EPREX 2000

1

רשואמןולע 09.2011

םיחקורהתונקתיפלןכרצלןולע ) םירישכת ( משתה " ו

) X ( אפורםשרמבתבייחוזהפורת

הפורתבשמתשתםרטבופוסדעןולעהתאןויעבארק :

. ותרוצורישכתהםש

סקרפא IU/0.5ml 1000 םיקרזמ

סקרפא IU/0.5ml 2000 םיקרזמ

סקרפא IU/0.3ml 3000 םיקרזמ

סקרפא IU/0.4ml 4000 םיקרזמ

סקרפא IU/0.5ml 5000 םיקרזמ

סקרפא IU/0.6ml 6000 םיקרזמ

סקרפא IU/0.8ml 8000 םיקרזמ

סקרפא IU/ml 10,000 םיקרזמ

סקרפא IU/0.5ml 20,000 םיקרזמ

סקרפא IU/0.75ml 30,000 םיקרזמ

סקרפא IU/ml 40,000 םיקרזמ

. בכרה : רמוחה ) םי ( ליעפה ) םי ( םתומכו / םזוכיר :

Epoetin alfa8.4mcg (1000), 16.8mcg (2000), 25.2mcg (3000), 33.6mcg (4000),

42mcg (5000), 50.4mcg (6000), 67.2mcg(8000), 84mcg (10,000), 168mcg (20,000),

252mcg (30,000), 336mcg(40,000).

] ןוגכםיביכרמליכמהרישכתל : רכוס , ןרתנ , וכוםטרפסא , ' לוכתתאןייצלשי ןונימדיחיבםת . ןתינשרישכתב

אפורםשרמאלל ) OTC ( דרוירדסבםתומכיפלםאולמבםיליעפיתלבהםיביכרמהתאןייצלשי [

םיליעפיתלבםירמוח :

Polysorbate80, Glycine,Water forinjection,Sodium dihydrogen phosphatedehydrate,

Disodium phosphate dehydrate, Sodium chloride.

2

. תיאופרתוליעפ ] הלוחלתנבומןושלבהלועפהןפואותוליעפהלערצקרבסה :[

תיטיופרתהצובק : םירישכת הימנאבלופיט

ינורכיתיילכלשכמםילבוסהםילוחבהימנאבלופיטלתדעוימההפורתהניהסקרפא , ןטרסילוחב

לופיטבםילפוטמה יפרתומיכ , םילוחב םיימנא תאםימרותה םמצעלםמד , חותינינפל , סדייאילוחב

ןידובודיזירישכתבםילפוטמה םילוחבןכו םיימנא ידפוטרואחותינינפלםידמועה לודג .

. ) X ( רישכתבשמתשהלןיאיתמ ?

בשמתשהלןיא לבוסךנהםאסקרפא / יתפורתלופיטידילעןזואמוניארשאהובגםדץחלמת .

שמתשהלןיא סקרפאב עודיםא הפורתהיביכרממדחאלתושיגרה .

דמועךנהםאסקרפאבשמתשהלןיא / ידפוטרואחותינרובעלת ) םייכרבואךרייחותינןוגכ ( תלבסו א ו

תאש / לבוסה / ת מ :

* בלתלחמ השק

* וםידירוהתכרעמלתורושקהתוערפה / םיקרועהוא .

* יחומץבשואבלףקתהבתיקלהנורחאלםא .

* סקרפאבשמתשהלןיא לוכיךניאםא / תויהלה השירקתודגונתופורתבלופיטלבקל .

שמתשהלןיא םאסקרפאב בא ו נח ה ךלצא םצעהחמידילעתומודאתוירודכרוצייבהיעב ) pure red cell

aplasia ( שומישתובקעב ב רבע תומודאהםדהתוירודכרוציתאםיריבגמהםירישכתב ) סקרפאללוכ .(

סקרפאבשמתשהלןיא הנכהכ תימצעםדתמורתל לוכיךניאםא / ואךלהמבתימצעםדתמורתלבקלה

חותינרחאל .

. ) X ( לופיטהתלחתהינפלאפורבץעוויהלילבמהפורתבשמתשהלןיא

) X ( םא ךנה ןוירהב תורהלתנווכתמוא לופיטהךלהמב

) X ( ךנהםא הקינמ

) X ( םא ךנה לבוס / יוקילמרבעבתלבסואת תב דוקפ :

) X ( בלה , בלתקועתללוכבלתלחמ

) X ( הובגםדץחל

3

) X ( דבכה דבכתלחמוא

) X ( לבוסךנהםא / םדישירקמרבעבתלבסואת לעבךנהםאוא / םדישירקבתוקללרבגומןוכיסת

) לעבךנהםאלשמל / ףדועלקשמת , ךנהשואתרכוסבהלוח קתורמ / ת הטימל ברןמז תובקעב

הלחמואחותינ .(

) X ( לבוסךנהםא / ואםייטפליפאםיפקתהמרבעבתלבסואת ץבש

) X ( לבוסךנהםא / מת ףיעסבראותמהןמתונושתוביסמהימנא " תיאופרהתוליעפה ."

) X ( לבוסךנהםא / ת היריפירופמ ) םדהתכרעמבהרידנהערפה ( .

) X ( לבוסךנהםא / חממת הלולעוזהפורתשןוויכןטרסהתל תיטרואת , הל ץיא תוחתפתה רתי לש תלחמ

ןטרס , הלידגרוטקפכתלעופאיהורחאמ . לפטלףידעיאפורהוןכתייאופרהךבצמלםאתהב ךב

םדייוריעתועצמאב .

) X ( ךנהםא לטונ / הפורתת / יאתתורצוויהתדדועמהתופורתהתצובקמתורחאתופורת םימודאםד

) ןוגכ סקרפא .(

. ךלשםויםויהייחלעהפורתהעיפשתךיא ?

) X ( לפוטמךנהשןמזברידסןפואבםדץחלתוקידבךלךורעיךאפור / סקרפאבת .

) X ( לופיטלעיגמךנהוהדימב / החפשמהאפורלואיהשלכהאפרמבואםילוחתיבבתוצעייתה – עדיי / תאי

השיאופרהתווצה לפוטמךנ / לעואםירחאםילופיטלעעיפשהללוכיסקרפאשןוויכסקרפאבת

ת תואצו הדבעמתוקידב .

) X ( עתומודאםדתוירודכרוציםידדועמהםירישכתהתצובקלעתינמנסקרפא " םצעהחמי . הדימב

וזהחפשממהנושהפורתתלביקוסקרפאבלפוטמךניהו , יכאפורהםעאדוואנ רובעללוכיהתא

רחאהרישכתבשומישל .

) X ( שדחמעיפוירוזחמהוןכתיסקרפאבתולפוטמהיתיילכלשכםעתולפוטמב , לעאפורבץעוויהלשי

לופיטידכךותתורהלתורשפאה סקרפאב .

. תורהזא :

) X ( םא ךנה שיגר / יהשלכהפורתלואוהשלכןוזמלה , עידוהלךילע תליטנינפלאפורלךכלע הפורתה .

. תויתפורתןיבתובוגת

םא ךנה לטונ / תפסונהפורתת , התעהזתרמגםאוא תא תרחאהפורתבלופיטה , אללתושכרנהתופורתללוכ

םשרמ , לפטמהאפורלחוודלךילע חקורלוא יאואםינוכיסעונמלידכ - תויתפורתןיבתובוגתמםיעבונהתוליעי .

) X ( דחוימב , צובקהמתופורתיבגל תואבהתו :

) X ( ןירופסולקיצ ) לתנתינההפורת לתשתייחדתעינמ ללשמ הילכתלתשהרחא ( , יךאפורוןכתי לעהרו

עוציב לםדתוקידב רוטינ סקרפאםעלופיטהןמזבןירופסולקיצהתמר .

4

10 . יאוולתועפות

הפורתהלשהיוצרהתוליעפלףסונב , יפוהלתולולעהבשומישהןמזב יאוולתועפשהע

) X ( הובגתוחיכשביאוולתועפות ה :

תולולעולאתועפות בעיפוהל לפוטמרתוי לכמדחא מ הרשע ה םישמתשמ ב סקרפא

ןוגכתעפשהתלחמלשםינימסת : שארבאכ , םיקרפמיבאכ , השלוח , תרוחרחסותופייע . תועפות

רישכתבלופיטהתליחתברתויתוצופנתויהלתולולעולא . הםא שחךנ / ךלהמבולאםינימסתבה

תידירוךותההקירזה , ולאםינימסתתעינמברוזעתדיתעברתויתיטיאהקרזה .

הליחב , תואקה , םילושלש , תומצעבואםייפגבםיבאכ , םירירשתשלוח , תוקצב , תמרבהילע

םדבןגלשאה , לועיש , המישנהיכרדמתושרפה

) X ( תוחיכשיאוולתועפות :

שערישכתה םילטונרשאהאמלכמםישמתשמהרשעמתוחפלעעיפשהליו סקרפא

וחבםדהץחלבהילע ל יתיילכלשכםעםילוחבוןטרסי .

לפוטמךנהםא / הזילאידומהבת :

רצוויהלםילוכיםדישירק טנאשב . לעבךנהםארתויריבסהזרבד / ואךומנםדץחלת

ךלשיש הלוטסיפבםירושקהםיכוביס .

וכיםדישירק הזילאידומההתכרעמבםגרצוויהלםיל . תאתולעהלטילחיאפורהוןכתי

הזילאידהךלהמבןירפההןונימ .

) X ( תורידניאוולתועפות

סקרפאםילטונרשאםישנאםיפלאתרשעלכמדחאשמשתשממתוחפלעעיפשהליושערישכתה

םצעהחמבםימודאםדיאתלשתקפסמתומכרציילתלוכירסוח ) ינימסת לשם PRCA pure

red cell aplasia – ( . ימסת ולאםינ לוכי םי בתנייפואמההרומחתימואתפהימנאלםורגל :

הליגריתלבתופייע

תרוחרחסתשוחת

המישניישק

PRCA םירחאםירישכתבןכוסקרפאבםינשףאוםישדוחלששומישרחאלרידנןפואבחווד

וסהםילוחבםימודאםדיאתתריציםידדועמה יתיילכלשכמםילב ינורכ .

הזילאידומהבלפוטמךנהםא , היהתוןכתי , תליחתברקיעב לופיטה , םיטיצובמורטהתמרבהילע

) תויסט ( םדישירקתריציבםיברועמללכךרדבולאםדיאת . תויסטהתמרתאקודביךאפור

ךלש .

5

שוחתוןכתיי / תוימומדאי , ההםוקמבבאכוהבירצתשוחת הקרז .

עדיי / תעפותשחךנהםאואורכזוהשיאוולהתועפותמתחאבשחךנהםאתידיימתוחאהואךאפורתאי

סקרפאבלופיטהךשמבואהקירזהתלבקןמזביהשלכיאוול .

הרימחמיאוולהתועפותבתחאםא , ןיחבמךנהםאוא / הזןולעבהמושרהניארשאיאוולתעפותבה , אנא

פטמהאפורהתאעדיי ל , תוחאה חקורהתאוא .

