PEGASYS 180 MCG/0.5 ML

2139PEGP0612

םיחקורה תונקת יפל ןכרצל ןולע

1986- ו"משתה )םירישכת(

דבלב אפור םשרמ םע קוושמ רישכתה

ןושלבחסונהזןולע,האירקהתלקהלותוטשפהםשל

.םינימה ינש ינבל תדעוימ הפורתה ,תאז ףא לע .רכז

סיסגפ

ל"מ0.5/ג"קמ 135

ל"מ0.5/ג"קמ180

שומישל ןכומ טע

:בכרה

:ליכמ טע לכ

Peginterferonalfa-2a135mcg/0.5mlor

180 mcg/0.5 ml

עדימ"6קרפהארםיליעפיתלבםיביכרמלעעדימל*

."ףסונ

שמתשתםרטבופוסדעןולעהתאןויעבארק

.הפורתהלעיתיצמתעדימליכמהזןולע.הפורתב

לאואאפורהלאהנפ,תופסונתולאשךלשיםא

.חקורה

,ןיריוובירםעסיסגפלשבלושמלופיטךלםשרנוהדימב

םרטבןיריוובירלשןכרצלןולעהתאםגןויעבארק

.לופיטב ליחתת

התואריבעתלא.ךתלחמבלופיטלהמשרנוזהפורת

ךלהארנםאוליפאםהלקיזהלהלולעאיה.םירחאל

.המוד םתלחמ יכ

ךנויעל בושח עדימ )1

תיפיגנדבכתקלדבלופיטלתדעוימסיסגפהפורתה

וא B גוסמ תינורכ

תחתמ(תירוע-תתהקרזהלתדעוימסיסגפהפורתה

םא.ימעפ-דחשומישלןכומטעבהעיגמאיהו)רועל

םאתהבלעפ,ךמצעלהפורתהתאקירזמהתא

ןולעהףוסבתוטרופמהתימצעהקרזהלתוארוהל

.)"תימצע הקרזהל תוארוה" -7קרפ האר(

ךשמוהקרזהידעומ,ןונימ(אפורהתויחנהלעהדפקה

הרקמלכב.המלחהליוכיסהתאהלידגמ)לופיטה

אפורהםעתוצעייתהאלללופיטהתאקיספהלןיא

יתוחיטבעדימל4-ו2םיקרפבןייעאנא.לפטמה

.בחרומ

ךורעלשיוכלהמבוסיסגפבלופיטהתליחתינפל

עדימל.רידסןפואבתופסונתוקידבוםדתוקידב

."בקעמו תוקידב" ףיעס3קרפ האר ףסונ

תירוקמההתזיראבררקמבהפורתהתאןסחאלבושח

.האיפקהל אלו

ךלהמבןוירהתעינמלתוריהזהנשמבטוקנלשי

-הקנהםעלופיטהתאבלשלתורשפאןיאולופיטה

."הקנהו ןוירה" ףיעס2קרפ האר

?הפורתה תדעוימ המל

ןורפרטניא.חווט-ךוראןורפרטניאאיהסיסגפהפורתה

לשןוסיחהתכרעמתבוגתתאהנשמרשאןובלחאוה

תולחמוםימוהיזםעתודדומתהבהלעייסלידכ,ףוגה

תויפיגנדבכתוקלדבלופיטלתשמשמהפורתה.תושק

וא B סיטיטפה( C וא B גוסמ תוינורכ

אוהשומישה: B גוסמתינורכתיפיגנדבכתקלדב

.דיחי לופיטכסיסגפב ללכ ךרדב

ץלמומהשומישה: C גוסמתינורכתיפיגנדבכתקלדב

הפורתה.ןיריוובירםעבולישבאוהסיסגפברתויב

לוטיללוכיךניאםאקר,דיחילופיטכשמשתסיסגפ

.איהש הביס לכמ ןיריווביר

תיטיופרת הצובק

.םינורפרטניא

הפורתב שומישה ינפל )2

:םא הפורתב שמתשהל ןיא

.הקינימךניה

peginterferon -(ליעפהרמוחלתושיגרךלהעודי

דחאלואאוהשגוסלכמןורפרטניאל,) alfa -2 a

.הפורתה יביכרממ

בלתלחממלבוסךנהםאואבלףקתהתרבע

.תרחא

.תינומיאוטואדבכתקלדמלבוסךנה

םאלשמל(תמדקתמדבכתלחממלבוסךנה

.)בוהצ ךלש רועה

ףיעסהאר( )Telbivudine( ןידוויבלטבלפוטמךנה

.)"תורחא תופורתוסיסגפ"

תחתמםידליותוקונית,םידולי,םיגפםניהםילפוטמה

.3ליגל

הפורתב שומישב תועגונה תודחוימ תורהזא

:םיאבה םירקמב לפטמה אפורל הנפ

.ןוירהלסנכיהלתננכתמואןוירהבתאםא

סיזאירוספה,)תחפס(סיזאירוספמלבוסךנהםא

.סיסגפב לופיטה ךלהמב רימחהל לולע

דבכתקלדדבלמדבכביהשלכהיעבמלבוסךנהםא

וא B גוסמ תיפיגנ

אפורהשןכתיי,םדץחלרתיואתרכוסמלבוסךנהםא

.םייניע תקידבל ךתוא הנפי

.הייארבםייונישבןיחבמךנהםא

תקלדומכ(םוהיזחתפמהתאשבשוחהתאםא

ינמזןפואבריבגהללולעסיסגפבלופיטה.)תואיר

.םימוהיזב תולחל ןוכיסה תא

תוררקתהבםירושקשםימוטפמיסחתפמהתאםא

ישוקואםוח,לועיש:ןוגכ(רחאיתמישנםוהיזבוא

.)המישנב

תועיצפואםימומידלשםינמיסחתפמהתאםא

.דימ לפטמה אפורל הנפ ,תוליגר אל

הרומחתיגרלאהבוגתלשםינמיסחתפמהתאםא

ךלהמב)תדפרסואםיפוצפצ,המישנבישוקןוגכ(

.דימ יאופר עויס תלבקל הנפ ,סיסגפב לופיטה

,)דיאורית(סירתהתטולבבהלחממלבוסךנהםא

.תופורת ידי-לע יוארכ תנזואמ הניאש

ואתישפנהערפהמרבעבתלבסואלבוסךנהםא

.הרומח תיבצע

התאםא,ןואכידמרבעבתלבסואלבוסךנהםא

תשוחתןוגכ(ןואכידבםירושקשםימוטפמיסחתפמ

האר(סיסגפבלופיטהךלהמב)המודכושואיי,תובצע

.)"יאוול תועפות" -4קרפ

.הימנאמרבעבתלבסואלבוסךנהםא

תננכותמשואהילכואדבכתלתשהתרבעםא

.בורקה דיתעב וזכ הלתשה ךרובע

דגנכ תופורתב לפוטמה HIV אשנהתאםא

גוסמתיפיגנדבכתקלדבםדוקלופיטתקספהםא

.הכומנ םד תריפס וא הימנא בקע C

,םייכינחתויעבותוילטנדתוערפהלשםירקמוחווד

בולישולטנשםילפוטמב,םיינישןדבואלליבוהלתולולעש

עוגפללולעהפבשבוי,ןכ-ומכ.ןיריוובירוסיסגפלש

בולישבךשוממלופיטךלהמבהפהימורקבוםיינישב

תוידוסיבםיינישחצחצלךילע.ןיריוובירםעסיסגפלש

.רידס ןפואב תוילטנד תוקידב רובעלו םויב םיימעפ

ךנהםא.תואקהמלובסלםילולעםילפוטמהןמקלח

תוידוסיבהפהתאףוטשלדפקה,וזהעפותמלבוס

.ןכמ רחאל

םירגבתמו םידלי

תחתמםילפוטמלללכךרדבתדעוימהניאוזהפורת

.18ליגל

תורחא תופורתו סיסגפ

,תורחאתופורתהנורחאלתלטנםאואחקולהתאםא

ךכלערפס,הנוזתיפסותוםשרמאללתופורתללוכ

ואאפורהתאעדיילשידחוימב.חקורלואאפורל

המתסאבלופיטלתופורת:חקולהתאםאחקורה

. HIV -ה סוריו דגנכ תופורתו

ךרוצהיהישןכתיי,המתסאלתופורתלטונךנהםא

.המתסאב לופיטל תופורתה לש ןונימה תא תונשל

ידוקפתבהרמחהו) Lactic acidosis (תיטקלתצמח

גוסמ HIV דגנלופיטבתורושקשיאוולתועפותןהדבכ

.) Highly Active Anti - Retroviral Therapy ( HAART

ןיריווביר+סיסגפתפסוה, HAART -בלפוטמךנהםא

תיטקלתצמחלךלשןוכיסהתאריבגהלהלולע

רחאבקעמעצבילפטמהאפורה.דבכתקיפס-יאו

.הלא םיבצמל םימוטפמיסו םינמיס

םעבולישב) zidovudine (ןידובודיזםילטונשםילפוטמ

תוחתפתהלרבגומןוכיסבםהאפלאןורפרטניאוןיריווביר

.הימנא

בולישב) azathioprine (ןירפויטאזאםילבקמהםילפוטמ

רבגומןוכיסבםיאצמנןורפרטניאגפוןיריוובירםע

ןולעבםגןייעלשי.םדבתושקתוערפהתוחתפתהל

.ןיריווביר לש ןכרצל

ןידוויבלטבלפוטמךנהוהדימבסיסגפבשמתשהלןיא

תאהלעמהלאתופורתבוליששללגב,) telbivudine (

peripheral (תיפקיהםיבצעתלחמתוחתפתהלןוכיסה

,ץוצקע,השוחתרסוחבאטבתהלהלוכיש,) neuropathy

ןיא,ןכל.םיילגרבוא/ותועורזבהפירשתשוחתוא/ו

אפורלרפס.ןידוויבלטםעבולישבסיסגפבשמתשהל

.ןידוויבלטב לפוטמ ךנה םא חקורל וא

הקנהו ןוירה

חקורבואאפורבץעוויהלשיהקינימואןוירהבךניהםא

.הפורתב שומישה ינפל

:הקנה

ןיאןכלו,םאבלחבתשרפומהפורתהםאעודיאל

בלושמלופיטב.סיסגפבלופיטהךלהמבקוניתקיניהל

םיאתמהעדימלבלםישלשי,ןיריוובירםעסיסגפלש

:ןוירה

.הלפהלםיתיעלומרגםינורפרטניא,תויחבםירקחמב

.העודי אל םדא-ינבב ןוירה לע העפשהה

שי,ןיריוובירםעבולישבסיסגפבםישמתשמרשאכ

םילפוטמבןה,ןוירהתעינמלתוריהזיעצמאבטוקנל

ןיריוובירןכש,הבקנןיממתולפוטמבןהורכזןיממ

:רבועל רכינ קזנל םורגל לולע

בולישבסיסגפתלטונהתוירופהליגבהשיאךניהםא

ינפלתילילשןוירהתקידבגיצהלךיילע,ןיריוובירםע

4ךשמבווכלהמבשדוחלתחא,לופיטהתליחת

יעצמאבשמתשהלךיילע.ותקספהרחאלםישדוח

לופיטהתאתלטונתאדועלכןוירהדגנליעיהעינמ

לעןודלןתינ.ותקספהרחאלםישדוח4ךשמבו

.לפטמה אפורה םע אשונה

,ןיריוובירםעבולישבסיסגפלטונהרבגהתאםא

התאםאאלאןוירהבהשיאםעינימעגמםייקתלא

ןיריוובירשיוכיסהתאתיחפיהז.םודנוקבשמתשמ

עגרכןוירהבהניאךגוז-תבםא.השיאהףוגבראשיי

ןוירהתקידבעצבלהילע,תוירופהליגבתאצמנךא

םישדוח7ךשמבולופיטהךלהמבשדוחלתחא

שמתשהלםיבייחךגוזתבואהתא.ותקספהרחאל

תאלטונךנהדועלכןוירהדגנליעיהעינמיעצמאב

ןודלןתינ.ותקספהרחאלםישדוח7ךשמבולופיטה

.לפטמה אפורה םע אשונה לע

תונוכמב שומישו הגיהנ

,ררחוסמשחךנהםאתונוכמליעפהלואבכרבגוהנלןיא

.סיסגפב לופיטה ךלהמב לבלובמ וא ףייע

?הפורתב שמתשת דציכ )3

.אפורה תוארוה יפל שמתשהל שי דימת

.חוטב ךניא םא חקורה וא אפורה םע קודבל ךילע

לבוקמ ןונימ

בולישבואדבל,ג"קמ180סיסגפאוהלבוקמהןונימה

ונכתי.תירוע-תתהקרזהב,עובשבםעפ,ןיריוובירםע

.לופיטה ךלהמב ןונימב םייוניש

הנמהלערובעלןיא.דבלבאפורהתוארוהיפלןונימ

.תצלמומה

לופיטה ךשמ

גוסבתולתכ,םישדוח18-ל4ןיבענלופיטהךשמ

תלביקרבכםאולופיטלהבוגתב,םוהיזלםרגשסוריוה

.ךתלחמל לופיט רבעב

הפורתב שומישה ןפוא

:רמולכ,)רועלתחתמ(תירוע-תתהקרזהלדעוימסיסגפ

תמקרךותלהרצקטחמתרזעבסיסגפקירזהלשי

.ךריה וא ןטבה רוזאב רועל תחתמש ןמושה

.הנישה ינפל הפורתה תא קירזהל ץלמומ

הדימב!ימעפ-דחשומישלתדעוימסיסגפהפורתה

דימשהלשי,טעבהיוצמהמהכומנהנמךלהמשרנו

!הקרזהה רחאל הרתיה תא

עבקנשיפכםיבוצקםינמזבוזהפורתבשמתשהלשי

העפשההשםשרתמהתאםא.לפטמהאפורהידי-לע

אפורלהנפ,ידמהשלחואידמהקזחסיסגפלש

.חקורל וא

םאתהבלעפ,ךמצעלהפורתהתאקירזמהתאםא

האר(ןולעהףוסבתוטרופמהתימצעהקרזהלתוארוהל

.)"תימצע הקרזהל תוארוה" -7קרפ

בקעמו תוקידב

ךורעלשיוכלהמבוסיסגפבלופיטהתליחתינפל

םייונישרחאבוקעלידכברידסןפואבםדתוקידב

,)םימוהיזבםימחלנשםיאת(םינבלהםדהיאתתריפסב

תויסט,)ןצמחםיאשונשםיאת(םימודאהםדהיאת

ואדבכידוקפת,)םדתשירקלםיארחאשםיאת(םדה

.םירחא הדבעמ יכרעב םייוניש

אפורהשןכתיי,םדץחלרתימואתרכוסמלבוסךנהםא

.םייניע תקידבל ךתוא הנפי

.רידס ןפואב תוילטנד תוקידב רובעל ךילע

תונפלךילע,רתויהובגןונימתועטבתלטנםא

.ירשפאה םדקהב חקורל וא לפטמה אפורל

גוהנלשי,שורדהןמזבוזהפורתלוטילתחכשםא

:תואבה תוארוהה יפל

,ןנכותמההקרזההדעוממםיימויואםויופלחםא

.ירשפאהםדקהבהחכשנשהנמהתאקירזהלשי

םינמזהחוללםאתהבלוטילשיהאבההנמהתא

.ןנכותמהיהאבהלופיטהובשםויותואב,ירוקמה

שי,ןנכותמההקרזההדעוממםימי3-5ופלחםא

תא.ירשפאהםדקהבהחכשנשהנמהתאקירזהל

דעםימי5לשםיחוורמבלוטילשיתואבהתונמה

.עובקה הקרזהה םויל הרזחל

םויב.ינשםויאוהךלשעובקההקרזההםוי:אמגודל

4(ינשםוילשהקירזהתאתחכששתרכזנישיש

דימהחכשנשהנמהתאקירזהלךילע.)רוחיאימי

יעיברםויבהאבההנמהתאקירזהלוישישםויב

האבההקירזה.)ישישםוילשהנמהירחאםימי5(

לשהקירזהרחאלםימי5,ינשםויבהיהתךלש

ךלשליגרהםינמזהחוללתרזחוישכע.יעיברםוי

.ינש םוי לכב תוקירז לבקל ךישמהל ךילעו

לוטילןיא,ןנכותמההקרזההדעוממםימי6ופלחםא

הנמהתאלוטילותוכחלשי.החכשנשהנמהתא

.ךלש עובקה הקרזהה םויב ,תרחמל םוי האבה

סיסגפתנמיבגלהטלחהבעויסלקוקזהתאםא

.חקורל וא לפטמה אפורל הנפ ,החכשנש

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.חקורה וא אפורה םע תוצעייתה אלל הפורתב

