ISENTRESS 400 MG TABLETS

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
RALTEGRAVIR AS POTASSIUM 400 MG
Available from:
MERCK SHARP & DOHME ISRAEL LTD
ATC code:
J05AX08
Pharmaceutical form:
TABLETS
Administration route:
PER OS
Manufactured by:
MERCK SHARP & DOHME B.V, HOLLAND
Therapeutic group:
RALTEGRAVIR
Therapeutic indications:
ISENTRESS is indicated in combination with other anti-retroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients and one double-blind, active-controlled trial in treatment-naive patients.
Authorization number:
140333179300
Authorization date:
2009-03-01

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Patient Information leaflet Patient Information leaflet - Arabic

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Patient Information leaflet Patient Information leaflet - Hebrew

16-01-2021

םיחקורהתונקתיפלןכרצלןולע ) םירישכת ( משתה " ו - 1986

אפורםשרמבתבייחוזהפורת

שמתשתםרטבואולמבןולעהתאןויעבארקלשי / הפורתבי

עעבקנהזןולעטמרופ " ודילערשואוקדבנונכותותואירבהדרשמי ב רבמצד 2011

סרטנסייא 400 מ " ג

תוילבט תופוצמ

בכרה :

הילבטלכ הפוצמ הליכמ :

Raltegravir 400 mg (as potassium salt)

סרטנסייא תוילבט תופוצמ זוטקלתוליכמ :

סרטנסייא 400 מ " תוילבטג תופוצמ תוליכמ 26.06 מ " טרדיהונומזוטקללשג .

םיליעפיתלבםיביכרמ :

Lactose monohydrate, microcrystalline cellulose, calcium phosphate dibasic anhydrous,

hypromellose 2208, poloxamer407, sodium stearylfumarate, and magnesium stearate.

םיאבהםיליעפיתלבהםיביכרמהתאףסונבליכמהילבטהיופיצ :

polyvinylalcohol, titanium dioxide (E 171), polyethylene glycol 3350, talc, red iron oxide (E 172) and

black iron oxide (E 172).

תילופיטהצובק :

סרטנסייא דגנכהפורתהניה HIV ) יטנא ורטר - ו תילארי ( ארקנשםיזנאתמסוחרשא HIV - זארגטניא , רשא ה סוריו ) HIV (

ולקוקז , סוריודוערציילתנמלע .

תיאופרתוליעפ :

סרטנסייא דגנכתלעופ ה - Human ImmunodeficiencyVirus (HIV) . הוהז ינוסיחהלשכהתנומסתלםרוגרשאסוריו

שכרנה ) סדייא .(

ארקנהםיזנארציימסוריוה HIV - זארגטניא . ךפוגברשאםיאתבומצעתאליפכהלסוריולרזוערשאהזאוה . סרטנסייא

הזםיזנאלשתוליעפהתאהקיספמ . תורחאתופורתםעשומישב , סרטנסייא התומכתאתיחפהלהיושע - HIV ב ךמד

רשא ארקנ " ילאריוהסמועה " ךלש ( היאתתריפסתאלידגהלו - CD4 ךלש ) דיקפתםיקחשמרשאםינבלםדיאתלשגוס

םוהיזבםחליהלרוזעלידכהאירבןוסיחתכרעמלעהרימשבבושח .( התומכתדרוה - HIV דוקפתתארפשלהיושעםדב

ךלשתינוסיחהתכרעמה . היזבםחליהללכויךפוגשאיהרבדהתועמשמ רתויבוטםו .

לוןכתיי סרטנסייא םילוחהלכבהלאתועפשהויהיאל .

סרטנסייא הניא הווהמ בםוהיזלאפרמ - HIV .

סרטנסייא בולחרשאםירגובמבלופיטלתשמשמ - HIV .

תליטנלעהרוהךלשאפורה סרטנסייא הםוהיזבטולשלרוזעלידכ - HIV .

רישכתבשמתשהלןיאיתמ ?

שמתשהלןיא ורתב וזהפ :

ךניהםא יגרלא / ת ) שיגר / ה ( ל - raltegravir לכלוא םיביכרמהמדחא תוילבטבםירחאה .

וזהפורתבשמתשהלןיא , אפורבץעוויהלילב , לופיטהתלחתהינפל

ןוירהבךניהםא , הקינמךניהםאואןוירהלסנכיהלהיושע . ןוירהלתסנכנםא , לתאזירפס דימךלשאפור . סרטנסייא

הניא ןוירהבתצלמומ , תורהםישנבהדמלנאלשןוויכמ . םעםישנלע HIV ןהלשתוקוניתהתאקינהלאל , ןוויכמ

בקבדיהלםילולעתוקוניתש - HIV ןהלשםאהבלחךרד . תאליכאהלרתויבהבוטהךרדהלעךלשאפורהםעירבד

ךלשקוניתה .

םעיצעייתה ךלשאפורה חקורהוא לכהפורתתלטונךניהשינפל הקינמואןוירהבךניהםאיהש .

רפס / דבכבתויעברבעבךלויהםאךלשאפורלי , דבכתקלדללוכ B וא C . הרומחהמכדעךירעהללכויךלשאפורה

תאםאטילחישינפלךלשדבכהתלחמ / לוכיה / לוטילה סרטנסייא .

ךלשםויםויהייחלעהפורתהעיפשתךיא ?

ליעפתלא / גהנתואתונוכמי /י , םא תא / שחה / ררחוסמה / תליטנרחאלת סרטנסייא .

תורהזא :

שיגרךניהםא / יהשלכהפורתלואוהשלכןוזמלה , וזהפורתבלופיטהתלחתהינפלאפורלךכלעעידוהלךילע .

יטנאלופיטלשבולישםילטונהםילוחהמקלח ורטר - ו ילארי סיזורקנואיטסואתארקנהםצעתלחמחתפלםייושע

תוומ תמקרלש רגנהםצע ם מהאצותכ םצעלםדתקפסאןדבא .( יטנאלופיטתליטנךשמ טר ר ו - וי בלושמילאר ,

וקיטרוקבשומיש - םידיאורטס , לוהוכלאתכירצ , יוכיד - רומחינוסיח , ףוגתסמדדמ ) BMI ( הובג , ראשהןיב , םייושע

וזהלחמחתפלןוכיסהימרוגמקלחתויהל . פמןוישקםהסיזורקנואיטסואהתלחמינמיס םיקר , םיבאכוםישוחימ

ךריהלשדחוימב , ךרבה ו ףתכה ( העונתבישוקו . ןיחבמךניהםא / ה יאב - וליא םינימסתהמ ליעלםיעיפומה , עדוה /י

ךלשאפורלהשקבב ) האר / םגי : " תדחוימתוסחייתהתובייחמהיאוולתועפות " ( .

רפס / דבכבתויעברבעבךלויהםאךלשאפורלי , דבכתקלדללוכ B וא C . ה המכדעךירעהללכויךלשאפור

תאםאטילחישינפלךלשדבכהתלחמהרומח / לוכיה / לוטילה סרטנסייא .

בםוהיז - HIV םעםדאםעינימעגמואםדםעעגמידילעטשפתמ HIV . תליטנ סרטנסייא אל איהיכהתארה

בםירחאתקבדהלןוכיסהתאהדירומ - HIV םדםעעגמואינימעגמךרד .

רפס / לי ןיחבמךניהםאדימךלשאפור / םוהיזלשםינימסתבה . םוהיזםעםילוחהמקלחב בםדקתמ - HIV

םימוהיזלשהירוטסיהו םייטסינוטרופוא , רחאלדימתורקלםילולעםימדוקםימוהיזמתקלדלשםינימסתוםינמיס

דגנכלופיטהתלחתה HIV . יכםינימאמ הלאםינימסת םיעיפומ הבוגתברופישמהאצותכ ףוגהלשתינוסיחה , רשא

םימוהיזבםחליהלףוגלרשפאמ םירורבםינימסתאללםיחכונתויהלויהםייושערשא ) האר / םגי : " יאוולתועפות

תדחוימתוסחייתהתובייחמה " ( .

רוצ / תוריהמבךלשאפורהםערשקי , םירבסומיתלבםירירשיבאכהווחךניהםא , תליטנןמזבהשלוחואתושיגר

סרטנסייא .

רוצ / תוריהמבךלשאפורהםערשקי , חתפמךניהםא / החירפת . תורומחןניהשתויגרלאתובוגתותוירועתובוגת

םילטונהםילוחהמקלחבוחוודםייחתונכסמו סרטנסייא .

סרטנסייא זוטקלהליכמ . יאךלשייכךלשאפורהידילעךלרמאנםא - םירכוסלתוליבס םימיוסמ , רבד / אפורהםעי

נפלךלש וזהפורתתליטני .

רוכז /י ש סרטנסייא בםוהיזלאפרמהווהמהניא - HIV . תאשאיהרבדהתועמשמ / ואםימוהיזבתולחללולעה

םעתורושקהתופסונתולחמ HIV . תליטנןמזבךלשאפורהלצאתויתרגשתוקידבבךישמהלךילע סרטנסייא .

ןיבתובוגת - תויתפורת :

לטונךניהםא / תפסונהפורתת , וא תרחאהפורתבלופיטהתעהזתמייסםא , תופורתללוכ תולטינה אפורםשרמאלל ,

אפרמיחמצוםינימטיו , לפטמהאפורלחוודלךילע , יאואםינוכיסעונמלידכ - ןיבתובוגתמםיעבונהתוליעי - תויתפורת .