( ) תדחוימתוסחייתהתובייחמהתועפות :

רתויבתיחטשואתיטיאהמישנ , ןולחכ , לובלבותוינונשי - . ידיימןפואבאפורלהיינפבייחמהזבצמ !

שאריבאכ , םיימואתפרקיעב , שאריבאכ הנרגמלםימודה תוריקדלשתושוחתםע , תשוחת

ואלובלב כרפ סו םדהץחלבתימואתפהילעלןמיסתויהלםילוכיםי . תידימאפורלתונפלשי . ץחל

תופורתבלופיטשרודהובגםד ) ץחלבלופיטלתומייקתופורתלןונימתמאתהוא םד .(

הזחבםיבאכ , המישניישק , לגרבתבאוכתוחפנתה םדישירקתורצוויהלעדיעהלםילולע , שי

אפורלתידימתונפל

ועבהחירפ םייניעהביבסתוחיפנור ) תקצב ( תיגרלאהבוגתמהאצותכםרגיהלםילוכיה – שי

אפורלתונפל

והגירחתוחיפנ / וםיילגרבםיגירחםיבאכוא / םידיבוא , הזחבדבוכתשוחתואימואתפבאכ ,

םיימואתפהמישניישקוארצוק , הרקהעיז , ןופלע – תידימאפורלינפולופיטיקספה .

השוחתרסוח תפ ימוא וםיידיב / וא םיילגר , היארבתוימואתפתוערפה , ימואתפלובלב , תוערפה

הנבהוארובידבתוימואתפ , זעשארבאכואלקשמהיווישבואהכילהבתוימואתפתוערפה

רבסומיתלבוימואתפ , אפורלינפותידיימלופיטיקספה

עורזלואןטבלןירקמהבאכואבגבואהזחבקזחץחלואףירחבאכ ףתכלוא , ךשמתמה 20

תוקד רתויוא . בלםאןיבובאכבהוולמםאןיבימואתפהמישנרצוק . לועיש , תרוחרחס , ואהליחב

תואקה , תימואתפהעזה , הפבשבוי . תיאופרהרזעתלבקלתידימהנפ .

שיגרמךניהובשהרקמלכב / הזןולעבונייוצאלשיאוולתועפותה , ךתשגרהביונישלחםאוא תיללכה

דימאפורהםעץעייתהלךילע .

. אפורהתרחאהארוהרדעהבלבוקמןונימ ] : לשופוגללקשיאפורםשרמםערישכתבהזףיעסיולימ

6

רישכתלכ [

) X ( דבלבאפורהתארוהיפלןונימ .

) X ( םיבוצקםינמזבוזהפורתבשמתשהלשי םיאתמהןונימבו קנשיפכ לעעב - לפטמהאפורהידי .

רועלתחתמהקירזבואדירולסקרפאקירזהלןתינ . תאםאהורישכתהקרזויךרדהזיאבעבקיאפורה / ה

לוכי / ךמצעברועלתחתמהקרזהבךמצעלקירזהלה . לשהכרדהתבייחמרועלתחתמתימצעהקרזה

תאשינפלתוחאואאפורה / ליחתמה / ךמצעלקירזהלה .

) X ( סקרפאבשמתשהלרוסאהרקמלכב :

א . הזיראהוקרזמהלעעיפומההגופתהךיראתרחאל

ב . תאםא / עדויה / ת דשוחוא / ת ש אפקוהרישכתה

ג . ררקמבהלקתהתיהםא תוחאבואאפורבץעווהלשי .

) X ( תוילכילוחםילפוטמ

ןיברמשיתךלשןיבולגומההתמרשךכלגאדיאפורה 10 ל – 1 1 רג '/ תמרשןוויכרטיליצד

תוומוםדישירקתורצוויהלןוכיסהתאתולעהלהלולעההובגןיבולגומה .

תוירשפאתורוציתשבהקירזבןתינסקרפא : רועלתחתמהקירזבואתידירוךותהקירזב . ךאפור

הקרזההתרוצלעטילחי .

ךאפור וי עוציבלעהר םאהקודבלתנמלעםדתוקידב ךבצמברופיששי . ןכתי טילחיאפורהו

ל נש תו ןונימהתא . ןונימביוניש אפורהתייחנהבהשעי לכללכךרדב 4 תועובש .

יוצרהןפואברפתשתהימנאהרשאכ , םדתוקידבעצבלךישמיךאפור . יכןכתי אפורה בוש הנשי

תא ה צרהבוגתרמשלתנמלעןונימ לופיטלהיו .

לבקתוןכתי / בוינפללזרביפסותבלופיטי ךלהמ עיתארפשלתנמלעסקרפאבלופיטה י תול

לופיטה .

רבועךנהוהדימב / סקרפאבלופיטהתעבהזילאידלופיטת , םילופיטהתינכותוןכתי ב הזילאיד

תצקמבהנתשת . ךכלעטילחיךאפור .

) X ( םילפוטמ ןטרסילוח

יטהתאליחתיאפורה סקרפאבלופ , יאדוולבורק , כ שא היהתךלשןיבולגומההתמרר 10

רג '/ תוחפוארטיליצד .

ןיברמשיתךלשןיבולגומההתמרשךכלגאדיאפורה 10 ל – 12 רג '/ תמרשןוויכרטיליצד

תוומוםדישירקתורצוויהלןוכיסהתאתולעהלהלולעההובגןיבולגומה .

ה רישכת רועלתחתמהקירזבןתני .

7

אפור ך עוציבלעהרוי לשהימנאהםאהקודבלתנמלעםדתוקידב ך תאהנשיולופיטלהביגמ

ןונימה ךרוצלםאתהב .

לבקתוןכתי / תולעיתארפשלתנמלעסקרפאבלופיטהךשמבוינפללזרביפסותבלופיטי

לופיטה .

ךישמתללכךרדב / סקרפאבלופיטהתאלבקלי םאתהבהיפרתומיכהםויסרחאלףסונשדוח

אפורהתויחנהל .

) X ( םילפוטמ םמצעלםמדתאםימרותה

לבקתוןכתי / תולעיתארפשלתנמלעסקרפאבלופיטהךשמבוינפללזרביפסותבלופיטי

לופיטה .

) X ( םילפוטמ ידפוטרואחותינינפלםידמועה לודג

חותינהינפלידימההובגהיהתךלשןיבולגומההתמרוהדימב , סקרפאבלופיטה קספוי .

לבקתוןכתי / עיתארפשלתנמלעסקרפאבלופיטהךשמבוינפללזרביפסותבלופיטי י תול

לופיטה .

) X ( תחכשםא התאקירזהל הפורת ה ןמזבוז . שי קירזהל תרכזנשכדימהנמ : ןיאןפואםושבךא

קירזהל דחיבתונמיתש !

ירזהינפלםויקירזהלתחכשוהדימב האבההק ךכמתוחפוא , גלד / ךשמהווזהקירזלעי / י

תירוקמהתוקרזההתינכתב .

) X ( תצלמומההנמהלערובעלןיא

רישכתבשומישהיבגלתופסונתולאשךלשיםא , חקורהתאואלפטמהאפורהתאלאש .

. שומישהןפוא :

) X ] ( מרבסהףרצלשיתטרופמהניאשןונימתרוצל םיאת : [

) X ( תוירשפאתורוציתשבהקירזבןתינסקרפא :

תידירוךותהקירזב

רועלתחתמהקירזב

ךלהמיאתמההקרזההתרוצלעטילחיךאפור . הפורתה הללוכי תוחאואאפורידילעךלןתני .

םימיוסמםילפוטמ ושקבתי יאופרהתווצהתוארוהיפלערועלתחתמםמצעלסקרפאהתאקירזהל .

מב יאופרהתווצההזהרק

) X ( שמתשהלןיא / ךתושרבשסקרפאהתאקירזהל :

8

א . הזיראהוקרזמהלעעיפומההגופתהךיראתרחאל

ב . תאםא / עדויה / ת דשוחוא / ת ש אפקוהרישכתה

ג . ררקמבהלקתהתיהםא

) X ( ווצהידילעךלקרזויסקרפאלופיטהתליחתב יאופרהת . לופיטהךשמהב , עצבלעיציךאפורוןכתי

תימצעהקרזה רועלתחתמ לפטמידילעואךדילעעצובתש / החפשמןב .

תימצעהקרזהעצבלןיא ואפורהידילעלשהכרדהתרבעםאאלאסקרפאלש / תוחאהוא .

ואפורהלשתוארוההיפלעדימתסקרפאבשמתשהלשי / תוחאהוא .

וולשי קירזמךנהיכאד / ואפורהךלהרוהשלזונהתומכתאקרוךאה / תוחאהוא .

הכלהכןסחואשסקרפאבקרוךאשמתשהלשי . ונסחואאלשסקרפאיקרזמבשמתשהלרתומ

םאקרררקמב רירקםוקמבונסחוא ) ןולחואוהשלכםוחרוקמדילאל ( ו ורבע רתויהלכל העבש

רוטרפמטהוררקמהמםתאצוהןמזמםימי לעהתלעאלררקמלץוחמקרזמהההשובםוקמבה

25°C .

) X ( סקרפאבשומישהינפל , ראשה / לשםוחלעיגמקרזמהרשאדעררקמלץוחמקרזמהתאיריאשה

רדחהתרוטרפמט . כךרואהזךילהת - 15 דע 30 תוקד . קרזמבשמתשהלשי ןכמרחאלתידימ .

) X ( תחאהנמקרלוטילשי לכמ קרזמ סקרפא .

) X ( רועלתחתמקרזומסקרפארשאכ , אלתקרזומהתומכה הלעת תדדובהקרזהבדחארטילילימלע .

) X ( לרוסאואיהשיפכהסימתהתאקירזהלשי בברע ה הקרזההינפלםירחאםילזונםע .

) X ( רענלןיא סקרפאהקרזמתא . קזחרועינ וא רישכתבםוגפללולעןמזךרואל . ב רעונרישכתהוהרקמ

הקזחב , ובשמתשהלןיא .

) X ( רועלתחתמתימצעהקרזהתוארוה :

הריקדינפמקירזמהלעןגמהתוריקדינפמהנגהןקתהלעבוניהסקרפאהקרזמ / קרזמהטחממהעיצפ

הקרזההרחאל . הילילגךותלטחמהוקרזמהתאתיטמוטואריזחיןקתהה תקרזהרחאלףוקשהקיטסלפ

הנכובהתביזעוקרזמהתלוכת .

אצוה /י ררקמהןמקרזמהתא . רדחהתרוטרפמטלעיגהלךירצקרזמבשלזונה .

קודב /י קרזמהתא ןוכנהןונימהוהזיכאדוולתנמלע , ףלחאלףקותהגפךיראת , םוגפוניאקרזמה

הו לולצוניהקרזמבשלזונ , םיקיקלחליכמאל אלו וה ק אפ .

רחב /י הקרזההםוקמתא . םיאתמהקרזהםוקמ ןטבהואךריהלשןוילעהקלחהוניה ) תברקבאל

רובטה .( הקרזההםוקמתאתונשלשי הקרזהלכב .

