REYATAZ 150 MG

Israel - English - Ministry of Health

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Active ingredient:
ATAZANAVIR AS SULFATE 150 MG
Available from:
BRISTOL, MYERS SQUIBB (ISRAEL) LIMITED
ATC code:
J05AE08
Pharmaceutical form:
CAPSULES
Administration route:
PER OS
Manufactured by:
BRISTOL MAYERS SQUIBB COMPANY , USA
Therapeutic group:
ATAZANAVIR
Therapeutic indications:
Reyataz is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Authorization number:
140783095900
Authorization date:
2009-05-01

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

18-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

18-01-2021

2018 יאמ :ךיראתב תואירבה דרשמ תוארוהל םאתהב ןכדוע הז ןולע ןכות 1986 – ו"משתה )םירישכת( םיחקורה תונקת יפל ןכרצל ןולע דבלב אפור םשרמ יפ לע תקוושמ הפורתה תוסומכ ג"מ 150 זאטאייר תוסומכ ג"מ 200 זאטאייר תוסומכ ג"מ 300 זאטאייר :ותומכו ליעפה רמוחה Atazanavir (as sulfate) 150 mg ג"מ 150 )טפלוסכ( ריבנזטא :הליכמ ג"מ 150 זאטאייר לש הסומכ לכ Atazanavir (as sulfate) 200 mg ג"מ 200 )טפלוסכ( ריבנזטא :הליכמ ג"מ 200 זאטאייר לש הסומכ לכ Atazanavir (as sulfate) 300 mg ג"מ 300 )טפלוסכ( ריבנזטא :הליכמ ג"מ 300 זאטאייר לש הסומכ לכ .זוטקל הליכמ הסומכה .6 ףיעס האר אנא ,םיליעפ יתלבה םירמוחה תמישרל תולאש ךל שי םא .הפורתה לע יתיצמת עדימ ליכמ הז ןולע .הפורתב שמתשת םרטב ופוס דע ןולעה תא ןויעב ארק .חקורה לא וא אפורה לא הנפ ,תופסונ םתלחמ יכ ךל הארנ םא וליפא םהל קיזהל הלולע איה .םירחאל התוא ריבעת לא .ךתלחמב לופיטל המשרנ וז הפורת .המוד .םישדוח השולש ליגל תחתמ תוקוניתל תדעוימ הניא וז הפורת .םינש 6 ליג לעמ םידלילו םירגובמל תדעוימ זאטאייר לשכה ףיגנ - Human Immunodeficiency Virus type 1) HIV-1 -ה ףיגנ דגנכ םשרמ תפורת הניה זאטאייר .HIV-1 ימוהיזב לופיטל תודעוימה תורחא תוילאריוורטר-יטנא תופורת םע בולישב תנתינה )1 גוסמ ישונאה ינוסיחה .)שכרנה ינוסיחה לשכה תנומסת( סדייאה תלחמל םרוג רשא ףיגנה וניה HIV-1 ףיגנ תומכ תדרוהב רוזעל היושע זאטאייר ,HIV-1-ה םוהיזב לופיטל תורחא תוילאריוורטר-יטנא תופורת םע שומישב םימוהיזב םחליהל םירזוע רשא CD4+ (T( גוסמ םדה יאת רפסמ תאלעהבו )יפיגנ סמוע םג תארקנ( םדב HIV-1-ה .םירחא תכרעמה תא רפשל רוזעל םייושע CD4+ (T) גוסמ םדה יאת רפסמ תאלעהו םדב HIV-1-ה ףיגנ תומכ תדרוה ךלש תינוסיחה תכרעמהשכ עיפוהל םילולעה םימוהיזל וא התומתל ךלש ןוכיסה תא דירוהל םילוכיו ,ךלש תינוסיחה .)םייטסינוטרופוא םימוהיז( השלח תנמ לע HIV-1 -ה תופורת תא לוטיל דיפקהל שי .סדייא תאפרמ הניאו HIV-1 םוהיז תאפרמ הניא זאטאייר .HIV -ל תורושקה תורחא תולחמ תיחפהלו HIV-1-ה םוהיזב טולשל

1

.