ליכעודיאל סרטנסייא העפשההנשי תיתועמשמ טלתושמשמהתורחאתופורתלשםדבתומרלע בלופי - HIV . ףסונב , אל

לשםדבתומרהיכעודי סרטנסייא רועישבתועפשומ יתועמשמ בלופיטלתושמשמהתורחאתופורתידילע - HIV . תורמל

תאז , בשומישבןויסינהרשאכןימזהיהיףסונעדימיכיופצ סרטנסייא לדגי .

רפס / לטונךניהםאךלשאפורלהשקבבי / הנורחאלתלטנואת :

ציפמאפיר ןי ) תפחשןוגכםימוהיזרפסמבלופיטלתשמשמההפורת (

תברצואהביקביכבלופיטלתושמשמהתופורת ) אמגודל : לוזארפמוא , ןידיטמיס , ןידיטינר (

םשרמאללואםשרמםעתרחאהפורתלכ

יאוולתועפות :

הפורתהלשהיוצרהתוליעפלףסונב , עיפוהלתולולעהבשומישהןמזב תועפות יאוול .

ות יאוולתועפ תוחיכש ) לעתועיפשמ 1 דע 10 ךותמםישמתשמ 100 ( :

ןושילישוק , םיילמרונאתומולח

תשגרה תרוחרחס , שארבאכ

תשוחת רורחס

תוחיפנ , ןטבבאכ , לושלש , יעמבואןטבבםיזגףדוע , האקהתשוחת , האקה

החירפלשםימיוסמםיגוס ) נורדםעףוריצבםילטונרשאכרתויההובגתורידתב ריבא (

תופייע , השלוחואהליגראלתופייע ; םוח

בהיילע תוידבכםדתוקידב , םיילמרונאםינבלםדיאת , בהיילע םדבםינמושתומר ; מרבהיילע תוטולבמםימיזנאת

ואקור בלבלהמ

אליאוולתועפות תוחיכש ) לעתועיפשמ 1 דע 10 ךותמםישמתשמ 1000 :(

והיז םימ ספרהב םיללוכה תרגוחתקבלש , רעישהישרושלשתקלד , תעפש , סוריומהאצותכרועבםוהיז ; ואהאקה

לושלש האצותכ םהזמםרוגמ ; תונוילעההמישנהיכרדבםוהיז

תלבי

הימנא הימנאללוכ ךומנלזרבמהאצותכ , הפמילרשקבבאכ , םוהיזבםימחלנהםינבלםדיאתלשהכומנהריפס ;

ראווצבתוחופנתוטולב , העשפמבויחשהתיב

תיגרלאהבוגת , םימוהיזמתקלדלשםינימסתוםינמיס דוק םימ

הדירי היילעוא ןובאיתב , תרכוס , םדבםינמושהולורטסלוכהתומרבהיילע , םדבתוהובגרכוסתומר ; רבגומאמצ ;

הדירי הדח לקשמב , םינמושלשתוהובגתומר ) םידירצילגירטולורטסלוכןוגכ ( םדב

תישפנהערפה , הדרחתשוחת , שוחת לובלבת ; ינואכדחורבצמ , ךרערסוחוהקומעתובצעתשוחת , בצמבםייוניש

חורה , םיטויס ; תודבאתהןויסנ ; הדרחףקתה

ןורכיזןדבוא , בצעהלעץחלמהאצותכדיבבאכ ; הערפה זוכירב ; הביציבםיריהמםייונישםעתרוחרחס ; םעט

ילמרונ ; תרבגומתוינונשי ; היגרנארסוח ; החכיש ; שאריבאכ הנרגיממהאצותכ ; השוחתןדבוא , ואהשוחתרסוח

ותועורזהלשהשלוח / םיילגרהוא ; ץוצקע ; תוינונשי ; חתממהאצותכשארבאכ ; תודיער

הייארבהערפה

םוזמז , ףוצפצ , הקירש , שערואלוצלצ דימתמ םיינזאברחא

בלתוקיפד ; יטיאבלבצק ; אלואתוריהמבלתוקיפד - תוליגר

םוחילג , ץחלרתי םד

השקונלוק , ץמואמואםרוצ ; ףאהמםומיד ; ףאבשדוג

ןטבבתקלד ; הנוילעןטבבבאכ ; תעבטהיפבתוחוניא ; תוריצע ; הפבשבוי ; לוכיעבתויעב ; קוהיג ; תברצ ; העילבבבאכ ;

בלבלהלשתקלד ; ןוילעהיעמבואןטבבהבירצואביכ ; יפבםומיד - תעבטה ; יא - ןטבבתוחונ ; םייכינחבתקלד ; ןושל

החופנ , תבאוכוהמודא

דבכהלשתקלד ; דבכבןמושלשתורבטצה

הנקא ; םיליגרםניאשקדרעישוארעישתרישנ ; רועהלשםדוא ; ףוגבןמושלשליגראלרוזיפ , לולכללולע הדירי

תומכב ה םיילגרבןמוש , םינפבוםיידי , ןטבבןמושהתומכבהיילעו ; תרבגומהעזה ; תילילהעזה ; הלשדרגויוביע רוע

רזוחדרגמהאצותכ ; תוירועתורובח ; שבירוע

םיקרפמבאכ ; תבאוכםיקרפמתלחמ ; בגבאכ ; םצעבבאכ / רירש ; םירירשתשלוחואתושיגר , ראווצבאכ ; באכ

םיילגרבואתועורזב ; םידיגהלשתקלד ; םצעבםילרנימהתומכבהדירי

תוילכבתומיוסמתויעב ; ילכבםינבא ו ת ; הלילבהנתשה ; בהטסיצ תוילכ

הפקזבתויעב ; םירבגבהזחתלדגה ; רבעמהליגינימסת

הזחבתוחונרסוח , תרומרמצ ; םינפהלשתוחיפנ ; תונבצעתשגרה ; תיללכהשגרה הבוטאל ; םיידיבתוחיפנ ,

םיילגרהתופכבואםיילוסרקב ; באכ

םינבלםדיאתתריפסבהדירי ; םדבתויסטהתריפסבהדירי ) תשירקבעייסמהאתלשגוס םד ( ; הארמהםדתקידב

הילכהדוקפתבהדירי ; םדבתוהובגרכוסתומר ; םדברירשהימיזנאתמרבהילע ; תוחכונ ןתשברכוס ; תוחכונ םדיאת

ןתשבםימודא ; לקשמבהיילע ; םיינתומהתדימבהיילע ; ןובלחבהדירי ב םד ) ןימובלא (

תליטנ תולודגהתויומכבהפורת ץלמומהמ

רחאלשןויסנךלהמב - ישה קוו , וחוודתואבהיאוולהתועפות ) תוחיכש = תוחיכשאל :(

תורומחתוירועתובוגת

תוינדבואתולועפותובשחמ

ןדבוא םצערמוחלשימוקמ

היצנידרואוקרסוחולוברס

םינבלהםדהיאתמקלחבהיילעאללואםעהחירפ

רירשבאכלעםיחווידויה , בלופיטךלהמבהשלוחואתושיגר סרטנסייא .

מב םיינילקםירקח , ולביקשםילוחבןטרסירקמופצנ סרטנסייא תורחאתופורתולביקשםילוחבהפצנשהזלהמודרועישב

םא חא ת רימחמיאוולהתועפותמ ה , הוהדימבוא י םשךנ / ה הזןולעבונייוצאלשיאוולתועפותלבל , עדוהאנ /י ךלשאפורל .

דחוימתוסחייתהתובייחמהיאוולתועפות ת :

םוהיזינמיס , םירבסומאלםירירשיבאכ , םירירשהלשתושיגרואהשלוח – אפורלתידיימתונפלשי ) האר /י םג " תורהזא " .(

םיקרפמןוישק , םיבאכוםישוחימ ) ךריהלשדחוימב , ףתכהוךרבה ( העונתבישוקו – הנפ / אפורלי ) האר /י םג " תורהזא " .(

שיגרמךניהובשהרקמלכב / יאוולתועפותה הזןולעבונייוצאלש , תופלוחןניאשואךתואתודירטמשיאוולתועפותוא וא

תיללכהךתשגרהביונישלחםא , אפורהםעץעייתהלךילע ךלש דימ .

ןונימוןתמ :

דבלבאפורהתוארוהיפלןונימ . תצלמומההנמהלערובעלןיא . ךלשאפורהםעקודבלךילע , חוטבךניאוהדימב / ה . שי

לוטיל ייא סרטנס לתורחאתופורתםעבולישב - HIV .

ןונימה ליגרה לש סרטנסייא תחאהילבטוניה ) 400 מ " ג ( , הפהךרד , םויבםיימעפ .

סועללאלץלמומ , תוילבטהתאתוצחלואקסרל .

לוטילןתינ סרטנסייא היתשואלכואילבואםע .

הנשתלא / קיספתואךלשןונימהתאי / לוטילי סרטנסייא ייתהלילבמ ןכינפלךלשאפורהםעץע .

לוטיתלא / אפורהךלץילמהשיפכמתוילבטרתויי . םא תלטנ רתיןונימ , רוצ /י ךלשאפורהםערשק .