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תופסונ יאוול תועפות

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םידליב תודחוימ יאוול תועפות

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הגופתהךיראתירחאהפורתבשמתשהלןיא

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הקרזהה םוקמ תא ןכהו רחב .4

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לוחכה הסכמה תא רסה .5

הסכמהתארסהותחאדיבהקזוחבטעהתאקזחה

.היינשה דיב לוחכה

תמושתל(.ףפוריתכתמרוניצליכמהסכמה:בלםיש

וניההזבצמ.ףפורתויהלרומאיתכתמהרוניצה,ךביל

שמתשהלשי,לוחכההסכמהרסוהשעגרמ.)ןיקת

ךותבטעבשומישהשענאלוהדימב.ידיימןפואבטעב

תוסנלןיא.שדחטעבשמתשהלווכילשהלשי,תוקד5

.ותרסה רחאל לוחכה הסכמה תא שדחמ רבחל

הקרזהה םוקמב טעה תא םקמ .6

לפקרוצהיינשהדיב.תוחונבטעהתאזוחאתחאדיב

טחמהןגמשךכותואקזחהוהקרזההםוקמברועב

.חוטבו ביצי ןפואב וילא דמציהל לכוי

לפקל)90 °(ךנואמבהקרזההםוקמבטעהתאםקמ

.רועה

.הלעפהה ןצחל לע ץוחלל ןיידע הסנת לא :בל םיש

טחמהןגמשדערועהדגנכהקזוחבטעהלעץחל

.טעה ךותל אלמ ןפואב סנכנ

.הקרזהל ןכומ אוהו הליענהמ תעכ ררחוש טעה ←

קרזה .7

םעץחל,הקרזההםוקמבהקזוחבטעהתאזחואךדועב

.דימ ותוא ררחשוהלעפהה ןצחל לע לדוגאה

.הקרזההתליחתלעדיעמרשא"קילק"עמשיי ←

הרקבהןולחבםודאהןמסההקרזההתומדקתהםע ←

.הטמ יפלכ עוני

ידכתוינש10ךשמברועהדגנכץוחלטעהתאקזחה

ריאשהלדואמבושח.הקרזההתמלשהתאחיטבהל

.הקרזהה תמלשהל דע רועה לפק לע טעה תא

הלעפההןצחלרשאכףסונ"קילק"עמשתוןכתיי ←

.ומוקמל רוזחי

.ןיטולחלםודאהיהיהרקבהןולחתעכ ←

תאםרה.הלעפההןצחלמלדוגאהתאתרסהיכאדוו

.הלעמ יפלכ )90 °( הרשי תיווזב טעה

ידכביטמוטואןפואבלענייוהצוחהאציטחמהןגמ ←

.תורקדיה עונמל

:תוריהז

,םודאה ןמסב ולוכ אלמ וניא הרקבה ןולח םא

.לעננאלטחמהןגמוןכתיי

לולעהתאשםושמטעההצקבעגיתלא

.רקדיהל

.התומלשבהנמהתאתלביקאלוןכתיי

.בוש טע ותואב שמתשהל הסנת לא

.הקרזהה לע רוזחת לא

.ךב לפטמה יאופרה תווצה םע רשק רוצ

:הקרזהה רחאל

תדימב,לוהוכלאדפםעהקרזההםוקמתאהקנ

.ךרוצה

שמושמה טעה תא ךלשה .8

טעהלעלוחכההסכמהתאשדחמםישלךרוצןיא

ולשלוחכההסכמהתאוטעהתאךלשה.שמושמה

קחרהלכימהתאןסחא.יתוחיטבורוגסחישקלכימל

.תע לכב םידלי לש םדי גשיהמ

PATIENT PACKAGE INSERT IN ACCORDANCE

WITH THE PHARMACISTS’ REGULATIONS

(PREPARATIONS) - 1986

The preparation is dispensed

only with a doctor’s prescription

Pegasys ®

135 mcg/0.5 ml

180 mcg/0.5 ml

Pre-filled Pen

COMPOSITION:

Each pre-filled pen contains:

Peginterferon alfa-2a 135 mcg/0.5 ml or 180 mcg/0.5 ml

*Forinformationabouttheinactiveingredientssee

section 6 “Further Information”.

Readthisleafletcarefullyinitsentiretybefore

usingthemedicine.Thisleafletcontainsconcise

informationaboutthemedicine.Ifyouhavefurther

questions, refer to the doctor or pharmacist.

Ifyouareprescribedcombinationtherapyof

Pegasys ® withribavirin,carefullyreadinaddition

theribavirinpatientpackageinsertbeforestarting

treatment.

Thismedicinehasbeenprescribedforthetreatment

ofyourailment.Donotpassitontoothers.Itmay

harmthemevenifitseemstoyouthattheirailment

is similar.

1)IMPORTANTINFORMATIONFORYOUR

ATTENTION

Pegasysisintendedfortreatmentofchronic

hepatitis B or C.

Pegasysisintendedforsubcutaneousinjection

)undertheskin(andcomesinapre-filledpen

forsingleuse.Ifyouareinjectingthemedicine

yourself,followtheinstructionsforself-injection

detailedattheendoftheleaflet)seeSection7–

“Instructions for Self-Injection”(.

Followingthedoctor’sinstructions)dosages,

injectiontimesanddurationoftreatment(

increasesthechanceforrecovery.Inanycase

donotstoptreatmentwithoutconsultingthe

attendingdoctor.Pleasereadsections2and4

for expanded safety information.

Beforestartingandduringtreatmentwith

Pegasys,bloodtestsandothertestsshouldbe

carriedoutregularly.Forfurtherinformationsee

section 3 “Tests and Follow-Up”.

Itisimportanttostorethemedicineinthe

refrigeratorinitsoriginalpackageandnotto

freeze it.

Youmusttakeextraprecautionarycontraceptive

measuresduringtreatment.Itisnotpossible

tocombinetreatmentwithbreastfeeding–

seeSection2paragraph“Pregnancyand

Breastfeeding”.

For what is the medicine intended?

Pegasysisalong-actinginterferon.Interferonis

aproteinthatmodifiestheresponseofthebody ’s

immunesystemtohelpcopewithinfectionsand

severediseases.Themedicineisusedforthe

treatment of chronic hepatitis B or C.

ChronicHepatitisB:Pegasysisusuallyused

alone.

ChronicHepatitisC:Pegasysisbestrecommended

foruseincombinationwithribavirin. Pegasysis

usedaloneonlyifyouareunabletotakeribavirin

for any reason.

Therapeutic group:Interferons.

2) BEFORE USING THE MEDICINE

Do not use this medicine if:

You are breastfeeding.

You have a known sensitivity to the active

ingredient)peginterferon-alfa-2a(,tointerferon

ofanykindortoanyingredientsofthe

medicine.

You had a heart attack or are suffering from

another heart disease.

You have autoimmune hepatitis.

You have advanced liver disease (e.g. if your

skin has become yellow(.

You are being treated with telbivudine (see

paragraph “ Pegasysand other medicines”(.

The patients are premature babies, newborns,

infants or children less than 3 years old.

Special warnings regarding use of the medicine

Refer to your doctor in the following cases:

If you are pregnant or planning on becoming

pregnant.

If you have psoriasis, it may get worse during

treatment with Pegasys.

If you have any problem with your liver other than

hepatitis B or C.

If you have diabetes or high blood pressure,

yourdoctormayaskyoutohaveaneye

examination.

If you notice changes in your vision.

If you think you are developing an infection

)suchaspneumonia(.Treatmentwith Pegasys

maytemporarilyincreasetheriskofgetting

infections.

If you develop symptoms associated with a cold

orotherrespiratoryinfection)suchascough,fever

or difficulty breathing(.

If you develop any signs of bleeding or unusual

bruising, check with your doctor immediately.

If you develop signs of a severe allergic reaction

)suchasdifficultybreathing,wheezingorhives(

whileundertreatmentwith Pegasys,seekmedical

help immediately.

If you have a thyroid disease that is not well

controlled with medicines.

If you have or have had a severe nervous or

mental disorder.

If you are suffering or have suffered in the past

fromdepression,ifyoudevelopsymptoms

associatedwithdepression)e.g.feelingsof

sadness,dejectionandthelike(whileontreatment

with Pegasys)see section 4 – “Side effects”(.

If you have or have ever had anemia.

If you have had a liver or kidney transplant or if

suchatransplantisbeingplannedforyouinthe

near future.

If you are an HIV carrier being treated with anti

HIV medicines.

If you have stopped previous therapy for hepatitis

C because of anemia or low blood count.

Dentalandgumdisorders,whichmayleadtolossof

teeth,havebeenreportedinpatientswhoreceived

Pegasysandribavirincombinationtherapy.In

addition,drymouthcouldhaveadamagingeffecton

teethandmembranesofthemouthduringlong-term

treatmentwiththecombinationof Pegasyswith

ribavirin.Youshouldbrushyourteeththoroughly

twice daily and have regular dental examinations.

Somepatientsmayexperiencevomiting.Ifyouhave

thisreaction,besuretorinseyourmouththoroughly

afterwards.

Children and adolescents

Thismedicineisnotusuallyintendedforpatients

under 18 years of age.

Pegasys and other medicines

Ifyouaretakingorhaverecentlytakenother

medicines,includingnon-prescriptionmedicines

andnutritionalsupplements,tellthedoctoror

pharmacist.Youshouldespeciallyinformthe

doctororpharmacistifyouaretaking:medicines

for treatment of asthma and anti-HIV medicines.

Ifyouaretakingmedicinesforasthma,thedosageof

the asthma medicines may need to be changed.

Lacticacidosisandworseningliverfunctionare

sideeffectsassociatedwithHighlyActiveAnti-

RetroviralTherapy)HAART(inHIVtreatment.Ifyou

arereceivingHAART,theadditionof Pegasys+

ribavirinmayincreaseyourriskoflacticacidosisor

liverfailure.Yourdoctorwillmonitoryouforsigns

and symptoms of these conditions.

Patientsreceivingzidovudineincombinationwith

ribavirinandinterferonalfaareatincreasedriskof

developing anemia.

Patientsreceivingazathioprineincombinationwith

ribavirinandpeginterferonareatincreasedriskof

developingsevereblooddisorders.Pleasebesure

to read the ribavirin patient leaflet also.

Donotuse Pegasysifyouaretakingtelbivudine

becausethecombinationofthesemedicines

increasestheriskofdevelopingperipheralneuropathy

whichcanbemanifestedbynumbness,tingling,

and/orburningsensationsinthearmsand/orlegs.

Therefore,donotuse Pegasysincombinationwith

telbivudine.Tellyourdoctororpharmacistifyouare

being treated with telbivudine.

Pregnancy and breastfeeding

Ifyouarepregnantorbreastfeedingconsultthe

doctor or pharmacist before using this medicine.

Breastfeeding:

Itisnotknownwhetherthisproductissecretedinto

thebreastmilk.Therefore,donotbreastfeedan

infantwhileyouaretaking Pegasys.Incombination

therapyof Pegasyswithribavirin,takenoticeof

theappropriateinformationintheribavirinpatient

leaflet.

Pregnancy:

Inanimalstudiesinterferonshavesometimescaused

miscarriage.Theeffectonhumanpregnancyisnot

When Pegasysisusedincombinationwith

ribavirin,bothmaleandfemalepatientsmusttake

precautionarycontraceptivemeasuresasribavirin

can be very damaging to an unborn baby:

If you are a woman of childbearing age who is

taking Pegasysincombinationwithribavirin,you

mustpresentanegativepregnancytestbefore

treatment,eachmonthduringtreatmentandfor

4monthsaftertreatmentisstopped.Youmust

useaneffectivecontraceptiveaslongasyou

aretakingthetreatmentandfor4monthsafter

stoppingtreatment.Thiscanbediscussedwith

your doctor.

If you are a man who is taking Pegasysin

combinationwithribavirin,donothavesexual

intercoursewithapregnantwomanunlessyou

useacondom.Thiswilllessenthechance

forribavirintobeleftinthewoman’sbody.If

yourfemalepartnerisnotpregnantnowbut

isofchildbearingage,shemustbetestedfor

pregnancy each month during treatment and for

7monthsaftertreatmenthasstopped.Youor

yourpartnermustuseaneffectivecontraceptive

duringthetimeyouaretakingthetreatmentand

for7monthsafterstoppingtreatment.Thiscan

be discussed with your doctor.

Driving and using machines

Donotdriveorusemachineryifyoufeeldizzy,tired,

or confused during the treatment with Pegasys.

3) HOW SHOULD YOU USE THE MEDICINE?

Alwaysuseaccordingtothedoctor‘sinstructions.

Checkwiththedoctororpharmacistifyouarenot

sure .

Recommended dosage

Theusualdosageis Pegasys180mcg,alone

orincombinationwithribavirin,onceweekly

bysubcutaneousinjection.Thedosagemaybe

changed in the course of treatment.

Thedosageisaccordingtodoctor’sinstructions

only. Do not exceed the recommended dose.

Duration of treatment

Thedurationoftreatmentvariesfrom4to18

monthsdependingonthetypeofvirusthatcaused

theinfection,onyourresponsetotreatmentand

whetheryouhavealreadyreceivedtreatmentfor

your illness in the past.

Directions for using the medicine

Pegasysisintendedforsubcutaneousinjection

)undertheskin(.Thismeansthat Pegasysshould

beinjectedusingashortneedleintothefattytissue

undertheskinintheabdomenorthigharea.Itis

recommended to inject the medicine at bedtime.

Pegasysisintendedforsingleuse!Ifyouhavebeen

prescribedadoselowerthanthatinthepre-filled

pen, discard the remainder after the injection!

Themedicineistobeusedatspecifictimesas

determinedbytheattendingdoctor.Ifyouhavethe

impressionthattheeffectof Pegasysistoostrong

or too weak, refer to the doctor or pharmacist.

Ifyouareinjectingthismedicineyourself,follow

theinstructionsforself-injectiongivenattheend

ofthisleaflet)seesection7-”InstructionsforSelf-

Injection”(.

Tests and follow-up

Beforestartingandduringtreatmentwith Pegasys

bloodtestsshouldbeperformedregularlyinorder

tomonitorchangesinthecountofwhitebloodcells

)cellsthatfightinfection(,redbloodcells)cellsthat

carryoxygen(,platelets)cellsthatareresponsiblefor

clottingofblood(,liverfunctionorchangesinother

laboratory values.

Ifyouhavediabetesorhighbloodpressure,the

doctor may refer you for an eye examination.

You should have dental examinations regularly.

Ifyouaccidentallytaketoohighadosage,contact

your doctor or pharmacist as soon as possible.

Ifyouforgettotakethemedicineatthespecified

time, follow the instructions below:

If 1 or 2 days have passed since the scheduled

injectiontime,youshouldinjectthemisseddose

assoonaspossible.Takeyournextinjection

accordingtotheoriginaltimeschedule,onthe

same day that the next treatment is scheduled.

If 3-5 days have passed since the scheduled

injectiontime,youshouldinjectthemissed

doseassoonaspossible.Takeyournext

dosesat5dayintervalsuntilyoureturnto

yourregularlyscheduleddayoftheweek.

Asanexample:Yourregularinjectiondayis

Monday.YourememberonFridaythatyouforgot

totakeyourinjectiononMonday)4dayslate(.You

shouldinjectthemisseddoseimmediatelyon

FridayandinjectthenextdoseonWednesday)5

daysafteryourFridaydose(.Yournextdosewillbe

onMonday,5daysaftertheWednesdayinjection.

Youarenowbackonyourregularlyscheduled

dayandshouldcontinueyourinjectionsevery

Monday.

If 6 days have passed since the scheduled

injectiontime,donottakethemisseddose.Wait

andtakethenextdoseonthefollowingday,your

regularly scheduled day.

Contactyourdoctororpharmacistifyouneedany

helpdetermininghowtomanageamisseddose

of Pegasys.

Donottaketwodosestogethertomakeupfora

forgotten dose.

Adheretothetreatmentrecommendedbythedoctor.

Evenifthereisanimprovementinourhealth,donot

stoptreatmentwiththemedicinewithoutconsulting

the doctor or pharmacist.

Howcanyoucontributetothesuccessofthe

treatment?

Donotmakeanychangesinthedosageofthe

medicineand/orthetreatmentwithoutexplicit

instructions from the attending doctor.

