REBIF 22 MCG

1986- ו"משתה )םירישכת( םיחקורה תונקת יפל ןכרצל ןולע

אפור םשרמב תבייח וז הפורת

הפורתב י/שמתשת םרטב ופוס דע ןולעה תא ןויעב י/ארק

תואירבה דרשמ י"ע עבקנ הז ןולע טמרופ

2010רבמבונב ודי-לע רשואו קדבנ ונכותו

ג"קמ 22 ® ףיבר

ג"קמ 44 ® ףיבר

תירוע-תת הקרזהל הסימת

הקרזהל ןכומ קרזמ

קרזמל הסנכהל תינסחמ

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.לוהוכלא ליזנב ג"מ2.5ליכמ רישכתה

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:םיליעפ יתלב םיביכרמ

Mannitol,poloxamer188,L-methionine,benzylalcohol,

sodiumacetate,aceticacid,sodiumhydroxideandwaterfor

injections

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רטשמהוןונימהיפ-לעואפורתחגשהתחתקרףיברבשמתשהלשי

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.3ליגל תחתמ םידליו

תטולבידוקפתודבכידוקפת,םדתוקידבךורעלשילופיטהתפוקתב

.סירתה

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:יאוול תועפות

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:שגומףיבר

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רטשמהיפלתננכותמהלופיטהתנמלשאבהםויהמקירזהל

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.ךתיא הפורתה תזירא תא י/אבהו ,םילוח-תיב לש ןוימ רדחל

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.המוגפ הניהש האור ךניהו הרקמב הפורתב שמתשהל ןיא

הליגרהךרדבהתואקורזלןיא,שומישאללהפורתלשהרקמב

תוכיאלערומשלידכתאז,תופורתלדעוימהחפלהכילשהלאלא

.הביבסה

:הפורתה םושיר 'סמ

110.94.29437.06:ג"קמ22ףיבר

116.35.29814.06:ג"קמ44ףיבר

:ןרצי

.ץיווש ,הבנ'ג , S.A. ונורס קרמ

:םושירה לעב

® ףיברב שומיש תוארוה

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ה/שיגרמךניהםא,הצופנתשרטילפוטמלצאחיכשוניהןואכיד

.אפורל דימ י/הנפ ,ןואכידב

1,000ךותמםירקמ10דע1(תוחיכשןניאשיאוולתועפות

:)םילפוטמ

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םישגרומםניאבורלםהינימסתוולאםייוניש.תוליעפתתבוארתיב

.תומיאתמה תוקידבה לע ךל ץילמי ךלש אפורה ,הלוחה ידי-לע

:העודי אל תוחיכשב יאוול תועפות

םעלופיטהתליחתםעשןכתיי-הצופנתשרטלשףקתהיומד

.הצופנ תשרט לש ףקתה םימדמה םינימסתב י/שוחתףיבר

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ה/תאםא.וזהקספבוראותשיפכתעפשייומדםינימסתוםוחםע

.אפורל חוודל שי ,ולא תועפותב ה/ןיחבמ

:תוירשפא תורחא יאוול תועפות

.שארבאכ:תוחיכשדואמ

,רועבהחירפוץוצקע,תואקה,הליחב,לושלש,הנישיישק:תוחיכש

.תויוררקתהו םוח ,תופייע ,םיקרפמו םירירש באכ

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,םיקומעהםידירווב)סיזובמורת(תקקפומכםדישירק,המישנ

תוערפהלםימרוגהםדישירקואתקלד:ןוגכ,ןיעהתיתשרבתוערפה

רסחוהשירקלשתנמגרא,)הייארןדבואואהייאריישק(הייארב

תנומסתוא) Thrombotic thrombocytopenic purpura (תויסט

הערפה:) Hemolytic uremic syndrome (תימרואתיטילומה

הדירי,םומיד,תולבחבהיילע,םינטקםדישירקידי-לעתנייפואמש

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,ןובאיתןדבוא,תונבצע,תרוחרחס:העודיאלתוחיכשבוחוודןכומכ

.ישדוחה רוזחמב םייוניש ,בל תוקיפדו םדה ילכ תבחרה

.אפורה תצלמה אלל הפורתה תא תונשל וא קיספהל ןיא

:תדחוימ תוסחייתה תובייחמה יאוול תועפות

לופיטהתאי/קספהוהפוחדתיאופרהרזעתלבקלאפורלי/הנפ

:םיאבה םירקמב ףיברב

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תועפותשהרקמב,הרכהןדבואבוהשלוחב,ףוגהלכבץוצקעב

יאופרזכרמלכלואאפורלתידיימתונפלךילע,תושחרתמולא

.םוריח יבצמל

לשםינימסתבה/שיגרמה/תאםאאפורלתידיימחוודלךילע

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יישק:ןוגכםיפסונםינמיסלתורושקתויהלתולוכידבכבתורומח

.לובלבו תוינונשי ,זוכיר

י/הנפ.תוינדבואתובשחמת/חתפמואת/אכודמדואמךניהםא

.אפורל דימ

ואהזןולעבוניוצאלשיאוולתועפותה/שיגרמךניהובשהרקמלכב

ךילע,תיללכהךתשגרהביונישלחםאוא,הרמחוהיאוולהתעפותש

.דימ אפור םע ץעייתהל

:ןונימ

ןונימהתאםיאתהלאפורהלע.דבלבאפורהתוארוהיפלןונימ

לעמםירגבתמלןכו,םינש16ליגמםירגובמלילופיטהרטשמהו

.םינש12ליג

םתואב,עובשבםימעפ3תנתינאפורהידי-לעתצלמומההנמה

דימתהנמהתאקירזהליוצר,תועש48תוחפללשםיחוורמב,םימי

.ברעב ףידע ,ןמז ותואב

.תצלמומה הנמה לע רובעל ןיא

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.12ליגמ םירגבתמלו ההובג הנמ םילבוס םניאש םילוחל