ץחר / ךיידיתאי . שמתשה / הקרזההםוקמתאאטחלתנמלעיוטיחתיגופסבי .

9

רסה / טחמהיוסיכתאי ) רופאה ( . זוחא /י קרזמב ) הנכובבזוחאלמענמה ( ךושמו / טחמהיוסיכתאי

התואבבוסלילבתוריהזב . קרזמהתנכובלעץוחללןיאהזבלשב , תארענלןיאוטחמבתעגלןיא

קרזמה .

ץחל / רועלתחתמהקרזההינפלקרזמהןמיוצראללזונררחשלתנמלעהנכובהלעטעמי לע

קירזהלךלורוהאפורהואתוחאשלזונהתומכלערומשלתנמ .

זוחא / רועלפכי ןיב הרומהעבצאהולדוגאה . ץחלתלא / הקזוחבי .

סנכה / רועלהאולמבטחמהתאי . תוחאהואאפורהלשהכרדההיפלעתאז .

קודב / םדילכבתעגפאלשי . ךושמ / הצוחהקרזמהתנכובתאטעמי . םדהארנוהדימב , אצוה / תאי

הסנוהזרוזאמטחמה / רחאםוקמבקירזהלי .

ץחל / הנכובהלעי לזונהתומכלכרשאדעלדוגאהתרזעב / הרדחוההנמה לםאתהב התואהנמ

רומאתייה / קירזהלה . תעב לערומשלןכוהקרזההןמזלכההזהרוצבהנכובהלעץוחללשיהקרזהה

רועהלפכ . קרזותהנמהלכרשאדעלעפיאלתוריקדינפמהנגההןקתה .

הנכובהרשאכ הצחלנ קרזמההצקדע , אצוה / מהתאי ררחשוטח / רועהלפכתאי .

רסה / הנכובהןמלדוגאהתאי רשפאו / עמיפלכעונלקרזמלי ל לעהסוכמהיהתטחמהלכרשאדעה

ידי ןקתה ה תוריקדינפמהנגה .

ץחל / יוטיחתיגופסרזעבי תוינשרפסמךשמלהקירזהםוקמלע .

שמושמהקרזמהתאךלשה תיאופרתלוספלכימלואהפשאהחפלהסכמהו .

םא תקרזה הנמתועטב עדוהשורדהמרתויהלודג / תידיימתוחאלואאפורלי . יאוולתועפות

תוחיכשןניאסקרפאלשרתיןוניממ .

. לכותדציכ / לופיטהתחלצהלעייסלי

) X ( לעץלמוהשלופיטהתאםילשהלךילע - אפורהידי

) X ( בלופיטהקיספהלןיאךתואירבבצמברופישלחםאםג אפורםעתוצעייתהאללהפורת .

תוחאלואאפורלחוודלשי א יוצרהמהלודגהנמהקרזוהם .

. הלערהענמ !

וםידלילשםדיגשיהלץוחמרוגסםוקמברומשלשיתרחאהפורתלכווזהפורת / ידילעותוקוניתוא - ךכ

הלערהענמת . ורתהןמדליעלבתועטבםאוארתיתנמתלטנםא הפ , דימהנפ ואלפטמהאפורל ןוימרדחל

תיבל - םילוח הןתינםאבו תזיראאב ךתאהפורתה .

האקהלםורגתלא אפורמתשרופמהארוהאלל !

10

. ךתלחמבלופיטלךלהמשרנוזהפורת . קיזהלהלולעאיהרחאהלוחב . ךיבורקלוזהפורתןתיתלא , ךינכש

ךירכמוא .

. רתלוטילןיא ךשוחבתופו !

הנמהותיוותהקודב םעפלכב הפורתלטונךניהש . בכרה / םהלקוקזךניהםאםייפקשמי .

. הנסחא :

) X ( שיהמקחרהרומש ג םידלילשםדי !

) X ( בשמתשהלןיא סקרפא הזיראהלעןמוסמרשאהגופתהךיראתרחאל קרזמהו .

) X ( ררקמבסקרפאןסחאלשי ) 2°C - 8°C .(

) X ( איפקהלאל רענלאלו קרזמהתא . אפקוהשקרזמבשמתשהלרוסא .

) X ( לתנמלעתירוקמהותזיראברישכתהתארומשלשי הפישחעונמ ל רוא .

) X ( רובשאוהיכתנחבהוהדימבסקרפאבשמתשהלןיא , לוכיךנהשואלולצוניאלזונה / ןיחבהלה

לזונהךותבםיקיקלחב .

) X ( הלעמלםירכזנהםירבדהדחאבתנחבהםאסקרפאבשמתשהלןיא . עדוה / חקורלואאפורלי .

) X ( הלסאלסקרפאהקרזמתאךילשהלןיא . ךלשהשומישהםותב /י הסכמהושמושמהקרזמהתא

תיאופרתלוספלכימלואהפשאהחפל .

הזיראהיאנתיפלםג / םיצלמומההנסחא , פורת דבלבתלבגומהפוקתלתורמשנתו . ךיראתלבלםישלאנ

רישכתהלשהגופתה ! קפסלשהרקמלכב , הפורתהתאךלקפיסשחקורבץעוויהלךילע . תופורתןסחאלןיא

הזיראהתואבתונוש .

סמ ' הפורתהםושיר

סקרפא 1000 חי ' תוימואלניב / 0.5 מ " ל : 116 7729670

סקרפא 2000 חי ' תוימואלניב / 0.5 מ " ל : 116 7829671

סקרפא 3000 חי ' תוימואלניב / 0.3 מ " ל : 116 7929672

סקרפא 4000 חי ' תוימואלניב / 0.4 מ " ל : 116 8029673

סקרפא 5000 חי ' תוימואלניב / 0.5 מ " ל : 123 4130339

11

סקרפא 6000 חי ' תוימואלניב / 0.6 מ " ל : 123 4230340

סקרפא 8000 חי ' תוימואלניב / 0.8 מ " ל : 123 44 30342

סקרפא 10000 חי ' תוימואלניב / מ " ל : 116 8129674

סקרפא 20000 חי ' תוימואלניב / 0.5 מ " ל : 13830 31794

סקרפא 30000 חי ' תוימואלניב 0.75 מ " ל : 138 31 31795

סקרפא 40000 חי ' תוימואלניב / מ " ל : 126 5230480

ןרצי : גליס , ןזואהפש , וש ץיו

םושירהלעב : ג ' יי - תלהיס ' עברק " מ . םיייפשץוביק 60990 , לארשי

Page 1 of 24

Eprex_SPC_FEB2017

"

טמרופ

ןולע

הז

עבקנ

"

דרשמ

תואירבה

ונכותו

קדבנ

רשואו

"

1.

NAME OF THE MEDICINAL PRODUCT

EPREX, solution for injection in pre-filled syringe.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Prefilled

syringes

Prefilled

syringes

Prefilled

syringes

Recombinant-human

1,000 U/0.5ml

2,000 U/0.5ml

3,000 U/0.3ml

Erythropoietin*

16.8

25.2

Prefilled

syringes

Prefilled

syringes

Prefilled

syringes

Recombinant-human

4,000 U/0.4ml

5,000 U/0.5ml

6,000 U/0.6ml

Erythropoietin*

33.6

50.4

Prefilled

Syringes

Prefilled

syringes

Prefilled

syringes

Recombinant-human

8,000 U/0.8 ml

10,000 U/ml

20,000 U/0.5ml

Erythropoietin*

67.2

84.0

Prefilled

Syringes

Prefilled

syringes

Recombinant-human

30,000 U/0.75 ml

40,000 U/ml

Erythropoietin*

336.0

*produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology

This medicinal product contains less than 1 mmol sodium (23 mg) per dose i.e essentially “sodium-free”.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM Solution

for injection in pre-filled syringe. Clear,

colourless solution.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of severe anemia associated with chronic renal failure, anemia in Zidovudine-treated HIV-infected

patients, anemia in cancer patients on chemotherapy.

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Eprex_SPC_FEB2017

To increase the yield of autologous blood from patients in a predonation programme initiated to avoid the

use of homologous blood.

Treatment is indicated in patients with moderate anemia (packed cell volume (PCV) approximately 33 to 39%

, no iron deficiency) if blood conserving procedures are not available or insufficient either: a: when the

scheduled major elective surgery requires a large volume of blood ( 4 or more units of blood for females or 5

or more units for males) or b: when the period necessary to obtain the required volume of autologous blood is

too short.

Perisurgery:

Reduction of allogeneic blood transfusion in surgery patients :

Eprex is indicated for the treatment of anemic patients (hemoglobin 9-11 g/dl) scheduled to undergo

elective, noncardiac, nonvascular surgery to reduce the need for allogeneic blood transfusions.

Eprex is indicated for patients at high risk for periopertive transfusions with significant, anticipated blood

loss.

Eprex is not indicated for anemic patients who are willing to donate autologous blood.

The safety of the perioperative use of Eprex has been studied only in patients who are receiving

anticoagulant prophylaxis.

Eprex is indicated before surgeries known be associated with excessive blood loss (at least 2 units).

4.2 Posology and method of administration

Method of administration

As with any other injectable product, check that there are no particles in the solution or change in colour.

Before use, leave the EPREX syringe to stand until it reaches room temperature. This usually

takes between 15 and 30 minutes.

Intravenous injection: Administer over at least one to five minutes, depending on the total dose. In

haemodialysed patients, a bolus injection may be given during the dialysis session through a

suitable venous port in the dialysis line. Alternatively, the injection can be given at the end of the

dialysis session via the fistula needle tubing, followed by 10 ml of isotonic saline to rinse the tubing

and ensure satisfactory injection of the product into the circulation.

A slower injection is preferable in patients who react to the treatment with “flu-like” symptoms (see

section 4.8)

Do not administer EPREX by intravenous infusion or in conjunction with other drug

solutions.

subcutaneous injection: A maximum volume of 1 ml at one injection site should generally not be

exceeded. In case of larger volumes, more than one site should be chosen for the injection.

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The injections are given in the limbs or the anterior abdominal wall.

In those situations, in which the physician determines that a patient or caregiver can safely and

effectively administer EPREX, subcutaneously, instruction as to the proper dosage and administration

should be provided.

Refer to section 3, How should the medicine be used? (instructions on how to inject EPREX) of the

package leaflet.

Posology

All other causes of anaemia (iron, folate or Vitamin B

deficiency, aluminium intoxication, infection

or inflammation, blood loss, haemolysis and bone marrow fibrosis of any origin) should be

evaluated and treated prior to initiating therapy with epoetin alfa, and when deciding to increase

the dose. In order to ensure optimum response to epoetin alfa, adequate iron stores should be

assured and iron supplementation should be administered if necessary (see section 4.4).

Treatment of symptomatic anaemia in adult and paediatric chronic renal failure patients:

In patients with chronic renal failure where intravenous access is routinely available (haemodialysis patients)

administration by the intravenous route is preferable. Where intravenous access is not readily available

(patients not yet undergoing dialysis and peritoneal dialysis patients), EPREX may be administered

subcutaneously.