Besuretofollowtheinjectionscheduleasinstructed

by the attending doctor.

Strictadherencetothedoctor ’sinstructions

)dosage,injectiontimes,andthelike(willincrease

your chance of recovery.

Duringtreatmentyoushouldbrushyourteeth

thoroughlytwiceadayandhaveregulardental

examinations.

Completethefullcourseoftreatmentasinstructed

by the doctor.

Ifyouhaveanyfurtherquestionsontheuseofthis

medicine, ask your doctor or pharmacist

4) SIDE EFFECTS:

Aswithanymedicine,useof Pegasysmaycause

sideeffectsinsomeusers.Donotbealarmed

whenreadingthelistofsideeffects,youmaynot

experience any of them.

Refertothedoctorimmediatelyinthefollowing

cases:

Somepeoplegetdepressedwhentaking Pegasys

aloneorincombinationwithribavirin,andinsome

casespeoplehavehadsuicidalthoughtsor

aggressive behavior)sometimes directed against

otherssuchasthoughtsaboutthreateningthelife

ofothers(.Somepatientshaveactuallycommitted

suicide.Proceedtoanemergencyroomifyou

feeldepressed,havesuicidalthoughtsorifyour

behaviorchanges.Youmaywanttoconsider

askingafamilymemberorclosefriendtohelp

youbealertforsignsofdepressionorchanges

in your behavior.

Severechestpain;persistentcough;irregular

heartbeat;troublebreathing;confusion;depression;

severeabdominalpain;bloodinthestool)orblack

stools(;severenosebleed;highfeverorchills;

problemswithorchangesinyoureyesight;signs

ofbleedingorunusualbruising;signsofsevere

allergicreaction)e.g.:difficultybreathing,wheezing

or urticaria(.

Thesesideeffectscanbeseriousandyoumayneed

urgent medical attention.

Other side effects

Sideeffectsthatoccurfrequentlywiththe

combination of Pegasysand ribavirin

(frequency of 1:100):

Lossofappetite;feelingdepressed,anxiety,

inabilitytosleep;headache,difficultyconcentrating,

dizziness;cough,shortnessofbreath;diarrhea,

nausea,abdominalpain;lossofhair,skinreactions

)e.g.itching,dermatitisanddryskin(;jointpain,

musclepain;fever,weakness,tiredness,shaking,

chills,pain,irritabilityandinjectionsiteirritation;

fungal,viralandbacterialinfections;upper

respiratorytractinfection,bronchitis,fungalinfection

ofthemouth,herpes;lowplateletcount)affecting

clottingofblood(,anemia)lowredbloodcellcount(,

enlargedlymphglands;overactiveandunderactive

thyroidgland;emotionalchangesormoodchanges,

aggression,nervousness,decreasedsexualdesire;

poormemory,fainting,decreasedmusclestrength,

migraines,numbness,tingling,burningsensation,

tremor,changesinthesenseoftaste,nightmares,

sleepiness;blurryvision,eyepain,eyeinflammation,

dryeyes;sensationofspinning,earpain;rapid

heartrate,palpitations,swellingofthehandsand

feet;flushing;shortnessofbreathoneffort,nose

bleeds,noseandthroatinflammation,infections

ofthenoseandsinuses,runnynose,sorethroat;

vomiting,indigestion,difficultyswallowing,mouth

ulceration,bleedinggums,inflammationofthe

tongueandmouth,flatulence,drymouth,lossof

weight;rash,increasedsweating,psoriasis,hives,

eczema,sensitivitytosunlight,nightsweats;back

pain,jointinflammation,muscleweakness,bone

pain,neckpain,musclepain,musclecramps;

impotence;chestpain,flu-likeillness,malaise,

Sideeffectsthatoccurinfrequentlywiththe

combination of Pegasysand ribavirin

(frequency of between 1:100 and 1:1,000):

Lungandskininfections;livercancer;sarcoidosis

)areasofinflamedtissueindifferentpartsof

thebody(,inflammationofthethyroid;diabetes;

dehydration;suicidalthoughts,hallucinations;

peripheralneuropathy;bleedingintheretina;hearing

loss;highbloodpressure;wheezing;gastrointestinal

bleeding and decline in liver function.

Sideeffectsthatoccurveryrarelywiththe

combination of Pegasysand ribavirin

(frequency of between 1:1,000 and 1:10,000):

Infectionoftheheart;infectionoftheexternal

ear;severereductioninredbloodcell,white

bloodcellandplateletcounts;severeallergic

reaction;lupus;rheumatoidarthritis;diabetic

ketoacidosis,acomplicationofuncontrolled

diabetes;suicide;psychoticdisorders;coma

)deepprolongedunconsciousness(;seizures;facial

palsy;inflammationandswellingoftheopticnerve;

inflammationoftheretina;ulcerationofthecornea;

heartattack;heartfailure;heartpain;rapidheart

rhythm;rhythmdisorders;inflammationofthelining

oftheheartandthecardiacmuscle;bleedingin

thebrainandinflammationofthebloodvessels;

interstitialpneumonia)inflammationofthelungs

thatmaybefatal(;bloodclotsinthelungs;stomach

ulcer;inflammationofthepancreas;liverfailure;bile

ductinflammation;fattyliver;inflammationofthe

muscles; renal failure; overdose.

Side effects of unknown frequency:

Pureredcellaplasia)PRCA()asevereformofanemia

whereredbloodcellsproductionisdecreasedor

stopped(,aneffectthatcanleadtosymptoms

suchasfeelingverytired,withnoenergy;Vogt

KoyanagiHarada)ararediseasecharacterizedby

lossofvision,lossofhearingandskinpigmentation(;

rejectionofliverorkidneytransplant;mania

)episodesofexaggeratedelevationofmood(

andbipolardisorders)episodesofexaggerated

elevationofmoodthatalternatingwithsadnessand

hopelessness(;thoughtsaboutthreateningthelife

ofothers;stroke;arareformofdetachmentofthe

retinawithfluidintheretina;peripheralischemia

)decreaseinthesupplyofbloodtotheextremities(;

ischemiccolitis)inflammationofthecolonduetoa

decreasedsupplyofbloodtothebowels(;serious

muscledamageandpain;dentaldisordersandgum

problems; dry mouth.

When Pegasysisusedalonefortreatmentof

hepatitisBorC)withoutribavirin(,thechanceof

someoftheaboveeffectsoccurringislower.Ifany

ofthesideeffectsgetsserious,orifyouhaveany

sideeffectsnotmentionedinthisleaflet,consult

your doctor.

Special side effects in children

Thismedicinemaycausetoxicandallergicreactions

in infants and children below 3 years of age.

5) HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine, and all other

medicines,mustbestoredinasafeplaceout

ofthereachofchildrenand/orinfants,toavoid

poisoning.Donotinducevomitingunlessexplicitly

instructed to do so by a doctor.

Do not take medicines in the dark! Check the label

andthedoseeachtimeyoutakeyourmedicine.

Wear glasses if you need them.

Donotusethemedicineaftertheexpirydate

)exp.date(appearingontheboxandonthepre-

filledpen.Theexpirydatereferstothelastday

of that month.

Storage conditions: Store in the refrigerator at a

temperatureof2°C–8°C.Donotfreeze.Keepthe

pre-filledpenintheoriginaloutercartontoprotect

it from light.

Do not use the medicine if the pre-filled pen

packagingorthepre-filledpenitselfisdamaged,if

thesolutioniscloudy,iftherearefloatingparticles

inthesolution,orifthecolorofthesolutionisnot

clear or light yellow.

The pre-filled pen is intended for single use and

shouldbediscardedaftertheinjection.Discard

theusedpenandthebluecapinahard,closed

and safe container.

6) FURTHER INFORMATION

Inadditiontotheactiveingredient,themedicine

also contains:

Sodiumchloride,polysorbate80,benzylalcohol,

sodiumacetate,aceticacidglacial,waterfor

injections.

Howdoesthemedicinelookandwhatarethe

contents of the package?

Pegasysisasolutionforinjectionthatcomesina

pre-filled pen)0.5 ml(in packages of 1 or 4 pens*

*Not all package sizes may be available.

Licenseholderandaddress:RochePharmaceuticals

)Israel(Ltd., P.O.B. 6391, Hod Hasharon 4524079.

Nameofmanufacturerandaddress:F.Hoffmann-La

Roche Ltd., Basel, Switzerland.

Thisleafletwascheckedandapprovedbythe

Ministry of Health in June 2012.

RegistrationnumberofthemedicineintheNational

Drug Registry of the Ministry of Health:

Pegasys ® 135 mcg/0.5 ml Pre-filled Pen:

129.10.30804

Pegasys ® 180 mcg/0.5 ml Pre-filled Pen:

129.11.30805

7) INSTRUCTIONS FOR SELF-INJECTION

Itisveryimportantforyoutoread,understand

andfollowtheseinstructionssothatyouoryour

caregiverwillknowhowtousethepre-filledpen

correctly.Injectionwiththepre-filledpenisshort

andsimpleandthestepsaredetailedbelow.These

instructionsdonotreplacetrainingbyahealth-care

provider.Refertoyourhealth-careproviderwithany

question.Donotattempttoadministertheinjection

untilyouaresurethatyouunderstandhowtouse

the pre-filled pen.

The Pegasyspre-filledpenisintendedforself-

injectionofthepatientinhishomeafterreceiving

appropriateinstruction.Thepre-filledpenisnot

intendedforuseby/inchildrenbelow18yearsof

age.Thepre-filledpenisintendedforsingleuse

only and should then be discarded.

Do not:

Attempt to open or dismantle the pre-filled pen.

Operate the pre-filled pen with excessive force or

shock.

Inject through clothing covering the skin.

Use the pre-filled pen if it appears to be

damaged.

Use the pre-filled pen if the solution is cloudy,

discolored or has particles in it.

Shake the pre-filled pen.

Remove the blue cap (see “Pre-filled pen

components”below(untilyouarereadyto

inject.

Try to re-use the same pre-filled pen.

Manipulate the needle-shield before, during or

after use, as this is a safety device.

Pre-filled pen components:

1.Blue cap

2.Viewing window

3.Activation button

4.Needle-shield)onlyvisibleoncethebluecapis

removed in Step 5(

What will you need?

Pegasyspre-filled pen

Alcohol pad

A hard, lidded, safe container

Outline of injection steps:

1(Visually check the pre-filled pen

2(Allowthepre-filledpentoadjusttoroom

temperature

3(Wash your hands

4(Choose and prepare an injection site

5(Remove the blue cap

6(Place pre-filled pen on the injection site

7(Give injection

8(Dispose of the used pre-filled pen

1. Visually check the pre-filled pen

Takethepre-filledpenoutoftherefrigerator.Donot

shakeit.Visuallyexaminethepre-filledpen,aswell

as the solution through the viewing window.

Disposeofthepre-filledpenanduseanotherinthe

following cases:

If the solution is cloudy.

If the solution contains particles.

If the solution is any color besides colorless to

light yellow.

If any part of the pre-filled pen appears to be

damaged.

If the expiration date has passed. You will find the

expirationdateontheouterpackageaswellas

on the label of the pre-filled pen itself.

Keepthebluecaponthepre-filledpenuntil

2.Allowthepre-filledpentoadjusttoroom

temperature

Allowtherefrigeratedpre-filledpentoadjustto

roomtemperatureforabout20minutes.Donottry

to warm up the pre-filled pen in any other way.

3. Wash your hands

Wash your hands well using soap and water.

4. Choose and prepare an injection site

Chooseaplaceonyourstomachorthigh)seethe

picture(.Avoidyournavelareaandareasthatcould

beirritatedbyabeltorwaistband.Youshould

chooseadifferentplaceeachtimeyougiveyourself

an injection.

Cleantheareausingthealcoholpadandputthe

padasidetowipethesiteagainafterinjection,if

necessary.Lettheskindryfor10seconds.Besure

not to touch the cleaned area prior to the injection.

5. Remove the blue cap

Holdthepre-filledpenfirmlywithonehandandpull

off the blue cap with the other hand.

NOTE:Thecapcontainsaloose-fittingmetaltube.

)Foryourinformationthemetaltubeismeanttobe

loose.Thisisthenormalsituation.(Oncetheblue

capisremoved,thepre-filledpenshouldbeused

immediately.Ifitisnotusedwithin5minutes,the

pre-filledpenshouldbedisposedandanewpre-

filledpenshouldbeused.Donottrytore-attachthe

blue cap after removal.

6. Place the pre-filled pen on the injection site

Holdthepre-filledpencomfortablyinonehand.

Pinchandholdafoldofskinattheinjectionsitewith

yourfreehand,suchthattheneedle-shieldcanrest

on the skin-fold firmly and safely.

Placethepre-filledpenstraightupontheskinfold

at a right angle)90°(to the skin fold.

NOTE:Donotyetattempttopresstheactivation

button.

Pressthepre-filledpenfirmlyagainsttheskinuntilthe

needle-shield is completely pushed into the pen.

Thepre-filledpenisnowunlockedandreadyfor

injection.

7. Give injection

Whileholdingthepre-filledpenfirmlyinplace,

presstheactivationbuttonwithyourthumband

immediately release the button.

A“click”soundwillindicatethestartofthe

injection.

Theredindicatorwillmovedownintheviewing

window as the injection progresses.

Keepthepre-filledpenpressedontheskinfor

10 secondsto ensure a complete injection.

Youmighthearasecond“click”astheactivation

button pops back up.

Theviewingwindowwillnowbecompletely

red.

Makesureyouhavetakenyourthumboffthe

activationbutton.Liftthepre-filledpenstraightup

)90° angle(.

Theneedle-shieldwillautomaticallymoveoutand

lock to prevent needle injuries.

Caution:

Iftheviewingwindowisnotcompletelyfilledbythe

red indicator,

the needle-shield may not have locked.

Donottouchthetipofthepre-filledpen,since

needlestick injuries may occur.

you may not have received an entire dose.

Do not try to re-use the same pre-filled pen.

Do not repeat the injection.

Contact your healthcare provider.

After the injection:

Wipetheinjectionsitewiththealcoholpad,if

necessary.

8. Dispose of pre-filled pen

Replacingthebluecapontheusedpenisnot

necessary.Disposeoftheusedpre-filledpenand

bluecapinahard,liddedandsafecontainer.Store

thecontaineroutofthereachofchildrenatall

times.

טמרופ ןולע הז עבקנ ע " י דרשמ תואירבה ונכותו קדבנ רשואו לע - ודי ינויב 2102

Pegasys ® 

Pre-FilledSyringe,Pre-FilledPen,135mcgand180mcg

1. NAMEOF THEMEDICINAL PRODUCT

Pegasys135microgramssolutionforinjectioninpre-filledsyringe.

Pegasys180microgramssolutionforinjectioninpre-filledsyringe.

Pegasys135microgramssolutionforinjectioninpre-filledpen.

Pegasys180microgramssolutionforinjectioninpre-filledpen.

2. QUALITATIVEANDQUANTITATIVECOMPOSITION

Pegasys135mcg:

Onepre-filledsyringeorone pre-filledpencontain

peginterferonalfa-2a*.................................................................135micrograms

Eachsyringeorpenof0.5mlsolution contains 135 microgramspeginterferonalfa-2a*.

Pegasys180mcg:

Onepre-filledsyringeorone pre-filledpencontain

peginterferonalfa-2a*.................................................................180micrograms

Eachsyringeorpenof0.5 mlsolution contains 180 microgramspeginterferonalfa-2a*.

Thestrengthindicatesthequantityoftheinterferon alfa-2amoietyofpeginterferonalfa-2a

withoutconsideration ofthepegylation.

*Theactive substance,peginterferonalfa-2a,isacovalentconjugateoftheprotein interferon

alfa-2aproduced byrecombinantDNAtechnologyinEscherichiacoliwith bis-[monomethoxy

polyethylene glycol].

Thepotencyofthisproductshouldnotbecomparedtotheoneofanotherpegylatedornon-

pegylatedprotein ofthesametherapeuticclass.Formoreinformation,see section5.1.

Forafulllistofexcipients,seesection6.1.

Excipient:

Benzylalcohol(10mg/1ml)

3. PHARMACEUTICAL FORM

Solutionforinjectionin pre-filledsyringeorpre-filledpen.

Thesolution isclearandcolourless tolightyellow.