ליגלתחתמםידלילותוקוניתלללכ-ךרדבתדעוימהניאוזהפורת

.םינש12

:שומישה ןפוא

:שגומףיבר

טחמתרבוחמקרזמל,הקרזהלןכומ,הסימתבאלוממקרזמב

.תירוע תת תימצע הקרזהל תדעוימה

,תינסחמלדעוימה,םיאתמהקרזמלהסינכהלשישתינסחמכ

.תירוע תת תימצע הקרזהל

.יאופר תווצ שיא תוחכונב עצבל תינושארה הקרזהה תא יוצר

שומישהלעהכרדהלבקל,לפטמוא,רבח,החפשמןבלעואךילע

ידכ,םיאתמהקרזמלהסינכהלשישףיברתינסחמבואףיברקרזמב

.תיבב רישכתה לש הקרזהה תא עצבל היהי ןתינש

תוארוהירחאבוקעלובטיהאורקלךילע,ףיברבשומישהתליחתינפל

םוקמבקמנלוהעיגפלןוכיסהתארעזמלידכ,הזןולעבששומישה

םוקמבתיתייעבתימוקמהבוגתבה/שחךניהוהדימב.הקרזהה

.אפורל חוודל ךילע ,הקרזהה

םאקררישכתבשמתשהלשי.דבלבישיאהךשומישלוניההזרישכת

.רישכתל קזנ לכ םרגנ אלו םיקיקלח אללו הלולצ הסימתה

האצותהתאגישהלידכ,ןכלידיימןפואבתשגרומהניאףיברהתעפשה

ןיאו,ילופיטהרטשמהתאואלופיטהתנמתאתונשלןיא,היוצרה

לכיבגל.אפורהםעתוצעייתהאללהפורתבלופיטהתאקיספהל

.יאופרה תווצל וא חקורל ,אפורל י/הנפףיברלע הלאש

ךישמהלאלאהלופכהנמתחקלןיאהפורתתנמקירזהלתחכשםא

רטשמהיפלתננכותמהלופיטהתנמלשאבהםויהמקירזהל

.ילופיטה

ךישמהלךילעךא,ידיימןפואבףיברהלשהעפשהבי/שוחתאלוןכתיי

ה/תאםא.הפוצמההאצותהתאלבקלידכרישכתבשמתשהלו

!עולבל אל:בל י/םיש

.דבלב הקרזהל תדעוימ וז הפורת

!הלערה י/ענמ

םתייארלץוחמרוגסםוקמברומשלשיתרחאהפורתלכווזהפורת

.הלערה י/ענמת ךכ ידי-לעו תוקונית וא/ו םידלי לש םדי גשיהלו

דימי/הנפ,הפורתהןמדליעלבתועטבםאוארתיתנמתלטנםא

.ךתיא הפורתה תזירא תא י/אבהו ,םילוח-תיב לש ןוימ רדחל

!אפורמ תשרופמ הארוה אללהאקהל םורגל ןיא

.קיזהלהלולעאיהת/רחאהלוחל,ךתלחמבלופיטלהמשרנוזהפורת

.ךירכמ וא ,ךינכש ,ךיבורקל וז הפורת י/ןתית לא

ךניהשםעפלכבהנמהותיוותהתאקודבלשי!ךשוחבתופורתלוטילןיא

.םהל ה/קוקז ךניה םא םייפקשמ ביכרהל שי .הפורת ת/לטונ

:הנסחא

.םידלי לש םתייארו םדי גשיהמ קיחרהל שי

רומשלןיא!איפקהלןיא.2 o C -8 o C ןיב,ררקמבהפורתהתאןסחאלשי

תורשפאעונמלידכתאז,איפקמלהדומצהןפודבררקמבהתוא

.ןואפיק לש

.רוא ינפמ ןגהל ידכ תירוקמה הזיראב ןסחאל שי

ונסחאלוררקמהמףיברהתאאיצוהלןתינלפוטמהלששומישהתוחונל

ןכמרחאל.ימעפדחןפואבתאז,דבלבםוי14דע25 o C -לתחתמ

.הגופתה ךיראת ינפל וב שמתשהלו ררקמל וריזחהל וילע

שמתשהלשיתינסחמבףיברלשהנושארהקרזהירחא:תינסחמ

.םוי28ךותב

הפוקתלתורמשנתופורת,םיצלמומההנסחאה/הזיראהיאנתיפלםג

הגופתהךיראתלרבעמהזרישכתבשמתשהלןיא.דבלבתלבגומ

לכב!רישכתהלשהגופתהךיראתלבלםישלאנ.הזיראהיבגלעעיפומה

.הפורתה תא ךל קפיסש חקורב ץעוויהל ךילע ,קפס לש הרקמ

ינפמהילעןגהלידכתירוקמההתזיראבהפורתהתאןסחאלשי

.רוא

.הזירא התואב תונוש תופורת ןסחאל ןיא

.המוגפ הניהש האור ךניהו הרקמב הפורתב שמתשהל ןיא

הליגרהךרדבהתואקורזלןיא,שומישאללהפורתלשהרקמב

תוכיאלערומשלידכתאז,תופורתלדעוימהחפלהכילשהלאלא

.הביבסה

:הפורתה םושיר 'סמ

110.94.29437.06:ג"קמ22ףיבר

116.35.29814.06:ג"קמ44ףיבר

:ןרצי

.ץיווש ,הבנ'ג , S.A. ונורס קרמ

:םושירה לעב

® ףיברב שומיש תוארוה

שמתשהלשי,םיאתמקרזמבשומישלתדעוימ,ףיברתינסחמ.1

.קרזמה תכרעב דרפנב תויוצמש תוארוהה יפ-לע

:ךינפל תוארוהה הקרזהל ןכומ קרזמב ףיבר.2

תוחאהוא/ותווצה,אפורהםעתוצעייתהירחאקרשמתשהלשי

.הקרזהה ןפוא יבגל הכירדמה

:ןונימ

.םרגורקימ44-ו םרגורקימ22םיזוכיר ינשב עיפומףיבר

םרגורקימ44וא)םינש12ליגלעמ(םרגורקימ22אוהץלמומהןונימה

ילופיטהרטשמהוןונימה.עובשבםימעפ3,)םינש16ליגלעמ(

.אפורה ידי-לע ועבקיי

:אמגודל(עובשבםיעובקםימיהשולשבהפורתהתאקירזהלץלמומ

.)ברעב ףידע( העש התואבו )ישימח ,ישילש ,ןושאר

הפורתהתאתחקלוךישמהלשיהיוצרההאצותהתאגישהלידכ

.רידס ןפואב

.תירוע תת הקרזהל דעוימףיבר

.לפטמה אפורה תחגשהב הנושארה הקרזהה תא עצבל שי

אלהסימתןוגכםינמיסבה/ןיחבמה/תאםאףיברבשמתשהלןיא

.םיקיקלח הליכמש וא ,הלולצ

ה/דידיואהחפשמת/ןב,ה/תא,תירועתתהקרזהלדעוימףיבר

קרזמבףיברתקרזהל.תיבבןוחטיבבהפורתהתאקירזהלםילוכי

.הדיפקב ןלהלש תוארוהה תא י/ארק ,הקרזהל ןכומ

)רועל תחתמ( תירוע-תת הקרזה

םיירשפאהקרזהירוזאךלעיציךלשאפורה.הקרזהרוזאבי/רחב-

ןטבהתאוךריהלשןוילעהקלחהתאםיללוכםיצלמומםירוזא(

ץלמומ.ןורפיעםיקיזחמשיפכקרזמהתאי/זוחא.)הנותחתה

קירזהלאלידכ,בבסבםפילחהלוהקרזההירוזאלשםושירךורעל

ןוכיסהתארעזמלידכתאז,דחארוזאבידמתופוכתםיתיעל

.הקרזהה רוזאב קמנלו העיגפל

תוחיפנ,םישוגבשוחלןתינםהבםירוזאבי/קירזתלא:הרעה-

ךניהםא,תוחאהםעואאפורהםעי/חחוש.באכבוא,תימוקמ

.הלאכ םירוזא הלגמ

.ןובסו םימ םע בטיה ךידי תא י/ץחר-

.יטסלפהיוסיכהףוליקידי-לעותזיראמףיברהקרזמתאי/אצוה-

י/ןת.הקרזההרוזאברועהיוקינללוהוכלאתיגופסבי/שמתשה-

שוחלה/לולעה/תארועהלעלוהוכלאראשנםא,שבייתהלרועל

.הבירצב

ביבסמשרועהתאטובצלשי-

ותואהיבגהלידכ(תונידעברוזאל

.1'סמ רויא י/האר .)טעמ

לעחנומךדיףכשרושרשאכ-

,הקרזההרוזאלבורק,רועה

הרשיתיווזבטחמהתאי/רדחה

הריהמהעונתברועהךותלא

.2'סמ רויא י/האר .הקזחו

ידי-לעהפורתהתאי/קרזה-

י/ףוחד(הביציותיטיאהפיחד

קרזמהשדעהמינפהנכובהתא

.2'סמ רויא י/האר .)ןקורתמ

רוזאלעתיגופסתרזעבי/ץחל-

ןמטחמהתאי/אצוה,הקרזהה

.רועה

רוזאתאתונידעבתוסעלשי-

ןפגרמצתיגופסםעהקרזהה

.השבי הזג וא

םיטירפהלכתאךילשהלשי-

.הקרזהה תא תמייסש רחאל

,הקרזההםותבדימךילשהלשי-

תא.םיאתמםוקמלקרזמהתא

ילכךותלךילשהלשיטחמה

.ףוסיא

?ףיברב שומישב ךישמהל שי ןמז המכ

תוארוהרחאאלמלשי.אפורהידי-לעועבקייומויסדעומולופיטהךשמ

.אפורב ץעוויהל ילב לופיטה תא קיספהל ןיא .אפורה

?ףיבר לש תפדוע הנמ יתקרזה םא תושעל המ

.דימ אפורה לא רשקתהל שי ,תפדוע הנמ לש הרקמב

?הנמ לע יתגליד םא תושעל המ

לופיטהתנמלשאבהםויהמהקרזהבךישמהלשיהזכהרקמב

1'סמ רויא

REB 11.10-p4-27.12.10

REB 11.10

PATIENT PACKAGE INSERT IN ACCORDANCE WITH

THE PHARMACISTS' REGULATIONS (PREPARATIONS) - 1986

The dispensing of this medicine

requires a doctor's prescription

Read this package insert carefully

in its entirety before using this medicine

The format of this leaflet was determined by the

Ministry of Health and its content was checked

and approved in November 2010

REBIF ® 22 mcg

REBIF ® 44 mcg

Solution for Subcutaneous Injection

Pre-filled syringe

Cartridge for insertion into syringe

Composition of the active ingredient and its quantity:

Interferon beta-1a

Eachpre-filledsyringeofRebif22mcgincludingneedle-

contains:

22micrograms)6 million IU(of interferon beta-1a in 0.5 ml.

The preparation contains 2.5 mg benzyl alcohol.

Eachpre-filledsyringeofRebif44mcgincludingneedle-

contains:

44micrograms)12 million IU(of interferon beta-1a in 0.5 ml.

The preparation contains 2.5 mg benzyl alcohol.

EachcartridgeofRebif22mcginsertedintoanappropriatesyringe

- contains:

66micrograms)18 million IU(of interferon beta-1a in 1.5 ml.

The preparation contains 7.5 mg benzyl alcohol.

EachcartridgeofRebif44mcginsertedintoanappropriatesyringe

- contains:

132micrograms)36 million IU(of interferon beta-1a in 1.5 ml.

The preparation contains 7.5 mg benzyl alcohol.

Inactive ingredients:

Mannitol,poloxamer188,L-methionine,benzylalcohol,sodium

acetate, acetic acid, sodium hydroxide and water for injections

Therapeutic group:

Immunostimulants - Interferons.

Therapeutic activity:

Rebif ® )interferonbeta-1a(belongstoaclassofmedicines

knownasinterferons.Thesearenaturalsubstancesthattransmit

messagesbetweencells.Interferonsareproducedbythebodyand

playanessentialroleintheimmunesystem.Throughamechanism

thatisnottotallyunderstood,interferonshelptolimitthecentral

nervoussystemdamageassociatedwithmultiplesclerosis.

Rebifisapurifiedsolubleinterferon-proteinproducedbygenetic

engineeringthatissimilartothenaturalinterferonbetaproduced

inthehumanbody,isusedforthetreatmentofrelapsingmultiple

sclerosis, reducesthefrequency andtheseverityofrelapses and

slows the progression of the disease.

When should the preparation not be used?

Do not use the medicine if you are pregnant or if you are

breastfeeding.

Do not use if there is a known sensitivity to natural or recombinant

interferon beta or to any of the medicine’s ingredients.

Do not use in case you are severely depressed.

Donottakethismedicinewithoutconsultingadoctorbefore

starting treatment:

YoumustnotstarttouseRebififyouarepregnant.Whiletaking

Rebifwomenofchildbearingagemustusecontraceptivemeasures.

Ifyoudobecomepregnantorplantobecomepregnant,youmust

report to and consult with a doctor!

Informyourdoctorifyouarebreastfeeding;Rebifisnot

recommended for use when breastfeeding.

Informyourdoctorifyouaresuffering,orhavesufferedinthepast,

fromimpairedfunctionoftheheartand/orvascularsystem,theliver,

thekidney,theurinarysystem,frombonemarrowproblems,thyroid

glandproblems,ifyousufferedfromseveredepressionorepileptic

attacks, so that the doctor can closely monitor your treatment.