Treatment of symptomatic anaemia in adult chronic renal failure patients

Anaemia symptoms and sequelae may vary with age, gender, and co-morbid medical conditions; a

physician’s evaluation of the individual patient’s clinical course and condition is necessary.

The recommended desired haemoglobin concentration range is between 10 g/dl to 12 g/dl (6.2 to

7.5 mmol/l).EPREX should be administered in order to increase haemoglobin to not greater than 12 g/dl

(7.5 mmol/l). A rise in haemoglobin of greater than 2g/dl (1.25 mmol/l) over a four-week period

should be avoided. If it occurs, appropriate dose adjustment should be made as provided.

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below

the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through

dose management, with consideration for the haemoglobin target range of 10g/dl (6.2 mmol/l) to

12g/dl (7.5mmol/l).

A sustained haemoglobin level of greater than 12g/dl (7.5mmol/l) should be avoided. If the

haemoglobin is rising by more than 2 g/dl (1.25 mmol/l) per month, or if the sustained haemoglobin

exceeds 12g/dl (7.5mmol/l) reduce the epoetin alfa dose by 25%. If the haemoglobin exceeds 13 g/dl

(8.1 mmol/l), discontinue therapy until it falls below 12 g/dl (7.5 mmol/l), and then reinstitute epoetin

alfa therapy at a dose 25% below the previous dose.

Patients should be monitored closely to ensure that the lowest approved effective dose of EPREX is

used to provide adequate control of anaemia and of the symptoms of anaemia whilst maintaining a

haemoglobin concentration below or at 12 g/dl (7.5 mmol/l).

Caution should be exercised with escalation of ESA doses in patients with chronic renal failure. In

patients with a poor haemoglobin response to ESA, alternative explanations for the poor response

should be considered (see section 4.4 and 5.1).

Adult haemodialysis patients:

In patients on haemodialysis where intravenous access is readily available, administration by the

intravenous route is preferable.

Page 4 of 24

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The treatment is divided into two stages:

Correction phase:

50 IU/kg, 3 times per week.

If necessary, increase or decrease the dose by 25 IU/kg (3 times per week) until the desired

haemoglobin concentration range between 10 g/dl to 12 g/dl (6.2 to 7.5 mmol/l) is achieved (this

should be done in steps of at least four weeks).

Maintenance phase:

The recommended total weekly dose is between 75 IU/Kg and 300 IU/kg.

Appropriate adjustment of the dose should be made in order to maintain haemoglobin values within the

desired concentration range between 10 g/dl to 12 g/dl (6.2 to 7.5 mmol/l).

The clinical data available suggest that those patients whose initial haemoglobin is very low (<6 g/dl or <3.75

mmol/l) may require higher maintenance doses than those whose initial anaemia is less severe (>8 g/dl or

>5 mmol/l).

Paediatric haemodialysis patients:

Anaemia symptoms and sequelae may vary with age, gender, and co-morbid medical conditions; a

physician

s evaluation of the individual patient

s clinical course and condition is necessary.

In paediatric patients the recommended target haemoglobin range is between 9.5 and 11 g/dl (5.9-6.8 mmol/l).

EPREX should be administered in order to increase haemoglobin to not greater than 11 g/dl (6.8

mmol/l).

Patients should be monitored closely to ensure that the lowest approved dose of EPREX is used

to provide adequate control of anaemia and of the symptoms of anaemia.

The treatment is divided into two stages:

In paediatric patients on haemodialysis where intravenous access is readily available,

administration by the intravenous route is preferable.

Correction phase:

The starting dose is 50 IU/kg intravenously, 3 times per week.

If necessary, increase or decrease the dose by 25 IU/kg (3 times per week) until the desired

haemoglobin concentration range of between 9.5 g/dl to 11 g/dl (5.9 to 6.8 mmol/l) is achieved

(this should be done in steps of at least four weeks).

Maintenance phase:

Appropriate adjustment of the dose should be made in order to maintain the haemoglobin levels within the

desired range between 9.5 g/dl and 11 g/dl (5.9 to 6.8 mmol/l).

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Generally, children under 30 kg require higher maintenance doses than children over 30 kg and adults. For

example, the following maintenance doses were observed in clinical trials after 6 months of treatment.

Dose (IU/kg given 3x week)

Weight (kg)

Median

Usual maintenance dose

< 10

75-150

10-30

60-150

> 30

30-100

Available data suggest that those patients whose initial haemoglobin is very low (<6.8 g/dl [4.25 mmol/l] )

may require higher maintenance doses than those whose initial haemoglobin is higher (>6.8 g/dl [4.25

mmol/l ]).

Adult patients with renal insufficiency not yet undergoing dialysis:

Where intravenous access is not readily available, EPREX may be administered subcutaneously.

The treatment is divided into two stages:

Correction phase:

Starting dose of 50 IU/kg, 3 times per week, followed if necessary by a dosage increase with 25 IU/kg

increments (3 times per week) until the desired goal is achieved (this should be done in steps of at least four

weeks).

Maintenance phase:

During the maintenance phase, EPREX can be administered either 3 times per week, and in the case of

subcutaneous administration, once weekly or once every 2 weeks.

Appropriate adjustment of dose and dose intervals should be made in order to maintain haemoglobin values

at the desired level: Hb between 10 and 12 g/dl (6.2 - 7.5 mmol/l). Extending dose intervals may require an

increase in dose.

The maximum dosage should not exceed 150 IU/kg, 3 times per week, 240 IU/kg (up to a maximum of

20,000 IU) once weekly, or 480 IU/kg (up to a maximum of 40,000 IU) once every 2 weeks.

Adult peritoneal dialysis patients:

Where intravenous access is not readily available, EPREX may be administered subcutaneously.

The treatment is divided into two stages:

Correction phase:

Starting dose of 50 IU/kg, 2 times per week.

Maintenance phase:

The recommended maintenance dose is between 25 IU/kg and 50 IU/kg, 2 times per week in 2

equal injections.

Page 6 of 24

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Appropriate adjustment of the dose should be made in order to maintain haemoglobin values at

the desired level between 10 g/dl to 12 g/dl (6.2 to 7.5 mmol/l).

Treatment of patients with chemotherapy-induced anaemia:

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician’s

evaluation of the individual patient’s clinical course and condition is necessary.

EPREX should be administered by the subcutaneous route to patients with anaemia (e.g. haemoglobin

concentration ≤ 10g/dl (6.2 mmol/l)).

Appropriate adjustment of the dose should be made in order to maintain haemoglobin concentrations

within the desired concentration range between 10 g/dl and 12 g/dl (6.2 and 7.5 mmol/l).

Due to intra-patient variability, occasional individual haemoglobin concentrations for a patient above and

below the desired haemoglobin concentration may be observed. Haemoglobin variability should be

addressed through dose management, with consideration for the haemoglobin concentration range between

10g/dl (6.2 mmol/l) and 12 g/dl (7.5mmol/l). A sustained haemoglobin concentration of greater than 12 g/dl

(7.5mmol/l) should be avoided; guidance for appropriate dose adjustment for when haemoglobin values

exceed 12 g/dl (7.5mmol/l) are described below.

Epoetin alfa therapy should continue until one month after the end of chemotherapy. However, the need to

continue Epoetin alfa therapy should be reevaluated periodically.

The initial dose is 150 IU/kg given subcutaneously 3 times per week.

Alternatively, EPREX can be administered at an initial dose of 40,000IU once weekly.

If the haemoglobin has increased by at least 1 g/dl (0.62 mmol/l) or the reticulocyte count has increased

≥40,000 cells/μl above baseline after 4 weeks of treatment, the dose should remain at 150 IU/kg 3 times per

week or 40,000IU once weekly.

If the haemoglobin increase is <1 g/dl (<0.62 mmol/l) and the reticulocyte count has increased <40,000

cells/μl above baseline, increase the dose to 300 IU/kg 3 times per week or 60,000 IU once weekly.

If after an additional 4 weeks of therapy at 300 IU/kg 3 times per week or 60,000 IU once weekly, the

haemoglobin has increased ≥1 g/dl (≥0.62 mmol/l) or the reticulocyte count has increased ≥40,000 cells/μl,

the dose should remain at 300 IU/kg 3 times per week or 60,000 IU once weekly.

However, if the haemoglobin has increased <1 g/dl (<0.62 mmol/l) and the reticulocyte count has increased

<40,000 cells/μl above baseline, response is unlikely and treatment should be discontinued.

The recommended dosing regimen is described in the following diagram:

Page 7 of 24

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Patients should be monitored closely to ensure that the lowest approved dose of erythropoiesis-stimulating

agent (ESA) is used to provide adequate control of the symptoms of anaemia.

Dose adjustment to maintain haemoglobin concentrations between 10g/dl 12 g/dl:

If the haemoglobin is rising by more than 2 g/dl (1.25 mmol/l) per month, or if the haemoglobin exceeds 12

g/dl (7.5 mmol/l), reduce the epoetin alfa dose by about 25 - 50%.

If the haemoglobin exceeds 12g/dL (7.5mmol/l), discontinue therapy until it falls below 12 g/dl (7.5 mmol/l)

and then reinstitute epoetin alfa therapy at a dose 25% below the previous dose.

Adult surgery patients in an autologous predonation programme:

The intravenous route of administration should be used. At the time of donating blood, epoetin alfa should

be administered after the completion of the blood donation procedure.

Mildly anaemic patients (haematocrit of 33-39%) requiring predeposit of ≥4 units of blood should be treated

with epoetin alfa at 600 IU/kg, 2 times weekly for 3 weeks prior to surgery.

Adult patients scheduled for major elective orthopaedic surgery:

The subcutaneous route of administration should be used.

Prior to initiating treatment with EPREX a hemoglobin level should be obtained to establish that it is 10g/dL ±

The recommended dose regimen is 600 IU/kg of epoetin alfa, given weekly for three weeks (days -21, -14

and -7) prior to surgery and on the day of surgery.

or

60,000

IU once

weekly

or 40,000 IU once weekly

or 40,000

IU once

weekly

Page 8 of 24

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In cases where there is a medical need to shorten the lead time before surgery to less than three weeks,

300 IU/kg epoetin alfa should be given daily for 10 consecutive days prior to surgery, on the day of surgery

and for four days immediately thereafter.

When performing haematologic assessments during the preoperative period, if the haemoglobin level

reaches 15 g/dl, or higher, administration of epoetin alfa should be stopped and further dosages should not

be given.

Care should be taken to ensure that at the outset of the treatment patients are not iron-deficient.

Zidovudine-treated HIV-infected patients

Prior to beginning EPREX, it is recommended that the endogenous serum erythropoietin level be

determined (prior to transfusion). Available evidence suggests that patients receiving zidovudine with

endogenous serum erythropoietin levels > 500 mUnits/mL are unlikely to respond to therapy with EPREX.

Responsiveness to EPREX in HIV-infected patients is dependent upon the endogenous serum

erythropoietin level prior to treatment. Patients with endogenous serum erythropoietin levels ≤ 500

mUnits/mL, and who are receiving a dose of zidovudine ≤ 4,200 mg/week, may respond to EPREX therapy.