4. CLINICAL PARTICULARS

4.1Therapeutic indications

PEGASYS ®

MoHApprovedPrescribingInformation

Pre-Filled Syringe,Pre-Filled Pen135&180mcg June2012

ChronichepatitisB:

PegasysisindicatedforthetreatmentofbothHBeAg-positiveandHBeAg-negative chronic

hepatitisBinnon-cirrhoticand cirrhoticadultpatientswith compensatedliverdiseaseand

evidenceofviralreplication and liverinflammation.

ChronichepatitisC:

Pegasysisindicatedforthetreatmentofchronichepatitis C inadultpatientswhoarepositive

forserumHCV-RNA,includingpatientswith compensatedcirrhosisand/orco-infectedwith

clinicallystable HIV(seesection 4.4).

Theoptimalwayto usePegasysin patientswith chronichepatitisCisin combinationwith

ribavirin.ThecombinationofPegasysandribavirin is indicatedinnaive patientsandpatients

whohave failedprevioustreatmentwith interferonalpha (pegylatedornon-pegylated)alone

orin combinationtherapywith ribavirin.

Monotherapyisindicatedmainlyin caseofintolerance orcontraindicationtoribavirin.

4.2Posologyand methodofadministration

Treatmentshould beinitiatedonlybya physicianexperiencedin thetreatmentofpatients

with hepatitisBorC.

Please referalsototheribavirinprescribinginformationwhen Pegasysisto beused in

combinationwith ribavirin.

Dosetobeadministeredand durationoftreatment

ChronichepatitisB:

Therecommended dosageand duration ofPegasysforbothHBeAg-positive and HBeAg-

negative chronichepatitisBis180microgramsonceweeklyfor48weeksbysubcutaneous

administrationintheabdomenorthigh.

ChronichepatitisC –treatment-naïve patients:

Therecommended doseforPegasysis180microgramsonceweeklybysubcutaneous

administrationintheabdomenorthighgivenin combinationwith oralribavirin oras

monotherapy.

Thedose ofribavirin to be used incombinationwith PegasysisgiveninTable 1.

Theribavirin dose should beadministeredwithfood.

Durationoftreatment

Thedurationofcombinationtherapywith ribavirin forchronichepatitisCdependsonviral

genotype.Patientsinfectedwith HCVgenotype1whohave detectable HCVRNAatweek4

regardlessofpre-treatmentviralload shouldreceive 48weeksoftherapy.

Treatmentfor24weeksmaybeconsideredin patientsinfectedwith

- genotype1 with lowviralload (LVL)(

800,000IU/mL)atbaselineor

- genotype4

whobecomeHCVRNAnegative atweek4 andremain HCVRNAnegative atweek24.

However,anoverall24weekstreatmentduration maybeassociatedwith ahigherriskof

relapse thana48weekstreatmentduration(seesection 5.1).Inthese patients,tolerabilityto

combinationtherapyandadditionalprognosticfactorssuchas degreeoffibrosisshould be

PEGASYS ®

MoHApprovedPrescribingInformation

Pre-Filled Syringe,Pre-Filled Pen135&180mcg June2012

takenintoaccountwhendecidingontreatmentduration.Shorteningthetreatmentdurationin

patientswithgenotype1and highviralload (HVL)(>800,000IU/ml)atbaselinewhobecome

HCVRNAnegative atweek4 andremain HCVRNAnegative atweek24should be

consideredwith evenmore cautionsincethelimiteddataavailable suggestthatthismay

significantlynegativelyimpactthesustained virologicresponse.

Patientsinfectedwith HCVgenotype2 or3whohave detectable HCVRNAatweek4,

regardlessofpre-treatmentviralload shouldreceive 24weeksoftherapy.Treatmentforonly

16weeksmaybeconsideredin selectedpatientsinfectedwithgenotype 2or3with LVL

800,000IU/mL)atbaselinewhobecomeHCVnegative byweek4oftreatmentand

remains HCVnegative byweek16.Overall16weeksoftreatmentmaybe associatedwith a

lowerchanceofresponse and is associatedwith ahigherriskofrelapsethan a24week

treatmentduration(seesection 5.1).Inthese patients,tolerabilitytocombinationtherapyand

thepresenceofadditionalclinicalorprognosticfactorssuchas degreeoffibrosisshould be

takenintoaccountwhenconsideringdeviationsfromstandard24weekstreatmentduration.

Shorteningthetreatmentdurationin patientsinfectedwithgenotype2 or3with HVL

(>800,000IU/mL)atbaselinewhobecomeHCVnegative byweek4should beconsidered

with more cautionasthismaysignificantlynegativelyimpactthesustainedvirological

response(seeTable 1).

Available dataforpatientsinfectedwithgenotype5 or6 are limited;therefore combination

treatmentwith 1000/1200mg ofribavirinfor48weeksisrecommended.

Table 1:DosingRecommendationsforCombinationTherapyforHCVPatients

Genotype Pegasys Dose Ribavirin Dose Duration

Genotype1LVL

with RVR* 180micrograms <75kg =1000mg

75kg =1200mg 24weeksor

48weeks

Genotype1HVL

with RVR* 180micrograms <75kg =1000mg

75kg =1200mg 48weeks

Genotype4with

RVR* 180micrograms <75kg =1000mg

75kg =1200mg 24weeksor

48weeks

Genotype1or4

withoutRVR* 180micrograms <75kg =1000mg

75kg =1200mg 48weeks

Genotype2or3

withoutRVR** 180micrograms 800mg 24weeks

Genotype2or3

LVL with RVR** 180micrograms 800mg (a) 16weeks (a) or

24weeks

Genotype2or3

HVL with RVR** 180micrograms 800mg 24weeks

*RVR =rapidviralresponse(HCV RNA undetectable)atweek4andHCV RNA undetectableatweek24;

**RVR=rapidviralresponse(HCV RNA negative) byweek4

LVL= ≤800,000IU/mL;HVL=>800,000IU/mL

Itispresentlynotclear whether ahigher doseofribavirin(e.g.1000/1200mg/daybasedonbodyweight)results

inhigher SVR ratesthandoesthe800mg/day,whentreatmentisshortenedto16weeks.

Theultimate clinicalimpactofashortenedinitialtreatmentof16weeksinstead of24weeks

isunknown,takinginto accounttheneedforretreating non-respondingand relapsing

patients.

Therecommended durationofPegasysmonotherapyis48weeks.

ChronichepatitisC –PriorTreatmentNon-responderandRelapserPatients:

TherecommendeddosageofPegasysandribavirincombinationtherapyisPEGASYS

180

gonce weeklybysubcutaneousadministrationintheabdomenorthigh.Ribavirin

PEGASYS ®

MoHApprovedPrescribingInformation

Pre-Filled Syringe,Pre-Filled Pen135&180mcg June2012

should beadministeredwithfood.Forpatients<75kg and

75kg,1000mg and 1200mg

ofribavirin respectively,should beadministereddaily.

Patientswhohave detectable virus atweek12should stoptherapy.

Therecommended durationoftherapyisupto72weeksingenotype1 or4 patientsand48

weeksingenotype2or3patients.

HIV-HCVco-infection

Therecommended dosageforPegasys,alone orin combinationwith 800milligramsof

ribavirin,is180microgramsonce weeklysubcutaneouslyfor48weeks,regardless of

genotype.Thesafetyandefficacyofcombinationtherapywith ribavirin dosesgreaterthan

800 milligramsdailyiscurrentlybeingstudied.Adurationoftherapylessthan48weekshas

notbeenadquatelystudied.

Predictabilityofresponse and non-response –treatment-naïvepatients

Earlyvirologicalresponse byweek12,definedasa 2logviralload decrease orundetectable

levelsofHCVRNAhasbeenshown to bepredictive forsustainedresponse (seeTables2

and 6).

Table 2:Predictive ValueofWeek12VirologicalResponse attheRecommended

DosingRegimenwhileonPegasys CombinationTherapy

Genotype Negative Positive

No

response

byweek

12 No

sustained

response Predictive

Value Response

byweek

12 Sustained

response Predictive

Value

Genotype1

(N=569) 102 97 95%

(97/102) 467 271 58%

(271/467)

Genotype2and3

(N=96) 3 3 100%

(3/3) 93 81 87%

(81/93)

Thenegative predictive valueforsustained responsein patientstreatedwith Pegasysin

monotherapywas 98%.

Asimilarnegative predictive valuehasbeenobservedin HIV-HCVco-infectedpatients

treatedwith Pegasysmonotherapyorin combinationwith ribavirin (100%(130/130)or98%

(83/85),respectively).Positive predictive valuesof45%(50/110)and70%(59/84)were

observedforgenotype1andgenotype2/3HIV-HCVco-infectedpatientsreceiving

combinationtherapy.

Predictabilityofresponse and non-response –treatment-experiencedpatients

In non-responderpatientsre-treatedfor48or72weeks,viralsuppressionatweek12

(undetectable HCVRNAdefined as<50IU/mL)has beenshown tobepredictivefor

sustained virologicalresponse.Theprobabilitiesofnotachievingasustained virological

responsewith 48or72weeksoftreatmentifviralsuppressionwas notachievedatweek12

were96%(363of380)and96%(324of339),respectively.Theprobabilities ofachievinga

sustained virologicalresponsewith 48or72weeksoftreatmentifviralsuppressionwas

achievedatweek12were35%(20of57)and57%(57of100),respectively.

Doseadjustmentforadversereactions

General

Wheredose adjustmentisrequiredformoderateto severeadversereactions(clinicaland/or

laboratory)initialdosereductionto135microgramsisgenerallyadequate.However,in some

PEGASYS ®

MoHApprovedPrescribingInformation

Pre-Filled Syringe,Pre-Filled Pen135&180mcg June2012

cases,dosereductionto90microgramsor45microgramsisnecessary.Doseincreasesto

ortowardstheoriginaldosemaybeconsideredwhen theadversereactionabates(see

sections 4.4 and4.8).

Haematological(seealso Table 3)

Dosereductionisrecommended iftheneutrophilcountis<750/mm 3 .Forpatientswith

AbsoluteNeutrophilCount(ANC)<500/mm 3 treatmentshouldbesuspended untilANC

valuesreturnto>1000/mm 3 .Therapyshouldinitiallybere-institutedat90micrograms

Pegasysandtheneutrophilcountmonitored.

Dosereductionto90microgramsisrecommended iftheplateletcountis<50,000/mm 3 .

Cessationoftherapyisrecommendedwhenplateletcountdecreasestolevels<25,000/mm 3 .

Specificrecommendationsformanagementoftreatment-emergentanaemia areasfollows:

ribavirin should bereducedto600milligrams/day(200milligramsinthemorningand

400milligramsin theevening)ifeitherofthefollowingapply:(1)apatientwithoutsignificant

cardiovasculardisease experiences afallin haemoglobin to<10 g/dland≥8.5g/dl,or(2)a

patient with stable cardiovasculardisease experiences afallin haemoglobin by≥2g/dl

duringany4weeksoftreatment.Areturnto originaldosingisnotrecommended.Ribavirin

should bediscontinuedifeitherofthefollowingapply:(1)Apatientwithoutsignificant

cardiovasculardisease experiences afallin haemoglobin confirmedto<8.5g/dl;(2)A

patientwith stable cardiovasculardisease maintains ahaemoglobin value<12g/dldespite

4weeksonareduceddose.Iftheabnormalityisreversed,ribavirin mayberestartedat

600milligramsdaily,andfurtherincreasedto 800milligramsdailyatthediscretionofthe

treatingphysician.Areturnto originaldosingisnotrecommended.

Table 3:DoseAdjustmentforAdverse Reaction(Forfurtherguidance see alsotext

above)

Reduce

Ribavirin

to 600mg Withhold

Ribavirin Reduce

Pegasys

to 135/90/45

micrograms Withhold

Pegasys Discontinue

Combination

Absolute

Neutrophil

Count <750/mm 3

<500/mm 3

PlateletCount <50,000/mm 3

>25,000/mm 3 <25,000/mm 3

Haemoglobin

-nocardiac

disease <10g/dl,and

≥8.5g/dl <8.5g/dl

Haemoglobin

-stable cardiac

disease decrease

≥2g/dlduring

any4 weeks <12g/dl

despite 4

weeksat

reduced dose

In caseofintolerancetoribavirin,Pegasysmonotherapyshould becontinued.

Liverfunction

Fluctuationsinabnormalities ofliverfunctiontestsarecommonin patientswith chronic

hepatitisC.Aswith otheralpha interferons,increases inALTlevelsabove baseline(BL)

have beenobservedin patientstreatedwith Pegasys,includingpatientswith avirological

response.

In chronichepatitisCclinicaltrials,isolated increases inALT( ≥10xULN,or≥2xBLfor

patientswith aBLALT≥10xULN)which resolvedwithoutdose-modification wereobserved

in 8of451 patientstreatedwith combinationtherapy.IfALTincrease isprogressive or

PEGASYS ®

MoHApprovedPrescribingInformation

Pre-Filled Syringe,Pre-Filled Pen135&180mcg June2012

persistent,thedoseshould bereducedinitiallyto135micrograms.Whenincrease inALT

levelsisprogressive despite dosereduction,orisaccompaniedbyincreasedbilirubin or

evidenceofhepaticdecompensation,therapyshould bediscontinued(seesection 4.4).

ForchronichepatitisBpatients,transientflares ofALTlevelssometimesexceeding10times

theupperlimitofnormalarenotuncommon,andmayreflectimmuneclearance.Treatment

should normallynotbeinitiatedifALTis>10timestheupperlimitofnormal.Consideration

should begiventocontinuingtreatmentwithmorefrequentmonitoringofliverfunctionduring

ALTflares.IfthePegasysdose isreducedorwithheld,therapycanberestoredoncethe

flare issubsiding(seesection4.4).

Specialpopulations

Elderly

Adjustmentsintherecommendeddosageof180microgramsonceweeklyarenotnecessary

when instituting Pegasystherapyin elderlypatients(seesection 5.2).

Childrenand adolescents

Onlylimitedsafetyandefficacydataareavailableinchildrenandadolescents(6-18years)

(seesection5.1).Pegasysiscontraindicatedinneonatesandyoungchildrenupto3years

oldbecause oftheexcipientbenzylalcohol(seesections 4.3 and4.4).

Patientswithrenalimpairment

In patientswith end stagerenaldisease,astartingdose of135microgramsshould beused

(seesection5.2).Regardless ofthestarting doseordegreeofrenalimpairment,patients

should bemonitoredandappropriatedosereductionsofPegasysduringthe courseof

therapyshould bemadein theeventofadversereactions.

Patientswithhepaticimpairment

In patientswith compensatedcirrhosis(eg,Child-Pugh A),Pegasyshasbeen shown to be

effective and safe.Pegasyshasnotbeenevaluatedin patientswith decompensatedcirrhosis

(eg,Child-PughBorCorbleedingoesophagealvarices)(seesection4.3).

TheChild-Pughclassification dividespatientsintogroupsA,B,and C,or"Mild","Moderate"

and "Severe"correspondingto scoresof5-6,7-9and 10-15,respectively

.

ModifiedAssessment

Assessment Degreeofabnormality Score

Encephalopathy None

Grade1-2

Grade3-4* 1

2

3

Ascites Absent

Slight

Moderate 1

2

3

S-Bilirubin (mg/dl)

SIunit=

mol/l) <2

2.0-3

>3

<34

34-51

>51 1

2

3

1

2

3

S-Albumin (g/dl) >3.5

3.5-2.8

<2.8 1

2

3

PEGASYS ®

MoHApprovedPrescribingInformation

Pre-Filled Syringe,Pre-Filled Pen135&180mcg June2012

Assessment Degreeofabnormality Score

INR <1.7

1.7-2.3

>2.3 1

2

3

*GradingaccordingtoTrey,BurnsandSaunders(1966)

4.3Contraindications

Hypersensitivityto theactive substance,to alpha interferons,orto anyoftheexcipients

Autoimmunehepatitis

Severehepaticdysfunctionordecompensatedcirrhosisoftheliver

Neonates andyoungchildrenupto3 yearsold,becauseoftheexcipientbenzylalcohol

(seesection4.4forbenzylalcohol)

Ahistoryofseverepre-existingcardiacdisease,includingunstable oruncontrolled

cardiac diseasein theprevioussixmonths(seesection 4.4)

Initiation ofPegasysiscontraindicatedin HIV-HCVpatientswith cirrhosisand aChild-

Pughscore≥6,exceptifonlydue toindirecthyperbilirubinemia causedbydrugssuch

as atazanavirand indinavir

CombinationofPegasyswith telbivudine(seesection4.5).

Forcontraindicationstoribavirin,please referalsototheribavirinprescribinginformation

when Pegasysistobeusedin combinationwith ribavirin.