BeforeusingRebif,youmustinformyourdoctorifyouareallergic

How will this medicine affect your daily life?

Useofthismedicineorthestateofyourailmentmayaffectyour

abilitytodriveortooperatedangerousmachinery.Incaseof

concern consult your doctor.

Warnings:

Rebifshouldbeusedonlyunderadoctor'ssupervisionand

accordingtothedosageandtreatmentregimen,recommended

by him.

Beforeusereadtheleafletandfollowtheinstructionsforuse,in

ordertopreventtheriskofnecrosis)damagetotheskinandtissue(

attheinjectionsite,whichhasbeenreportedbypatientstreated

withRebif. If you notice a problem, refer to your doctor.

This preparation contains benzyl alcohol. Do not administer it to

premature babies and neonates.

Thepreparationmaycauseatoxicreactionandallergicreactions

in infants and children under 3 years of age.

During treatment blood, liver function and thyroid gland function

tests should be performed.

Ifyouaresensitivetoanytypeoffoodormedicine,informyour

doctor before commencing treatment with this medicine.

Do not discontinue treatment with this medicine without consulting

your doctor.

Drug interactions:

Ifyouaretakinganothermedicine,includingnon-prescription

medicines,orifyouhavejustfinishedtreatmentwithanother

medicine,informtheattendingdoctor,inordertopreventhazards

orlackofefficacyarisingfromdruginteractions,especiallywhen

taking antidepressants and antiepileptics concomitantly.

Side effects:

Inadditiontothedesiredeffectofthemedicine,adversereactions

mayoccurduringthecourseoftakingthismedicine,buttheydo

not occur in everyone.

Very common side effects)1 case in 10 patients(:

Flu-like symptoms, such as: headache, fever, chill, muscle and

jointpains,fatigueandnausea.Theseeffectsaremoderate,

areusuallymorecommonatthestartoftreatment,andmostof

themsubsideastreatmentcontinues.Inordertoreducethese

symptoms,yourdoctormayadviseyoutotakeafever-reducing

painkillerbeforestartingtheinjectionandfor24hoursaftereach

injection.

At the injection site there may be a reaction of redness,

swelling,discoloration,inflammation,pain,andaskinproblem

-theoccurrenceofinjectionsitereactionsusuallydecreases

overtime.Tissuedamage)necrosis(,abscessormassatthe

injectionsitearenotcommon.Insomecases,theinjectionsite

canbecomeinfected,theskinmaybecomeswollen,tender,

hard and very painful. In such cases, refer to the doctor.

There may be changes in a number of laboratory test results.

Thesechangesarenotusuallynoticedbythepatientsince

theyarenotaccompaniedbysymptomsandtheyaregenerally

moderateandsubsideanddonotrequireanyspecialtreatment.

Incasessuchas:adecreaseinthenumberofredandwhite

bloodcellsorplatelets,theremaybesymptomsresultingfrom

thesechanges,e.g.,tiredness,reducedabilitytofightinfection,

bruisingorunexplainedbleeding,liverfunctiontestdisturbances.

Inflammationoftheliverhasalsobeenreported)frequencynot

known(.

Ifyouexperiencesymptomssuggestingaliverfunctiondisorder,

suchaslossofappetiteaccompaniedbynausea,vomiting,

jaundice, refer to the doctor immediately.

Common side effects)1-10 cases in 100 patients(:

Depression is common in multiple sclerosis patients. If you feel

depressed, refer to the doctor immediately.

Uncommon side effects)1-10 cases in 1,000 patients(:

Thyroid dysfunction, the thyroid gland may be over- or

underactive.Thesechangesandtheirsymptomsaremostly

notfeltbythepatient.Yourdoctormayrecommendtoyouthe

appropriate tests.

Side effects of unknown frequency:

Pseudo-relapse of multiple sclerosis - There is a possibility that

atthebeginningoftreatmentwithRebifyouwillexperience

symptomsthatresemblethoseofamultiplesclerosisrelapse.

For example, your muscles may feel very tense or very weak,

preventingyoufrommovingasyouwish.Insomecasessuch

symptomsareassociatedwithfeverorflu-likesymptomsas

describedinthissection.Ifyounoticeanyoftheseeffects,

inform your doctor.

Other possible side effects:

Common: sleeping difficulties, diarrhea, nausea, vomiting,

itchingandskinrash,muscleandjointpain,fatigue,feverand

chills.

Frequency not known: allergic (hypersensitivity) reactions,

swellingoftheface,hives,suicideattempt,epilepticseizures,

seriousskinreactions-somewithmucosallesions,liver

inflammation)hepatitis(,hairloss,breathingdifficulties,blood

clotssuchasdeepvenousthrombosis,disordersoftheretina,

suchasinflammationorbloodclotswithconsequentvision

disorders)visiondisturbancesorlossofvision(,thrombotic

thrombocytopenicpurpuraorhemolyticuremicsyndrome:a

disordercharacterizedbysmallbloodclots,increasedbruising,

bleeding,decreasedplatelets,anemia,extremeweakness,and

kidney disorders.

Also reported with unknown frequency: dizziness, nervousness,

lossofappetite,dilatationofthebloodvesselsandpalpitations,

changes in menstrual cycle.

Do not stop taking or change the medicine without the doctor’s

instruction.

Side effects that require special attention:

Refertothedoctorforurgentmedicalhelpandstoptreatment

with Rebif in the following cases:

In cases of serious allergic reactions. If immediately after taking

adoseofRebifyouexperiencesuddendifficultybreathingthat

maybeaccompaniedbyswellingoftheface,lips,tongueor

throat,skinrash,tinglingalloverthebody,weaknessandloss

ofconsciousness.Iftheseeffectsoccur,youmustrefertothe

doctor or a medical center for emergency conditions.

You must notify the doctor immediately if you experience

symptomsofliverproblems:jaundice)yellowingoftheskin

orwhitesoftheeyes(,widespreadstinging,lossofappetite

accompaniedbynauseaandvomitingandbruisingoftheskin.

Severeliverproblemscanbeassociatedwithadditionalsigns,

e.g., difficulty concentrating, sleepiness and confusion.

If you feel very depressed or develop thoughts of suicide. Refer

to the doctor immediately.

Intheeventthatyouexperiencesideeffectsnotmentionedin

thisleaflet,orifsideeffectworsen,orifthereisachangeinyour

general health, consult your doctor immediately.

Dosage:

Dosage is according to doctor's instructions only. The doctor will

determinethedosageandtreatmentregimenforadultsfrom16

years of age and for adolescents from 12 years of age.

Thedoserecommendedbythedoctorshouldbeadministered

threetimesperweek,onthesamedays,atintervalsofatleast

48hours.Itisadvisabletoalwaysinjectthedoseatthesametime,

preferably in the evening.

Do not exceed the recommended dose.

Itisadvisabletoadjusttothelowerdose)22mcg(giventhreetimes

perweekforpatientswhocannottoleratethehigherdoseand

adolescents from the age of12 years.

Thismedicineisnotusuallyintendedforadministrationtoinfants

and children under 12 years of age.

Directions for use:

Rebifis presented:

In a syringe filled with solution, ready for injection with a needle

attachedtothesyringeintendedforselfinjectionunderthe

skin.

As a cartridge to be inserted into an appropriate syringe intended

for a cartridge, for self injection under the skin.

Itisadvisabletoadministerthefirstinjectioninthepresenceofa

person from a medical team.

Youorafamilymember,afriendorcaregiver,shouldbeinstructed

ontheuseoftheRebifsyringeorRebifcartridgeforinsertioninto

anappropriatesyringe,sothatinjectionofthepreparationcan

be done at home.

BeforestartingtouseRebif,youshouldcarefullyreadand

followtheinstructionsforusingRebifinthisleaflet,inorderto

minimizetheriskofdamageandnecrosisattheinjectionsite.If

youexperienceaproblematiclocalreactionattheinjectionsite,

inform your doctor.

Thispreparationisforyourpersonaluseonly.Usethepreparation

onlyifthesolutionisclear,withoutparticlesandwithnoharmto

the preparation.

TheeffectofRebifisnotfeltimmediately.Therefore,inorderto

achievethedesiredresult,donotchangethetreatmentdoseor

treatmentregimen,anddonotstoptreatmentwiththismedicine

without consulting your doctor. For any question about Rebif,refer

to the doctor, pharmacist or the medical team.

Ifyouforgottoinjectthedose,donottakeadoubledose;but

according to the treatment regimen.

TheeffectofRebifmaynotbenoticedimmediately,butyoushould

continue to use it in order to achieve the desired result. If you are

concerned about this matter, refer to your doctor.

Attention:

Do not swallow!

This medicine is intended for injection only.

Avoid poisoning!

Thismedicine,andallothermedicines,mustbestoredinasafe

placeoutofthereachandsightofchildrenand/orinfants,toavoid

poisoning.

Ifyouhavetakenanoverdose,orifachildhasaccidentally

swallowedthemedicine,proceedimmediatelytoahospital

emergencyroomandbringthepackageofthemedicinewith

you.

Do not induce vomitingunlessexplicitlyinstructedtodosoby

a doctor!

Thismedicinehasbeenprescribedforthetreatmentofyour

ailment; in another patient it may cause harm.

Donotgivethismedicinetoyourrelatives,neighborsor

acquaintances.

Do not take medicines in the dark!Checkthelabelandthedose

eachtimeyoutakeyourmedicine.Wearglassesifyouneed

them.

Storage:

Keep out of the reach and sight of children.

Storethemedicineinarefrigeratorbetween2 o Cto8 o C. Do not

freeze! Do not store near the wall of the refrigerator adjacent to the

freezer, in order to prevent the possibility of freezing.