Patients with endogenous serum erythropoietin levels > 500 mUnits/mL do not appear to

respond to EPREX therapy. In a series of four clinical trials involving 255 patients, 60% to 80% of HIV-

infected patients treated with zidovudine had endogenous serum erythropoietin levels ≤ 500 mUnits/mL.

Response to EPREX in zidovudine-treated HIV-infected patients is manifested by reduced transfusion

requirements and increased hematocrit.

In zidovudine-treated HIV-infected patients the dosage of Eprex should be titrated for each patient to

achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion and not

to exceed the upper safety limit of 12 g/dL.

Starting Dose: For adult patients with serum erythropoietin levels ≤500 mUnits/mL who are receiving a

dose of zidovudine ≤4200 mg/week, the recommended starting dose of EPREX is 100 IU/kg as an I.V. or

S.C. injection TIW (three times a week) for 8 weeks.

Increase Dose: During the dose adjustment phase of therapy, the hemoglobin should be monitored weekly.

If the response is not satisfactory in terms of reducing transfusion requirements or increasing hemoglobin

after 8 weeks of therapy, the dose of EPREX can be increased by 50 to 100 Units/kg TIW. Response should

be evaluated every 4 to 8 weeks thereafter and the dose adjusted accordingly by 50 to 100 Units/kg

increments TIW. If patients have not responded satisfactorily to an EPREX dose of 300 Units/kg TIW, it is

unlikely that they will respond to higher doses of EPREX. Discontinue EPREX if an increase in hemoglobin is

not achieved at a dose of 300 Units/kg for 8 weeks.

Maintenance Dose: After attainment of the desired response (ie, reduced transfusion requirements or

increased hemoglobin), the dose of EPREX should be titrated to maintain the response based on factors

such as variations in zidovudine dose and the presence of intercurrent infectious or inflammatory episodes.

If the haemoglobin exceeds the upper safety limit of 12 g/dL, the dose should be discontinued until the

hemoglobin drops to 11 g/dL. The dose should be reduced by 25% when treatment is resumed and then

titrated to maintain the desired hemoglobin.

4.3 Contraindications

Patients who develop pure red cell aplasia (PRCA) following treatment with any erythropoietin should not

receive EPREX or any other erythropoietin (see section 4.4 - Pure Red Cell Aplasia).

Page 9 of 24

Eprex_SPC_FEB2017

Uncontrolled hypertension.

All contraindications associated with autologous blood predonation programmes should be respected in

patients being supplemented with epoetin alfa.

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

The use of epoetin alfa in patients scheduled for major elective orthopaedic surgery and not participating

an autologous blood predonation programme is contraindicated in patients with severe coronary,

peripheral

arterial,

carotid

cerebral

vascular

disease,

including

patients

with

recent

myocardial

infarction or cerebral vascular accident.

Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis.

4.4 Special warnings and precautions for use

General

In all patients receiving epoetin alfa, blood pressure should be closely monitored and controlled as

necessary. Epoetin alfa should be used with caution in the presence of untreated, inadequately treated or

poorly controllable hypertension. It may be necessary to add or increase anti-hypertensive treatment. If

blood pressure cannot be controlled, epoetin alfa treatment should be discontinued.

Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and

intensive medical care, have occurred also during epoetin alfa treatment in patients with previously normal

or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a

possible warning signal (see section 4.8).

Epoetin alfa should be used with caution in patients with epilepsy, history of seizures, or medical conditions

associated with a predisposition to seizure activity, such as CNS infections and brain metastases.

Epoetin alfa should also be used with caution in the presence of chronic liver failure. The safety of Epoetin

alfa has not been established in patients with hepatic dysfunction. Due to decreased metabolism, patients

with hepatic dysfunction may have increased erythropoiesis with Epoetin alfa.

An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs

(see section 4.8). These include venous and arterial thromboses and embolism (including some with fatal

outcomes), such as deep venous thrombosis, pulmonary emboli, retinal thrombosis, and myocardial

infarction. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral haemorrhage and

transient ischaemic attacks) have been reported.

The reported risk of TVEs should be carefully weighed against the benefits to be derived from treatment with

Epoetin alfa particularly in patients with pre-existing risk factors for TVE, including obesity and prior history

of TVEs (e.g., deep venous thrombosis, pulmonary embolism, and cerebral vascular accident).

In all patients, haemoglobin concentration should be closely monitored due to a potential increased risk of

thromboembolic events and fatal outcomes when patients are treated at haemoglobin levels above the

concentration range for the indication of use.

There may be a moderate dose-dependent rise in the platelet count within the normal range during

treatment with epoetin alfa. This regresses during the course of continued therapy. In addition,

thrombocythaemia above the normal range has been reported. It is recommended that the platelet count is

regularly monitored during the first 8 weeks of therapy.

All other causes of anaemia (iron deficiency, haemolysis, blood loss, Vitamin B12 or folate deficiencies,

aluminium intoxication, infection or inflammation and bone marrow fibrosis of any origin) should be

Page 10 of 24

Eprex_SPC_FEB2017

evaluated and treated prior to initiating therapy with epoetin alfa , and when deciding to increase the dose. In

most cases, the ferritin values in the serum fall simultaneously with the rise in packed cell volume. In order

to ensure optimum response to epoetin alfa, adequate iron stores should be assured and iron

supplementation should be administered if necessary:

For chronic renal failure patients, iron supplementation (elemental iron 200 to 300 mg/day orally for

adults and 100 to 200 mg/day orally for paediatrics) is recommended if serum ferritin levels are below

100 ng/ml.

For cancer patients, iron supplementation (elemental iron 200 to 300 mg/day orally) is

recommended if transferrin saturation is below 20%.

For patients in an autologous predonation programme, iron supplementation (elemental iron 200mg/day

orally) should be administered several weeks prior to initiating the autologous predeposit in order to

achieve high iron stores prior to starting Epoetin alfa therapy, and throughout the course of Epoetin alfa

therapy.

For patients scheduled for major elective orthopaedic surgery, iron supplementation (elemental iron

200mg/day orally) should be administered throughout the course of Epoetin alfa therapy. If possible, iron

supplementation should be initiated prior to starting Epoetin alfa therapy to achieve adequate iron

stores.

Very rarely, development of or exacerbation of porphyria has been observed in epoetin alfa-treated patients.

Epoetin alfa should be used with caution in patients with porphyria.

In order to improve the traceability of the erythropoiesis-stimulating agents (ESA) the trade name of the

administered ESA should be clearly recorded (or stated) in the patient file. Furthermore, patients should only

be switched from one ESA to another under appropriate supervision.

The safety and efficacy of Epoetinum alfa therapy have not been established in patients with underlying

haematologic diseases (e.g. haemolytic anaemia, sickle cell anaemia, thalassemia).

Pure Red Cell Aplasia

Antibody-mediated pure red cell aplasia (PRCA) has been reported after months to years of subcutaneous

epoetin treatment mainly in chronic renal failure patients. Cases have also been reported in patients with

hepatitis C treated with interferon and ribavirin, when ESAs are used concomitantly. EPREX is not approved

in the management of anaemia associated with hepatitis C.

In patients developing sudden lack of efficacy defined by a decrease in haemoglobin (1 to 2 g/dl per month)

with increased need for transfusions, a reticulocyte count should be obtained and typical causes of non-

response (e.g. iron, folate or Vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood

loss and haemolysis and bone marrow fibrosis of any origin) should be investigated.

A paradoxical decrease in haemoglobin and development of severe anaemia associated with low

reticulocyte counts should prompt to discontinue treatment with EPREX and perform anti-erythropoietin

antibody testing. A bone marrow examination should also be considered for diagnosis of PRCA. No other

ESA therapy should be commenced because of the risk of cross-reaction.

Treatment of symptomatic anaemia in adult and chronic renal failure patients

Chronic renal failure patients being treated with epoetin alfa should have haemoglobin levels

measured on a regular basis until a stable level is achieved, and periodically thereafter.

In chronic renal failure patients, the rate of increase in haemoglobin should be approximately 1 g/dl (0.62

mmol/l) per month and should not exceed 2 g/dl (1.25 mmol/l) per month to minimise risks of an increase in

hypertension.

Page 11 of 24

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In patients with chronic renal failure maintenance haemoglobin concentration should not exceed the upper

limit of the haemoglobin concentration range as recommended in section 4.2. In clinical trials, an increased

risk of death and serious cardiovascular events was observed when ESAs were administered to achieve a

haemoglobin of greater than 12 g/dl (7.5mmol/l).

Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins

when haemoglobin concentration is increased beyond the level necessary to control symptoms of anaemia

and to avoid blood transfusion.

Caution should be exercised with escalation of EPREX doses in patients with chronic renal failure since high

cumulative epoetin doses may be associated with an increased risk of mortality, serious cardiovascular and

cerebrovascular events. In patients with a poor haemoglobin response to epoetins, alternative explanations

for the poor response should be considered (see sections 4.2 and 5.1).

Chronic renal failure patients treated with EPREX by the subcutaneous route should be monitored regularly

for loss of efficacy, defined as absent or decreased response to EPREX treatment in patients who previously

responded to such therapy. This is characterised by a sustained decrease in haemoglobin despite an

increase in EPREX dosage

see section 4.8).

Some patients with more extended dosing intervals (greater than once weekly) of epoetin alfa may not

maintain adequate haemoglobin levels (see section 5.1) and may require an increase in epoetin alfa dose.

Haemoglobin levels should be monitored regularly.

Shunt thromboses have occurred in haemodialysis patients, especially in those who have a tendency to

hypotension or whose arteriovenous fistulae exhibit complications (e.g. stenoses, aneurysms, etc.). Early

shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, is

recommended in these patients.

Hyperkalaemia has been observed in isolated cases though causality has not been established. Serum

electrolytes should be monitored in chronic renal failure patients. If an elevated or rising serum potassium

level is detected, then in addition to appropriate treatment of the hyperkalaemia, consideration should be

given to ceasing epoetin alfa administration until the serum potassium level has been corrected.

An increase in heparin dose during haemodialysis is frequently required during the course of therapy with

epoetin alfa as a result of the increased packed cell volume. Occlusion of the dialysis system is possible if

heparinisation is not optimum.

Based on information available to date, correction of anaemia with epoetin alfa in adult patients with renal

insufficiency not yet undergoing dialysis does not accelerate the rate of progression of renal insufficiency.

Patients with chronic renal failure and insufficient hemogloblin response to ESA therapy may be at even

greater risk for cardiovascular events and mortality than other patients.

In some female chronic renal failure patients, menses have resumed following Epoetinum alfa therapy; the

possibility of potential pregnancy should be discussed and the need for contraception evaluated.

Treatment of patients with chemotherapy-induced anaemia

Cancer patients being treated with epoetin alfa should have haemoglobin levels measured on a regular

basis until a stable level is achieved, and periodically thereafter.

Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may

be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that

epoetins could stimulate the growth of tumours.