4.4Specialwarningsand precautionsforuse

Psychiatric andCentralNervous System(CNS):SevereCNSeffects,particularly

depression,suicidalideation and attemptedsuicide have beenobservedin somepatients

duringPegasystherapy,and evenaftertreatmentdiscontinuationmainlyduringthe6-month

follow-upperiod.OtherCNSeffectsincludingaggressive behaviour(sometimes directed

againstotherssuchas homicidalideation),bipolardisorders,mania,confusionand

alterationsofmentalstatus have beenobservedwith alpha interferons.Patientsshould be

closelymonitoredforanysignsorsymptomsofpsychiatricdisorders.Ifsuch symptoms

appear,thepotentialseriousnessofthese undesirable effectsmustbebornein mindbythe

prescribingphysicianand theneedforadequatetherapeuticmanagementshould be

considered.Ifpsychiatricsymptomspersistorworsen,orsuicidalideation isidentified,itis

recommendedthattreatmentwith Pegasysbediscontinued,andthepatientfollowed,with

psychiatricinterventionasappropriate.

Patientswithexistence of,orhistoryofseverepsychiatricconditions:Iftreatmentwith

Pegasysisjudgednecessaryin patientswith existence orhistoryofseverepsychiatric

conditions,thisshouldonlybeinitiatedafterhavingensuredappropriateindividualised

diagnosticandtherapeuticmanagementofthepsychiatriccondition.

Please referalsototheribavirinprescribinginformationwhen Pegasysisto beused in

combinationwith ribavirin.

AllpatientsinthechronichepatitisCstudies hada liverbiopsybefore inclusion,butin certain

cases(ie,patientswith genotype2 or3),treatmentmaybepossible withouthistological

confirmation.Currenttreatmentguidelinesshouldbeconsultedastowhetheraliverbiopsyis

neededpriortocommencingtreatment.

In patientswith normalALT,progressionoffibrosisoccursonaverageataslowerratethan

in patientswith elevatedALT.Thisshouldbeconsideredin conjunctionwith otherfactors,

suchasHCVgenotype,age,extrahepaticmanifestations,riskoftransmission,etc.which

influencethedecisiontotreatornot.

PEGASYS ®

MoHApprovedPrescribingInformation

Pre-Filled Syringe,Pre-Filled Pen135&180mcg June2012

Excipient:Benzylalcohol.Pegasysiscontraindicatedin infantsoryoungchildrenupto3

yearsold becauseoftheexcipientbenzylalcohol.

Laboratorytestspriortoand duringtherapy

Priorto beginningPegasystherapy,standardhaematologicaland biochemicallaboratory

testsarerecommendedforallpatients.

Thefollowingmaybeconsideredasbaselinevaluesforinitiation oftreatment:

- Plateletcount

90,000/mm 3

- Absoluteneutrophilcounts

1500/mm 3

- Adequatelycontrolledthyroid function(TSHandT4)

Haematologicaltestsshould berepeatedafter2and 4weeksand biochemicaltestsshould

beperformedat4weeks.Additionaltestingshould beperformedperiodicallyduringtherapy.

In clinicaltrials,Pegasystreatmentwas associated with decreasesin bothtotalwhite blood

cell(WBC)countand absoluteneutrophilcount(ANC),usuallystartingwithin thefirst2

weeksoftreatment(seesection 4.8).Progressive decreasesafter8weeksoftherapywere

infrequent.Thedecreasein ANCwas reversible upondosereductionorcessation oftherapy

(seesection4.2),reached normalvaluesby8 weeksinthemajorityofpatientsandreturned

to baselinein allpatientsafterabout16weeks.

Pegasystreatmenthasbeen associatedwith decreases inplateletcount,which returnedto

pre-treatmentlevelsduringthepost-treatmentobservation period(seesection4.8).In some

cases,dosemodificationmaybenecessary(seesection 4.2).

Theoccurrenceofanaemia (haemoglobin <10g/dl)hasbeenobservedinupto 15%of

chronichepatitisCpatientsinclinicaltrialsonthecombinedtreatmentofPegasyswith

ribavirin.Thefrequencydependsonthetreatmentduration andthedoseofribavirin (see

section 4.8).Theriskofdevelopinganaemia is higherinthefemale population.

Aswith otherinterferons,cautionshould beexercisedwhen administeringPegasysin

combinationwith otherpotentiallymyelosuppressive agents.

Pancytopeniaand bonemarrowsuppressionhave beenreportedintheliteratureto occur

within 3to7 weeksaftertheadministrationofapeginterferonandribavirin concomitantlywith

azathioprine.Thismyelotoxicitywas reversiblewithin 4to6 weeksuponwithdrawalofHCV

antiviraltherapyand concomitantazathioprineand did notrecuruponreintroduction ofeither

treatmentalone(seesection4.5).

TheuseofPegasysandribavirin combinationtherapyin chronichepatitisCpatientswho

failedpriortreatmenthasnotbeenadequatelystudiedin patientswhodiscontinuedprior

therapyforhematologicaladverseevents.Physiciansconsideringtreatmentinthesepatients

should carefullyweigh the risksversusthebenefitsofre-treatment.

Endocrinesystem

Thyroidfunctionabnormalities orworseningofpre-existingthyroid disordershave been

reportedwith theuseofalpha interferons,includingPegasys.Priorto initiation ofPegasys

therapy,TSHandT4levelsshould beevaluated.Pegasystreatmentmaybeinitiatedor

continuedifTSHlevelscanbemaintained inthenormalrange bymedication.TSHlevels

should bedetermined duringthecourse oftherapyifapatientdevelopsclinicalsymptoms

consistentwith possible thyroid dysfunction(seesection 4.8).Aswith otherinterferons,

hypoglycaemia,hyperglycaemia anddiabetesmellitus have beenobservedwith Pegasys

(seesection4.8).Patientswith theseconditionswhocannotbeeffectivelycontrolledby

PEGASYS ®

MoHApprovedPrescribingInformation

Pre-Filled Syringe,Pre-Filled Pen135&180mcg June2012

medication shouldnotbegin PegasysmonotherapynorPegasys/ribavirin combination

therapy.Patientswhodevelopthese conditionsduring treatmentandcannotbecontrolled

with medicationshould discontinue PegasysorPegasys/ribavirin therapy.

Cardiovascularsystem

Hypertension,supraventriculararrhythmias,congestive heartfailure,chestpain and

myocardialinfarctionhave beenassociatedwith alphainterferontherapies,including

Pegasys.Itisrecommended thatpatientswhohave pre-existingcardiac abnormalities have

anelectrocardiogrampriorto initiation ofPegasystherapy.Ifthere is anydeteriorationof

cardiovascularstatus,therapyshould be suspended ordiscontinued.Inpatientswith

cardiovasculardisease,anaemiamaynecessitate dosereductionordiscontinuation of

ribavirin (seesection4.2).

Liverfunction

In patientswhodevelopevidenceofhepaticdecompensationduringtreatment,Pegasys

should bediscontinued.Aswith otheralpha interferons,increasesin ALT levelsabove

baselinehave beenobservedin patientstreatedwith Pegasys,includingpatientswith aviral

response.Whentheincrease inALTlevelsisprogressive and clinicallysignificant,despite

dose reduction,orisaccompaniedbyincreaseddirectbilirubin,therapyshould be

discontinued(seesections4.2and 4.8).

In chronichepatitisB,unlike chronichepatitisC,disease exacerbationsduringtherapyare

notuncommonandarecharacterisedbytransientand potentiallysignificantincreases in

serumALT.Inclinicaltrialswith Pegasysin HBV,markedtransaminaseflareshave been

accompaniedbymild changesin othermeasuresofhepaticfunctionandwithoutevidenceof

hepaticdecompensation.Inapproximatelyhalfthe caseofflaresexceeding10timesthe

upperlimitofnormal,Pegasysdosingwas reducedorwithheld untilthetransaminase

elevations subsided,while intheresttherapywascontinuedunchanged.Morefrequent

monitoring ofhepaticfunctionwas recommendedin allinstances.

Hypersensitivity

Serious,acutehypersensitivityreaction(eg,urticaria,angioedema,bronchoconstriction,

anaphylaxis)have beenrarelyobservedduringalpha interferontherapy.Ifthisoccurs,

therapymustbediscontinuedand appropriatemedicaltherapyinstitutedimmediately.

Transientrashesdonotnecessitateinterruptionoftreatment.

Autoimmunedisease

Thedevelopmentofauto-antibodies andautoimmune disordershasbeenreportedduring

treatmentwith alpha interferons.Patientspredisposedtothedevelopmentofautoimmune

disordersmaybeatincreasedrisk.Patientswith signsorsymptomscompatible with

autoimmunedisordersshould beevaluatedcarefully,andthebenefit-riskofcontinued

interferontherapyshould bereassessed(seealsoEndocrine Systemin sections4.4and 4.8).

CasesofVogt-Koyanagi-Harada (VKH)syndromehave beenreportedin patientswith

chronichepatitisCtreated with interferon.Thissyndromeisagranulomatousinflammatory

disorderaffectingtheeyes,auditorysystem,meninges,andskin.IfVKHsyndromeis

suspected,antiviraltreatmentshould bewithdrawn and corticosteroidtherapydiscussed (see

section 4.8).

Fever/infections

Whilefevermaybeassociatedwith theflu-like syndromereportedcommonlyduring

interferontherapy,othercauses ofpersistentfever,particularlyserious infections(bacterial,

viral,fungal)mustberuledout,especiallyin patientswith neutropenia.Serious infections

(bacterial,viral,fungal)andsepsishave beenreportedduringtreatmentwith alpha

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interferonsincludingPegasys.Appropriate anti-infective therapyshould bestarted

immediatelyand discontinuation oftherapyshould beconsidered.

Ocularchanges

Aswith otherinterferonsretinopathyincludingretinalhaemorrhages,cotton woolspots,

papilloedema,opticneuropathyand retinalarteryorvein obstruction which mayresultin loss

ofvisionhave beenreportedin rare instances with Pegasys.Allpatientsshouldhavea

baselineeyeexamination.Anypatientcomplainingofdecreaseorlossofvisionmusthave a

promptandcompleteeye examination.Patientswithpreexistingophthalmologicdisorders(eg,

diabeticorhypertensiveretinopathy)shouldreceiveperiodicophthalmologicexamsduring

Pegasystherapy.Pegasystreatmentshould bediscontinuedin patientswhodevelopnewor

worseningophthalmologicdisorders.

Pulmonarychanges

Aswith otheralpha interferons,pulmonarysymptoms,includingdyspnoea,pulmonary

infiltrates,pneumonia,andpneumonitishave beenreportedduringtherapywith Pegasys.In

caseofpersistentorunexplained pulmonaryinfiltratesorpulmonaryfunctionimpairment,

treatmentshouldbediscontinued.

Skin disorder

Use ofalpha interferonshasbeenassociatedwith exacerbationorprovocationofpsoriasis

and sarcoidosis.Pegasysmustbeusedwith cautionin patientswith psoriasis,andin cases

ofonsetorworseningofpsoriatic lesions,discontinuation oftherapyshould beconsidered.

Transplantation

Thesafetyand efficacyofPegasysandribavirintreatmenthave notbeenestablished in

patientswith liverand othertransplantations.Liverandrenalgraftrejections have been

reportedwith Pegasys,alone orincombinationwithribavirin.

HIV-HCVcoinfection

Please refertotherespectiveprescribinginformationoftheantiretroviralmedicinalproducts

thataretobetakenconcurrentlywith HCVtherapyforawareness andmanagementof

toxicities specificforeach productandthepotentialforoverlappingtoxicities with Pegasys

with orwithoutribavirin.In studyNR15961,patientsconcurrentlytreatedwith stavudineand

interferontherapywith orwithoutribavirin,theincidenceofpancreatitisand/orlactic acidosis

was 3%(12/398).

Patientsco-infectedwithHIVandreceivingHighlyActiveAnti-RetroviralTherapy(HAART)

maybeatincreasedriskofdevelopinglacticacidosis.Cautionshouldthereforebeexercised

whenaddingPegasysandribavirintoHAARTtherapy(seeribavirinPI).

Co-infectedpatientswithadvancedcirrhosisreceivingHAARTmayalsobeatincreasedrisk

ofhepaticdecompensationandpossiblydeathiftreatedwithribavirinincombinationwith

interferons,includingPegasys.Baselinevariablesinco-infectedcirrhoticpatientsthatmay

beassociatedwithhepaticdecompensationinclude:increasedserumbilirubin,decreased

haemoglobin,increasedalkalinephosphataseordecreasedplateletcount,andtreatment

with didanosine(ddI).

Theconcomitantuseofribavirinwithzidovudineisnotrecommendedduetoanincreased

riskofanaemia (seesection4.5).

Duringtreatment,co-infectedpatientsshould becloselymonitoredforsignsand symptoms

ofhepaticdecompensation(includingascites,encephalopathy,varicealbleeding,impaired

hepaticsyntheticfunction;e.g.,Child-Pugh scoreof7 orgreater).TheChild-Pughscoring

maybeaffectedbyfactorsrelatedtotreatment(i.e.indirecthyperbilirubinemia,decreased

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albumin)andnotnecessarilyattributableto hepaticdecompensation.Treatmentwith

Pegasysshould bediscontinued immediatelyin patientswith hepaticdecompensation.

In patientsco-infectedwith HIV-HCV,limitedefficacyand safetydataareavailable in

subjectswith CD4 countslessthan 200cells/uL.Cautionistherefore warrantedinthe

treatmentofpatientswith lowCD4 counts.

Dentaland periodontaldisorders

Dentaland periodontaldisorders,which mayleadto lossofteeth,have beenreportedin

patientsreceivingPegasysand ribavirin combinationtherapy.Inaddition,drymouthcould

have adamagingeffectonteeth andmucousmembranesofthemouthduringlong-term

treatmentwith thecombinationofPegasysandribavirin.Patientsshouldbrushtheirteeth

thoroughlytwice dailyand have regulardentalexaminations.Inadditionsome patientsmay

experience vomiting.Ifthisreactionoccurs,theyshould beadvisedtorinseouttheirmouth

thoroughlyafterwards.

Use ofpeginterferonaslong termmaintenancemonotherapy(unapproveduse)

In arandomised,controlledUSstudy(HALT-C)ofHCVnon-responderpatientswith varied

degreesoffibrosiswhere 3.5yearsoftreatmentwith 90micrograms/weekofPegasys

monotherapywas studied,nosignificantreductionswereobservedintherateoffibrosis

progressionorrelatedclinicalevents.

4.5Interactionwith othermedicinalproductsand otherformsofinteraction

Interactionstudieshave onlybeenperformedin adults.

AdministrationofPegasys180microgramsonceweeklyfor4 weeksin healthymale subjects

did notshowanyeffecton mephenytoin,dapsone,debrisoquineandtolbutamide

pharmacokineticsprofiles,suggestingthatPegasyshasnoeffectonin vivo metabolicactivity

ofcytochromeP450 3A4,2C9,2C19and2D6 isozymes.

Inthesamestudy,a25%increase intheAUCoftheophylline(markerofcytochromeP450

1A2 activity)was observed,demonstrating thatPegasysisaninhibitorofcytochromeP450

1A2 activity.Serumconcentrationsoftheophyllineshould bemonitoredand appropriatedose

adjustmentsoftheophyllinemadeforpatientstakingtheophyllineandPegasysconcomitantly.

Theinteractionbetween theophyllineand Pegasysislikelytobemaximalaftermorethan4

weeksofPegasystherapy.

HCVmonoinfectedpatientsandHBVmonoinfectedpatients

In apharmacokineticstudyof24HCVpatientsconcomitantlyreceivingmethadone

maintenancetherapy(mediandose 95mg;range30mgto 150mg),treatmentwith Pegasys

180micrograms sc onceweeklyfor4 weekswasassociatedwith meanmethadonelevels

thatwere10%to15%higherthan atbaseline.The clinicalsignificanceofthisfindingis

unknown;nonetheless,patientsshould bemonitoredforthesignsandsymptomsof

methadonetoxicity.Especiallyin patientsonahighdose ofmethadone,theriskforQTc

prolongationshould beconsidered.