Store in the original package to protect from light.

For the patient's convenient use, Rebifcanberemovedfromthe

refrigeratorandstoredbelow25 o Cupto14daysonly,forone

singletime.Itmustthenbereturnedtotherefrigeratorandused

before the expiry date.

Cartridge:afterthefirstinjectionofRebifinacartridgeitmustbe

used within 28 days.

Evenifkeptintheiroriginalcontainerandstoredasrecommended,

medicines may be kept for a limited period only. Do not use this

medicine beyond the expiry date marked on the package. Please

notetheexpirydateofthemedicine!Incaseofdoubt,consultthe

pharmacist who dispensed the medicine to you.

Storethemedicineinitsoriginalpackageinordertoprotectit

from light.

Do not store different medications in the same package.

Do not use the medicine if you see that it is damaged.

Anyunusedmedicineshouldnotbethrownawayintheusual

manner,butdiscardedinabinintendedformedicines,inorderto

protect the environment.

License number:

Rebif 22 mcg:110.94.29437.06

Rebif 44 mcg:116.35.29814.06

Manufacturer:

Merck Serono S.A., Geneva, Switzerland.

License holder:

Instructions for Using Rebif ®

1.TheRebifcartridge,intendedforuseinanappropriatesyringe,

shouldbeusedaccordingtotheinstructionstobefound

separately in the syringe kit.

2.ForRebifinapre-filledsyringetheinstructionsareas

follows:

Tobeusedonlyafterconsultingthedoctor,medicalteam

and/ortheinstructingnursewithregardtoadministrationof

the injection.

Dosage:

Rebifispresentedintwodosagestrengths,22microgramsand

44 micrograms.

Therecommendeddosageis22micrograms)from12yearsofage(

or44micrograms)from16yearsofage(,threetimesaweek.The

dosage and treatment regimen will be determined by the doctor.

Itisrecommendedtoinjectthemedicineonthreefixeddaysofthe

week)forexample:Sunday,Tuesday,Thursday(andatthesame

time)preferably in the evening(.

Inordertoachievethedesiredresultyoushouldcontinuetotake

the medicine regularly.

Rebifis intended for subcutaneous injection.

Thefirstinjectionshouldbeadministeredunderthesupervision

of the attending doctor.

Do not use Rebififyounoticethatthesolutionisunclearorcontains

particles.

Rebifisintendedforsubcutaneousinjection.You,afamilymember

or friend can inject the medicine safely at home. For injection of Rebif

in a pre-filled syringe, read the following instructions carefully.

Subcutaneous (under the skin) injection

-Chooseaninjectionsite.Yourdoctorwilladviseyouaboutthe

possibleinjectionsites)recommendedsitesincludetheupper

thighandthelowerabdomen(.Holdthesyringeasyouwould

holdapencil.Itisrecommendedthatyoukeeptrackofand

rotateyourinjectionsites,sothatoneareaisnotinjectedtoo

frequently,inordertominimizetheriskofdamageandnecrosis

at the injection site.

-Note: Do not inject in areas where you feel lumps, local swelling,

or pain. Talk to the doctor or nurse if you discover such areas.

-Wash your hands thoroughly with soap and water.

-RemovetheRebifsyringefromitspackbypeelingbackthe

plastic cover.

-Useanalcoholwipetocleantheskinattheinjectionsite.

Lettheskindry.Ifsomeofalcoholisleftontheskin,youmay

feel a burning sensation.

-Gentlypinchtheskinaround

thesite)toliftitupslightly(.See

Figure No. 1.

-Restingyourwristontheskin

neartheinjectionsite,insertthe

needleatarightanglestraight

intotheskinwithaquick,firm

motion. See Figure No. 2.

-Injectthemedicinebyusing

aslow,steadypush)pushthe

plungerallthewayinuntilthe

syringe is empty). See Figure

No. 2.

- Press on the injection site with

aswab,andremovetheneedle

from the skin.

-Gentlymassagetheinjectionsite

with a dry cotton ball or gauze.

- Dispose of all used items once

you have finished the injection.

-Immediatelyfollowingthe

injectiondiscardthesyringein

an appropriate disposal unit.

Discard the needle in a

receptacle for collection.

How long should you continue using Rebif?

Thedurationandtheendoftreatmentwillbedeterminedbyyour

doctor. Follow the doctor’s instructions. You should not discontinue

the treatment without consulting your doctor.

What to do if you inject more Rebif than you should?

In case of overdose, contact your doctor immediately.

What to do if you miss a dose?

Insuchacase,continuetoinjectfromthenextscheduleddosing

Fig. No. 1

REB 11.10-p4-27.12.10

PATIENT PACKAGE INSERT IN ACCORDANCE WITH

THE PHARMACISTS' REGULATIONS (PREPARATIONS) - 1986

The dispensing of this medicine

requires a doctor's prescription

Read this package insert carefully

in its entirety before using this medicine

The format of this leaflet was determined by the

Ministry of Health and its content was checked

and approved in November 2010

REBIF ® 22 mcg

REBIF ® 44 mcg

Solution for Subcutaneous Injection

Pre-filled syringe

Cartridge for insertion into syringe

Composition of the active ingredient and its quantity:

Interferon beta-1a

Eachpre-filledsyringeofRebif22mcgincludingneedle-

contains:

22micrograms)6 million IU(of interferon beta-1a in 0.5 ml.

The preparation contains 2.5 mg benzyl alcohol.

Eachpre-filledsyringeofRebif44mcgincludingneedle-

contains:

44micrograms)12 million IU(of interferon beta-1a in 0.5 ml.

The preparation contains 2.5 mg benzyl alcohol.

EachcartridgeofRebif22mcginsertedintoanappropriatesyringe

- contains:

66micrograms)18 million IU(of interferon beta-1a in 1.5 ml.

The preparation contains 7.5 mg benzyl alcohol.

EachcartridgeofRebif44mcginsertedintoanappropriatesyringe

- contains:

132micrograms)36 million IU(of interferon beta-1a in 1.5 ml.

The preparation contains 7.5 mg benzyl alcohol.

Inactive ingredients:

Mannitol,poloxamer188,L-methionine,benzylalcohol,sodium

acetate, acetic acid, sodium hydroxide and water for injections

Therapeutic group:

Immunostimulants - Interferons.

Therapeutic activity:

Rebif ® )interferonbeta-1a(belongstoaclassofmedicines

knownasinterferons.Thesearenaturalsubstancesthattransmit

messagesbetweencells.Interferonsareproducedbythebodyand

playanessentialroleintheimmunesystem.Throughamechanism

thatisnottotallyunderstood,interferonshelptolimitthecentral

nervoussystemdamageassociatedwithmultiplesclerosis.

Rebifisapurifiedsolubleinterferon-proteinproducedbygenetic

engineeringthatissimilartothenaturalinterferonbetaproduced

inthehumanbody,isusedforthetreatmentofrelapsingmultiple

sclerosis, reducesthefrequency andtheseverityofrelapses and

slows the progression of the disease.

When should the preparation not be used?

Do not use the medicine if you are pregnant or if you are

breastfeeding.

Do not use if there is a known sensitivity to natural or recombinant

interferon beta or to any of the medicine’s ingredients.

Do not use in case you are severely depressed.

Donottakethismedicinewithoutconsultingadoctorbefore

starting treatment:

YoumustnotstarttouseRebififyouarepregnant.Whiletaking

Rebifwomenofchildbearingagemustusecontraceptivemeasures.

Ifyoudobecomepregnantorplantobecomepregnant,youmust

report to and consult with a doctor!

Informyourdoctorifyouarebreastfeeding;Rebifisnot

recommended for use when breastfeeding.

Informyourdoctorifyouaresuffering,orhavesufferedinthepast,

fromimpairedfunctionoftheheartand/orvascularsystem,theliver,

thekidney,theurinarysystem,frombonemarrowproblems,thyroid

glandproblems,ifyousufferedfromseveredepressionorepileptic

attacks, so that the doctor can closely monitor your treatment.

BeforeusingRebif,youmustinformyourdoctorifyouareallergic

How will this medicine affect your daily life?

Useofthismedicineorthestateofyourailmentmayaffectyour

abilitytodriveortooperatedangerousmachinery.Incaseof

concern consult your doctor.

Warnings:

Rebifshouldbeusedonlyunderadoctor'ssupervisionand

accordingtothedosageandtreatmentregimen,recommended

by him.

Beforeusereadtheleafletandfollowtheinstructionsforuse,in

ordertopreventtheriskofnecrosis)damagetotheskinandtissue(

attheinjectionsite,whichhasbeenreportedbypatientstreated

withRebif. If you notice a problem, refer to your doctor.

This preparation contains benzyl alcohol. Do not administer it to

premature babies and neonates.

Thepreparationmaycauseatoxicreactionandallergicreactions

in infants and children under 3 years of age.

During treatment blood, liver function and thyroid gland function

tests should be performed.

Ifyouaresensitivetoanytypeoffoodormedicine,informyour

doctor before commencing treatment with this medicine.

Do not discontinue treatment with this medicine without consulting

your doctor.

Drug interactions:

Ifyouaretakinganothermedicine,includingnon-prescription

medicines,orifyouhavejustfinishedtreatmentwithanother

medicine,informtheattendingdoctor,inordertopreventhazards

orlackofefficacyarisingfromdruginteractions,especiallywhen

taking antidepressants and antiepileptics concomitantly.

Side effects:

Inadditiontothedesiredeffectofthemedicine,adversereactions

mayoccurduringthecourseoftakingthismedicine,buttheydo

not occur in everyone.