םא לוטילתחכש הנמ , חק /י תרכזנשעגרבהתוא . ןפואלכב , םא האבההנמהתאלוטילןמזהעיגה , גלד /י הנמהלע

החכשנש רוזחו /י ינמזחולל - ליגרההליטנה .

ןיא לשתונמיתשלוטיל סרטנסייא החכשנשהנמהלעתוצפלתנמלע .

לוטיתיכבושח / י סרטנסייא אפורהךלהרוהשיפכקוידב . קיספתלא / לוטילי סרטנסייא שןוויכמ :

לךלשתופורתהתאלוטילדאמבושח - HIV םשרנשיפכ , םויהלשםימיאתמהםינמזבו . תופורתלעייסללוכירבדה

יבוטדובעלךלש רתו . ןכומכ , בםחליהלתלוכיהתאודבאיךלשתופורתהשיוכיסהתאתיחפמרבדה - HIV ) ארקנ

םג " תיתפורתתודימע .("

לשהקפסאהרשאכ סרטנסייא תדרלהליחתמךתושרבש , גשה / ךלשאפורהמףסונםשרמי . בושחשןוויכמתאז

ראשיהלאלדאמ ילב הפורת , רצקןמזלוליפא . יטנבהרצקהקספהןמזב הפורתהתל , היושעךמדבסוריוהתומכ

תולעל . הסוריושאיהרבדהתועמשמ - HIV לתודימעחתפי סרטנסייא רתויהשקלךופהיובלופיטהו .

וימהניאוזהפורת דע םידליבןתמלת ליגלתחתמםירגבתמו 16 ש םינ .

שומישהןפוא :

לוטילןתינ סרטנסייא היתשואלכואילבואםע .

סועללאלץלמומ , תוילבטהתאתוצחלואקסרל .

לכותדציכ / לופיטהתחלצהלעייסלי ?

עץלמוהשיפכלופיטהתאםילשהלךילע " אפורהי .

ךתואירבבצמברופישלחםאםג , אפורהםעתוצעייתהאללהפורתבלופיטהתאקיספהלןיא .

ענמ / הלערהי :

וזהפורת , תרחאהפורתלכומכ , םוקמברומשלשי חוטב ץוחמ םדיגשיהל םתייארו וםידלילש / תוקוניתוא , ךכידילעו

הלערהענמת .

הפורתהןמדליעלבתועטבםאוארתיתנמתלטנםא , הנפ / אבהוםילוחתיבלשןוימרדחלדימי / ךתיאהפורתהתזיראי .

האקהלםורגלןיא אפורמתשרופמהארוהאלל !

ךתלחמבלופיטלהמשרנוזהפורת ; רחאהלוחב / ת , יה קיזהלהלולעא . ןתיתלא / ךיבורקלוזהפורתי , ךירכמואךינכש .

ךשוחבתופורתלוטילןיא ! הנמהותיוותהקודבלשי םעפלכב לטונךניהש / הפורתת . קוקזךניהםאםייפקשמביכרהלשי / ה

םהל .

א הנסח :

לתחתמוזהפורתןסחאלשי - 30ºC .

הזיראהיאנתיפלםג / ה א םיצלמומההנסח , שנתופורת דבלבתלבגומהפוקתלתורמ .

רישכתהלשהגופתהךיראתלבלםישלאנ ! קפסלשהרקמלכב , הפורתהתאךלקפיסשחקורבץעוויהלךילע .

הזיראהתואבתונושתופורתןסחאלןיא .

תיתיבההפשאלואהלסאלתופורתךילשהלןיא . ץעוויה /י ךרוצדועןהבןיאשתופורתדימשהלדציכחקורב . הטיקנ

אב הביבסהתוכיאלעהרימשבעייסתולאםיעצמ .

סמ ' הפורתהםושיר : 140 33 31793 00

ידילערצוימ : קרמ ש א םהודופר , B.V. , םלראה , דנלוה

םושירהלעב : שקרמתרבח א םהודופר ) לארשי - 1996 ( עב " מ , ת . ד . 7121 , חתפ - הוקת 49170 .

1. NAMEOFTHE MEDICINALPRODUCT

ISENTRESS 400mgfilm-coated tablets

2. QUALITATIVE ANDQUANTITATIVE COMPOSITION

Eachfilm-coated tabletcontains 400mg ofraltegravir (as potassium).

Excipient: Eachtabletcontains26.06 mglactose monohydrate.

For a full listof excipients,see section6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Pink,ovaltablet,markedwith"227" ononeside.

4. CLINICAL PARTICULARS

4.1Therapeutic indications

ISENTRESSis indicated incombination withother anti-retroviral medicinal products for the

treatment ofhumanimmunodeficiencyvirus(HIV-1) infectioninadult patients.

This indication is basedonsafetyand efficacydatafromtwo double-blind,placebo-controlledtrialsin

treatment-experiencedpatients andonedouble-blind, active-controlledtrial intreatment-naïve patients

(see sections 4.4 and5.1).

4.2 Posologyand methodofadministration

Therapyshouldbeinitiated bya physician experienced in themanagementofHIV infection.

ISENTRESSshouldbeusedincombinationwithother activeanti-retroviraltherapies (ARTs) (see

sections 4.4 and5.1). Theuseofraltegravir inpreviouslyART-naïvepatients isbasedon a studyin

which it wasco-administered withtwo NRTIs (seesections4.4 and5.1).

Posology

Adults

The recommendeddosageofISENTRESSis400mgadministered twicedailywithorwithoutfood.

Theeffect of foodonabsorption ofraltegraviris uncertain (see section5.2).Itisnot recommended to

chew,crushorsplitthe tablets.

Elderly

Thereislimited information regarding the useofISENTRESS in the elderly(see section5.2).

Therefore ISENTRESSshouldbe usedwithcautioninthis population.

Children and adolescents

Safetyand efficacyhavenot beenestablished inpatients below 16years ofage (see sections5.1 and

5.2).

Renal impairment

Nodosage adjustment isrequired for patients withrenal impairment(see section5.2).

Hepatic impairment

Nodosage adjustment isrequired for patients withmildtomoderate hepatic impairment.The safety

andefficacyof ISENTRESS havenot beenestablishedin patientswithsevereunderlyingliver

disorders.ThereforeISENTRESS shouldbeusedwith caution inpatientswith severe hepatic

impairment(see sections4.4 and5.2).

Methodofadministration

Oral

4.3 Contraindications

Hypersensitivitytotheactive substance or to anyofthe excipients.

4.4 Specialwarningsand precautionsfor use

Patients shouldbeadvisedthatcurrent anti-retroviral therapydoesnot cureHIVand has not been

provento preventthetransmissionof HIV toothersthroughbloodor sexualcontact. Appropriate

precautionsshouldcontinue tobe employed.

Overall, considerableinter-and intra-subjectvariabilitywas observedin thepharmacokineticsof

raltegravir(seesections4.5and5.2).

Raltegravir hasarelativelylowgeneticbarriertoresistance. Therefore, wheneverpossible,raltegravir

shouldbeadministered with twoother active ARTstominimisethe potentialfor virologicalfailure

andthedevelopment of resistance (seesection 5.1).

In treatmentnaïvepatients, the clinicalstudydata onuse ofraltegravirarelimitedto use in

combinationwith two nucleotide reverse transcriptase inhibitors (NRTIs)(emtricitabineandtenofovir

disoproxil fumarate).

The safetyand efficacyofISENTRESShavenot beenestablished inpatients withsevereunderlying

liver disorders.ThereforeISENTRESS shouldbeusedwithcautioninpatientswithsevere hepatic

impairment(see sections4.2 and5.2).

Patientswith pre-existingliver dysfunctionincludingchronichepatitishave anincreasedfrequencyof

liver function abnormalitiesduringcombinationanti-retroviraltherapyandshouldbe monitored

according to standardpractice.Ifthereisevidenceofworseningliver disease insuchpatients,

interruption ordiscontinuationoftreatment should be considered.

There are verylimiteddataonthe useof raltegravirinpatients co-infectedwithHIV and hepatitisB

virus(HBV)orhepatitisC virus(HCV). Patientswithchronichepatitis B or C and treated with

combination anti-retroviraltherapyareat an increasedriskforsevereandpotentiallyfatal hepatic

adverse events.

Osteonecrosis

Althoughthe etiologyisconsideredtobe multifactorial (includingcorticosteroiduse,alcohol

consumption,severe immunosuppression, higher bodymassindex),cases of osteonecrosishavebeen

reported particularlyin patientswith advancedHIVdisease and/orlong-term exposure tocombination

anti-retroviraltherapy.Patients shouldbe advisedtoseekmedical advice iftheyexperiencejoint aches

andpain, jointstiffnessor difficultyinmovement.

Immunereactivation syndrome

In HIV-infectedpatients withsevere immunedeficiencyat the timeofinstitution ofcombination anti-

retroviral therapy(CART),an inflammatoryreaction to asymptomatic or residualopportunistic

pathogensmayarise andcauseserious clinicalconditions,oraggravation of symptoms. Typically,

suchreactionshave been observedwithinthefirstweeks or monthsofinitiation of CART. Relevant

examples are cytomegalovirusretinitis,generalised and/or focalmycobacterial infectionsand

pneumonia causedbyPneumocystis jiroveci(formerlyknownasPneumocystis carinii). Any

inflammatorysymptomsshouldbeevaluatedand treatment instituted when necessary.