Ribavirin,byhavinganinhibitoryeffectoninosinemonophosphatedehydrogenase,may

interfere with azathioprinemetabolismpossiblyleadingto anaccumulationof6-

methylthioinosinemonophosphate(6-MTIMP),which hasbeenassociatedwith myelotoxicity

in patientstreatedwith azathioprine.Theuseofpeginterferonalfa-2aandribavirin

concomitantlywith azathioprin should beavoided.Inindividualcaseswhere thebenefitof

administeringribavirin concomitantlywith azathioprinewarrantsthepotentialrisk,itis

recommendedthatclosehematologicmonitoringbedoneduringconcomitantazathioprine

usetoidentifysigns ofmyelotoxicity,atwhich time treatmentwith thesedrugsshould be

stopped(seesection4.4).

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Resultsfrompharmacokineticsubstudies ofpivotalphaseIIItrialsdemonstratedno

pharmacokineticinteractionoflamivudineonPegasysin HBVpatientsorbetween Pegasys

and ribavirin inHCVpatients.

Aclinicaltrialinvestigating thecombinationoftelbivudine600mgdaily,with pegylated

interferonalfa-2a,180microgramsonceweeklybysubcutaneous administrationforthe

treatmentofHBV,indicates thatthecombinationisassociatedwith anincreasedriskfor

developingperipheralneuropathy.Themechanismbehindtheseeventsisnotknown; thus,

co-treatmentwith telbivudineand otherinterferons(pegylatedorstandard)mayalso entailan

excess risk.Moreover,the benefitofthecombinationoftelbivudinewith interferonalfa

(pegylatedorstandard)isnotcurrentlyestablished.Therefore,thecombinationofPegasys

with telbivudineiscontraindicated(seesection4.3).

HIV-HCVco-infectedpatients

No apparentevidenceofdrug interactionwas observedin 47HIV-HCVco-infectedpatients

whocompleteda 12 weekpharmacokineticsubstudyto examinetheeffectofribavirin onthe

intracellularphosphorylation ofsomenucleosidereversetranscriptase inhibitors(lamivudine

and zidovudineorstavudine).However,dueto highvariability,theconfidence intervalswere

quitewide.Plasmaexposureofribavirin did notappearto beaffectedbyconcomitant

administrationofnucleosidereversetranscriptaseinhibitors(NRTIs).

Co-administrationofribavirin and didanosineisnotrecommended.Exposureto didanosine

oritsactive metabolite(dideoxyadenosine5 ’-triphosphate)isincreasedinvitrowhen

didanosineisco-administeredwith ribavirin.Reportsoffatalhepaticfailureas wellas

peripheralneuropathy,pancreatitis,andsymptomatic hyperlactataemia/lacticacidosishave

beenreportedwith useofribavirin.

Exacerbationofanaemiaduetoribavirin hasbeen reportedwhen zidovudineispartofthe

regimenusedtotreatHIValthoughtheexactmechanismremainstobeelucidated.The

concomitantuseofribavirin with zidovudineisnotrecommended duetoanincreasedriskof

anaemia (seesection4.4).Considerationshouldbegivento replacingzidovudinein a

combinationARTregimen ifthisisalreadyestablished.Thiswould beparticularlyimportant

in patientswith aknown historyofzidovudineinduced anaemia.

4.6Fertility,pregnancyand lactation

There are noadequatedataontheuseofpeginterferonalfa-2ain pregnantwomen.Studies

in animalswith interferonalfa-2ahave shown reproductive toxicity(seesection5.3)andthe

potentialriskforhumansisunknown.Pegasysisto beused duringpregnancyonlyifthe

potentialbenefitjustifiesthepotentialrisktothefoetus.

Itisnotknownwhetherthecomponentsofthismedicinalproductareexcretedinhumanmilk.

Becauseofthepotentialforadversereactionsinnursinginfants,nursing should be

discontinuedpriortoinitiation oftreatment.

Use withribavirin

Significantteratogenicand/orembryocidaleffectshave beendemonstratedin allanimal

speciesexposedto ribavirin.Ribavirintherapyiscontraindicatedinwomenwhoarepregnant.

Extremecaremustbetakentoavoid pregnancyinfemale patientsorinpartnersofmale

patientstakingPegasysin combinationwith ribavirin.Female patientsofchildbearing

potentialmustuseaneffective contraceptive duringtreatmentandfor4months after

treatmenthasbeenconcluded.Male patientsortheirfemale partnersmustuseaneffective

contraceptive duringtreatmentandfor7monthsaftertreatmenthasbeenconcluded.Please

refertotheribavirinprescribinginformation(PI).

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4.7Effectsonabilityto drive anduse machines

Pegasyshasaminorormoderate influenceonthe abilityto drive and usemachines.

Patientswhodevelopdizziness,confusion,somnolence orfatigueshouldbecautionedto

avoid drivingoroperating machinery.

4.8Undesirableeffects

Experience fromclinicaltrials

ChronichepatitisC

Thefrequencyand severityofthemostcommonlyreportedadversereactions with Pegasys

aresimilartothosereportedwith interferonalfa-2a (seeTable 4).Themostfrequently

reportedadversereactionswith Pegasys180microgramsweremostlymild tomoderatein

severityand weremanageable withouttheneedformodificationofdosesordiscontinuation

oftherapy.

ChronichepatitisB

In clinicaltrialsof48weektreatmentand24weeksfollow-up,thesafetyprofileforPegasys

in chronichepatitisBwassimilartothatseenin chronichepatitisC.Withtheexceptionof

pyrexia thefrequencyofthemajorityofthereportedadversereactionswasnotablyless in

CHBpatientstreatedwith Pegasysmonotherapycomparedwith HCVpatientstreatedwith

Pegasysmonotherapy(seeTable 4)Adverseeventswereexperiencedby88%ofPegasys-

treatedpatientsas comparedwith 53%ofpatientsin thelamivudinecomparatorgroup,while

6%ofthePegasys-treatedand 4%ofthelamivudine-treatedpatientsexperiencedserious

adverseeventsduring the studies.Adverseeventsorlaboratoryabnormalities ledto 5%of

patientswithdrawingfromPegasystreatment,while lessthan1%ofpatientswithdrewfrom

lamivudinetreatmentforthesereasons.Thepercentage ofpatientswith cirrhosiswho

withdrewfromtreatmentwas similartothatoftheoverallpopulation ineach treatmentgroup.

ChronichepatitisCin priornon-responderpatients

Overall,thesafetyprofileforPegasysin combinationwith ribavirin inpriornon-responder

patientswas similartothatin naïve patients.Inaclinicaltrialofnon-responderpatientsto

priorpegylatedinterferonalfa-2b/ribavirin,which exposedpatientsto either48or72weeks

oftreatment,thefrequencyofwithdrawalforadverseeventsorlaboratoryabnormalitiesfrom

Pegasystreatmentandribavirin treatmentwas 6%and7%,respectively,in the48week

armsand 12%and13%,respectively,inthe72weekarms.Similarlyforpatientswith

cirrhosisortransitiontocirrhosis,thefrequenciesofwithdrawalfromPegasystreatmentand

ribavirin treatmentwerehigherin the72-weektreatmentarms(13%and 15%)thanin the48-

weekarms(6%and 6%).Patientswhowithdrewfromprevioustherapywith pegylated

interferonalfa-2b/ribavirin because ofhematologicaltoxicitywereexcludedfromenrollingin

thistrial.

In anotherclinicaltrial,non-responderpatientswith advancedfibrosisorcirrhosis(Ishak

scoreof3to6)andbaselineplateletcountsaslowas50,000/mm 3

weretreatedfor48weeks.

Haematologiclaboratoryabnormalities observedduringthefirst20weeksofthetrial

includedanemia(26%ofpatientsexperiencedahemoglobin levelof<10g/dL),neutropenia

(30%experiencedanANC<750/mm 3 ),andthrombocytopenia (13%experienceda platelet

count<50,000/mm 3 )(see section4.4).

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ChronichepatitisCandHIVco-infection

In HIV-HCVco-infectedpatients,theclinicaladverseeventprofilesreportedforPegasys,

alone orincombinationwith ribavirin,weresimilartothose observedin HCVmono-infected

patientsForHIV-HCVpatientsreceivingPegasysand ribavirin combinationtherapyother

undesirable effectshavebeenrepo rtedin≥1%to≤2%ofpatients:

hyperlactacidaemia/lacticacidosis,influenza,pneumonia,affectlability,apathy,tinnitus,

pharyngolaryngealpain,cheilitis,acquiredlipodystrophyand chromaturia.Pegasystreatment

was associatedwith decreases inabsoluteCD4+cellcountswithin thefirst4 weekswithout

a reductionin CD4+cellpercentage.Thedecrease inCD4+cellcountswas reversible upon

dose reductionorcessationoftherapy.TheuseofPegasyshad noobservable negative

impactonthecontrolofHIVviraemia during therapyorfollow-up.Limitedsafetydata are

available inco-infectedpatientswith CD4+cellcounts<200/µl.

Table 4summarisestheundesirable effectsreportedwith Pegasysmonotherapyin CHBor

CHCpatientsandwith Pegasysin combinationwithribavirin inCHCpatients.

Table 4:UndesirableEffectsReportedwithPegasys MonotherapyforHBVorHCVor

in CombinationwithRibavirin forHCVPatientsinClinicalTrials andPostMarketing

Bodysystem Very

Common

≥1/10 Common

≥1/100 to< 1/10 Uncommon

≥1/1000to

< 1/100 Rare

≥1/10,000to<

1/1000 Veryrare

<1/10,000 Frequency

notknown

Infectionsand

infestations

Upper respiratory

infection,

bronchitis, oral

candidiasis, herpes

simplex,fungal,

viralandbacterial

infections Pneumonia,

skininfection Endocarditis,

otitisexterna Sepsis

Neoplasms

benign and

malignant Hepatic

neoplasm

Bloodand

lymphaticsystem

disorders

Thrombocytopenia,

anaemia,

lymphadenopathy Pancytopenia Aplastic

anemia

Pure red cell

aplasia

Immunesystem

disorders

Sarcoidosis,

thyroiditis Anaphylaxis,

systemiclupus

erythematosus,

rheumatoid

arthritis Idiopathic

or

thrombotic

thrombocy

topenic

purpura Liver and

renalgraft

rejection,

Vogt-

Koyanagi-

Harada

disease

Endocrine

disorders

Hypothyroidism,

hyperthyroidism

Diabetes Diabetic

ketoacidosis

Metabolismand

Nutrition

Disorders Anorexia Dehydration

Psychiatric

disorders

Depression*,

anxiety,

insomnia* Emotional

disorders, mood

alteration

Aggression,

nervousness, libido

decreased Suicidal

ideation,

hallucinations Suicide,

psychotic

disorder Mania,

bipolar

disorders,

homicidal

ideation

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Bodysystem Very

Common

≥1/10 Common

≥1/100 to< 1/10 Uncommon

≥1/1000to

< 1/100 Rare

≥1/10,000to<

1/1000 Veryrare

<1/10,000 Frequency

notknown

Nervoussystem

disorders

Headache,

dizziness*,

concentration

impaired Memory

impairment,

syncope,

weakness,

migraine,

hypoaesthesia,

hyperaesthesia,

paraesthesia,

tremor, taste

disturbance,

nightmares,

Peripheral

neuropathy Coma,

convulsions,

facialpalsy Cerebral

ischaemia

Eye disorders

Vision blurred, eye

pain, eye

inflammation,

xerophthalmia

Retinal

hemorrhage Optic

neuropathy,papi

lledema, retinal

vascular

disorder,

retinopathy,

cornealulcer VisionlossSerous

retinal

detachment

Ear and labyrinth

disorders Vertigo, earache Hearing loss

Cardiacdisorders

Tachycardia,

palpitations,

oedema peripheral Myocardial

infarction,

congestive

heart failure,

angina,

supraventricular

tachycardia,

arrhythmia,

atrialfibrillation,

pericarditis,

Vascular

disorders Flushing

HypertensionCerebral

haemorrhage,

vasculitis Peripheral

ischaemia

Respiratory,

thoracicand

mediastinal

disorders

Dyspnoea,

cough Dyspnoea

exertional,

epistaxis,

nasopharyngitis,

sinuscongestion,

nasalcongestion,

rhinitis,sore throat Wheezing Interstitial

pneumonitis

including fatal

outcome,

pulmonary

embolism

Gastrointestinal

disorders

Diarrhoea*,

nausea*,

abdominal

pain* Vomiting,

dyspepsia,

dysphagia, mouth

ulceration, gingival

bleeding, glossitis,

stomatitis,

flatulence,

drymouth Gastrointestin

albleeding Pepticulcer,

pancreatitis Ischaemic

colitis

Hepato-biliary

disorders

Hepatic

dysfunction Hepaticfailure,

cholangitis,

fattyliver

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Bodysystem Very

Common

≥1/10 Common

≥1/100 to< 1/10 Uncommon

≥1/1000to

< 1/100 Rare

≥1/10,000to<

1/1000 Veryrare

<1/10,000 Frequency

notknown

Skin and

subcutaneous

tissue disorders

Alopecia,

dermatitis,

pruritis, dry

skin Rash, sweating

increased,

psoriasis, urticaria,

eczema, skin

disorder,

photosensitivity

reaction, night

sweats Toxic

epidermal

necrolysis,

Stevens-

Johnson

syndrome,

angioede

ma,

erythema

multiforme

Musculoskeletal

connective tissue

and bone

disorders

Myalgia,

arthralgia Backpain, arthritis,

muscle weakness,

bone pain, neck

pain,

musculoskeletal

pain, muscle

cramps Myositis Rhabdomyol

ysis

Renalandurinary

disorders Renal

insufficiency

Reproductive

systemandbreast

disorders Impotence

Generaldisorders

andadministration

site conditions

Pyrexia,

rigors*, pain*,

asthenia,

fatigue,

injection site

reaction*,

irritability* Chest pain,

influenza like

illness, malaise,

lethargy, hot

flushes, thirst

Investigations Weight decreased

Injuryand

poisoning

Substance

overdose

*Theseadversereactionswerecommon( ≥1/100to<1/10)inCHB patientstreatedwithPegasysmonotherapy

Laboratoryvalues

Pegasystreatmentwasassociatedwith abnormallaboratoryvalues:ALT increase,bilirubin

increase,electrolyte disturbance(hypokalaemia,hypocalcaemia,hypophosphataemia),

hyperglycaemia,hypoglycaemia andelevatedtriglycerides (seesection 4.4.).With both

Pegasysmonotherapy,andalso thecombinedtreatmentwith ribavirin,upto 2%ofpatients

experiencedincreasedALTlevelsthatledtodosemodificationordiscontinuationofthe

treatment.

Treatmentwith Pegasyswas associatedwith decreases inhaematologicalvalues

(leucopenia,neutropenia,lymphopenia,thrombocytopenia and haemoglobin),which

generallyimprovedwithdose modification,andreturnedtopre-treatmentlevelswithin 4-8

weeksupon cessationoftherapy(seesections4.2and 4.4).

Moderate (ANC:0.749-0.5x10 9 /l)and severe(ANC:<0.5x10 9 /l)neutropenia was

observedrespectivelyin 24%(216/887)and5%(41/887)ofpatientsreceivingPegasys

180microgramsandribavirin 1000/1200milligramsfor48weeks.

Anti-interferonantibodies

1-5%ofpatientstreatedwith Pegasysdevelopedneutralisinganti-interferon antibodies.As

with otherinterferons,ahigherincidenceofneutralisingantibodies was seenin chronic

hepatitisB.Howeverin neitherdiseasewas thiscorrelatedwith lackoftherapeuticresponse.

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Thyroid function

Pegasystreatmentwasassociatedwith clinicallysignificantabnormalitiesin thyroid

laboratoryvaluesrequiringclinicalintervention(seesection4.4).Thefrequencies observed

(4.9%)in patientsreceivingPegasys/ribavirin (NV15801)are similartothose observedwith

otherinterferons.

LaboratoryvaluesforHIV-HCVco-infectedpatients

Althoughhaematologicaltoxicities ofneutropenia,thrombocytopenia andanaemiaoccurred

morefrequentlyin HIV-HCVpatients,themajoritycould bemanagedbydose modification

and theuseofgrowthfactorsand infrequentlyrequiredpremature discontinuation of

treatment.Decreasein ANClevelsbelow500 cells/mm 3 was observedin 13%and11%of

patientsreceivingPegasysmonotherapyand combinationtherapy,respectively.Decreasein

plateletsbelow50,000/mm 3 was observedin 10%and 8%ofpatientsreceivingPegasys

monotherapyand combinationtherapy,respectively.Anaemia(haemoglobin <10g/dL)was

reportedin 7%and14%ofpatientstreatedwith Pegasysmonotherapyorin combination

therapy,respectively.