Very common side effects)1 case in 10 patients(:

Flu-like symptoms, such as: headache, fever, chill, muscle and

jointpains,fatigueandnausea.Theseeffectsaremoderate,

areusuallymorecommonatthestartoftreatment,andmostof

themsubsideastreatmentcontinues.Inordertoreducethese

symptoms,yourdoctormayadviseyoutotakeafever-reducing

painkillerbeforestartingtheinjectionandfor24hoursaftereach

injection.

At the injection site there may be a reaction of redness,

swelling,discoloration,inflammation,pain,andaskinproblem

-theoccurrenceofinjectionsitereactionsusuallydecreases

overtime.Tissuedamage)necrosis(,abscessormassatthe

injectionsitearenotcommon.Insomecases,theinjectionsite

canbecomeinfected,theskinmaybecomeswollen,tender,

hard and very painful. In such cases, refer to the doctor.

There may be changes in a number of laboratory test results.

Thesechangesarenotusuallynoticedbythepatientsince

theyarenotaccompaniedbysymptomsandtheyaregenerally

moderateandsubsideanddonotrequireanyspecialtreatment.

Incasessuchas:adecreaseinthenumberofredandwhite

bloodcellsorplatelets,theremaybesymptomsresultingfrom

thesechanges,e.g.,tiredness,reducedabilitytofightinfection,

bruisingorunexplainedbleeding,liverfunctiontestdisturbances.

Inflammationoftheliverhasalsobeenreported)frequencynot

known(.

Ifyouexperiencesymptomssuggestingaliverfunctiondisorder,

suchaslossofappetiteaccompaniedbynausea,vomiting,

jaundice, refer to the doctor immediately.

Common side effects)1-10 cases in 100 patients(:

Depression is common in multiple sclerosis patients. If you feel

depressed, refer to the doctor immediately.

Uncommon side effects)1-10 cases in 1,000 patients(:

Thyroid dysfunction, the thyroid gland may be over- or

underactive.Thesechangesandtheirsymptomsaremostly

notfeltbythepatient.Yourdoctormayrecommendtoyouthe

appropriate tests.

Side effects of unknown frequency:

Pseudo-relapse of multiple sclerosis - There is a possibility that

atthebeginningoftreatmentwithRebifyouwillexperience

symptomsthatresemblethoseofamultiplesclerosisrelapse.

For example, your muscles may feel very tense or very weak,

preventingyoufrommovingasyouwish.Insomecasessuch

symptomsareassociatedwithfeverorflu-likesymptomsas

describedinthissection.Ifyounoticeanyoftheseeffects,

inform your doctor.

Other possible side effects:

Common: sleeping difficulties, diarrhea, nausea, vomiting,

itchingandskinrash,muscleandjointpain,fatigue,feverand

chills.

Frequency not known: allergic (hypersensitivity) reactions,

swellingoftheface,hives,suicideattempt,epilepticseizures,

seriousskinreactions-somewithmucosallesions,liver

inflammation)hepatitis(,hairloss,breathingdifficulties,blood

clotssuchasdeepvenousthrombosis,disordersoftheretina,

suchasinflammationorbloodclotswithconsequentvision

disorders)visiondisturbancesorlossofvision(,thrombotic

thrombocytopenicpurpuraorhemolyticuremicsyndrome:a

disordercharacterizedbysmallbloodclots,increasedbruising,

bleeding,decreasedplatelets,anemia,extremeweakness,and

kidney disorders.

Also reported with unknown frequency: dizziness, nervousness,

lossofappetite,dilatationofthebloodvesselsandpalpitations,

changes in menstrual cycle.

Do not stop taking or change the medicine without the doctor’s

instruction.

Side effects that require special attention:

Refertothedoctorforurgentmedicalhelpandstoptreatment

with Rebif in the following cases:

In cases of serious allergic reactions. If immediately after taking

adoseofRebifyouexperiencesuddendifficultybreathingthat

maybeaccompaniedbyswellingoftheface,lips,tongueor

throat,skinrash,tinglingalloverthebody,weaknessandloss

ofconsciousness.Iftheseeffectsoccur,youmustrefertothe

doctor or a medical center for emergency conditions.

You must notify the doctor immediately if you experience

symptomsofliverproblems:jaundice)yellowingoftheskin

orwhitesoftheeyes(,widespreadstinging,lossofappetite

accompaniedbynauseaandvomitingandbruisingoftheskin.

Severeliverproblemscanbeassociatedwithadditionalsigns,

e.g., difficulty concentrating, sleepiness and confusion.

If you feel very depressed or develop thoughts of suicide. Refer

to the doctor immediately.

Intheeventthatyouexperiencesideeffectsnotmentionedin

thisleaflet,orifsideeffectworsen,orifthereisachangeinyour

general health, consult your doctor immediately.

Dosage:

Dosage is according to doctor's instructions only. The doctor will

determinethedosageandtreatmentregimenforadultsfrom16

years of age and for adolescents from 12 years of age.

Thedoserecommendedbythedoctorshouldbeadministered

threetimesperweek,onthesamedays,atintervalsofatleast

48hours.Itisadvisabletoalwaysinjectthedoseatthesametime,

preferably in the evening.

Do not exceed the recommended dose.

Itisadvisabletoadjusttothelowerdose)22mcg(giventhreetimes

perweekforpatientswhocannottoleratethehigherdoseand

adolescents from the age of12 years.

Thismedicineisnotusuallyintendedforadministrationtoinfants

and children under 12 years of age.

Directions for use:

Rebifis presented:

In a syringe filled with solution, ready for injection with a needle

attachedtothesyringeintendedforselfinjectionunderthe

skin.

As a cartridge to be inserted into an appropriate syringe intended

for a cartridge, for self injection under the skin.

Itisadvisabletoadministerthefirstinjectioninthepresenceofa

person from a medical team.

Youorafamilymember,afriendorcaregiver,shouldbeinstructed

ontheuseoftheRebifsyringeorRebifcartridgeforinsertioninto

anappropriatesyringe,sothatinjectionofthepreparationcan

be done at home.

BeforestartingtouseRebif,youshouldcarefullyreadand

followtheinstructionsforusingRebifinthisleaflet,inorderto

minimizetheriskofdamageandnecrosisattheinjectionsite.If

youexperienceaproblematiclocalreactionattheinjectionsite,

inform your doctor.

Thispreparationisforyourpersonaluseonly.Usethepreparation

onlyifthesolutionisclear,withoutparticlesandwithnoharmto

the preparation.

TheeffectofRebifisnotfeltimmediately.Therefore,inorderto

achievethedesiredresult,donotchangethetreatmentdoseor

treatmentregimen,anddonotstoptreatmentwiththismedicine

without consulting your doctor. For any question about Rebif,refer

to the doctor, pharmacist or the medical team.

Ifyouforgottoinjectthedose,donottakeadoubledose;but

according to the treatment regimen.

TheeffectofRebifmaynotbenoticedimmediately,butyoushould

continue to use it in order to achieve the desired result. If you are

concerned about this matter, refer to your doctor.

Attention:

Do not swallow!

This medicine is intended for injection only.

Avoid poisoning!

Thismedicine,andallothermedicines,mustbestoredinasafe

placeoutofthereachandsightofchildrenand/orinfants,toavoid

poisoning.

Ifyouhavetakenanoverdose,orifachildhasaccidentally

swallowedthemedicine,proceedimmediatelytoahospital

emergencyroomandbringthepackageofthemedicinewith

you.

Do not induce vomitingunlessexplicitlyinstructedtodosoby

a doctor!

Thismedicinehasbeenprescribedforthetreatmentofyour

ailment; in another patient it may cause harm.

Donotgivethismedicinetoyourrelatives,neighborsor

acquaintances.

Do not take medicines in the dark!Checkthelabelandthedose

eachtimeyoutakeyourmedicine.Wearglassesifyouneed

them.

Storage:

Keep out of the reach and sight of children.

Storethemedicineinarefrigeratorbetween2 o Cto8 o C. Do not

freeze! Do not store near the wall of the refrigerator adjacent to the

freezer, in order to prevent the possibility of freezing.

Store in the original package to protect from light.

For the patient's convenient use, Rebifcanberemovedfromthe

refrigeratorandstoredbelow25 o Cupto14daysonly,forone

singletime.Itmustthenbereturnedtotherefrigeratorandused

before the expiry date.

Cartridge:afterthefirstinjectionofRebifinacartridgeitmustbe

used within 28 days.

Evenifkeptintheiroriginalcontainerandstoredasrecommended,

medicines may be kept for a limited period only. Do not use this

medicine beyond the expiry date marked on the package. Please

notetheexpirydateofthemedicine!Incaseofdoubt,consultthe

pharmacist who dispensed the medicine to you.

Storethemedicineinitsoriginalpackageinordertoprotectit

from light.

Do not store different medications in the same package.

Do not use the medicine if you see that it is damaged.

Anyunusedmedicineshouldnotbethrownawayintheusual

manner,butdiscardedinabinintendedformedicines,inorderto

protect the environment.

License number:

Rebif 22 mcg:110.94.29437.06

Rebif 44 mcg:116.35.29814.06

Manufacturer:

Merck Serono S.A., Geneva, Switzerland.

License holder:

Instructions for Using Rebif ®

1.TheRebifcartridge,intendedforuseinanappropriatesyringe,

shouldbeusedaccordingtotheinstructionstobefound

separately in the syringe kit.

2.ForRebifinapre-filledsyringetheinstructionsareas

follows:

Tobeusedonlyafterconsultingthedoctor,medicalteam

and/ortheinstructingnursewithregardtoadministrationof

the injection.

Dosage:

Rebifispresentedintwodosagestrengths,22microgramsand

44 micrograms.

Therecommendeddosageis22micrograms)from12yearsofage(

or44micrograms)from16yearsofage(,threetimesaweek.The

dosage and treatment regimen will be determined by the doctor.