Severe SkinandHypersensitivityReactions

Severe, potentiallylife-threatening, andfatalskinreactionshavebeenreportedin patientstaking

ISENTRESSconcomitantlywith otherdrugs associatedwith these reactions. Theseinclude casesof

Stevens-Johnson syndromeand toxicepidermalnecrolysis. Hypersensitivityreactionshavealso been

reported andwere characterizedbyrash, constitutional findings, andsometimes, organ dysfunction,

includinghepaticfailure. DiscontinueISENTRESS and othersuspect agents immediatelyifsigns or

symptomsofsevereskinreactionsor hypersensitivityreactions develop (including, butnot limitedto,

severerashor rashaccompaniedbyfever, generalmalaise,fatigue, muscle orjointaches,blisters,oral

lesions,conjunctivitis, facial edema,hepatitis, eosinophilia, angioedema).Clinical status including

liveraminotransferasesshouldbemonitoredand appropriate therapyinitiated.Delayin stopping

ISENTRESStreatment or othersuspectagents after theonsetof severerash may resultinalife-

threatening reaction.

Caution shouldbeusedwhenco-administeringISENTRESS withstronginducers ofuridine

diphosphate glucuronosyltransferase(UGT) 1A1 (e.g.,rifampicin). Rifampicinreducesplasmalevels

of raltegravir;theimpact ontheefficacyof raltegravir isunknown.However, ifco-administrationwith

rifampicinisunavoidable,a doublingof the doseofISENTRESScan beconsidered (seesection4.5).

Myopathyandrhabdomyolysishave beenreported. Usewith cautionin patients whohavehad

myopathyor rhabdomyolysis in the pastor haveanypredisposingissues includingothermedicinal

products associatedwiththeseconditions(see section 4.8).

Rashoccurred morecommonlyintreatment-experienced patientsreceivingregimenscontaining

ISENTRESS +darunavir comparedtopatientsreceivingISENTRESSwithoutdarunaviror darunavir

without ISENTRESS (see section 4.8).

ISENTRESScontains lactose. Patients with rarehereditaryproblems of galactoseintolerance,the

Lapp lactasedeficiencyor glucose-galactosemalabsorptionshouldnot takethis medicine.

4.5 Interactionwith other medicinal products andother forms ofinteraction

In vitrostudies indicatethat raltegravir isnota substrate of cytochromeP450(CYP) enzymes,does

not inhibit CYP1A2,CYP2B6, CYP2C8,CYP2C9,CYP2C19,CYP2D6 orCYP3A, does notinduce

CYP3A4anddoesnot inhibit P-glycoprotein-mediatedtransport. Basedonthese data,ISENTRESSis

not expected toaffectthepharmacokinetics ofmedicinalproductsthataresubstrates ofthese enzymes

or P-glycoprotein.

Based oninvitroandinvivostudies, raltegravir is eliminatedmainlybymetabolismvia aUGT1A1-

mediatedglucuronidationpathway.

Althoughin vitrostudies indicated that raltegravir isnot aninhibitor oftheUDP

glucuronosyltransferases(UGTs) 1A1and2B7,oneclinical studyhassuggestedthat some inhibition

ofUGT1A1mayoccurin vivobasedon effects observedonbilirubinglucuronidation. However, the

magnitude oftheeffect seemsunlikelytoresult in clinicallyimportant drug-drug interactions.

Considerable inter-andintra-individualvariabilitywasobservedinthepharmacokinetics of

raltegravir.The followingdruginteractioninformation isbasedonGeometric Meanvalues; the effect

foran individual patient cannot bepredictedprecisely.

Effect of raltegravir onthepharmacokinetics ofother medicinalproducts

In interaction studies,raltegravir did nothavea clinicallymeaningful effect onthepharmacokinetics

of etravirine,maraviroc,tenofovir,hormonal contraceptives, methadone, ormidazolam.

Effect ofother agentsonthe pharmacokinetics of raltegravir

Given that raltegravir ismetabolised primarilyviaUGT1A1, caution shouldbe usedwhen

co-administeringISENTRESSwithstronginducers ofUGT1A1 (e.g.,rifampicin).Rifampicin reduces

plasmalevelsofraltegravir;the impactontheefficacyofraltegravirisunknown.However,if

co-administrationwithrifampicinis unavoidable, a doubling ofthedose of ISENTRESScan be

considered(see section 4.4). Theimpactofotherstronginducers ofdrug metabolizingenzymes,such

as phenytoinand phenobarbital,on UGT1A1isunknown.Lesspotentinducers (e.g.,efavirenz,

nevirapine,etravirine,rifabutin,glucocorticoids,St. John'swort,pioglitazone)maybe usedwith the

recommendeddoseofISENTRESS.

Co-administrationofISENTRESS withmedicinalproductsthatare knowntobepotentUGT1A1

inhibitors(e.g., atazanavir)mayincreaseplasmalevels of raltegravir. Less potent UGT1A1 inhibitors

(e.g., indinavir,saquinavir)mayalso increaseplasmalevelsof raltegravir,but toa lesser extent

comparedwithatazanavir. Inaddition,tenofovirmayincreaseplasmalevels ofraltegravir, however,

themechanism forthis effect is unknown (seeTable1).Fromtheclinicaltrials,alarge proportionof

patientsused atazanavirand/ ortenofovir, bothagentsthat resultinincreases inraltegravirplasma

levels,inthe optimised backgroundregimens. Thesafetyprofile observed inpatientswho used

atazanavir and/ortenofovir was generallysimilartothe safetyprofileofpatients who didnotuse

these agents.Therefore nodose adjustment is required.

In healthysubjects, co-administrationof ISENTRESS with omeprazole increases raltegravirplasma

levels.Asthe effects ofincreasinggastricpH onthe absorption ofraltegravir inHIV-infectedpatients

are uncertain, use ISENTRESS withmedicinal products that increase gastricpH(e.g.,protonpump

inhibitorsand H2antagonists) onlyif unavoidable.

Table 1

Pharmacokinetic Interaction Data

Medicinalproductsby therapeutic

area

Interaction

(mechanism,if known) Recommendations

concerning

co-administration

ANTI-RETROVIRAL

Protease inhibitors(PI)

atazanavir /ritonavir

(raltegravir400 mgTwiceDaily)

raltegravir AUC ↑41 %

raltegravir C

12hr ↑77 %

raltegravir C

↑24 %

(UGT1A1inhibition) Nodose adjustment required

for ISENTRESS.

tipranavir /ritonavir

(raltegravir400 mgTwiceDaily)

raltegravir AUC ↓24 %

raltegravir C

12hr ↓55 %

raltegravir C

↓18 %

(UGT1A1 induction) Nodose adjustment required

for ISENTRESS.

Non-nucleoside reverse transcriptaseinhibitors (NNRTIs)

efavirenz

(raltegravir400 mgSingle Dose)

raltegravir AUC ↓36 %

raltegravir C

12hr ↓21 %

raltegravir C

↓36 %

(UGT1A1induction) Nodose adjustment required

for ISENTRESS.

Medicinalproductsby therapeutic

area

Interaction

(mechanism,if known) Recommendations

concerning

co-administration

etravirine

(raltegravir400 mgTwiceDaily)

raltegravir AUC ↓10 %

raltegravir C

12hr ↓34 %

raltegravir C

↓11 %

(UGT1A1 induction)

etravirine AUC ↑10%

etravirine C

12hr ↑17%

etravirine C

↑4 % Nodose adjustment required

for ISENTRESS oretravirine.

Nucleoside/tide reverse transcriptase inhibitors

tenofovir

(raltegravir400 mgTwiceDaily) raltegravir AUC ↑49 %

raltegravir C

12hr ↑3%

raltegravir C

↑64%

(mechanismofinteraction

unknown)

tenofovirAUC ↓10%

tenofovirC

12hr ↓13%

tenofovirC

Nodose adjustment required

for ISENTRESS ortenofovir

disoproxilfumarate.

CCR5 inhibitors

maraviroc

(raltegravir400 mgTwiceDaily) raltegravir AUC ↓37 %

raltegravir C

12hr ↓28 %

raltegravir C

↓33%

(mechanismofinteraction

unknown)

maraviroc AUC ↓14%

maraviroc C

12hr ↓10%

maraviroc C

Nodose adjustment required

for ISENTRESS ormaraviroc.

ANTIMICROBIALS

Antimycobacterial

rifampicin

(raltegravir400 mgSingle Dose) raltegravir AUC ↓40 %

raltegravir C

12hr ↓61 %

raltegravir C

↓38 %

(UGT1A1 induction) Rifampicin reduces plasma

levelsofISENTRESS.If

co-administration with

rifampicin isunavoidable,a

doubling ofthedose of

ISENTRESScan beconsidered

(see section 4.4).

SEDATIVE

midazolam

(raltegravir400 mgTwiceDaily) midazolamAUC ↓8 %

midazolamC

↑3 %

Nodosage adjustment required

for ISENTRESS ormidazolam.

These resultsindicate that

raltegravir is notaninduceror

inhibitorofCYP3A4,and

raltegravir is thus not

anticipated toaffect the

pharmacokinetics ofmedicinal

productswhichareCYP3A4

substrates.