?הפורתה תדעוימ המל ינוסיחה לשכה ףיגנ - Human Immunodeficiency Virus type 1) HIV-1 -ה ףיגנב לופיטל תדעוימ זאטאייר Antiretroviral) HIV-1-ב לופיטל תודעוימה תורחא תוילאריוורטר-יטנא תופורת םע בולישב תנתינה )1 גוסמ ישונאה .םינש 6 ליג לעמ םידליבו םירגובמב )agents .םישדוח השולש ליגל תחתמ תוקוניתל תדעוימ הנניא זאטאייר .תוזאטורפ יבכעמ :תיטיופרת הצובק

2

.

:הפורתב שומיש ינפל :םא הפורתב שמתשהל ןיא

.(6 ףיעס האר( םירחאה הפורתה יביכרממ דחא לכל וא )טפלוס ריבנזטא( ליעפה רמוחל )יגרלא( שיגר התא

זאטאייר .התוליעפ לע עיפשהל הלולע תואבה תופורתה םע זאטאייר תליטנ .תואבה תופורתהמ תחא לטונ התא :תואבה תופורתה םע שומישב תוומל וא םייח תונכסמ ,תורומח יאוול תועפותל םורגל הלולע ןימאטוגרא ,ןימאטוגרא :תוללוכה טוגראה תחפשממ תופורת ;ריברפוזרג/ריבסבלא ;דירפאסיצ ;ןיסוזופ לא /ריברפצלג ;ןיבונוגרא ,ןיבונוגראליתמ ,טאליסמ ןימאטוגראורדיהיד ,ןימאטוגראורדיהיד ,טארטרט ;)ריבאנוטיר םע בולישב תנתינ זאטאיירו הדימב( ןודיסרול ;ןאקטוניריא ;ריבאנידניא ;ריבסטנרביפ לופיטל ליפאנדליס ;ןיפמאפיר ;דיזומיפ ;ןיפאריבנ ;)העגרה ךרוצל הפה ךרד ןתמב( םלוזאדימ ;ןיטאטסאבול .םלוזאירט ;)St. John’s wort( םוטארופרפ םוקירפיהה חמצ ;ןיטטסבמיס ;יקרוע יתאיר םד ץחל רתיב

זאטאייר םע הלעמל תומושרה תופורתהמ תחא לטונ ךדלי וא התא םא עיפוהל תולולע תורומח תויעב

.הקינמ ךנה :הפורתב שומישל תועגונה תודחוימ תורהזא .םשרנ המשלש וזמ הנוש הרטמל רישכתב שמתשהל ןיא .הפורתה תליטנ ינפל אפורל ךכ לע עידוהל ךילע ,יהשלכ הפורתל וא והשלכ ןוזמל שיגר ךנה םא .הפורתה תליטנ ינפל אפורב ץעוויה - םימיוסמ םירכוסל תוליבס יא ךלצא הנחבוא םא .זוטקל ליכמ רישכתה :םא אפורל רפס זאטאיירב לופיטה ינפל

.יהשלכ הפורתל וא והשלכ ןוזמל שיגר התא

.בלב תויעבמ לבוס התא

.C וא B סיטיטפהה ףיגנב םוהיז ללוכ דבכה דוקפתב יוקילמ לבוס התא

.הזילאיד לופיט רבוע התא

.תרכוסמ לבוס התא

.היליפומהמ לבוס התא

.תורחא תויאופר תויעבמ לבוס התא

תירוע הקבדמ ,תילניגו תעבט וא ימחר ךות ןקתה ,תוקירז ןוגכ םיילאנומרוה העינמ יעצמאב תשמתשמ ךנה אפורב ץעוויהל שי .זאטאייר םע לופיטה ךלהמב לועפל אל םילולע רשא ןויריה תעינמל תולולגו ןויריה תעינמל .זאטאיירב לופיטה ךלהמב םהב שמתשהל ןתינש העינמ יעצמאל רשאב

