebo (0.17 L, p<0.001) and to salmeterol (0.06

L, p<0.001).

In a 52-week, placebo-and active (formoterol)-controlled study in 1,732 patients which

evaluated the ONBREZ BREEZHALER 300 microgramonce-daily dose and a higher dose,

the mean improvement in FEV

, relative to baseline, at 5 minutes was 0.14 L with a peak

improvement of 0.20 L relative to baseline after the first dose (Day 1). At the primary end

point (Week 12), treatment with ONBREZ BREEZHALER 300 microgramonce-daily

resulted in a significantly higher trough FEV

value compared to placebo (0.17 L, p<0.001)

and to formoterol (0.1 L,p<0.001). This improvement of lung function was maintained over

the 52-weektreatment period with noevidence ofloss of efficacy over this period. ONBREZ

BREEZHALER was superiorto formoterol withregard to trough FEV

at all visits.

In a 2-week,placebo-and active (open labelsalmeterol)-controlled crossover study, 24-hour

spirometry was assessed in 68 patients. Serialspirometry values over 24 hours are displayed

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ONB ASPI APR12 CL V2 REF CDS 270112

in Figure 12-3. After 14 days of once-daily treatment, improvement of lung function

compared to placebo was maintainedfor 24 hours, and in addition, the trough FEV

value was

statistically significantly higher compared to salmeterol (0.09 L, p=0.011). Similar results

from24-hour serial spirometry were observed after 26 weeks in a subset of patients (n=236)

fromthe 26-week study. Both studies further support the improvement in FEV

1 over placebo

with ONBREZ BREEZHALERadministered once-daily, and thatbronchodilation was

maintained throughout the 24-hour dosing interval, in comparison to placebo.

Figure12-324 h profile of least squares means of FEV1 (L) after 14days treatment

(Modified ITT population)

1.15 1.20 1.25 1.30 1.35 1.40 1.45 1.50 1.55

Time(h) FE V 1 (L )

Indacaterol300µgo.d. Salmeterol50µgb.i.d. Placebo

The following health outcome effects were demonstrated in the long-termstudies of 12-, 26-

and 52-week treatment duration:

ONBREZ BREEZHALER significantly improved dyspnea compared to baseline in the 26-

week study (as evaluated using the Transitional Dyspnea Index, TDI) by the first assessment

(day 29), and this was maintained for the entire 26 weeks in the 150 microgramand 300

microgramonce-daily treatments compared to placebo. ONBREZ BREEZHALER 300

microgramonce-daily was also statistically superior to openlabel tiotropiumat all timepoints

(p≤0.01) The proportion of patients who achieved a score of≥1.0 (corresponding to a

clinically importantdifference)in TDI focal scorewas significantly greaterin the indacaterol

group at all 4 assessment points compared to the placebo group (p≤0.001). At 26 weeks, the

proportions were 62.4% and70.8% with ONBREZ BREEZHALER 150 microgramonce-

daily and 300 microgram once-daily, respectively, compared to 57.3% and 46.6% with

tiotropiumand with placebo, respectively.In the 26-week, placebo- and active (blind

salmeterol)-controlled study ONBREZ BREEZHALER 150 microgramonce-daily also

significantly improved dyspnea over the entire26-week treatment period. The proportion of

patients who achieved a TDI focal score of≥1.0 (corresponding to a clinically important

difference) was significantly greater in theindacaterol group at allfour assessment points

(Day 29, Day 57, Day 84, and Day 182) than in the placebo group (p≤0.005).

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ONB ASPI APR12 CL V2 REF CDS 270112

In this studystatistically significant differences between either active treatment and placebo

were seen for the changefrombaseline in mean daily, daytime and nighttime number ofpuffs

of rescue medication at every 4-weekly interval of the 26-week treatment period. ONBREZ

BREEZHALER-treatedpatients required numerically fewer daily, daytime and nighttime

puffs of rescue medication compared with salmeterol-treated patients atcertain 4-week

intervals, but none of the differences between active treatments were statistically significant.

In the 52-week study there was astatistically significant reduction in the number of puffs of

rescue short-acting beta

-adrenergic agonists with ONBREZ BREEZHALER 300 microgram

once-daily compared to formoteroland placebo (1.69, 1.35 and 0.02 fewer puffs,

respectively). Similarly, in the 26-week study, reductions in rescueuse in the ONBREZ

BREEZHALER 150 microgramonce-daily and300 microgramonce-daily groups were

statistically significant compared to open label tiotropiumand placebo (1.45 and 1.56

compared to 0.99 and 0.39 fewer puffs, respectively). In the 12-week study (which had no

active comparator) a similar pattern was observed with ONBREZ BREEZHALER 150

microgramonce-daily.