Medicinalproductsby therapeutic

area

Interaction

(mechanism,if known) Recommendations

concerning

co-administration

ANTIULCER

omeprazole

(raltegravir400 mgSingle Dose) raltegravir AUC↑212 %

raltegravir C

12 hr ↑46 %

raltegravir C

↑315 %

Co-administration ofproton

pumpinhibitors or other

antiulcermedicinalproducts

may increase plasmalevelsof

raltegravir.

Donot use ISENTRESSwith

medicinal productsthat

increasegastricpHunless this

is unavoidable.

HORMONAL CONTRACEPTIVES

Ethinyl Estradiol

Norelgestromin

(raltegravir400 mgTwiceDaily) Ethinyl EstradiolAUC ↓2%

Ethinyl EstradiolC

↑1%

NorelgestrominAUC↑14%

NorelgestrominC

↑29% Nodosage adjustment required

for ISENTRESSorhormonal

contraceptives (estrogen-

and/orprogesterone-based).

OPIOIDANALGESICS

methadone

(raltegravir400 mgTwiceDaily) methadoneAUC↔

methadoneC

↔ Nodose adjustment required

for ISENTRESS ormethadone.

4.6 Pregnancy and lactation

Pregnancy

There are noadequate datafromtheuseofraltegravirinpregnantwomen.Studiesinanimalshave

shown reproductivetoxicity(see section5.3).The potential risk forhumansisunknown.ISENTRESS

shouldnotbeused duringpregnancy.

Anti-retroviralPregnancyRegistry

To monitor maternal-foetal outcomes inpatientsinadvertentlyadministered ISENTRESS while

pregnant,an Anti-retroviral PregnancyRegistryhasbeenestablished.Physicians are encouraged to

register patients in this registry.

Lactation

It isnot knownwhetherraltegravir issecretedinhuman milk. However,raltegravir issecretedinthe

milkoflactating rats.In rats,at amaternaldoseof 600mg/kg/day,meanactive substance

concentrationsinmilkwereapproximately3-fold greater than inmaternal plasma. Breastfeeding isnot

recommended while taking ISENTRESS. Inaddition,it isrecommendedthatHIV-infected mothers

shouldnot breastfeedtheirinfantstoavoidrisking postnataltransmissionofHIV.

4.7 Effects on ability to driveand usemachines

Nostudies have beenperformedonthe effectsofISENTRESS on the abilitytodriveand use

machines. However,dizziness has beenreportedinsomepatientsduringtreatment with regimens

containingISENTRESS, which mayinfluence somepatients'abilityto drive and usemachines (see

section 4.8).

4.8 Undesirable effects

The safetyprofileof ISENTRESSwasbasedonthepooledsafetydatafromtwoPhaseIIIclinical

studies intreatment-experiencedpatientsandone Phase IIIclinical studyintreatment-naïvepatients;

described below.

In treatment-experiencedpatients, thetworandomised clinical studiesused the recommended dose of

400mgtwice dailyincombination withoptimisedbackgroundtherapy(OBT) in462patients, in

comparison to237patientstakingplacebo incombinationwith OBT. Duringdouble-blindtreatment,

the total follow-upwas 708 patient-years in the groupreceiving ISENTRESS400mgtwicedaily,and

244 patient-years inthe groupreceiving placebo.

In treatment-naïvepatients, themulti-centre, randomised,double-blind, active-controlled clinical study

usedthe recommendeddoseof400 mg twice dailyincombination withafixeddoseof

emtricitabine200mg(+)tenofovir 245 mgin281patients, incomparisonto282patients taking

efavirenz (EFV)600mg(at bedtime)incombinationwithemtricitabine (+) tenofovir.Duringdouble-

blind treatment,the total follow-up was480patient-years inthegroup receivingISENTRESS 400mg

twicedaily,and463patient-yearsinthegroupreceivingefavirenz 600mgat bedtime.

In the pooledanalysis oftreatment-experiencedpatients, the ratesofdiscontinuationof therapydue to

adversereactionswere 3.9 % inpatients receivingISENTRESS +OBTand4.6%inpatientsreceiving

placebo+ OBT.The rates ofdiscontinuationoftherapyin naïve patientsdue to adversereactionswere

3.6 %in patients receivingISENTRESS+emtricitabine (+) tenofovir and6.7% in patients receiving

efavirenz + emtricitabine(+) tenofovir.

Adverse reactions consideredbyinvestigators tobecausallyrelatedtoISENTRESS (alone or in

combinationwith otherART)are listedbelowbySystemOrgan Class.Anyterm thatincludes atleast

one seriousadverse reactionisidentified with adagger( † ).Adversereactions identifiedfrompost-

marketing experienceareincluded initalics. Frequencies are defined ascommon(≥1/100to<1/10),

uncommon (≥1/1,000to<1/100),and not known(cannotbeestimatedfromthe available data).

SystemOrganClass Frequency Adverse reactions

ISENTRESS (aloneorin combination with other

ART)

Infections andinfestations uncommon genital herpes † , folliculitis, gastroenteritis, herpes

simplex,herpesvirusinfection,herpeszoster,

influenza, molluscumcontagiosum,

nasopharyngitis, upper respiratorytract infection

Neoplasmsbenign,malignant

andunspecified(includingcysts

andpolyps) uncommonskin papilloma

Blood andlymphatic system

disorders uncommon

uncommon anemia †, irondeficiencyanaemia,lymphnodepain,

lymphadenopathy,neutropenia

thrombocytopenia ‡‡

Immune systemdisorders uncommon immune reconstitution syndrome † , drug

hypersensitivity, hypersensitivity

Metabolismand nutrition

disorders uncommon anorexia, cachexia, decreasedappetite, diabetes

mellitus, dyslipidaemia,hypercholesterolaemia,

hyperglycaemia,hyperlipidaemia,hyperphagia,

increased appetite, polydipsia

Psychiatric disorders common

uncommon

uncommon

abnormal dreams,insomnia

mental disorder † , suicide attempt †, anxiety,

confusional state,depressedmood, depression,

majordepression,middleinsomnia,moodaltered,

nightmare, panicattack,sleepdisorder

suicidalideation ‡‡

, suicidalbehaviour(particularly

inpatientswitha pre-existing history of psychiatric

illness) ‡‡

SystemOrganClass Frequency Adverse reactions

ISENTRESS (aloneorin combination with other

ART)

Nervoussystemdisorders common

uncommon

dizziness, headache

amnesia, carpaltunnelsyndrome,cognitive

disorder, disturbanceinattention, dizziness

postural,dysgeusia,hypersomnia, hypoaesthesia,

lethargy, memoryimpairment, migraine,

neuropathyperipheral,paraesthesia,somnolence,

tension headache,tremor

cerebellar ataxia ‡‡

Eye disorders uncommon visual impairment

Ear and labyrinthdisorders common

uncommon vertigo

tinnitus

Cardiacdisorders uncommon palpitations, sinus bradycardia,ventricular

extrasystoles

Vascular disorders uncommon hotflush,hypertension

Respiratory,thoracicand

mediastinal disorders uncommon dysphonia, epistaxis,nasal congestion

Gastrointestinal disorders common

uncommon abdominal distention,abdominalpain, diarrhoea,

flatulence, nausea, vomiting

gastritis † ,abdominaldiscomfort,abdominalpain

upper, abdominal tenderness,anorectal discomfort,

constipation, drymouth,dyspepsia, epigastric

discomfort, erosiveduodenitis, eructation,

gastrooesophageal refluxdisease,gingivitis,

glossitisodynophagia, pancreatitis acute, peptic

ulcer, rectalhaemorrahage

Hepato-biliarydisorders uncommon hepatitis † , hepaticsteatosis,hepatitisalcoholic

Skinandsubcutaneoustissue

disorders common

uncommon

uncommon

rash ‡

acne,alopecia, dermatitisacneiforme, dryskin,

erythema,facialwasting,hyperhidrosis,

lipodystrophyacquired,lipohypertrophy,night

sweats, prurigo,pruritis, pruritusgeneralised, rash

macular,rash maculo-papular,rashpruritic, skin

lesion, urticaria,xeroderma

Stevens Johnsonsyndrome,

drugrashwith

eosinophilia andsystemic symptoms(DRESS) ‡‡

Musculoskeletal and connective

tissue disorders Uncommon

uncommon arthralgia, arthritis,back pain, flankpain, ,

musculoskeletal pain,myalgia, neck pain,

osteopenia, painin extremity,tendonitis

rhabdomyolysis ‡‡

Renal andurinarydisorders Uncommon renal failure † ,nephritis,nephrolithiasis,nocturia,

renalcyst, renal impairment, tubulointerstitial

nephritis

Reproductivesystemandbreast

disorders uncommon erectile dysfunction, gynaecomastia, menopausal

symptoms

SystemOrganClass Frequency Adverse reactions

ISENTRESS (aloneorin combination with other

ART)

General disordersand

administrationsiteconditions common

uncommon asthenia, fatigue,pyrexia

chestdiscomfort, chills, face oedema, fattissue

increased,feelingjittery,malaise, oedema

peripheral,pain,

Investigationscommon

uncommon alanine aminotransferaseincreased,atypical

lymphocytes, aspartateaminotransferaseincreased,

blood triglycerides increasedlipase increased

absolute neutrophilcountdecreased,alkaline

phosphataseincreased, blood albumindecreased,

blood amylase increased,blood bilirubinincreased,

blood cholesterol increased,blood creatinine

increased,blood glucoseincreased, bloodurea

nitrogenincreased, creatine phosphokinase

increased,fasting bloodglucose increased,glucose

urine present, highdensitylipoproteinincreased,

lowdensitylipoprotein decreased, low density

lipoprotein increased,platelet countdecreased, red

blood cellsurinepositive,waistcircumference

increased, weight increased,white bloodcell count

decreased

Injury, poisoningand

procedural complications uncommonaccidental overdose †

includesat least one seriousadversereaction

‡ Inclinical studiesoftreatment-experienced patients, rash,irrespectiveofcausality, was more

commonlyobservedwith regimenscontainingISENTRESS + darunavir compared to thosecontaining

ISENTRESS without darunavirordarunavir withoutISENTRESS. Rashconsidered bythe

investigatorto bedrug-relatedoccurredat similarrates. Theexposure-adjusted ratesofrash(all

causality) were 10.9, 4.2, and3.8per100 patient-years (PYR), respectively;andfordrug-related rash

were 2.4,1.1,and2.3per 100PYR, respectively.The rashesobserved inclinical studies weremildto

moderate inseverityanddid not resultin discontinuationoftherapy(seesection4.4).