Page 12 of 24

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The role of ESAs on tumour progression or reduced progression-free survival cannot be excluded. In

controlled clinical studies, use of EPREX and other ESAs have been associated with

decreased locoregional tumour control or decreased overall survival

decreased locoregional control in patients with advanced head and neck cancer receiving radiation

therapy when administered to target a haemoglobin of greater than 14 g/dl (8.7 mmol/l),

shortened overall survival and increased deaths attributed to disease progression at 4 months in

patients

with

metastatic

breast

cancer

receiving

chemotherapy

when

administered

target

haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l),

increased risk of death when administered to achieve a haemoglobin concentration level of 12 g/dl

(7.5 mmol/l) in patients with active malignant disease receiving neither chemotherapy nor

radiation therapy. ESAs are not indicated for use in this patient population.

an observed 9% increase in risk for PD or death in the epoetin alfa plus SOC group from

a primary analysis and a 15% increased risk that cannot be statistically ruled out in

patients with metastatic breast cancer receiving chemotherapy when administered to

achieve a haemoglobin concentration range of 10 to 12 g/dl (6.2 to 7.5 mmol/l).

In view of the above, in some clinical situations blood transfusion should be the preferred treatment

for the management of anaemia in patients with cancer. The decision to administer recombinant

erythropoietin treatment should be based on a benefit-risk assessment with the participation of the individual

patient, which should take into account the specific clinical context. Factors that should be considered in this

assessment should include the type of tumour and its stage; the degree of anaemia; life-expectancy; the

environment in which the patient is being treated; and patient preference (see section 5.1).

In cancer patients receiving chemotherapy, the 2 to 3-week delay between ESA administration and the

appearance of erythropoietin-induced red cells should be taken into account when assessing if epoetin alfa

therapy is appropriate (patient at risk of being transfused).

Surgery patients in autologous predonation programmes

All special warnings and special precautions associated with autologous predonation programmes,

especially routine volume replacement, should be respected.

Patients scheduled for major elective orthopaedic surgery

Good blood management practices should always be used in the perisurgical setting.

Patients scheduled for major elective orthopaedic surgery should receive adequate antithrombotic

prophylaxis, as thrombotic and vascular events may occur in surgical patients, especially in those with

underlying cardiovascular disease. In addition, special precaution should be taken in patients with

predisposition for development of DVTs. Moreover, in patients with a baseline haemoglobin of > 13 g/dl (8.1

mmol/l), the possibility that epoetin alfa treatment may be associated with an increased risk of postoperative

thrombotic/vascular events cannot be excluded. Therefore, it should not be used in patients with baseline

haemoglobin > 13 g/dl (8.1 mmol/l).

HIV-infected patients

If HIV-infected patients fail to respond or maintain a response to Epoetinum alfa, other etiologies including

iron deficiency anaemia should be considered and evaluated.

Seizures

Page 13 of 24

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EPREX increases the risk of seizures in patients with CKD. During the first several months following

initiation of EPREX, monitor patients closely for premonitory neurologic symptoms. Advise patients to

contact their healthcare practitioner for new-onset seizures, premonitory symptoms or change in seizure

frequency.

Serious Allergic Reactions

Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and

urticaria may occur with EPREX. Immediately and permanently discontinue EPREX and administer

appropriate therapy if a serious allergic or anaphylactic reaction occurs.

4.5 Interaction with other medicinal products and other forms of interaction

No evidence exists that indicates that treatment with epoetin alfa alters the metabolism of other drugs. Drugs

that decrease erythropoiesis may decrease the response to Epoetin alfa.

Since cyclosporin is bound by RBCs, there is potential for a drug interaction. If epoetin alfa is given

concomitantly with cyclosporin, blood levels of cyclosporin should be monitored and the dose of cyclosporin

adjusted as the haematocrit rises.

No evidence exists that indicates an interaction between epoetin alfa and G-CSF or GM-CSF with regard to

haematological differentiation or proliferation of tumour biopsy specimens in vitro.

The effect of Epoetinum alfa may be potentiated by the simultaneous therapeutic administration of a

haematinic agent, such as ferrous sulphate, when a deficiency state exists.

In female adult patients with metastatic breast cancer, subcutaneous co-administration of 40,000 IU/mL

Epoetinum alfa with trastuzumab (6 mg/kg) had no effect on the pharmacokinetics of trastuzumab.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Studies in animals have shown

reproduction toxicity (see section 5.3). Consequently:

Epoetin alfa should be used in pregnancy only if the potential benefit outweighs the potential risk to the

foetus.

The use of epoetin alfa is not recommended in pregnant surgical patients participating in an

autologous blood predonation.

Breast-feeding

It is not known whether exogenous epoetin alfa is excreted in human milk. Epoetin alfa should be used with

caution in nursing women. A decision on whether to continue/discontinue breast-feeding or to

continue/discontinue therapy with epoetin alfa should be made taking into account the benefit of breast-

feeding to the child and the benefit of epoetin alfa therapy to the woman.

The use of epoetin alfa is not recommended in lactating surgical patients participating in an autologous

blood predonation programme.

Fertility

There are no studies assessing the potential effect of epoetin alfa on male or female fertility.

4.7 Effects on ability to drive and use machines

No studies on the effects of epoetin alfa on the ability to drive and use machines have been performed.

Page 14 of 24

Eprex_SPC_FEB2017

4.8 Undesirable effects

Summary of Safety Profile

The most frequent adverse drug reaction during treatment with epoetin alfa is a dose-dependent increase in

blood pressure or aggravation of existing hypertension. Monitoring of the blood pressure should be

performed, particularly at the start of therapy (see section 4.4).

The most frequently occurring adverse drug reactions observed in clinical trials of epoetin alfa are diarrhoea,

nausea, vomiting, pyrexia and headache. Influenza-like illness may occur especially at the start of treatment.

Respiratory tract congestion, which includes events of upper respiratory tract congestion, nasal congestion

and nasopharyngitis, have been reported in studies with extended interval dosing in adult patients with renal

insufficiency not yet undergoing dialysis.

An increased incidence of thrombotic vascular events (TVEs) has been observed in patients receiving ESAs

(see section 4.4).

Tabulated List of Adverse Reactions

Of a total 3,262 subjects in 23 randomized, double-blinded, placebo or standard of care controlled studies,

the overall safety profile of EPREX was evaluated in 1,992 anaemic subjects. Included were 228 epoetin

alfa-treated CRF subjects in 4 chronic renal failure studies (2 studies in pre-dialysis [N = 131 exposed CRF

subjects] and 2 in dialysis [N = 97 exposed CRF subjects]; 1,404 exposed cancer subjects in 16 studies of

anaemia due to chemotherapy; 147 exposed subjects in 2 studies for autologous blood donation; and 213

exposed subjects in 1 study in the perisurgical period). Adverse drug reactions reported by ≥1% of subjects

treated with epoetin alfa in these trials are shown in the table below.

Frequency estimate: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to <

1/100), Rare (≥ 1/10,000 to < 1/1,000), Very Rare (< 1/10,000), Not known (cannot be estimated from the

available data).

System Organ

Class

Frequency

Very common

Common

Uncommon

Rare Very rare

Not Known

Blood and lymphatic

system disorders

Erythropoietin

antibody-mediated

pure red cell

aplasia

Thrombocythaemia

Metabolism and

nutrition disorders

Hyperkalaemia

Immune system

disorders

Anaphylactic

reaction

Hypersensitivity

Nervous system

disorders

Headache

Convulsions

Vascular disorders

Venous and

arterial

thromboses

Hypertension

Hypertensive

crisis

Respiratory, thoracic

and mediastinal

disorders

Cough

Respiratory

tract congestion

Gastrointestinal

disorders

Diarrhoea,

Nausea,

Vomiting

Skin and

subcutaneous tissue

disorders

Rash

Angioneurotic

oedema

Urticaria

Musculoskeletal and

Arthralgia,

Page 15 of 24

Eprex_SPC_FEB2017

connective tissue

disorders

Bone pain,

Myalgia, Pain in

extremity

Congenital and

familial/genetic

disorders

Porphyria

General

disorders

and administration

site conditions

Pyrexia

Chills,

Influenza-like

illness, Injection

site reaction,

Oedema

peripheral

Drug ineffective

1 Identified during postmarketing experience and frequency category estimated from spontaneous reporting

rates

Common in dialysis

3 Includes arterial and venous, fatal and non-fatal events, such as deep venous thrombosis, pulmonary

emboli, retinal thrombosis, arterial thrombosis (including myocardial infarction), cerebrovascular accidents

(including cerebral infarction and cerebral haemorrhage) transient ischaemic attacks, and shunt thrombosis

(including dialysis equipment) and thrombosis within arteriovenous shunt aneurisms

Addressed in the subsection below and/or in section 4.4.

Description of selected adverse reactions

Hypersensitivity reactions, including cases of rash (including urticaria), anaphylactic reactions, and

angioneurotic oedema have been reported.

Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and

intensive medical care, have occurred also during epoetin alfa treatment in patients with previously normal

or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a

possible warning signal (see section 4.4).

Antibody-mediated pure red cell aplasia has been very rarely reported in < 1/10,000 cases per patient year

after months to years of treatment with EPREX (see section 4.4).

Paediatric population with chronic renal failure on haemodialysis

The exposure of paediatric patients with chronic renal failure on haemodialysis in clinical trials and post-

marketing experience is limited. No paediatric-specific adverse reactions not mentioned previously in the table

above, or any that were not consistent with the underlying disease were reported in this population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product.

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

National Regulation by using an online form:

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@mo

h.health.gov.il

4.9 Overdose

The therapeutic margin of epoetin alfa is very wide. Overdosage of epoetin alfa may produce effects that are

extensions of the pharmacological effects of the hormone. Phlebotomy may be performed if excessively high

haemoglobin levels occur. Additional supportive care should be provided as necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anti-anaemic

, ATC Classification: B03XA01

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Mechanism of action

Erythropoietin (EPO) is a glycoprotein hormone produced primarily by the kidney in response to hypoxia and

regulator

blood

cell

(RBC)

production.

involved

phases

erythroid

development, and has its principal effect at the level of erythroid precursors. After EPO binds to its cell

surface

receptor,

activates

signal

transduction

pathways

that

interfere

with

apoptosis

and stimulates

erythroid cell proliferation. Recombinant human EPO (Epoetin alfa), expressed in Chinese hamster ovary

cells, has a 165 amino acid sequence identical to that of human urinary EPO; the two are indistinguishable

on the basis of functional assays. The apparent molecular weight of erythropoietin is 32,000 to 40,000 dalton.

Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin

receptors may be expressed on the surface of a variety of tumour cells.

Pharmacodynamic effects

Healthy volunteers

After single doses (20,000 to 160,000 IU subcutaneously) of epoetin alfa, a dose-dependent

response was observed for the pharmacodynamic markers investigated including: reticulocytes,

RBCs, and haemoglobin. A defined concentration-time profile with peak and return to baseline was

observed for changes in percent reticulocytes. A less defined profile was observed for RBCs and

haemoglobin. In general, all pharmacodynamic markers increased in a linear manner with dose

reaching a maximum response at the highest dose levels.