4.9Overdose

Overdoses involvingbetween two injections onconsecutive days(insteadofweeklyinterval)

uptodailyinjectionsfor1week(ie,1260micrograms/week)have beenreported.None of

these patientsexperiencedunusual,seriousortreatment-limitingevents.Weeklydosesofup

to 540and 630microgramshave beenadministeredinrenalcellcarcinoma and chronic

myelogenous leukaemiaclinicaltrials,respectively.Doselimitingtoxicitieswerefatigue,

elevatedliverenzymes,neutropenia andthrombocytopenia,consistentwith interferon

therapy.

5. PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeuticgroup:ImmunostimulatingAgent/Cytokine,ATCcode:L03AB11

TheconjugationofPEGreagent(bis-monomethoxypolyethylene glycol)to interferonalfa-2a

formsapegylatedinterferonalfa-2a(Pegasys).Pegasyspossessesthein vitroantiviraland

antiproliferative activitiesthatare characteristicofinterferonalfa-2a.

Interferonalfa-2aisconjugatedwith bis-[monomethoxypolyethylene glycol]ata degreeof

substitutionofonemoleofpolymer/mole ofprotein.Theaveragemolecularmassis

approximately60,000 ofwhich theproteinmoietyconstitutes approximately20,000.

HCVRNAlevelsdeclinein abiphasicmannerin respondingpatientswith hepatitisCwho

have receivedtreatmentwith 180microgramsPegasys.Thefirstphaseofdeclineoccurs24

to 36hoursafterthefirstdose ofPegasysand isfollowedbythesecondphase ofdecline

whichcontinuesoverthenext4to16weeksinpatientswhoachieveasustainedresponse.

Ribavirinhadnosignificanteffectontheinitialviralkineticsoverthefirst4to6weeksin

patientstreatedwiththecombinationofribavirinandpegylatedinterferonalfa-2aorinterferon

alfa.

ChronichepatitisB:

Clinicaltrialresults

Allclinicaltrialsrecruitedpatientswith chronichepatitisBwhohad active viralreplication

measuredbyHBVDNA,elevatedlevelsofALT anda liverbiopsyconsistentwith chronic

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hepatitis.StudyWV16240 recruitedpatientswhowerepositive forHBeAg,while study

WV16241recruitedpatientswhowerenegativeforHBeAgandpositiveforanti-HBe.In both

studiesthetreatmentduration was 48weeks,with 24weeksoftreatment-freefollow-up.Both

studies comparedPegasysplus placebovsPegasysplus lamivudinevslamivudinealone.

No HBV-HIVco-infectedpatientswereincludedintheseclinicaltrials.

Response rates attheendoffollow-upforthetwo studiesarepresentedinTable 5.Instudy

WV16240,theprimaryefficacyendpointswereHBeAgseroconversion and HBV-DNAbelow

copies/ml.In studyWV16241,theprimaryefficacyendpointswereALT normalisation

and HBV-DNAbelow2 x10 4 copies/ml.HBV-DNAwas measuredbytheCOBAS

AMPLICOR 

HBVMONITORAssay(limitofdetection200copies/ml).

Atotalof283/1351(21%)ofpatientshad advancedfibrosisorcirrhosis,85/1351(6%)had

cirrhosis.Therewas nodifferenceinresponserate between these patientsandthosewithout

advancedfibrosisorcirrhosis.

Table5:Serological,Virologicaland BiochemicalResponsesinChronicHepatitis B

HBeAgpositive

StudyWV16240 HBeAgnegative /anti-HBe positive

StudyWV16241

Response

Parameter Pegasys

180mcg

&

Placebo

(N=271) Pegasys

180mcg

&

Lamivudine

100mg

(N=271) Lamivudine

100mg

(N=272) Pegasys

180mcg

&

Placebo

(N=177) Pegasys

180mcg

&

Lamivudine

100mg

(N=179) Lamivudine

100mg

(N=181)

HBeAg

Sero-

conversion 32% #

27% 19% N/A

N/A N/A

HBVDNA

response * 32% # 34% 22% 43% # 44% 29%

ALT

Normal-

isation 41% #

39% 28% 59% #

60% 44%

HBsAg

Sero-

conversion 3% #

3% 0% 3%

2% 0%

*For HBeAg-positivepatients:HBV DNA<10 5 copies/ml

For HBeAg-negative/anti-HBe-positivepatients:HBV DNA<2x10 4

copies/ml

#p-value(vs.lamivudine)<0.01(stratifiedCochran-Mantel-Haenszeltest)

Histologicalresponse was similaracrossthethreetreatmentgroupsin each study;however,

patientsshowinga sustained response24weeksaftertheendoftreatmentweresignificantly

morelikelytoalso showhistologicalimprovement.

AllpatientswhocompletedthephaseIIIstudieswereeligible forentryintoa long-term

follow-upstudy(WV16866).Among patientsfromstudyWV16240,whoreceivedPegasys

monotherapyand entered thelong-termfollow-upstudy,therate ofsustained HBeAg

seroconversion 12months aftertheend oftherapywas 48%(73/153).Inpatientsreceiving

Pegasysmonotherapyin studyWV16241,therate ofHBVDNAresponseand ALT

normalisation 12monthsafterend oftreatmentwere42%(41/97)and59%(58/99),

respectively.

ChronichepatitisC

Predictabilityofresponse

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Please referto section 4.2,inTable 2.

Dose-responseinmonotherapy

In adirectcomparisonwith 90micrograms,the180micrograms-dosewas associatedwith

superiorsustained virologicalresponseinpatientswith cirrhosis,butin astudyin non-

cirrhoticpatientsverysimilarresultswereobtained with doses of135microgramsand

180micrograms.

Confirmatoryclinicaltrialsin treatment-naïve patients

Allclinicaltrialsrecruitedinterferon-naïve patientswith chronichepatitisCconfirmedby

detectable levelsofserumHCVRNA,elevatedlevelsofALT(with theexceptionofstudy

NR16071)and aliverbiopsyconsistentwith chronichepatitis.StudyNV15495specifically

recruitedpatientswith ahistologicaldiagnosisofcirrhosis(about80%)ortransitionto

cirrhosis(about20%).OnlyHIV-HCVco-infectedpatientswereincludedinthestudy

NR15961 (seeTable14).Thesepatientshadstable HIVdisease andmeanCD4T-cellcount

was about500 cells/µL.

ForHCVmonoinfectedpatientsandHIV-HCVco-infectedpatients,fortreatmentregimens,

duration oftherapyandstudyoutcome seeTables6,7,8 andTable 14,respectively.

Virologicalresponsewas defined asundetectableHCVRNAasmeasuredbytheCOBAS

AMPLICOR 

HCVTest,version 2.0(limitofdetection100copies/mlequivalentto 50

InternationalUnits/ml)and sustainedresponseasone negative sampleapproximately6

monthsafterendoftherapy.

Table 6:VirologicalResponseinHCVPatients

Pegasys Monotherapy PegasysCombinationTherapy

non-cirrhoticand

cirrhotic cirrhotic non-cirrhoticandcirrhotic

StudyNV15496+

NV15497 +NV15801 StudyNV15495 Study

NV15942 StudyNV15801

Pegasys

180mcg

(N=701)

Interferon

alfa-2a

6 MIU/3

MIU

&

3 MIU

(N=478)

Pegasys

180mcg

(N=87)

Interferon

alfa-2a

3 MIU

(N=88)

Pegasys

180mcg

&

Ribavirin

1000/120

0mg

(N=436)

Pegasys

180mcg

&

Ribavirin

1000/1200

mg

(N=453)

Interferon

alfa-2b

3 MIU

&

Ribavirin

1000/1200

mg

(N=444)

48weeks

Response

atEndof

Treatment 55-69% 22-28% 44% 14% 68% 69% 52%

Overall

Sustained

Response 28-39% 11-19% 30%* 8%* 63% 54%** 45%**

* 95%CIfor difference:11%to33% p-value(stratifiedCochran-Mantel-Haenszeltest) =0.001

**95%CIfor difference:3%to16% p-value(stratifiedCochran-Mantel-Haenszeltest)=0.003

ThevirologicalresponsesofHCVmonoinfectedpatientstreatedwith Pegasysmonotherapy

and with Pegasysandribavirin combinationtherapyin relation togenotypeand pre-treatment

viralload and inrelationtogenotype,pre-treatmentviralload andrapidvirologicalresponse

atweek4 are summarisedinTable 7andTable8,respectively.Theresultsofstudy

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NV15942 providetherationaleforrecommendingtreatmentregimensbased ongenotype,

baselineviralload and virologicalresponseatweek 4(seeTables1,7 and 8).

Thedifferencebetween treatmentregimenswas ingeneralnotinfluencedby

presence/absence ofcirrhosis;thereforetreatmentrecommendationsforgenotype1,2or3

areindependentofthisbaselinecharacteristic.

Table 7:SustainedVirologicalResponseBasedonGenotypeand Pre-treatmentViral

LoadafterPegasys CombinationTherapywith RibavirininHCVPatients

StudyNV15942 StudyNV15801

Pegasys

180mcg

&

Ribavirin

800mg

24weeks

Pegasys

180mcg

&

Ribavirin

1000/1200mg

24weeks Pegasys

180mcg

&

Ribavirin

800mg

48weeks

Pegasys

180mcg

&

Ribavirin

1000/1200mg

48weeks

Pegasys

180mcg

&

Ribavirin

1000/1200mg

48weeks

Interferon

alfa-2b

3MIU

&

Ribavirin

1000/1200mg

48weeks

Genotype1

Lowviralload

Highviralload

29%

(29/101)

41%(21/51)

16%(8/50) 42%(49/118)*

52%(37/71)

26%(12/47) 41%

(102/250)*

55%(33/60)

36%(69/190) 52%(142/271)*

65%(55/85)

47%(87/186) 45%(134/298)

53%(61/115)

40%(73/182) 36%(103/285)

44%(41/94)

33%(62/189)

Genotype2/3

Lowviralload

Highviralload 84%(81/96)

85%(29/34)

84%(52/62) 81%(117/144)

83%(39/47)

80%(78/97) 79%(78/99)

88%(29/33)

74%(49/66) 80%(123/153)

77%(37/48)

82%(86/105) 71%(100/140)

76%(28/37)

70%(72/103) 61%(88/145)

65%(34/52)

58%(54/93)

Genotype4

(0/5) (8/12) (5/8) (9/11) (10/13) (5/11)

Lowviralload=≤ 800,000IU/mL;Highviralload=>800,000IU/mL

* Pegasys180mcgribavirin1000/1200mg,48wvs.Pegasys180mcgribavirin800mg,48w:OddsRatio(95%CI)=

1.52(1.07to2.17) P-value(stratifiedCochran-Mantel-Haenszeltest)=0.020

* Pegasys180mcgribavirin1000/1200mg,48wvs.Pegasys180mcgribavirin1000/1200mg,24w:OddsRatio(95%

CI) =2.12(1.30to3.46) P-value(stratifiedCochran-Mantel-Haenszeltest)=0.002.

Thepossibilityto considershorteningtreatmentdurationto 24weeksingenotype1 and 4

patientswas examinedbased onasustained rapid virologicalresponseobservedin patients

with rapid virologicalresponseatweek4in studies NV15942 andML17131 (seeTable 8).

Table 8:SustainedVirologicalResponseBasedonRapidViralResponse atweek4for

Genotype1 and4 afterPegasys CombinationTherapywith Ribavirinin HCVPatients

StudyNV15942 StudyML17131

Pegasys

180mcg

&

Ribavirin

1000/1200mg

24weeks Pegasys

180mcg

&

Ribavirin

1000/1200mg

48weeks Pegasys

180mcg

&

Ribavirin

1000/1200mg

24weeks

Genotype1RVR

Lowviralload

Highviralload 90%(28/31)

93%(25/27)

75%(3/4) 92%(47/51)

96%(26/27)

88%(21/24) 77%(59/77)

80%(52/65)

58%(7/12)

Genotype1non

RVR

Lowviralload

Highviralload 24%(21/87)

27%(12/44)

21%(9/43) 43%(95/220)

50%(31/62)

41%(64/158) -

-

-

Genotype4RVR (5/6)

(5/5)

92%(22/24)

Genotype4non

RVR

(3/6)

(4/6) -

Low viralload=≤ 800,000IU/mL;Highviralload=>800,000IU/mL

RVR=rapidviralresponse(HCV RNA undetectable)atweek4andHCV RNA undetectableatweek24

Althoughlimited,dataindicatedthatshorteningtreatmentto 24weeksmightbeassociated

with ahigherriskofrelapse (seeTable 9).

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Table 9:Relapse ofVirologicalResponseattheEndofTreatmentforRapidVirological

Response Population

StudyNV15942 StudyNV15801

Pegasys

180mcg

&

Ribavirin

1000/1200mg

24weeks Pegasys

180mcg

&

Ribavirin

1000/1200mg

48weeks Pegasys

180mcg

&

Ribavirin

1000/1200mg

48weeks

Genotype1RVR

Lowviralload

Highviralload 6.7%(2/30)

3.8%(1/26)

25%(1/4) 4.3%(2/47)

0%(0/25)

9.1%(2/22) 0%(0/24)

0%(0/17)

0%(0/7)

Genotype4RVR (0/5) (0/5)

0%(0/4)

Thepossibilityofshorteningtreatmentdurationto16weeksingenotype2or3patientswas

examinedbasedonasustained virologicalresponseobservedin patientswith rapid

virologicalresponse byweek4 instudyNV17317 (seeTable 10).

In studyNV17317 inpatientsinfectedwith viralgenotype2 or3,allpatientsreceived

Pegasys180

gscqwand aribavirin dose of800mg and wererandomizedtotreatmentfor

either16or24weeks.Overalltreatmentfor16weeksresultedin lowersustained viral

response(65%)thantreatmentfor24weeks(76%)(p<0.0001).

Thesustainedviralresponse achievedwith 16weeksoftreatmentandwith 24weeksof

treatmentwas also examined ina retrospective subgroup analysisofpatientswhowereHCV

RNAnegative byweek4and hada LVLatbaseline(seeTable 10).

Table 10:SustainedVirologicalResponseOveralland BasedonRapid ViralResponse

byWeek4forGenotype 2or3afterPegasys CombinationTherapywith Ribavirinin

HCVPatients

StudyNV17317

Pegasys

180mcg

&

Ribavirin

800mg

16weeks Pegasys

180mcg

&

Ribavirin

800mg

24weeks Treatment

difference

CI p value

Genotype2or3 65%

(443/679) 76%

(478/630) -10.6% [-15.5%;-

0.06%] P<0.0001

Genotype2or3

RVR

Lowviralload

Highviralload

82%

(378/461)

89%

(147/166)

78%

(231/295) 90%

(370/410)

94%

(141/150)

88%

(229/260) -8.2% [-12.8% ;-

3.7%]

-5.4% [-12% ;

0.9%]

-9.7% [-15.9% ;-

3.6%] P=0.0006

P=0.11

P=0.002

Low viralload=≤ 800,000IU/mL;Highviralload=>800,000IU/mL

RVR=rapidviralresponse(HCV RNA undetectable)atweek4

Itispresentlynotclearwhethera higherdoseofribavirin (e.g.1000/1200mg/daybasedon

bodyweight)resultsin higherSVRratesthandoesthe800mg/day,when treatmentis

shortenedto16weeks.

Thedataindicatedthatshorteningtreatmentto16 weeksisassociatedwith ahigherriskof

relapse (seeTable 11).

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Table 11:RelapseofVirologicalResponseaftertheEndofTreatmentinGenotype2 or

3Patientswitha RapidViralResponse

StudyNV17317

Pegasys

180mcg

&

Ribavirin

800mg

16weeks Pegasys

180mcg

&

Ribavirin

800mg

24weeks Treatment

difference 95%CI p value

Genotype2or3

RVR

Lowviralload

Highviralload

15%

(67/439)

6%

(10/155)

20%

(57/284) 6% (23/386)

1% (2/141)

9% (21/245) 9.3% [5.2%;

13.6%]

5% [0.6% ;10.3%]

11.5%[5.6% ;

17.4%] P<0.0001

P=0.04

P=0.0002

Low viralload=≤ 800,000IU/mL;Highviralload=>800,000IU/mL

RVR=rapidviralresponse(HCV RNA undetectable)atweek4

SuperiorefficacyofPegasyscomparedtointerferonalfa-2awas demonstratedalso interms

ofhistologicalresponse,includingpatientswith cirrhosisand/orHIV-HCVco-infection.