Itisrecommendedtoinjectthemedicineonthreefixeddaysofthe

week)forexample:Sunday,Tuesday,Thursday(andatthesame

time)preferably in the evening(.

Inordertoachievethedesiredresultyoushouldcontinuetotake

the medicine regularly.

Rebifis intended for subcutaneous injection.

Thefirstinjectionshouldbeadministeredunderthesupervision

of the attending doctor.

Do not use Rebififyounoticethatthesolutionisunclearorcontains

particles.

Rebifisintendedforsubcutaneousinjection.You,afamilymember

or friend can inject the medicine safely at home. For injection of Rebif

in a pre-filled syringe, read the following instructions carefully.

Subcutaneous (under the skin) injection

-Chooseaninjectionsite.Yourdoctorwilladviseyouaboutthe

possibleinjectionsites)recommendedsitesincludetheupper

thighandthelowerabdomen(.Holdthesyringeasyouwould

holdapencil.Itisrecommendedthatyoukeeptrackofand

rotateyourinjectionsites,sothatoneareaisnotinjectedtoo

frequently,inordertominimizetheriskofdamageandnecrosis

at the injection site.

-Note: Do not inject in areas where you feel lumps, local swelling,

or pain. Talk to the doctor or nurse if you discover such areas.

-Wash your hands thoroughly with soap and water.

-RemovetheRebifsyringefromitspackbypeelingbackthe

plastic cover.

-Useanalcoholwipetocleantheskinattheinjectionsite.

Lettheskindry.Ifsomeofalcoholisleftontheskin,youmay

feel a burning sensation.

-Gentlypinchtheskinaround

thesite)toliftitupslightly(.See

Figure No. 1.

-Restingyourwristontheskin

neartheinjectionsite,insertthe

needleatarightanglestraight

intotheskinwithaquick,firm

motion. See Figure No. 2.

-Injectthemedicinebyusing

aslow,steadypush)pushthe

plungerallthewayinuntilthe

syringe is empty). See Figure

No. 2.

- Press on the injection site with

aswab,andremovetheneedle

from the skin.

-Gentlymassagetheinjectionsite

with a dry cotton ball or gauze.

- Dispose of all used items once

you have finished the injection.

-Immediatelyfollowingthe

injectiondiscardthesyringein

an appropriate disposal unit.

Discard the needle in a

receptacle for collection.

How long should you continue using Rebif?

Thedurationandtheendoftreatmentwillbedeterminedbyyour

doctor. Follow the doctor’s instructions. You should not discontinue

the treatment without consulting your doctor.

What to do if you inject more Rebif than you should?

In case of overdose, contact your doctor immediately.

What to do if you miss a dose?

Insuchacase,continuetoinjectfromthenextscheduleddosing

Fig. No. 1

REB 11.10-p4-27.12.10

Prescribing information

REBIF

®

22mcg

REBIF

®

44mcg

1.

NAME OF THE MEDICINAL PRODUCT

Rebif 22 micrograms/0.5 mL solution for injection in pre-filled syringe

Rebif

micrograms/0.5 mL solution for injection in pre-filled syringe

Rebif 22 micrograms/0.5 mL solution for injection in cartridge

Rebif

micrograms/0.5 mL solution for injection in cartridge

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Rebif 22 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe (0.5 mL) contains 22 micrograms (6 MIU*) of

interferon beta-1a**.

Excipient with known effect: 2.5 mg benzyl alcohol.

For the full list of excipients, see section 6.1.

Rebif 44 micrograms solution for injection in pre-filled syringe

Each pre-filled syringe (0.5 mL) contains 44 micrograms (12 MIU*) of

interferon beta-1a**.

Excipient with known effect: 2.5 mg benzyl alcohol

For the full list of excipients, see section 6.1.

Rebif 22 micrograms solution for injection in cartridge

Each pre-filled cartridge contains 66 micrograms (18 MIU*) of interferon beta-1a** in

1.5 mL

solution, corresponding to 44 micrograms/mL.

Excipient with known effect: 7.5 mg benzyl alcohol

For the full list of excipients, see section 6.1.

Rebif 44 micrograms solution for injection in cartridge

Each pre-filled cartridge contains 132 micrograms (36 MIU*) of interferon beta-1a** in

1.5 mL

solution, corresponding to 88 micrograms/mL.

Excipient with known effect: 7.5 mg benzyl alcohol

For the full list of excipients, see section 6.1.

* Million International Units, measured by cytopathic effect (CPE) bioassay against the

in-house

interferon beta-1a standard which is calibrated against the current

international NIH standard (GB-23-902-531).

** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA

technology.

3.

PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe

Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/L.

Solution for injection in a cartridge

Clear to opalescent solution, with pH 3.7 to 4.1 and osmolarity 250 to 450 mOsm/L.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Rebif

22/44 mcg is indicated for the treatment of patients with relapsing forms

of multiple sclerosis to decrease the frequency of clinical exacerbations and

delay

the accumulation of physical disability. Efficacy of Rebif in chronic progressive

multiple sclerosis has not been established.

Rebif 44 mcg is indicated for the treatment of patients with a single

demyelinating event with an active inflammatory process, if alternative

diagnoses have been excluded, and if they are determined to be at high risk of

developing clinically definite multiple sclerosis (see section 5.1). These patients

should have MRI findings which are compatible with the diagnosis of multiple

sclerosis.

Efficacy has not been demonstrated in patients with secondary progressive multiple

sclerosis without ongoing relapse activity (see section 5.1).

4.2

Posology and method of administration

Treatment should be initiated under supervision of a physician experienced in the

treatment of the disease.

Rebif is available in two strengths: 22 micrograms and 44 micrograms.

Posology

When first starting treatment with Rebif, the dose should be gradually escalated in

order to allow tachyphylaxis to develop thus reducing adverse reactions. It is

recommended that patients be started according to the doctor recommended dose

subcutaneously.

When first starting treatment it is recommended that 8.8 micrograms (0.1 ml of the 44

mcg strength or 0.2 ml of the 22 mcg strength) be administered by subcutaneous

injection three times per week during the initial 2 weeks of therapy. Thereafter, 22

micrograms (0.25 ml of the 44 mcg strength or the total of 22 mcg strength) be

administered by subcutaneous injection three times per week in weeks 3 and 4, and

the total of the 44 micrograms strength be administered from the fifth week onwards.

First demyelinating event

The posology for patients who have experienced a first demyelinating event is

44 micrograms of Rebif given three times per week by subcutaneous injection.

Relapsing multiple sclerosis

The recommended posology of Rebif is 44 micrograms given three times per week by

subcutaneous injection. A lower dose of 22 micrograms, also given three times per

week by subcutaneous injection, is recommended for patients who cannot tolerate the

higher dose in view of the treating specialist.

Paediatric population

No formal clinical trials or pharmacokinetic studies have been conducted in children or

adolescents. However, a paediatric retrospective cohort study collected safety data

with Rebif from medical records in children (n=52) and adolescents (n=255). The

results of this study suggest that the safety profile in children (2 to 11 years old) and

in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or 44 micrograms

subcutaneous three times per week is similar to that seen in adults.

The safety and efficacy of Rebif in children below 2 years of age have not yet been

established. Rebif should not be used in this age group.

Method of administration

Rebif is administered by subcutaneous injection, in a pre-filled-syringe or in cartridge.

Prior to injection and for an additional 24 hours after each injection, an antipyretic

analgesic is advised to decrease flu-like symptoms associated with Rebif

administration.

Rebif solution for subcutaneous injection in cartridge is intended for multidose use with

RebiSmart electronic injection device following adequate training of the patient and/or

carer.

For administration, the instructions provided in the package leaflet and in the

instruction manual provided with RebiSmart autoinjector should be followed.

At the present time, it is not known for how long patients should be treated. Safety and

efficacy with Rebif have not been demonstrated beyond 4 years of treatment. It is

recommended that patients should be evaluated at least every second year in the

4-year period after initiation of treatment with Rebif and a decision for longer term

treatment should then be made on an individual basis by the treating physician.

4.3

Contraindications

Hypersensitivity to natural or recombinant interferon beta or to any excipients

listed in section 6.1.

Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8).

4.4

Special warnings and precautions for use

Traceability

In order to imporve the traceabilty of biological medicinal products, the name and the

batch number of the administered product should be clearly recorded.

General recommendations

Patients should be informed of the most frequent adverse reactions associated with

interferon beta administration, including symptoms of the flu-like syndrome (see

section 4.8). These symptoms tend to be most prominent at the initiation of therapy

and decrease in frequency and severity with continued treatment.

Thrombotic microangiopathy (TMA)

Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic

purpura (TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, have been

reported with interferon beta products. Events were reported at various time points

during treatment and may occur several weeks to several years after starting

treatment with interferon beta. Early clinical features include thrombocytopenia, new

onset hypertension, fever, central nervous system symptoms (e.g. confusion, paresis)

and impaired renal function. Laboratory findings suggestive of TMA include decreased

platelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and

schistocytes (erythrocyte fragmentation) on a blood film. Therefore if clinical features

of TMA are observed,

further testing of blood platelet levels, serum LDH, blood films and renal function is

recommended. If TMA is diagnosed, prompt treatment is required (considering plasma

exchange) and immediate discontinuation of Rebif is recommended.

Depression and suicidal ideation

Rebif should be administered with caution to patients with previous or current

depressive disorders in particular to those with antecedents of suicidal ideation (see

section 4.3). Depression and suicidal ideation are known to occur in increased

frequency in the multiple sclerosis population and in association with interferon use.