Further pharmacodynamic studies explored 40,000 IU once weekly versus 150 IU/kg 3 times per

week. Despite differences in concentration-time profiles the pharmacodynamic response (as

measured by changes in percent reticulocytes, haemoglobin, and total RBCs) was similar between

these regimens. Additional studies compared the 40,000 IU once-weekly regimen of epoetin alfa

with biweekly doses ranging from 80,000 to 120,000 IU subcutaneously. Overall, based on the

results of these pharmacodynamic studies in healthy subjects, the 40,000 IU once-weekly dosing

regimen seems to be more efficient in producing RBCs than the biweekly regimens despite an

observed similarity in reticulocyte production in the once-weekly and biweekly regimens.

Chronic renal failure

Epoetin alfa has been shown to stimulate erythropoiesis in anaemic patients with CRF, including

dialysis and pre-dialysis patients. The first evidence of a response to epoetin alfa is an increase in

the reticulocyte count within 10 days, followed by increases in the red cell count, haemoglobin and

haematocrit, usually within 2 to 6 weeks. The haemoglobin response varies between patients and

may be impacted by iron stores and the presence of concurrent medical problems.

Chemotherapy-induced anaemia

Epoetin alfa administered 3 times per week or once weekly has been shown to increase

haemoglobin and decrease transfusion requirements after the first month of therapy in anaemic

cancer patients receiving chemotherapy.

In a study comparing the 150 IU/kg, 3-times-per-week and 40,000 IU, once-weekly dosing

regimens in healthy subjects and in anaemic cancer subjects the time profiles of changes in

percent reticulocytes, haemoglobin, and total red blood cells were similar between the two dosing

regimens in both healthy and anaemic cancer subjects. The AUCs of the respective

pharmacodynamic parameters were similar between the 150 IU/kg, 3-times-per-week and 40,000

IU, once-weekly dosing regimens in healthy subjects and also in anaemic cancer subjects.

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Adult surgery patients in an autologous predonation programme

Epoetin alfa has been shown to stimulate red blood cell production in order to augment autologous

blood collection, and to limit the decline in haemoglobin in adult patients scheduled for major

elective surgery who are not expected to predeposit their complete perioperative blood needs. The

greatest effects are observed in patients with low haemoglobin (

13 g/dl).

Treatment of adult patients scheduled for major elective orthopaedic surgery

In patients scheduled for major elective orthopaedic surgery with a pretreatment haemoglobin of >

10 to

13 g/dl, epoetin alfa has been shown to decrease the risk of receiving allogeneic

transfusions and hasten erythroid recovery (increased haemoglobin levels, haematocrit levels, and

reticulocyte counts).

Clinical efficacy and safety

Chronic renal failure

Epoetin alfa has been studied in clinical trials in adult anaemic CRF patients, including haemodialysis and

pre-dialysis patients, to treat anaemia and maintain haematocrit within a concentration range of 30 to 36%.

In clinical trials at starting doses of 50-150 IU/kg three times per week, approximately 95% of all patients

responded with a clinically significant increase in haematocrit. After approximately two months of therapy,

virtually all patients were transfusion-independent. Once the target haematocrit was achieved, the

maintenance dose was individualised for each patient.

In the three largest clinical trials conducted in adult patients on dialysis, the median maintenance dose

necessary to maintain the haematocrit between 30-36% was approximately 75 IU/kg given three times per

week.

In a double-blind, placebo-controlled, multicentre, quality of life study in CRF patients on haemodialysis,

clinically and statistically significant improvement was shown in the patients treated with poet alfa compared

to the placebo group when measuring fatigue, physical symptoms, relationships and depression (Kidney

Disease Questionnaire) after six months of therapy. Patients from the group treated with Epoetin alfa were

also enrolled in an open-label extension study, which demonstrated improvements in their quality of life, were

maintained for an additional 12 months.

Adult patients with renal insufficiency not yet undergoing dialysis

In clinical trials conducted in patients with CRF not on dialysis treated with Epoetin alfa, the average duration

of therapy was nearly five months. These patients responded to Epoetin alfa therapy in a manner similar to

that observed in patients on dialysis. Patients with CRF not on dialysis demonstrated a dose-dependent and

sustained

increase

haematocrit

when

Epoetin

alfa

administered

either

intravenous

subcutaneous route. Similar rates of rise of haematocrit were noted when Epoetin alfa was administered by

either route. Moreover, Epoetin alfa doses of 75- to 150 IU/kg per week have been shown to maintain

haematocrits of 36- to 38% for up to six months.

In t w o studies with extended interval dosing of EPREX®, ERYPO® (3 times per week , once weekly,

once

every 2 weeks, and once every 4 weeks) some patients with longer dosing intervals did not maintain

adequate haemoglobin levels and reached protocol-defined haemoglobin withdrawal criteria (0% in once

weekly, 3.7% in once-every-2-weeks, and 3.3% in the once-every-4-weeks groups).

A randomised prospective trial (CHOIR) evaluated 1,432 anaemic chronic renal failure patients who were not

undergoing dialysis. Patients were assigned to Epoetin alfa treatment targeting a maintenance haemoglobin

level of 13.5 g/dL (higher than the recommended target haemoglobin concentration level) or 11.3 g/dL. A

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major cardiovascular event (death, myocardial infarction, stroke or hospitalization for congestive heart failure)

occurred among 125 (18%) of the 715 patients in the higher haemoglobin group compared to 97 (14%)

among the 717 patients in the lower haemoglobin group (hazard ratio [HR] 1.3, 95% CI: 1.0, 1.7, p = 0.03).

Pooled post hoc analyses of clinical studies of ESAs have been performed in chronic renal failure

patients (on dialysis, not on dialysis, in diabetic and non-diabetic patients). A tendency towards

increased risk estimates for all-cause mortality, cardiovascular and cerebrovascular events

associated with higher cumulative ESA doses independent of the diabetes or dialysis status was

observed (see section 4.2 and 4.4).

Treatment of patients with chemotherapy-induced anaemia

Epoetin alfa has been studied in clinical trials in adult anaemic cancer patients with lymphoid and solid

tumors, and patients on various chemotherapy regimens, including platinum and non-platinum-containing

regimens. In these trials, Epoetin alfa administered three times a week (TIW) and once weekly has been

shown to increase haemoglobin and decrease transfusion requirements after the first month of therapy in

anaemic cancer patients. In some studies, the double-blind phase was followed by an open-label phase

during which all patients received Epoetin alfa and a maintenance of effect was observed.

Available evidence suggests patients with haematological malignancies and solid tumours respond

equivalently to epoetin alfa therapy, and that patients with or without tumour infiltration of the bone

marrow respond equivalently to epoetin alfa therapy. Comparable intensity of chemotherapy in the Epoetin

alfa and placebo groups in the chemotherapy trials was demonstrated by a similar area under the neutrophil

time curve in patients treated with Epoetin alfa and placebo-treated patients, as well as by a similar proportion

of patients in groups treated with Epoetin alfa and placebo-treated groups whose absolute

neutrophil counts

fell below 1,000 and 500 cells/μL.

In a prospective, randomised, double-blind, placebo-controlled trial conducted in 375 anaemic patients with

various non-myeloid malignancies receiving non-platinum chemotherapy, there was a significant reduction of

anaemia-related sequelae (e.g. fatigue, decreased energy, and activity reduction), as measured by the

following instruments and scales: Functional Assessment of Cancer Therapy-Anaemia (FACT-An) general

scale, FACT-An fatigue scale, and Cancer Linear Analogue Scale (CLAS).

Two other smaller, randomised,

placebo-controlled trials failed to show a significant improvement in quality of life parameters on the

EORTC-QLQ-C30 scale or CLAS, respectively.

Survival and tumour progression have been examined in five large controlled studies involving a

total of 2,833 patients, of which four were double-blind placebo-controlled studies and one was an

open-label study. The studies either recruited patients who were being treated with chemotherapy

(two studies) or used patient populations in which ESAs are not indicated: anaemia in patients with

cancer not receiving chemotherapy, and head and neck cancer patients receiving radiotherapy.

The desired haemoglobin concentration level in two studies was > 13 g/dl; in the remaining three

studies it was 12 to 14 g/dl. In the open-label study there was no difference in overall survival

between patients treated with recombinant human erythropoietin and controls. In the four placebo-

controlled studies the hazard ratios for overall survival ranged between 1.25 and 2.47 in favour of

controls. These studies have shown a consistent unexplained statistically significant excess

mortality in patients who have anaemia associated with various common cancers who received

recombinant human erythropoietin compared to controls. Overall survival outcome in the trials

could not be satisfactorily explained by differences in the incidence of thrombosis and related

complications between those given recombinant human erythropoietin and those in the control

group.

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A patient-level data analysis has also been performed on more than 13,900 cancer patients

(chemo-, radio-, chemoradio-, or no therapy) participating in 53 controlled clinical trials involving

several epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of

1.06 in favour of controls (95% CI: 1.00, 1.12; 53 trials and 13,933 patients) and for the cancer

patients receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38

trials and 10,441 patients). Meta-analyses also indicate consistently a significantly increased

relative risk of thromboembolic events in cancer patients receiving recombinant human

erythropoietin (see section 4.4).

A random, open-label, multicenter study was conducted in 2,098 anemic women with metastatic

breast cancer, who received first-line or second-line chemotherapy. This was a non-

inferiority study designed to rule out a 15% risk increase in tumor progression or death of epoetin

alfa plus standard of care (SOC) as compared with SOC alone. The median progression-free

survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm

(HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. At clinical cutoff, 1,337

deaths were reported. Median overall survival in the epoetin alfa plus SOC group was 17.2 months

compared with 17.4 months in the SOC alone group (HR 1.06, 95% CI: 0.95, 1.18). Significantly

fewer patients received RBC transfusions in the epoetin alfa plus SOC arm (5.8% versus 11.4%);

however, significantly more patients had thrombotic vascular events in the epoetin alfa plus SOC

arm (2.8% versus 1.4%).

Autologous predonation programme

The effect of epoetin alfa in facilitating autologous blood donation in patients with low haematocrits

39% and no underlying anaemia due to iron deficiency) scheduled for major orthopaedic

surgery was evaluated in a double-blind, placebo-controlled study conducted in 204 patients, and a

single-blind placebo controlled study in 55 patients.

In the double-blind study, patients were treated with epoetin alfa 600 IU/kg or placebo

intravenously once daily every 3 to 4 days over 3 weeks (total 6 doses). On average, patients

treated with epoetin alfa were able to predeposit significantly more units of blood (4.5 units) than

placebo-treated patients (3.0 units).

In the single-blind study, patients were treated with epoetin alfa 300 IU/kg or 600 IU/kg or placebo

intravenously once daily every 3 to 4 days over 3 weeks (total 6 doses). Patients treated with

epoetin alfa were also able to predeposit significantly more units of blood (epoetin alfa 300 IU/kg =

4.4 units; epoetin alfa 600 IU/kg = 4.7 units) than placebo-treated patients (2.9 units).

Epoetin alfa therapy reduced the risk of exposure to allogeneic blood by 50% compared to patients

not receiving epoetin alfa.

Major elective orthopaedic surgery

The effect of epoetin alfa (300 IU/kg or 100 IU/kg) on the exposure to allogeneic blood transfusion

has been evaluated in a placebo-controlled, double-blind clinical trial in non-iron-deficient adult

patients scheduled for major elective orthopaedic hip or knee surgery. Epoetin alfa was

administered subcutaneously for 10 days prior to surgery, on the day of surgery, and for four days

after surgery. Patients were stratified according to their baseline haemoglobin (

10 g/dl, > 10 to

13 g/dl and > 13 g/dl).