‡‡ This adverse reactionwasidentified throughpost-marketing surveillance butnotreported as drug-

related in randomisedcontrolledPhaseIII clinicaltrials (Protocols018, 019, and021).The frequency

categoryof"uncommon" was definedper the SummaryofProductCharacteristics (SmPC)guidance

(rev. 2, Sept2009) onthe basis ofan estimatedupperboundofthe95% confidenceinterval for 0

eventsgiven thenumberofsubjectstreatedwithISENTRESS in thePhase III clinicalprogram

(n=743).

Cancers were reportedintreatment-experienced andtreatment-naïve patientswho initiated

ISENTRESSinconjunctionwithother antiretroviralagents.The types andrates of specificcancers

werethose expectedinahighlyimmunodeficientpopulation. The riskofdevelopingcancerinthese

studieswassimilarinthe groupsreceivingISENTRESSand inthe groupsreceivingcomparators.

Grade 2-4creatinekinase laboratoryabnormalities were observedin subjectstreatedwith

ISENTRESS.Myopathyandrhabdomyolysishave beenreported. Usewith cautionin patientswho

havehadmyopathyor rhabdomyolysisinthepastorhave anypredisposingissuesincluding other

medicinal productsassociatedwiththese conditions(seesection 4.4).

Cases ofosteonecrosishavebeen reported, particularlyinpatientswith generallyacknowledgedrisk

factors,advancedHIV disease or long-termexposuretocombination antiretroviraltherapy(CART).

Thefrequencyofthisisunknown(seesection4.4).

Patientsco-infectedwithhepatitisB and/orhepatitis C virus

InPhase IIIstudies,treatment-experiencedpatients (N=114/699or16%;HBV=6%,HCV=9%,

HBV+HCV=1 %)and treatment-naïve patients (N =34/563 or6 %;HBV=4 %,HCV=2%,

HBV+HCV=0.2%) withchronic (but not acute) activehepatitis Band/orhepatitis C co-infection were

permitted toenrollprovidedthatbaseline liverfunctiontestsdid not exceed5timesthe upperlimit of

normal. In generalthesafetyprofile of ISENTRESSinpatientswithhepatitisB and/orhepatitisC

virusco-infectionwas similar to that inpatients withouthepatitisB and/orhepatitis C virusco-

infection, althoughtherates ofAST and ALT abnormalitiesweresomewhat higherinthesubgroup

withhepatitis Band/or hepatitisCvirus co-infectionforbothtreatmentgroups. Intreatment-

experiencedpatients,Grade2orhigher laboratoryabnormalities that represent aworseningGrade

frombaselineofAST,ALT ortotal bilirubinoccurredin 29%,34% and 13 %,respectively,of co-

infectedsubjectstreated with ISENTRESSas comparedto 11%,10% and9 % of allothersubjects

treated with ISENTRESS. In treatment-naïve patients,Grade 2 or higher laboratoryabnormalitiesthat

represent aworsening GradefrombaselineofAST,ALT ortotalbilirubin occurredin17%, 28% and

17%, respectively, of co-infectedsubjects treated with ISENTRESSas comparedto6 %,6% and3 %

of all other subjects treatedwith ISENTRESS.

4.9Overdose

Nospecific informationis available onthetreatmentofoverdosage with ISENTRESS.

In the eventofanoverdose,it is reasonable toemploythe standardsupportivemeasures,e.g.,remove

unabsorbedmaterial from the gastrointestinal tract,employclinicalmonitoring(includingobtaining an

electrocardiogram), and institute supportivetherapyifrequired. It shouldbetaken intoaccount that

raltegravir ispresented forclinical use as thepotassiumsalt. The extent to which ISENTRESSmaybe

dialysable is unknown.

5. PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeuticgroup: Antiviral forsystemicuse,OtherAntivirals,ATC code: J05AX08.

Mechanism ofaction

Raltegravir is anintegrase strandtransferinhibitoractiveagainst the HumanImmunodeficiencyVirus

(HIV-1). Raltegravirinhibits the catalytic activityofintegrase, anHIV-encodedenzyme that is

required forviral replication.Inhibitionofintegrase preventsthecovalentinsertion, orintegration,of

the HIV genome intothehost cell genome.HIVgenomes that failto integrate cannotdirect the

productionof newinfectiousviralparticles, soinhibitingintegrationpreventspropagationofthe viral

infection.

Antiviral activityin vitro

Raltegravir atconcentrations of31 ±20nMresulted in95%inhibition(IC

)ofHIV-1 replication

(relative to anuntreatedvirus-infectedculture)inhumanT-lymphoid cell cultures infectedwiththe

cell-line adaptedHIV-1variantH9IIIB.In addition, raltegravir inhibited viral replicationinculturesof

mitogen-activated human peripheralbloodmononuclear cells infected withdiverse, primaryclinical

isolatesof HIV-1,includingisolatesfrom5non-B subtypes,andisolatesresistanttoreverse

transcriptase inhibitorsand proteaseinhibitors.Ina single-cycleinfectionassay,raltegravirinhibited

infection of23HIVisolates representing5 non-B subtypes and 5 circulatingrecombinant formswith

IC50valuesrangingfrom5to 12 nM.

Resistance

Most virusesisolated frompatientsfailingraltegravir hadhigh-levelraltegravir resistanceresulting

from the appearanceoftwoormoremutations. Most had a signaturemutationatamino acid155

(N155changedtoH),amino acid 148(Q148 changedtoH, K, orR),or aminoacid 143(Y143

changed to H,C, or R), alongwithone ormoreadditional integrasemutations (e.g., L74M,E92Q,

T97A, E138A/K, G140A/S,V151I,G163R, S230R).The signaturemutationsdecreaseviral

susceptibilitytoraltegravir and additionofothermutationsresultsinafurtherdecrease inraltegravir

susceptibility. Factors thatreduced the likelihoodofdeveloping resistance included lowerbaseline

viral load and useofother activeanti-retroviralagents. Preliminarydata indicatethat there ispotential

for atleast somedegree ofcross-resistanceto occurbetweenraltegravirand other integrase inhibitors.

Clinical experience

TheevidenceofefficacyofISENTRESS is basedon theanalysesof 96-weekdatafromtwo ongoing,

randomised,double-blind,placebo-controlled trials, (BENCHMRK 1 andBENCHMRK2,Protocols

018and019) inantiretroviral treatment-experienced HIV-1 infected adult patientsand the analysis of

96-week datafromanongoing, randomised, double-blind, active-control trial, (STARTMRK,

Protocol021)inantiretroviral treatment-naïveHIV-1infected adult patients.

Efficacy

Treatment-experienced patients

BENCHMRK 1 andBENCHMRK2 (ongoingmulti-centre,randomised,double-blind,placebo-

controlledtrials)evaluate the safetyandanti-retroviralactivity ofISENTRESS 400mgtwicedailyvs.

placeboina combination with optimizedbackgroundtherapy(OBT), inHIV-infected patients,

16yearsorolder, withdocumentedresistancetoatleast 1 drug in eachof3classes (NRTIs, NNRTIs,

PIs) of anti-retroviral therapies.Prior torandomization,OBT were selected by the investigator based

on thepatient's priortreatment history,aswellasbaseline genotypic and phenotypic viralresistance

testing.

Patientdemographics(gender, age and race)and baseline characteristics werecomparablebetweenthe

groups receiving ISENTRESS 400mgtwicedailyandplacebo.Patientshadprior exposure toa

medianof12anti-retroviralsfor amedianof10years.A medianof4ARTswasusedinOBT.

Results 48weekand 96week analyses

Durable outcomes(Week48andWeek96) forpatients ontherecommendeddoseISENTRESS

400mgtwice dailyfromthe pooled studies BENCHMRK 1 andBENCHMRK2 are shown in

Table 2.