Patients treated with Rebif should be advised to immediately report any symptoms of

depression and/or suicidal ideation to their prescribing physician. Patients exhibiting

depression should be monitored closely during therapy with Rebif and treated

appropriately. Cessation of therapy with Rebif should be considered (see sections 4.3

and 4.8).

Seizure disorders

Rebif should be administered with caution to patients with a history of seizures, to

those receiving treatment with anti-epileptics, particularly if their epilepsy is not

adequately controlled with antiepileptics (see sections 4.5 and 4.8).

Cardiac disease

Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia,

should be closely monitored for worsening of their clinical condition during initiation of

therapy with interferon beta-1a. Symptoms of the flu-like syndrome associated with

interferon beta-1a therapy may prove stressful to patients with cardiac conditions.

Injection site necrosis

Injection site necrosis (ISN) has been reported in patients using Rebif (see section

4.8). To minimise the risk of injection site necrosis patients should be advised to:

use an aseptic injection technique.

rotate the injection sites with each dose.

The procedure for the self-administration by the patient should be reviewed periodically

especially if injection site reactions have occurred.

If the patient experiences any break in the skin, which may be associated with swelling

or drainage of fluid from the injection site, the patient should be advised to consult

with their physician before continuing injections with Rebif. If the patient has multiple

lesions, Rebif should be discontinued until healing has occurred. Patients with single

lesions may continue provided that the necrosis is not too extensive.

Hepatic dysfunction

In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases

(particularly alanine aminotransferase (ALT)) were common and 1-3% of patients

developed elevations of hepatic transaminases above 5 times the upper limit of normal

(ULN). In the absence of clinical symptoms, serum ALT levels should be monitored

prior to the start of therapy, at months 1, 3 and 6 on therapy and periodically

thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times the

ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be

initiated with caution in patients with a history of significant liver disease, clinical

evidence of active liver disease, alcohol abuse or increased serum ALT (>2.5 times

ULN). Treatment with Rebif should be stopped if icterus or other clinical symptoms of

liver dysfunction appear.

Rebif, like other interferons beta, has a potential for causing severe liver injury

including acute hepatic failure (see section 4.8). The majority of the cases of severe

liver injury occurred within the first six months of treatment. The mechanism for the

rare symptomatic hepatic dysfunction is not known. No specific risk factors have been

identified.

Renal and urinary disorders

Nephrotic syndrome

Cases of nephrotic syndrome with different underlying nephropathies including

collapsing focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD),

membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy

(MGN) have been reported during treatment with interferon-beta products. Events

were reported at various time points during treatment and may occur after several

years of treatment with interferon-beta. Periodic monitoring of early signs or

symptoms, e.g. oedema, proteinuria and impaired renal function is recommended,

especially in patients at higher risk of renal disease. Prompt treatment of nephrotic

syndrome is required and discontinuation of treatment with Rebif should be considered.

Laboratory abnormalities

Laboratory abnormalities are associated with the use of interferons. The overall

incidence of these is slightly higher with Rebif 44 than Rebif 22 micrograms. Therefore,

in addition to those laboratory tests normally required for monitoring patients with

multiple sclerosis, liver enzyme monitoring and complete and differential blood cell

count, and platelet counts are recommended at regular intervals (1, 3 and 6 months)

following introduction of Rebif therapy and then periodically thereafter in the absence

of clinical symptoms. These should be more frequent when initiating Rebif 44

micrograms.

Thyroid disorders

Patients being treated with Rebif may occasionally develop new or worsening thyroid

abnormalities. Thyroid function testing is recommended at baseline and if abnormal,

every 6-12 months following initiation of therapy. If tests are normal at baseline,

routine testing is not needed but should be performed if clinical findings of thyroid

dysfunction appear (see section 4.8).

Severe renal or hepatic failure and severe myelosuppression

Caution should be used, and close monitoring considered when administering

interferon beta-1a to patients with severe renal and hepatic failure and to patients with

severe myelosuppression.

Neutralising antibodies

Serum neutralising antibodies against interferon beta-1a may develop. The precise

incidence of antibodies is as yet uncertain. Clinical data suggest that after 24 to 48

months of treatment with Rebif 22 micrograms, approximately 24% of patients develop

persistent serum antibodies to interferon beta-1a, with Rebif 44 micrograms,

approximately 13 to 14% of patients develop persistent serum antibodies to interferon

beta-1a. The presence of antibodies has been shown to attenuate the

pharmacodynamic response to interferon beta-1a (beta-2 microglobulin and

neopterin). Although the clinical significance of the induction of antibodies has not been

fully elucidated, the development of neutralising antibodies is associated with reduced

efficacy on clinical and MRI variables. If a patient responds poorly to therapy with

Rebif, and has neutralising antibodies, the treating physician should reassess the

benefit/risk ratio of continued Rebif therapy.

The use of various assays to detect serum antibodies and differing definitions of

antibody positivity limits the ability to compare antigenicity among different products.

Other forms of multiple sclerosis

Only sparse safety and efficacy data are available from non-ambulatory patients with

multiple sclerosis.

Rebif has not yet been investigated in patients with primary progressive multiple

sclerosis and should not be used in these patients.

Benzyl alcohol

This medicinal product contains 2.5 mg benzyl alcohol per dose. It must not be given

to premature babies or neonates. It may cause toxic reactions and anaphylactoid

reactions in infants and children up to 3 years old.

4.5

Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with interferon beta-1a in humans.

Interferons have been reported to reduce the activity of hepatic cytochrome P450-

dependent enzymes in humans and animals. Caution should be exercised when

administering Rebif in combination with medicinal products that have a narrow

therapeutic index and are largely dependent on the hepatic cytochrome P450 system

for clearance, e.g. antiepileptics and some classes of antidepressants.

The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has

not been studied systematically. Clinical studies indicate that multiple sclerosis patients

can receive Rebif and corticosteroids or ACTH during relapses.

4.6

Fertility, pregnancy and lactation

Pregnancy

A large amount of data (more than 1,000 pregnancy outcomes) from registries and

post-marketing experience indicates no increased risk of major congenital anomalies

after pre-conception exposure to interferon beta or such exposure during the first

trimester of pregnancy. However, the duration of exposure during the first trimester is

uncertain, because data were collected when interferon beta use was contraindicated

during pregnancy, and treatment likely interrupted when the pregnancy was detected

and/or confirmed. Experience with exposure during the second and third trimester is

very limited.

Based on animal data (see section 5.3), there is a possibly increased risk for

spontaneous abortion. The risk of spontaneous abortions in pregnant women exposed

to interferon beta cannot adequately be evaluated based on the currently available

data, but the data do not suggest an increased risk so far.

If clinically needed, the use of Rebif may be considered during pregnancy.

Breast-feeding

Limited information available on the transfer of interferon beta-1a into breast milk,

together with the chemical/physiological characteristics of interferon beta, suggests

that levels of interferon beta-1a excreted in human milk are negligible. No harmful

effects on the breastfed newborn/infant are anticipated.

Rebif can be used during breast-feeding

Fertility

The effects of Rebif on fertility have not been investigated.

4.7

Effects on ability to drive and use machines

Central nervous system-related adverse events associated with the use of interferon

beta (e.g. dizziness) might influence the patient's ability to drive or use machines (see

section 4.8).

4.8

Undesirable effects

Summary of the safety profile

The highest incidence of adverse reactions associated with Rebif therapy is related to

flu-like syndrome. Flu-like symptoms tend to be most prominent at the initiation of

therapy and decrease in frequency with continued treatment. Approximately 70% of

patients treated with Rebif can expect to experience the typical interferon flu-like

syndrome within the first six months after starting treatment.

Approximately 30% of patients will also experience reactions at the injection site,

predominantly mild inflammation or erythema. Asymptomatic increases in laboratory

parameters of hepatic function and decreases in white blood cells are also common.

The majority of adverse reactions observed with interferon beta-1a are usually mild

and reversible, and respond well to dose reductions. In case of severe or persistent

undesirable effects, the dose of Rebif may be temporarily lowered or interrupted, at

the discretion of the physician.

List of adverse reactions

The adverse reactions presented have been identified from clinical studies as well as

from post-marketing reports (an asterisk [*] indicates adverse reactions identified

during post-marketing surveillance). The following definitions apply to the frequency

terminology used hereafter: 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), frequency not known (cannot be estimated from the available data).

Blood and the lymphatic system disorders

Very common:

Neutropenia, lymphopenia, leukopenia,

thrombocytopenia,

anaemia

Rare:

Thrombotic microangiopathy including thrombotic

thrombocytopenic purpura/haemolytic uraemic syndrome*

(class label for interferon beta products, see section 4.4),

pancytopenia*

Endocrine disorders

Uncommon:

Thyroid dysfunction, most often presenting as

hypothyroidism or hyperthyroidism

Immune system disorders

Rare:

Anaphylactic reactions*

Hepatobiliary disorders

Very common:

Asymptomatic transaminase increase

Common:

Severe elevations in transaminases

Uncommon:

Hepatitis with or without icterus*

Rare:

Hepatic failure* (see section 4.4), autoimmune hepatitis*

Psychiatric disorders

Common:

Depression, insomnia

Rare:

Suicide attempt*

Nervous system disorders

Very common:

Headache

Uncommon:

Seizures*

Frequency not known:

Transient neurological symptoms (i.e. hypoesthesia, muscle

spasm, paraesthesia, difficulty in walking, musculoskeletal

stiffness) that may mimic multiple sclerosis exacerbations*

Eye disorders

Uncommon:

Retinal vascular disorders (i.e. retinopathy, cotton wool

spots, obstruction of retinal artery or vein)*

Vascular disorders

Uncommon:

Thromboembolic events*

Respiratory, thoracic and mediastinal disorders

Uncommon:

Dyspnoea*

Frequency not known:

Pulmonary arterial hypertension* (class label for interferon

products, see below Pulmonary arterial hypertension)

Gastrointestinal disorders

Common:

Diarrhoea, vomiting, nausea

Skin and subcutaneous tissue disorders

Common:

Pruritus, rash, erythematous rash, maculo-papular rash,

alopecia*

Uncommon:

Urticaria*

Rare:

Quincke’s oedema (angio-oedema)*, erythema multiforme*,

erythema multiforme-like skin reactions*, Stevens Johnson

syndrome*

Musculoskeletal and connective disorders

Common:

Myalgia, arthralgia

Rare:

Drug-induced lupus erythematosus*

Renal and urinary disorders

Rare:

Nephrotic syndrome*, glomerulosclerosis* (see section 4.4)

General disorders and administration site conditions

Very common:

Injection site inflammation, injection site reaction, influenza-

like symptoms

Common:

Injection site pain, fatigue, rigors, fever

Uncommon:

Injection site necrosis, injection site mass, injection site

abscess, injection site infections*, increased sweating*

Rare:

Injection site cellulitis*

Frequency not known:

Panniculitis (occurred in the injection site)

Paediatric population

No formal clinical trials or pharmacokinetic studies have been conducted in children or

adolescents. Limited safety data suggest that the safety profile in children and

adolescents (2 to 17 years old) receiving Rebif 22 micrograms or 44 micrograms three

times weekly is similar to that seen in adults.