Patients treated with ONBREZ BREEZHALER 150 microgramand 300 microgramonce-

daily had numerically lower risks of COPD exacerbation compared to placebo in long-term

trials of 12-,26- and 52-week treatment duration. Time-to-first-COPD exacerbation as

compared to placebo was significantly longerin the 26-week study under treatment with 150

microgramonce-daily and inthe 52-week study under treatmentwith 300 microgramonce-

daily (p=0.019 and p=0.03, respectively). Pooled analyses showedthat patients treated with

ONBREZ BREEZHALER 150 microgramand 300 microgram once-daily had statistically

lower risks of COPD exacerbations compared to placebo inboth the 6-month and 12-month

pooled populations. Time-to-first-COPD exacerbation as compared to placebo was

significantly longer in the 6-month population under treatment with 150 microgramand 300

microgramdoses once-daily (p=0.005 andp=0.006, respectively) and in the 12-month

population under treatment with 300 microgramonce-daily (p=0.022). Pooled efficacy

analysis over 6 and 12 months of treatment demonstrated that the rate of COPD exacerbations

was statistically significantly lower than theplacebo rate. Treatment comparisons to placebo

over 6 months showed a ratio of ratesof 0.70 (95% CI [0.53,0.94]; p-value 0.014) and 0.74

(95% CI [0.57,0.96]; p-value 0.024) forONBREZ BREEZHALER 150 microgramand

300 microgram, respectively, and over 12 monthsthe ratio ofrates was of0.78 (95% CI

[0.62,0.98]; p-value 0.034) for treatment with 300 microgramonce-daily.

ONBREZ BREEZHALER also significantly improved health-related quality of life (as

measured using the St. George’s Respiratory Questionnaire) in long-termtrials of 12-, 26- and

52-week treatment duration. Both doses of150 microgramand 300 microgramonce-daily

demonstrated a significantly lower (improved) mean total score in the SGRQ, as well as each

component score, in comparison to placebo: Animprovementcompared to placebo exceeding

the minimal clinically importantdifference of4 units was shown at 8 and 12 weeks in the 12-

week study, and in the 52-week study this was shown for treatment with 300 microgramonce-

daily at 8, 24, 44 and 52 weeks. In the 26-week study, patients treated with 150 microgram

once-daily showed a significantly lower meantotal score in the SGRQ compared to

tiotropium(p≤0.05), andat the end ofthe 26-week, placebo-controlled safety extension to this

study the mean change in SGRQ total score was a decrease (improvement) of 3.2 units for

ONBREZ BREEZHALER 150 microgramversus placebo after 52 weeks of treatment. In the

other 26-week study, treatment with both ONBREZ BREEZHALER 150 microgramand

salmeterol resulted in a significantlylower (improved) mean SGRQ total scores compared to

Page 17

ONB ASPI APR12 CL V2 REF CDS 270112

placebo with mean differences of 6.3 units (p<0.001) and 4.2 units (p<0.001), respectively,

that exceeded the minimal clinically importantdifference of 4 units after 12weeks and thus

were also clinically relevant. ONBREZ BREEZHALER also achieved statistical superiority

over salmeterol by 2.1 units (p=0.033).

ONBREZ BREEZHALER 150 microgramand 300microgram once-daily treatment over 26

weeks significantly improved the percentage ofdays with no daytime symptoms(p<0.02) and

the percentage of days where patients were able to performtheir normal daily activities as

compared to placebo (p<0.001).

14 Non-clinical safety data

Non-clinical data reveal no special hazard forhumans based on conventional studies of safety

pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to

reproduction.The effects of indacaterol seen in toxicity studies in dogs were mainly on the

cardiovascular systemand consisted of tachycardia, arrhythmias and myocardial lesions.

These effects are known pharmacological effects and could be explained by the beta

agonistic properties of indacaterol. Other relevant effects noted in repeated-dose toxicity

studies were mild irritancy ofthe upper respiratory tract in ratsconsisting of rhinitis and

epithelial changes of the nasal cavity and larynx. All these findings were observed only at

exposures considered sufficiently in excess ofthe maximum human exposure indicating little

relevance to clinical use.

Adverse effects with respect to fertility, pregnancy, embryonal/foetal development, pre- and

postnatal development could only be demonstratedat doses more than 195-fold the maximum

recommended daily inhalation dose of300 microgramin humans (on a mg/m 2 basis). The

effects, namely an increased incidence of oneskeletal variation, were observed in rabbits.

Indacaterol was not teratogenic in rats orrabbits following subcutaneous administration.