Table 2

EfficacyOutcome atWeeks48and96

48 Weeks 96Weeks

BENCHMRK 1and2Pooled

Parameter ISENTRESS

400 mgtwice

daily + OBT

(N=462) Placebo +OBT

(N=237) ISENTRESS

400 mgtwice

daily + OBT

(N=462) Placebo +

OBT

(N = 237)

Percent HIV-RNA<400 copies/ml (95%

CI)

All patients † 72 (68, 76) 37 (31, 44) 62 (57, 66) 28 (23,34)

Baseline Characteristic ‡

HIV-RNA> 100,000copies/ml 62 (53, 69) 17 (9,27) 53 (45, 61) 15(8,25)

≤100,000copies/ml 82 (77, 86) 49 (41, 58) 74 (69, 79) 39 (31,47)

CD4-count≤50 cells/mm 3 61 (53, 69) 21 (13, 32) 51 (42,60) 14(7,24)

>50 and

≤200cells/mm 3 80 (73, 85) 44 (33, 55) 70 (62,77) 36 (25,48)

>200 cells/mm 3 83 (76, 89) 51 (39, 63) 78 (70,85) 42 (30,55)

Sensitivity score (GSS) §

0 52 (42, 61) 8 (3,17) 46 (36,56) 5 (1,13)

1 81 (75, 87) 40 (30, 51) 76 (69,83) 31 (22,42)

2 andabove 84 (77, 89) 65 (52, 76) 71 (63,78) 56 (43,69)

PercentHIV-RNA<50copies/ml(95%

CI)

All patients † 62 (57, 67) 33 (27, 39) 57 (52, 62) 26 (21,32)

Baseline Characteristic ‡

HIV-RNA> 100,000copies/ml 48 (40, 56) 16 (8,26) 47 (39, 55) 13(7,23)

≤100,000copies/ml 73 (68, 78) 43 (35, 52) 70 (64, 75) 36 (28,45)

CD4-count≤50 cells/mm 3 50 (41, 58) 20 (12, 31) 50 (41, 58) 13(6,22)

> 50and

≤200cells/mm 3 67 (59, 74) 39 (28, 50) 65 (57, 72) 32 (22,44)

>200 cells/mm 3 76 (68, 83) 44 (32, 56) 71 (62, 78) 41 (29,53)

Sensitivity score (GSS) §

0 45 (35, 54) 3 (0,11) 41 (32, 51) 5 (1,13)

1 67 (59, 74) 37 (27, 48) 72 (64, 79) 28 (19,39)

2 andabove 75 (68, 82) 59 (46, 71) 65 (56, 72) 53 (40,66)

MeanCD4CellChange (95 %CI),

cells/mm 3

All patients ‡ 109( 98, 121) 45( 32, 57) 123(110,

137) 49 (35,63)

Baseline Characteristic ‡

HIV-RNA> 100,000copies/ml 126( 107,144) 36 (17,55) 140 (115,

165) 40 (16,65)

≤100,000copies/ml 100 (86,115) 49 (33,65) 114 (98, 131) 53 (36,70)

CD4-count≤50 cells/mm 3 121( 100,142) 33 (18,48) 130 (104,

156) 42 (17,67)

>50 and

≤200cells/mm 3 104( 88, 119) 47( 28, 66) 123 (103,

144) 56 (34,79)

>200 cells/mm 3

104 (80,129) 54 (24,84) 117 (90, 143) 48 (23,73)

Sensitivity score (GSS) §

0 81 (55,106) 11 (4,26) 97(70, 124) 15 (-0,31)

1 113( 96, 130) 44( 24, 63) 132 (111,

154) 45 (24,66)

2 andabove 125( 105,144) 76( 48,103) 134 (108,

159) 90 (57, 123)

Non-completerisfailureimputation: patients whodiscontinued prematurelyareimputedasfailure thereafter.Percent of patientswith response

and associated95 %confidenceinterval(CI)arereported.

For analysis by prognosticfactors,virologicfailureswerecarriedforward forpercent <400 and 50copies/ml.FormeanCD4changes,baseline-

carry-forward wasusedforvirologicfailures.

TheGenotypic Sensitivity Score(GSS)wasdefinedasthetotaloralARTs in theoptimisedbackground therapy(OBT)to whichapatient'sviral

isolateshowedgenotypicsensitivitybased upon genotypicresistancetest.Enfuvirtideusein OBT inenfuvirtide-naïvepatientswascountedas

oneactivedrug inOBT.Similarly,darunavir usein OBTin darunavir-naïvepatientswascountedasoneactivedrug in OBT.

Raltegravir achieved virologicresponses(using Not Completer=Failureapproach) of HIV RNA

<50copies/mlin61.7% ofpatientsat Week16,in 62.1%at Week 48andin 57.0%atWeek96.

Somepatientsexperiencedviral reboundbetweenWeek16and Week96.Factors associatedwith

failureincludehighbaselineviral loadand OBT that did notinclude atleastone potentactive agent.

Switchto raltegravir

The SWITCHMRK1&2(Protocols 032 & 033)studies evaluatedHIV-infectedpatientsreceiving

suppressive(screening HIVRNA <50copies/ml; stable regimen>3months)therapywithlopinavir

200 mg (+) ritonavir 50mg2tabletstwicedailyplusatleast2nucleosidereversetranscriptase

inhibitorsand randomizedthem1:1tocontinue lopinavir(+) ritonavir 2 tabletstwice daily(n=174and

n=178,respectively)or replace lopinavir(+) ritonavir withraltegravir400mgtwicedaily(n=174and

n=176,respectively). Patients witha prior historyof virological failure were notexcludedand the

number ofprevious antiretroviral therapies wasnot limited.

These studies wereterminatedafterthe primaryefficacyanalysisat Week 24 because theyfailedto

demonstratenon-inferiorityofraltegravir versus lopinavir (+) ritonavir. Inboth studiesatWeek24,

suppression ofHIV RNA toless than 50copies/ml wasmaintainedin 84.4% ofthe raltegravir group

versus90.6 %of the lopinavir (+) ritonavir group,(Non-completers =Failure).See section 4.4

regardingthe needtoadministerraltegravirwithtwo otheractiveagents.

Treatment-naive patients

STARTMRK (ongoingmulti-centre,randomised,double-blind,active-control trial) evaluates the

safetyand anti-retroviral activityofISENTRESS 400mgtwice dailyvs.efavirenz600mgat

bedtime, ina combination withemtricitabine(+)tenofovir, intreatment-naïve HIV-infectedpatients

with HIV RNA>5000 copies/ml. Randomizationwasstratified byscreening HIV RNA level

(≤50,000copies/ml;and>50,000copies/ml)and byhepatitis BorCstatus(positiveornegative).

Patientdemographics(gender, age and race)and baseline characteristics werecomparablebetweenthe

groupreceivingISENTRESS 400mgtwice dailyandthe groupreceivingefavirenz 600mgat

bedtime.

Results48-weekand96-weekanalyses

Withrespecttothe primaryefficacyendpoint,the proportion (%)ofpatientsachievingHIV RNA

<50copies/ml at Week 96was 228/281(81.1%) inthe groupreceivingISENTRESSand 222/282

(78.7%) in the group receiving efavirenz. Thetreatment difference (ISENTRESS – efavirenz)was

2.4%withanassociated95% CI of(-4.3, 9.0)establishingthat ISENTRESSis non-inferiorto

efavirenz(p-valuefornon-inferiority<0.001). Durableoutcomes(Week 48and Week 96)for

patientsontherecommendeddoseofISENTRESS400 mgtwice dailyfromSTARTMRK are

shown in Table3.

Table 3

EfficacyOutcomeatWeeks 48 and96

48 Weeks 96 Weeks STARTMRK Study

Parameter ISENTRESS

400 mgtwice

daily

(N =281) Efavirenz

600 mg

atbedtime

(N = 282) ISENTRESS

400mgtwice

daily

(N = 281) Efavirenz

600 mg

atbedtime

(N=282)

PercentHIV-RNA< 50copies/ml

(95 %CI)

All patients † 86(81,90) 82 (77,86) 81 (76,86) 79(73,83)

Baseline Characteristic ‡

HIV-RNA > 100,000 copies/ml 91(85,95) 89 (83,94) 89 (83,94) 90(84,95)

≤100,000copies/ml 93(86,97) 89 (82,94) 91 (84,96) 89(82,94)

CD4-count≤50 cells/mm 3 84 (64, 95) 86(67,96) 80(59, 93) 86 (68, 96)

>50 and

≤200cells/mm 3 89 (81, 95) 86(77,92) 89(81, 95) 86 (77, 92)

>200 cells/mm 3 94 (89, 98) 92(87,96) 93(87, 96) 93 (87, 97)

ViralSubtypeCladeB 90 (85, 94) 89(83,93) 89(83, 93) 90 (84, 93)

Non-CladeB 96 (87,100) 91 (78,97) 95(85,99) 88(75,96)

MeanCD4CellChange (95 %CI),

cells/mm 3

All patients ‡ 189 (174,

204) 163 (148,

178) 240 (220, 259) 225 (206,244)

Baseline Characteristic ‡

HIV-RNA > 100,000 copies/ml 196(174,

219) 192 (169,

214) 253 (224, 282) 257 (229,286)

≤100,000copies/ml 180(160,

200) 134 (115,

153) 223 (197, 249) 191 (168,215)

CD4-count≤50 cells/mm 3 170 (122,

218) 152 (123,

180) 222 (164, 280) 223 (178,269)

>50 and

≤200cells/mm 3 193 (169,

217) 175 (151,

198) 260 (229, 291) 233 (200,266)

>200 cells/mm 3 190 (168,

212) 157 (134,

181) 229 (200, 258) 219 (192,247)

Viral SubtypeCladeB 187 (170,

204) 164 (147,

181) 243 (220, 266) 227 (206,248)

Non-CladeB 189 (153,

225) 156 (121,

190) 221 (182, 261) 220 (169,271)

48 Weeks 96 Weeks STARTMRK Study

Parameter ISENTRESS

400 mgtwice

daily

(N =281) Efavirenz

600 mg

atbedtime

(N = 282) ISENTRESS

400mgtwice

daily

(N = 281) Efavirenz

600 mg

atbedtime

(N=282)

Non-completer isfailureimputation: patientswho discontinuedprematurelyareimputedasfailurethereafter.Percent ofpatientswith

responseandassociated95 %confidenceinterval(CI)arereported.