ChronichepatitisCpriortreatmentnon-responderpatients

In studyMV17150,patientswhowerenon-respondersto previoustherapywith pegylated

interferonalfa-2bplusribavirinwererandomizedtofourdifferenttreatments:

Pegasys360mcg/weekfor12weeks,followedby180mcg/weekforafurther60weeks

Pegasys360mcg/weekfor12weeks,followedby180mcg/weekforafurther36weeks

Pegasys180mcg/weekfor72weeks

Pegasys180mcg/weekfor48weeks

Allpatientsreceivedribavirin (1000or1200mg/day)in combinationwith Pegasys.All

treatmentarmshad24weektreatment-freefollow-up.

Multiple regressionandpooledgroup analyses evaluatingtheinfluenceoftreatmentduration

and useofinductiondosingclearlyidentifiedtreatmentdurationfor72weeksastheprimary

driverforachievingasustained virologicalresponse.Differencesin sustained virological

response(SVR)basedon treatmentduration,demographicsand bestresponsestoprevious

treatmentare displayedinTable 12.

Table 12:Week12VirologicalResponse (VR)andSustainedVirologicalResponse

(SVR)in PatientswithVirologicalResponse atWeek12afterTreatmentwith Pegasys

and RibavirinCombinationTherapyin NonresponderstoPeginterferonalfa-2bplus

Ribavirin.

Pegasys360/180 or

180

g

&

Ribavirin

1000/1200mg

72or 48Weeks

(N =942)

Pts with

VR at Wk12 a

Pegasys360/180

or 180

g

&

Ribavirin

1000/1200mg

72Weeks

(N =473)

SVRin Ptswith

VR at Wk12 b

Pegasys360/180 or

180

g

&

Ribavirin

1000/1200mg

48Weeks

(N =469)

SVRin PtswithVR

at Wk 12 b

(N =57)

Overall

Low viralload

Highviralload 18% (157/876)

35% (56/159)

14% (97/686) 57%(57/100)

63%(22/35)

54%(34/63) 35% (20/57)

38% (8/21)

32% (11/34)

Genotype1/4

Low viralload

Highviralload 17% (140/846)

35% (54/154)

13% (84/663) 55% (52/94)

63% (22/35)

52% (30/58) 35% (16/46)

37% (7/19)

35% (9/26)

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Pegasys360/180 or

180

g

&

Ribavirin

1000/1200mg

72or 48Weeks

(N =942)

Pts with

VR at Wk12 a

Pegasys360/180

or 180

g

&

Ribavirin

1000/1200mg

72Weeks

(N =473)

SVRin Ptswith

VR at Wk12 b

Pegasys360/180 or

180

g

&

Ribavirin

1000/1200mg

48Weeks

(N =469)

SVRin PtswithVR

at Wk 12 b

(N =57)

Genotype2/3

Low viralload

Highviralload 58% (15/26)

(2/5)

(11/19) (4/5)

—

(3/4) (3/10)

(1/2)

(1/7)

CirrhosisStatus

Cirrhosis

Noncirrhosis

8% (19/239)

22% (137/633)

(6/13)

59%(51/87)

(3/6)

34% (17/50)

Best Responseduring

Previous Treatment

2log

declineinHCVRNA

<2log

declineinHCVRNA

Missingbestpreviousresponse

28% (34/121)

12% (39/323)

19% (84/432)

68%(15/22)

64%(16/25)

49%(26/53)

(6/12)

(5/14)

29% (9/31)

Highviralload=>800,000IU/mL,low viralload=

800,000IU/mL.

aPatientswhoachievedviralsuppression(undetectableHCV RNA, <50IU/mL) atweek12wereconsideredto

haveavirologicalresponseatweek12.PatientsmissingHCV RNA resultsatweek12havebeenexcludedfrom

theanalysis.

bPatientswhoachievedviralsuppressionatweek12butweremissingHCV RNA resultsattheendoffollow-up

wereconsideredtobenonresponders

IntheHALT-Cstudy,patientswith chronichepatitisCand advancedfibrosisorcirrhosiswho

werenon-responderstoprevioustreatmentwith interferonalfa orpegylated interferonalfa

monotherapyorincombinationtherapywith ribavirin weretreatedwith Pegasys

180mcg/weekandribavirin 1000/1200mg daily.Patientswhoachievedundetectable levels

ofHCVRNAafter20weeksoftreatmentremained onPegasysplusribavirin combination

therapyforatotalof48weeksand werethenfollowedfor24weeksaftertheendof

treatment.Theprobabilityforsustained virologicalresponsevaried dependinguponthe

previoustreatmentregimen;seeTable 13.

Table 13:SustainedVirologicalResponseinHALT-CbyPrevious TreatmentRegimen

in Non-responderPopulation

Previous Treatment Pegasys180mcg

&

Ribavirin1000/1200mg

48weeks

Interferon 27% (70/255)

Pegylatedinterferon 34% (13/38)

Interferonplusribavirin 13% (90/692)

Pegylatedinterferonplusribavirin 11% (7/61)

HIV-HCVco-infectedpatients

ThevirologicalresponsesofpatientstreatedwithPegasysmonotherapyand with Pegasys

and ribavirin combinationtherapyin relationtogenotypeand pre-treatmentviralloadforHIV-

HCVco-infectedpatientsaresummarisedbelowinTable14.

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Table14:SustainedVirologicalResponsebasedonGenotypeand Pre-treatmentViral

LoadafterPegasys CombinationTherapywith RibavirininHIV-HCVCo-infected

Patients

StudyNR15961

Interferonalfa-2a

3 MIU

&

Ribavirin 800mg

48weeks Pegasys

180mcg

&

Placebo

48weeks Pegasys

180mcg

&

Ribavirin 800mg

48weeks

Allpatients 12%(33/285)* 20%(58/286)* 40%(116/289)*

Genotype1 7%(12/171) 14%(24/175) 29%(51/176)

Lowviralload 19%(8/42) 38%(17/45) 61%(28/46)

Highviralload 3%(4/129) 5%(7/130) 18%(23/130)

Genotype2-3 20%(18/89) 36%(32/90) 62%(59/95)

Lowviralload 27%(8/30) 38%(9/24) 61%(17/28)

Highviralload 17%(10/59) 35%(23/66) 63%(42/67)

Lowviralload=≤ 800,000IU/mL;Highviralload=>800,000IU/mL

* Pegasys180mcgribavirin800mgvs.Interferonalfa-2a3MIU ribavirin800mg:OddsRatio(95%CI)=5.40

(3.42to8.54),….P-value(stratifiedCochran-Mantel-Haenszeltest)=<0.0001

* Pegasys180mcgribavirin800mgvs.Pegasys180 g:OddsRatio(95%CI)=2.89(1.93to4.32),….P-value

(stratifiedCochran-Mantel-Haenszeltest)=<0.0001

* Interferonalfa-2a3MIU ribavirin800mgvs.Pegasys180 mcg:OddsRatio(95%CI)=0.53(0.33to0.85),…P-

value(stratifiedCochran-Mantel-Haenszeltest)=<0.0084

Asubsequentstudy(NV18209)in patientsco-infectedwith HCVgenotype 1andHIV

comparedtreatmentusing Pegasys180mcg/weekandeitherribavirin 800mg or1000mg

(<75kg)/1200mg(

75kg)dailyfor48weeks.The studywas notpoweredforefficacy

considerations.Thesafetyprofiles inbothribaviringroupswereconsistentwith theknown

safetyprofile ofPegasysplus ribavirin combination treatmentand notindicative ofany

relevantdifferences,with theexceptionofaslightincrease inanaemia inthe highdose

ribavirin arm.

HCVpatientswithnormalALT

In studyNR16071,HCVpatientswith normalALT valueswererandomisedtoreceive

Pegasys180micrograms/weekandribavirin800milligrams/dayforeither24or48weeks

followedbya 24weektreatmentfreefollow-upperiod ornotreatmentfor72weeks.The

SVRsreportedinthetreatmentarmsofthisstudyweresimilartothecorresponding

treatmentarmsfromstudyNV15942.

Childrenand adolescents

IntheinvestigatorsponsoredCHIPSstudy(ChronicHepatitis CInternationalPaediatric

Study),65childrenandadolescents(6-18years)with chronicHCVinfection weretreated

with PEG-IFNalfa2a100mcg/m 2

sconce weeklyand ribavirin 15mg/kg/dayfor24weeks

(genotypes2and 3)or48 weeks(allothergenotypes).Preliminaryand limitedsafetydata

demonstratednoobviousdeparturefromtheknown safetyprofile ofthecombinationin

adultswith chronicHCVinfection,but,importantly,thepotentialimpactongrowth hasnot

beenreported.Efficacyresultsweresimilartothose reportedin adults.

5.2Pharmacokineticproperties

Followinga single subcutaneous injection ofPegasys180microgramsinhealthysubjects,

serumconcentrationsofpeginterferonalfa-2aaremeasurable within 3to6hours.Within 24

hours,about80%ofthepeak serumconcentrationisreached.TheabsorptionofPegasysis

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sustained with peakserumconcentrationsreached 72to 96hoursafterdosing.Theabsolute

bioavailabilityofPegasysis84%andissimilartothatseenwith interferonalfa-2a.

Peginterferonalfa-2aisfoundpredominantlyin the bloodstreamand extracellularfluid as

seen bythevolumeofdistributionatsteady-state(V

)of6to 14litresin humansafter

intravenousadministration.Frommassbalance,tissuedistributionandwhole body

autoradioluminographystudies performedin rats,peginterferonalfa-2aisdistributedtothe

liver,kidneyand bonemarrowin additiontobeing highlyconcentratedintheblood.

ThemetabolismofPegasysisnotfullycharacterised;howeverstudies inratsindicatethat

thekidneyisamajororganforexcretionofradiolabelledmaterial.Inhumans,thesystemic

clearance ofpeginterferon alfa-2aisabout100-fold lowerthanthatofthenative interferon

alfa-2a.Afterintravenousadministration,theterminalhalf-life ofpeginterferonalfa-2ain

healthysubjectsisapproximately60to 80hourscomparedtovaluesof3-4hoursfor

standardinterferon.Theterminalhalf-lifeaftersubcutaneousadministration inpatientsis

longerwith ameanvalueof160 hours(84to353hours).Theterminalhalf-lifemaynotonly

reflecttheeliminationphaseofthecompound,butmayalso reflectthesustained absorption

ofPegasys.

Dose-proportionalincreases inexposureofPegasysareseenin healthysubjectsandin

patientswith chronichepatitis BorCafteronce-weeklydosing.

In chronichepatitisBorCpatients,peginterferonalfa-2aserumconcentrationsaccumulate2

to 3fold after6to 8weeksofonceweeklydosingcomparedtosingledose values.Thereis

nofurtheraccumulationafter8weeksofonce weeklydosing.Thepeaktotroughratio after

48weeksoftreatmentisabout1.5to 2.Peginterferonalfa-2aserumconcentrationsare

sustainedthroughoutonefullweek(168hours).

Patientswithrenalimpairment

Renalimpairmentisassociatedwith slightlydecreasedCL/Fand prolonged half-life.In

patients(n=3)with CL

crea between 20and40ml/min,theaverageCL/Fisreducedby25%

comparedwith patientswith normalrenalfunction.In patientswith end stagerenaldisease

undergoinghaemodialysis,thereisa25%to45%reduction intheclearance,anddosesof

135microgramsresultin similarexposureas 180microgramsdosesin patientswith normal

renalfunction(seesection 4.2).

Please referalsototheribavirinPrescribingInformation(PI)when Pegasysisto beusedin

combinationwith ribavirin.

Gender

ThepharmacokineticsofPegasysaftersinglesubcutaneous injectionswerecomparable

between male andfemale healthysubjects.

Elderly

In subjectsolderthan 62years,theabsorptionofPegasysafterasinglesubcutaneous

injection of180microgramswas delayedbutstillsustained comparedto younghealthy

subjects(t

of115 hoursvs.82hours,olderthan 62yearsvs.younger,respectively).The

AUCwas slightlyincreased(1663vs.1295ng·h/ml)butpeakconcentrations(9.1 vs.

10.3ng/ml)weresimilarin subjectsolderthan62years.Basedondrugexposure,

pharmacodynamicresponseandtolerability,alowerdoseofPegasysisnotneededinthe

geriatricpatient(seesection4.2).

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Hepatic impairment

ThepharmacokineticsofPegasysweresimilarbetween healthysubjectsandpatientswith

hepatitisBorC.Comparable exposureand pharmacokineticprofileswereseen incirrhotic

(Child-PughGrade A)and non-cirrhoticpatients.

Site ofadministration

Subcutaneous administration ofPegasysshouldbelimitedtotheabdomen andthigh,asthe

extentofabsorption basedonAUCwas about20%to 30%higheruponinjection inthe

abdomenandthigh.Exposureto Pegasyswas decreasedinstudiesfollowingadministration

ofPegasysinthearmcomparedtoadministrationin theabdomenandthigh.

5.3Preclinicalsafetydata

TheNon-clinicaltoxicitystudies conductedwith Pegasyswerelimiteddueto species

specificityofinterferons.Acuteandchronictoxicitystudies have beencarriedoutin

cynomolgusmonkeys,andthefindingsobservedin peginterferondosedanimalsweresimilar

in naturetothose producedbyinterferonalfa-2a.

Reproductive toxicitystudies have notbeenperformedwith Pegasys.Aswith otheralpha

interferons,prolongationofthemenstrualcycle was observedfollowingadministrationof

peginterferonalfa-2atofemale monkeys.Treatmentwith interferonalfa-2a resultedin a

statisticallysignificantincrease inabortifacientactivityin rhesusmonkeys.Althoughno

teratogeniceffectswereseen intheoffspringdeliveredatterm,adverseeffectsin humans

cannotbeexcluded.

Pegasys plusribavirin

When usedin combinationwith ribavirin,Pegasysdid notcauseanyeffectsinmonkeysnot

previouslyseen with eitheractive substancealone.Themajortreatment-relatedchangewas

reversible mild tomoderateanaemia,theseverityofwhich was greaterthanthatproduced

byeitheractive substance alone.

6. PHARMACEUTICAL PARTICULARS

6.1Listofexcipients

sodiumchloride

polysorbate 80

benzylalcohol(10mg/1ml)

sodiumacetate

aceticacid,glacial

waterforinjections

6.2Incompatibilities

Intheabsence ofcompatibilitystudies,thismedicinalproductmustnotbemixedwith other

medicinalproducts.

6.3Shelflife

Pre-filledsyringe:3years

Pre-filledpen:2 years

6.4Specialprecautionsforstorage

Storeinarefrigerator(2°C-8°C).Do notfreeze.

PEGASYS ®

MoHApprovedPrescribingInformation

Pre-Filled Syringe,Pre-Filled Pen135&180mcg June2012

Keep thepre-filledsyringe and pre-filledpenin the outercartonin ordertoprotectfrom

light.

6.5Natureandcontents ofcontainer

Pre-filledsyringe:

0.5mlofsolutionforinjectionin pre-filledsyringe(siliconisedTypeIglass)with aplunger

stopperandtip cap(butylrubberlaminatedontheproductfacingsidewith fluororesin)with a

needle.Available inpacksof1or4.Notallpacksizes maybemarketed.

Pre-filledpen:

0.5mlofsolutionforinjectionin pre-filledsyringe(siliconisedTypeIglass)with afixed

needle (stainlesssteel),plungerstopper(butylrubberlaminatedwithfluororesin)anda

needleshield (polyisoprene)in prefilledpen.Available inpacksof1or4.Notallpacksizes

maybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Thesolutionforinjectionisforsingle useonly.Itshould beinspectedvisuallyforparticulate

matterand discolorationbeforeadministration.

Anyunused productorwastematerialshould bedisposedofin accordance with local

requirements.

Comprehensive instructionsforthepreparationandadministrationaregivenin the

packageleaflet.

7. MARKETINGAUTHORISATIONHOLDER

Roche Pharmaceuticals(Israel)Ltd.,P.O.B6391,HodHasharon4524079.

8. MARKETINGAUTHORISATIONNUMBERS

PegasysPre-filledSyringe135mcg/0.5ml 129.10.30804.00

PegasysPre-filledSyringe180mcg/0.5ml 129.11.30805.00

PegasysPre-filledPen135mcg/0.5ml129.10.30804.00

PegasysPre-filledPen180mcg/0.5ml129.11.30805.00

Medicine:keepoutofreachofchildren

Pegasys ® ismanufacturedbyF.Hoffmann-LaRoche Ltd.,Basel,Switzerland

1173PEGA0612