Studies on genotoxicity did notreveal any mutagenic orclastogenic potential. The

carcinogenic potential of indacaterol has been evaluated in a 2-year inhalation study in rats

and a 26-week oral transgenicmouse study. Lifetimetreatment of rats resulted in increased

incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in

females at doses approximately 68-times the maximum recommended dose of 300 microgram

once-daily for humans (on a mg/m 2 basis). Increases in leiomyomasof the rat female genital

tract have been similarlydemonstrated with otherβ

-adrenergic agonist drugs. A 26-week oral

(gavage) study in CB6F1/TgrasH2 hemizygous mice with indacaterol did not show any

evidence of tumorigenicity at doses approximately 9800-times the maximumrecommended

dose of 300 microgramonce-daily for humans (on a mg/m 2 basis).

15 Pharmaceutical information

Special precautions for storage

Do not store above 30°C and protect frommoisture.

ONBREZ BREEZHALER must bekept out of the reach andsight of children.

Special precautions for disposal and other handling

Page 18

ONB ASPI APR12 CL V2 REF CDS 270112

The Onbrez Breezhaler inhaler provided with each new prescription should beused. Dispose of each

inhaler after 30 daysofuse.

Instructionsfor handlingand use

Pull off the cap.

Open inhaler:

Hold the base of the inhaler firmlyand tilt the

mouthpiece.This opens the inhaler.

Prepare capsule:

Immediatelybefore use,with dryhands, remove

one capsule fromthe blister.

Insert capsule:

Place the capsule into the capsule chamber.

Never placea capsule directly into the

mouthpiece.

Close the inhaler:

Close the inhaler untilyouhear a “click”.

Page 19

ONB ASPI APR12 CL V2 REF CDS 270112

Pierce the capsule:

Hold the inhaler upright with the

mouthpiece pointing up.

Pierce the capsule byfirmly pressing

together bothside buttons atthe same

time.Do this only once.

You should hear a “click”as the capsule

is being pierced.

Release the side buttons fully.

Breathe out:

Before placingthe mouthpiece in your mouth,

breathe out fully.

Do not blowinto the mouthpiece.

Inhale the medicine

To breathe themedicine deeply intoyour

airways:

Hold the inhaler as shown in the picture.

The side buttons should befacing left and

right. Donotpress the sidebuttons.

Place themouthpiece inyour mouth and

close your lips firmlyaround it.

Breathe in rapidlybut steadilyand as

deeply as you can.

Note:

As you breathe in throughthe inhaler, the capsule

spins aroundin the chamber andyou shouldhear

a whirring noise. You will experience asweet

flavour as the medicine goes intoyourlungs.

Additional information

Occasionally, very small pieces of the capsule can

get past the screen and enter your mouth. If this

happens,youmaybe able to feel these pieces on

your tongue.It is not harmful if these piecesare

swallowed orinhaled. Thechances of the capsule

shattering will be increasedif the capsule is

accidentallypiercedmore than once (step 6).

Page 20

ONB ASPI APR12 CL V2 REF CDS 270112

If you do nothear a whirring noise:

The capsule maybe stuckin the capsule chamber.

If this happens:

Open the inhaler and carefullyloosen the

capsule bytapping the base of the inhaler.

Do not press the side buttons.

Inhale the medicine again byrepeating

steps 8 and 9.

Hold breath:

After youhaveinhaled themedicine:

Holdyour breath for at least 5-10 seconds

or as long asyou comfortablycan while

taking the inhaler out ofyour mouth.

Then breathe out.

Open the inhaler to see ifanypowder is

left in the capsule.

If there is powder left in the capsule:

Close the inhaler.

Repeat steps8, 9,10 and 11.

Most peopleare able to emptythe capsule with

one or two inhalations.

Additional information

Some people mayoccasionallycoughbriefly

soon after inhaling the medicine. If youdo, don’t

worry.As longas the capsule is empty,you have

received enough ofyour medicine.

After you have finished takingyour medicine:

Open the mouthpiece again, and remove

the emptycapsule bytipping it out ofthe

capsule chamber. Put the emptycapsule

inyour household waste.

Close the inhaler and replace the cap.

Do not store the capsulesin the Onbrez

Breezhaler inhaler.

Mark dailydose tracker:

On the insideof the pack there is a dailydose

tracker. Put a mark in today’s box if ithelps to

remind you ofwhenyournext dose is due.

Manufacturer:

Page 21

ONB ASPI APR12 CL V2 REF CDS 270112

Novartis PharmaStein AG, Switzerland

For Novartis PharmaAG, Basel, Switzerland

License Holder:

Novartis PharmaServices AG

36 Shacham St., Petach-Tikva

RegistrationNumbers:

Onbrez Breezhaler 150 MCG : 144 76 33112 00

Onbrez Breezhaler 300 MCG : 144 75 33111 00