Foranalysisbyprognosticfactors,virologicfailures werecarriedforward forpercent <50and 400copies/ml.For meanCD4 changes,

baseline-carry-forward wasusedfor virologicfailures.

Notes: Theanalysisisbasedon allavailabledata.

ISENTRESSandefavirenzwereadministeredwithemtricitabine(+)tenofovir.

5.2Pharmacokinetic properties

Absorption

As demonstrated inhealthyvolunteersadministeredsingleoraldosesofraltegravir in thefastedstate,

raltegravir israpidlyabsorbed withat

max ofapproximately3 hourspostdose.RaltegravirAUCand

increase dose proportionallyover the doserange 100mgto1600mg.Raltegravir C

12hr increases

dose proportionallyoverthedoserange of 100to800 mgandincreases slightlylessthandose

proportionallyoverthe doserange100 mg to1600 mg. Doseproportionalityhasnotbeenestablished

in patients.

Withtwice-dailydosing,pharmacokinetic steadystate is achievedrapidly,within approximatelythe

first 2 daysof dosing. There is littletono accumulation inAUC andC

andevidenceofslight

accumulation in C

12hr .Theabsolute bioavailabilityof raltegravir hasnot beenestablished.

ISENTRESSmaybe administeredwithorwithout food. Raltegravir wasadministered without regard

to foodin the pivotalsafetyandefficacystudiesinHIV-infected patients. Administrationofmultiple

doses of raltegravir following a moderate-fat mealdidnot affect raltegravir AUC to aclinically

meaningfuldegreewithanincreaseof13%relativetofasting.RaltegravirC

12hr was 66 %higherand

was5% higherfollowingamoderate-fatmealcomparedtofasting. Administrationof raltegravir

following ahigh-fatmeal increased AUCand C

byapproximately2-fold and increased C

12hr by

4.1-fold. Administrationofraltegravirfollowing alow-fatmeal decreased AUCand C

by46 %and

52%, respectively; C

12hr was essentiallyunchanged. Food appears to increasepharmacokinetic

variabilityrelative tofasting.

Overall, considerablevariabilitywasobserved inthe pharmacokineticsofraltegravir.Forobserved

12hr inBENCHMRK 1and2the coefficient of variation(CV)for inter-subject variability=212 %

andthe CVfor intra-subject variability= 122%.Sources ofvariabilitymayincludedifferencesin

co-administration withfoodand concomitantmedications.

Distribution

Raltegravir is approximately83%boundto humanplasma proteinover the concentration range of2to

10µM.

Raltegravir readily crossedthe placenta inrats,butdid notpenetrate the braintoanyappreciable

extent.

Metabolismand excretion

The apparentterminal half-lifeofraltegraviris approximately9 hours, witha shorterα-phase half-life

(~1hour)accountingformuch oftheAUC. Followingadministrationofanoraldoseofradiolabeled

raltegravir, approximately51and32%ofthedosewasexcreted infaeces and urine, respectively.In

faeces, onlyraltegravir waspresent, mostofwhichis likelytobederivedfrom hydrolysisof

raltegravir-glucuronidesecretedinbileasobserved inpreclinical species.Two components, namely

raltegravirand raltegravir-glucuronide,weredetectedin urine andaccounted forapproximately9 and

23% ofthedose,respectively.Themajor circulating entitywas raltegravir and represented

approximately70%of the total radioactivity;theremainingradioactivityin plasmawas accounted for

byraltegravir-glucuronide.Studies usingisoform-selective chemical inhibitorsand cDNA-expressed

UDP-glucuronosyltransferases(UGT) showthatUGT1A1 is the mainenzymeresponsible forthe

formation ofraltegravir-glucuronide.Thusthe dataindicate that themajormechanismofclearance of

raltegravirinhumansisUGT1A1-mediatedglucuronidation.

UGT1A1 Polymorphism

In a comparisonof 30 subjectswith*28/*28 genotypeto27 subjects withwild-type genotype,the

geometric meanratio(90 %CI)of AUC was 1.41(0.96, 2.09)andthegeometricmean ratio ofC

12hr

was1.91(1.43,2.55).Doseadjustmentisnotconsiderednecessaryinsubjects withreduced UGT1A1

activitydue to genetic polymorphism.

Special populations

Children

Thepharmacokineticsof raltegravir inpaediatricpatientshas notbeenestablished.

Elderly

Therewasnoclinicallymeaningfuleffectofageon raltegravirpharmacokineticsover the age range

studied(19 to71 years,with few(8)subjectsovertheageof 65).

Gender, Raceand BMI

There were noclinicallyimportantpharmacokineticdifferences due to gender, raceorbodymass

index (BMI).

Renal impairment

Renal clearance ofunchangedmedicinal productisa minor pathwayofelimination. Therewere no

clinicallyimportant pharmacokinetic differences betweenpatients withsevererenal insufficiencyand

healthy subjects (seesection 4.2).Because the extenttowhichISENTRESS maybe dialysableis

unknown, dosingbeforeadialysissession shouldbe avoided.

Hepatic impairment

Raltegravir is eliminatedprimarilybyglucuronidationintheliver. There were noclinicallyimportant

pharmacokineticdifferences betweenpatientswith moderate hepatic insufficiencyand healthy

subjects. The effectofsevere hepatic insufficiencyonthepharmacokineticsofraltegravir has notbeen

studied (see sections4.2 and4.4).

5.3 Preclinical safety data

Non-clinical toxicologystudies,including conventionalstudies of safetypharmacology,repeated-dose

toxicity, genotoxicity,anddevelopmental toxicity, havebeen conducted withraltegravir, inmice,rats,

dogs andrabbits. Effectsat exposure levelssufficientlyinexcess of clinicalexposurelevels indicate

nospecialhazardforhumans.

Mutagenicity

Noevidence ofmutagenicityorgenotoxicitywas observedininvitromicrobial mutagenesis

(Ames) tests,in vitroalkalineelution assaysfor DNAbreakageandinvitroandinvivo

chromosomal aberrationstudies.

Carcinogenicity

A carcinogenicitystudyofraltegravirinmice didnotshowanycarcinogenic potential.At thehighest

dose levels,400mg/kg/dayinfemalesand250mg/kg/dayinmales,systemicexposure wassimilar to

thatat the clinical dose of400mgtwicedaily.Inrats,tumours(squamouscell carcinoma)ofthe

nose/nasopharynxwere identified at 300and 600mg/kg/dayin females and at300mg/kg/dayin

males.These neoplasia couldresultfromlocal depositionand/oraspirationofdrugonthemucosaof

the nose/nasopharynx duringoralgavagedosingand subsequent chronic irritationand inflammation;it

is likelythat theyare oflimited relevance forthe intendedclinical use.At theNOAEL,systemic

exposurewas similarto thatattheclinical dose of400mgtwice daily.Standard genotoxicitystudies

toevaluatemutagenicityand clastogenicitywere negative.

Developmental Toxicity

Raltegravirwas not teratogenicindevelopmental toxicitystudies in ratsandrabbits.A slightincrease

in incidenceofsupernumeraryribs wasobservedinratpupsof damsexposedtoraltegravirat

approximately4.4-foldhuman exposureat 400mgtwice dailybased onAUC

0-24hr .Nodevelopment

effectswere seenat3.4-foldhumanexposureat 400 mg twice dailybasedonAUC

0-24hr (see

section4.6).Similar findingswerenotobservedinrabbits.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

-microcrystalline cellulose

- lactose monohydrate

- calciumphosphate dibasic anhydrous

-hypromellose2208

- poloxamer407

-sodiumstearylfumarate

- magnesiumstearate

Film-coating

- polyvinylalcohol

- titaniumdioxide (E 171)

-polyethylene glycol 3350

- talc

- rediron oxide(E172)

-blackironoxide(E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30months

6.4 Special precautions forstorage

Store thismedicinebelow 30ºC.

6.5 Natureand contents of container

Highdensitypolyethylene(HDPE) bottlewithachild-resistantpolypropylene closure.

Twopacksizesare available: 1bottlewith60tablets,anda multi-pack containing3bottlesof

60tablets.

Not allpacksizesmaybe marketed.

6.6 Special precautions fordisposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp& Dohme (Israel –1996)CompanyLtd.

P.O.B. 7121,Petah-Tikva49170,Israel

8. MARKETING AUTHORISATIONNUMBER

Reg.number:1403331793 00

Theformatofthis leaflet was determinedbythe MinistryofHealthanditscontent was checked and

approvedinDecember2011.

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