Class effects

The administration of interferons has been associated with anorexia, dizziness, anxiety,

arrhythmias, vasodilation and palpitation, menorrhagia and metrorrhagia.

An increased formation of auto-antibodies may occur during treatment with interferon

beta.

Pulmonary arterial hypertension

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon

beta products. Events were reported at various time points including up to several

years after starting treatment with interferon beta.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product.

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

the National Regulation by using an online form

https://sideeffects.health.gov.il/

4.9

Overdose

In case of overdose, patients should be hospitalised for observation and appropriate

supportive treatment should be given.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07.

Interferons are a group of endogenous glycoproteins endowed with

immunomodulatory, antiviral and antiproliferative properties.

Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous

human interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and

is therefore glycosylated like the natural protein.

Regardless of the route of dosing, pronounced pharmacodynamic changes are

associated with the administration of Rebif. After a single dose, intracellular and serum

activity of 2’5’OAS synthetase and serum concentrations of beta-2 microglobulin and

neopterin increase within 24 hours, and start to decline within 2 days. Intramuscular

and subcutaneous administrations produce fully superimposable responses. After

repeated subcutaneous administration every 48 hours for 4 doses, these biological

responses remain elevated, with no signs of tolerance development

Biological response markers (e.g., 2',5'-OAS activity, neopterin and beta 2-

microglobulin) are induced by interferon beta-1a following subcutaneous doses

administered to healthy volunteer subjects. Time to peak concentrations following a

single subcutaneous injection were 24 to 48 hours for neopterin, beta-2-microglobulin

and 2',5'OAS, 12 hours for MX1 and 24 hours for OAS1 and OAS2 gene expression.

Peaks of similar height and time were observed for most of these markers after first

and sixth administration.

The precise mechanism of action of Rebif in multiple sclerosis is still under

investigation.

Single clinical event suggestive of multiple sclerosis

One 2-year controlled clinical trial with Rebif was performed in patients with a single

clinical event suggestive of demyelination due to multiple sclerosis. The patients

enrolled into the trial had at least two clinically silent lesions on the T2-weighted MRI

scan, with a size of at least 3 mm, at least one of which is ovoid or periventricular or

infratentorial. Any disease other than multiple sclerosis that could better explain signs

and symptoms of the patient had to be excluded.

Patients were randomised in a double-blind manner to either Rebif 44 micrograms

given three times per week, Rebif 44 micrograms once weekly, or placebo. If a second

clinical demyelinating event occurred confirming definite multiple sclerosis, patients

switched to the recommended posology of Rebif 44 micrograms three times per week

in an open label manner, while maintaining blinding as to initial randomisation.

Efficacy results of Rebif 44 micrograms given three times per week compared to

placebo from this study are as follows:

Parameter

Statistics

Treatment

Treatment Comparison

Rebif 44 mcg tiw versus Placebo

Placebo

(n=171)

Rebif 44

mcg tiw*

(n=171)

Risk

Reduction

Cox’s

Proportional

Hazard Ratio

[95% CI]

Log-Rank

p-value

McDonald (2005) Conversion

Number of events

0.49

[0.38;0.64]

<0.001

KM Estimate

85.8%

62.5%

CDMS Conversion

Number of events

0.48

[0.31;0.73]

<0.001

KM Estimate

37.5%

20.6%

Mean CUA Lesions per Subject per Scan During the Double Blind Period

Least Square

Means (SE)

2.58 (0.30)

0.50 (0.06)

0.19

[0.14;0.26]

<0.001

* tiw – three times per week

For the time being there is no well established definition of a high risk patient, although

a more conservative approach is to accept at least nine T2 hyperintense lesions on the

initial scan and at least one new T2 or one new Gd-enhancing lesion on a follow-up

scan taken at least 1 month after the initial scan. In any case, treatment should only

be considered for patients classified as high risk.

Relapsing-remitting multiple sclerosis

The safety and efficacy of Rebif has been evaluated in patients with relapsing-

remitting multiple sclerosis at doses ranging from 11 to 44 micrograms

(3-12 million IU), administered subcutaneously three times per week. At licensed

posology, Rebif 22/44 micrograms has been demonstrated to decrease the incidence

(approximately 30% over 2 years) and severity of clinical relapses in patients with at

least 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The

proportion of patients with disability progression, as defined by at least one point

increase in EDSS confirmed three months later, was reduced from 39% (placebo) to

30% (Rebif 22 micrograms) and was reduced from 39% (placebo) to 27% (Rebif 44

micrograms). Over 4 years, the reduction in the mean exacerbation rate was 22% in

patients treated with Rebif 22 micrograms, and 29% in patients treated with

Rebif 44 micrograms group compared with a group of patients treated with placebo for

2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years.

Secondary progressive multiple sclerosis

In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-

6.5) with evidence of clinical progression in the preceding two years and who had not

experienced relapses in the preceding 8 weeks, Rebif had no significant effect on

progression of disability, but relapse rate was reduced by approximately 30%. If the

patient population was divided into 2 subgroups (those with and those without relapses

in the 2-year period prior to study entry), there was no effect on disability in patients

without relapses, but in patients with relapses, the proportion with progression in

disability at the end of the study was reduced from 70% (placebo) to 57% (Rebif 22

micrograms and 44 micrograms combined). These results obtained in a subgroup of

patients a posteriori should be interpreted cautiously.

Primary progressive multiple sclerosis

Rebif has not yet been investigated in patients with primary progressive multiple

sclerosis, and should not be used in these patients.

5.2

Pharmacokinetic properties

Absorption

In healthy volunteers after intravenous administration, interferon beta-1a exhibits a

sharp multi-exponential decline, with serum levels proportional to the dose.

Subcutaneous and intramuscular administrations of Rebif produce equivalent exposure

to interferon beta.

Distribution

Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif

maximum concentrations were typically observed after 8 hours, but this was highly

variable.

Elimination

After repeated subcutaneous doses in healthy volunteers, the main PK parameters

(AUC

and C

) increased proportional to the increased in dose from 22 micrograms

to 44 micrograms. The estimated apparent half-life is 50 to 60 hours, which is in line

with the accumulation observed after multiple dosing.

Metabolism

Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys.

5.3

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of

safety pharmacology, repeated-dose toxicity, and genotoxicity.

Rebif has not been investigated for carcinogenicity.

A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive

disturbances. An increased risk of abortions has been reported in animal studies of

other alpha and beta interferons. No information is available on the effects of the

interferon beta-1a on male fertility.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

D-Mannitol

Benzyl alcohol

Poloxamer 188

L-methionine

Sodium acetate

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

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

6.4

Special precautions for storage

Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store

in the original package in order to protect from light.

The device (RebiSmart) containing a pre-filled cartridge of Rebif must be stored in the

device storage box in a refrigerator (2°C – 8°C).

After first injection with the Rebif cartridge use within 28 days.

For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator

and store it not above 25°C for one single period of up to 14 days. Rebif must then be

returned to the refrigerator and used before the expiry date.

6.5

Nature and contents of container

Rebif 22/44 micrograms (Interferon beta-1a) pre-filled syringe is available as 1 mL (Type

1 glass) syringe with a stainless steel needle, containing 0.5 mL solution.

Rebif 22/44 micrograms (Interferon beta-1a) cartridge is available as cartridges (type 1

glass) with a plunger stopper (rubber) and crimp cap (aluminium and halobutyl rubber)

containing 1.5 mL solution for injection.

Package size of 1,3 or 12 syringes are available.

Pack size of 4 cartridges is available.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

The solution for injection in a pre-filled syringe is ready for use. It may also be

administered with a suitable auto-injector.

The solution for injection in a pre-filled syringe is for single use only.

The solution for injection in a pre-filled cartridge is ready for use with the RebiSmart

electronic injection device. For storage of the device with the cartridge, see section 6.4.

The cartridge is for multidose use.

Only clear to opalescent solution without particles and without visible signs of

deterioration should be used.

Any unused medicinal product or waste material should be disposed of in accordance

with local requirements.

7.

MANUFACTURER

Merck Europe B.V., Amsterdam, The Netherlands

8.

REGISTRATION AUTHORIZIED HOLDER

Merck Serono Ltd., 18 Hakishon, Yavne 81220

Rebif 22 mcg Registration No. 110 94 29437 06

Rebif 44 mcg Registration No. 116 35 29814 06

Revised in April 2020.