Epoetin alfa 300 IU/kg significantly reduced the risk of allogeneic transfusion in patients with a

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pretreatment haemoglobin of > 10 to

13 g/dl. Sixteen percent of epoetin alfa 300 IU/kg, 23% of

epoetin alfa 100 IU/kg and 45% of placebo-treated patients required transfusion.

An open-label, parallel-group trial in non-iron-deficient adult subjects with a pretreatment

haemoglobin of

10 to

13 g/dl who were scheduled for major orthopaedic hip or knee surgery

compared epoetin alfa 300 IU/kg subcutaneously daily for 10 days prior to surgery, on the day of

surgery and for four days after surgery to epoetin alfa 600 IU/kg subcutaneously once weekly for

3 weeks prior to surgery and on the day of surgery.

From pretreatment to presurgery, the mean increase in haemoglobin in the 600 IU/kg weekly group

(1.44 g/dl) was twice than that observed in the 300 IU/kg daily group (0.73 g/dl). Mean haemoglobin

levels were similar for the two treatment groups throughout the postsurgical period.

The erythropoietic response observed in both treatment groups resulted in similar transfusion rates

(16% in the 600 IU/kg weekly group and 20% in the 300 IU/kg daily group).

Paediatric population

Chronic Renal Failure

Epoetin alfa was evaluated in an open-label, non-randomised, open dose-range, 52-week clinical

study in paediatric CRF patients undergoing haemodialysis. The median age of patients enrolled in

the study was 11.6 years (range 0.5 to 20.1 years).

Epoetin alfa was administered at 75 IU/kg/week intravenously in 2 or 3 divided doses post-dialysis,

titrated by 75 IU/kg/week at intervals of 4 weeks (up to a maximum of 300 IU/kg/week), to achieve

a 1 g/dl/month increase in haemoglobin. The desired haemoglobin concentration range was 9.6 to

11.2 g/dl. Eighty-one percent of patients achieved the haemoglobin concentration level. The

median time to target was 11 weeks and the median dose at target was 150 IU/kg/week. Of the

patients who achieved the target, 90% did so on a 3-times-per-week dosing regimen.

After 52 weeks, 57% of patients remained in the study, receiving a median dose of 200

IU/kg/week.

Clinical data with subcutaneous administration in children are limited. In 5 small, open-label,

uncontrolled studies (number of patients ranged from 9-22, total N=72), Epoetin alfa has been

administered subcutaneously in children at starting doses of 100 IU/kg/week to 150 IU/kg/week

with the possibility to increase up to 300 IU/kg/week. In these studies, most were pre-dialysis

patients (N=44), 27 patients were on peritoneal dialysis and 2 were on haemodialysis, with age

ranging from 4 months to 17 years. Overall, these studies have methodological limitations but

treatment was associated with positive trends towards higher haemoglobin levels. No unexpected

adverse events were reported (see section 4.2).

Chemotherapy-induced anaemia

Epoetin alfa 600 IU/kg (administered intravenously or subcutaneously once weekly) has been

evaluated in a randomised, double-blind, placebo-controlled, 16-week study and in a randomised,

controlled, open-label, 20-week study in anaemic paediatric patients receiving myelosuppressive

chemotherapy for the treatment of various childhood non-myeloid malignancies.

In the 16-week study (N=222), in the epoetin alfa-treated patients there was no statistically

significant effect on patient-reported or parent-reported Paediatric Quality of Life Inventory or

Cancer Module scores compared with placebo (primary efficacy endpoint). In addition, there was

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no statistical difference between the proportion of patients requiring pRBC transfusions between

the Epoetin alfa group and placebo.

In the 20-week study (N=225), no significant difference was observed in the primary efficacy

endpoint, i.e. the proportion of patients who required a RBC transfusion after Day 28 (62% of

epoetin alfa patients versus 69% of standard therapy patients).

5.2 Pharmacokinetic properties

Absorption

Following subcutaneous injection, serum levels of epoetin alfa reach a peak between 12 and 18 hours

post-dose. There was no accumulation after multiple-dose administration of 600 IU/kg administered

subcutaneously weekly.

The absolute bioavailability of subcutaneous injectable epoetin alfa is approximately 20% in healthy

subjects.

Distribution

The mean volume of distribution was 49.3 ml/kg after intravenous doses of 50 and 100 IU/kg in

healthy subjects. Following intravenous administration of epoetin alfa in subjects with chronic renal

failure, the volume of distribution ranged from 57-107 ml/kg after single dosing (12 IU/kg) to 42-

64 ml/kg after multiple dosing (48-192 IU/kg), respectively. Thus, the volume of distribution is

slightly greater than the plasma space.

Elimination

The half-life of epoetin alfa following multiple-dose intravenous administration is approximately

4 hours in healthy subjects. The half-life for the subcutaneous route is estimated to be approximately

24 hours in healthy subjects.

The mean CL/F for the 150 IU/kg 3 times-per-week and 40,000 IU once-weekly regimens in healthy

subjects were 31.2 and 12.6 ml/h/kg, respectively. The mean CL/F for the 150 IU/kg,3-times-per-week and

40,000 IU once-weekly regimens in the anaemic cancer subjects were 45.8 and 11.3 ml/h/kg, respectively.

In most anaemic subjects with cancer receiving cyclic chemotherapy, CL/F was lower after subcutaneous

doses of 40,000 IU once weekly and 150 IU/kg, 3 times per week compared with the values for healthy

subjects.

Linearity/Nonlinearity

In healthy subjects, a dose-proportional increase in serum epoetin alfa concentrations was observed

after intravenous administration of 150 and 300 IU/kg, 3 times per week. Administration of single doses

of 300 to 2,400 IU/kg subcutaneous epoetin alfa resulted in a linear relationship between mean

and dose and between mean AUC and dose. An inverse relationship between apparent clearance

and dose was noted in healthy subjects.

In studies to explore extending the dosing interval (40,000 IU once weekly and 80,000, 100,000, and

120,000 IU biweekly), a linear but non-dose-proportional relationship was observed between mean

and dose, and between mean AUC and dose at steady state.

PK/PD relationships

Epoetin alfa exhibits a dose-related effect on haematological parameters which is independent of route

of administration.

Paediatric population

A half-life of approximately 6.2 to 8.7 hours has been reported in paediatric subjects with chronic

renal failure following multiple-dose intravenous administration of epoetin alfa. The pharmacokinetic

profile of epoetin alfa in children and adolescents appears to be similar to that of adults.

Pharmacokinetic data in neonates are limited.

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A study of 7 preterm very low birth weight neonates and 10 healthy adults given i.v. erythropoietin

suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm

neonates than in the healthy adults, and clearance was approximately 3 times higher in the

preterm neonates than in healthy adults.

Renal impairment

In chronic renal failure patients, the half-life of intravenously administered epoetin alfa is slightly

prolonged, approximately 5 hours, compared to healthy subjects.

5.3 Preclinical Safety Data

In repeated dose toxicological studies in dogs and rats, but not in monkeys, epoetin alfa therapy was

associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of

chronic renal failure in humans and may be related to secondary hyperparathyroidism or unknown

factors. The incidence of bone marrow fibrosis was not increased in a study of haemodialysis patients

who were treated with epoetin alfa for 3 years compared to a matched control group of dialysis

patients who had not been treated with epoetin alfa.

Epoetin alfa does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in

mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus.

Long-term carcinogenicity studies have not been carried out. Conflicting reports in the literature, based

on in vitro findings from human tumour samples, suggest erythropoietins may play a role as tumour

proliferators. This is of uncertain significance in the clinical situation.

In cell cultures of human bone marrow cells, epoetin alfa stimulates erythropoiesis specifically and

does not affect leucopoiesis. Cytotoxic actions of epoetin alfa on bone marrow cells could not be

detected.

In animal studies, epoetin alfa has been shown to decrease foetal body weight, delay ossification and

increase foetal mortality when given in weekly doses of approximately 20 times the recommended

human weekly dose. These changes are interpreted as being secondary to decreased maternal body

weight gain, and the significance to humans is unknown given therapeutic dose levels.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Polysorbate 80

Glycine

Water for injections

Sodium dihydrogen phosphate dihydrate

Disodium phosphate dihydrate

Sodium chloride

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal

products.

6.4 Special precautions for storage

Store in a refrigerator (2°C-8°C). This temperature range should be closely maintained until administration to

the patient. Store in the original package in order to protect from light. Do not freeze or shake.

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For the purpose of ambulatory use, the patient may remove EPREX from the refrigerator and store it

above 25°C for one single period of up to 7 days.

6.5 Nature and contents of container

Solution for injection in a pre-filled syringe (type I glass) with plunger (Teflon-faced rubber) and

needle with a needle shield (rubber with polypropylene cover) and a needle safety device

(polycarbonate) attached to the syringe.

Prefilled syringes fitted with the PROTECS™ needle guard device

The pre-filled syringes are fitted with the PROTECS™ (copolyester and polycarbonate) needle guard

safety device to help prevent needle stick injuries after use.

6.6

Special precautions for disposal and other handling

Do not administer by intravenous infusion or in conjunction with other drug solutions.

Before use, leave the EPREX syringe to stand until it reaches room temperature. This usually takes

between

15 and 30 minutes.

The product should not be used, and discarded

if the seal is broken,

if the liquid is coloured or you can see particles floating in it,

if you know, or think that it may have been accidentally frozen, or

if there has been a refrigerator failure.

The product is for single use only. Only take one dose of EPREX from each syringe, removing

unwanted solution before injection. Refer to section 3, How should the medicine be used? (instructions

on how to inject EPREX) of the package leaflet.

The pre-filled syringes are fitted with a needle safety device to help prevent needle stick injuries after

use.

The package leaflet includes full instructions for the use and handling of pre-filled syringes

with

the PROTECS

needle guard.

Any unused product or waste material should be disposed of in accordance with local requirements.

PRESENTATION

Packages of 6 syringes 1,000 IU/0.5 ml of r-HuEPO

Packages of 6 syringes 2,000 IU/0.5 ml of r-HuEPO

Packages of 6 syringes 3,000 IU/0.3 ml of r-HuEPO

Packages of 6 syringes 4,000 IU/0.4 ml of r-HuEPO

Packages of 6 syringes 5,000 IU/0.5 ml of r-HuEPO

Packages of 6 syringes 6,000 IU/0.6 ml of r-HuEPO

Packages of 6 syringes 8,000 IU/0.8 ml r-HuEPO

Packages of 6 syringes 10,000 IU/1 ml of r-HuEPO

Packages of 1 syringe 20,000 IU/0.5 ml of r-HuEPO

Packages of 1 syringe 30,000 IU/0.75 ml of r-HuEPO

Packages of 1 syringe 40,000 IU/1 ml of r-HuEPO

Manufacturer

Cilag AG, Schaffhausen, Switzerland.

Registration Holder: J-C Health Care Ltd., Kibbutz Shefayim 6099000, Israel.