."הקנהו ןויריה" ףיעס יאר ,ןויריהל סנכיהל תננכתמ וא ןויריהב ךנה

.בוהצל ךפוה ויניע לש ןבלה קלחה וא ורוע ןווג םא אפורל רפסל שי ,דלוויי ךקוניתש רחאל :בקעמו תוקידב .לופיטה ךלהמבו זאטאייר תליטנ םרט דבכה ידוקפת תא קודבל תנמ לע םד תוקידב ךל עצבי ךלש אפורה .לופיטה ךלהמבו זאטאייר תליטנ םרט ,תוילכה ידוקפת תא קודבל תנמ לע ןתשו םד תוקידב ךל עצבי ךלש אפורה ךכ לע רפס ,הנוזת יפסותו םשרמ אלל תופורת ללוכ תורחא תופורת ,הנורחאל תחקל םא וא ,חקול התא םא .תויתפורת-ןיב תובוגתמ םיעבונה תוליעי-יא וא םינוכיס עונמל ידכ חקורל וא אפורל חקורב וא אפורב ץעוויה .חקורלו לפטמה אפורל הגיצהל תנמ לע לטונ ךנה ןתוא תופורתה תמישר תא רומש אפורה םע תמדקומ תוצעייתה אלל השדח הפורת לוטיל ןיא .זאטאייר םע תוביגמ רשא תופורתה תמישרל עגונב .החוטב הניה זאטאייר תליטנ םע דחי תורחא תופורת תליטנ םא ךל ץעייל לוכי לפטמה אפורה .ךלש לפטמה תופורתה םע זאטאייר תליטנ .תואבה תופורתהמ תחא לטונ התא םא הפורתב שמתשהל ןיא םייח תונכסמ ,תורומח יאוול תועפותל םורגל הלולע זאטאייר .התוליעפ לע עיפשהל הלולע תואבה :תואבה תופורתה םע שומישב תוומל וא ,ןימאטוגרא :תוללוכה טוגראה תחפשממ תופורת ;ריברפוזרג/ריבסבלא ;דירפאסיצ ;ןיסוזופלא ;ןיבונוגרא ,ןיבונוגראליתמ ,טאליסמ ןימאטוגראורדיהיד ,ןימאטוגראורדיהיד ,טארטרט ןימאטוגרא בולישב תנתינ זאטאיירו הדימב( ןודיסרול ;ןאקטוניריא ;ריבאנידניא ;ריבסטנרביפ/ריברפצלג ;דיזומיפ ;ןיפאריבנ ;)העגרה ךרוצל הפה ךרד ןתמב( םלוזאדימ ;ןיטאטסאבול ;)ריבאנוטיר םע םוקירפיהה חמצ ;ןיטטסבמיס ;יקרוע יתאיר םד ץחל רתיב לופיטל ליפאנדליס ;ןיפמאפיר .םלוזאירט ;)St. John’s wort( םוטארופרפ םע הלעמל תומושרה תופורתהמ תחא לטונ ךדלי וא התא םא עיפוהל תולולע תורומח תויעב .זאטאייר וא ןונימב יוניש שורדי )ריבאנוטיר ילב וא םע( זאטאייר םע דחי תואבה תופורתב שומישהו ןכתיי התא םא לפטמה אפורב ץעוויהל שי .הטמ תועיפומה תופורתה לש וא זאטאייר לש ןונימה רטשמב :תואבה תופורתהמ רתוי וא תחא לטונ

,ריבניווקס ,זנריבאפא ,טראמופ ליסקורפוזיד ריבופונט ,ןיזונאדיד :ןוגכ HIV –ב לופיטל תופורת ריבאנוטיר

C גוסמ דבכ תקלדב לופיטל ריברפאליסקוו ,ריבסאטאפלו ,ריבובסופוס ,ריברפצוב

לוזארפמוא ,ןידיטומפ :ןוגכ הצמוח תשרפה תובכעמ תופורת ,הצמוח תורתוס תופורת

ןידיניווק ,)ימטסיס ןתמב( ןיאקודיל ,לידירפב ,ןורדוימא :בל בצק תוערפהב לופיטל תופורת

השירק דגונ - ןירפרוו

ןודוזארט ,םיילקיצירטה תחפשמ :ןוגכ ןואכידב לופיטל תופורת

ןי'גירטומל ,לאטיברבונפ ,ןיאוטינפ ,ןיפזמברק :ןוגכ היספליפאב לופיטל םיסוכרפ תודגונ תופורת

לוזאנוקירוו ,לוזאנוקארטיא ,לוזאנוקוטק :ןוגכ םיתיירטפ-יטנא

(Gout( ןודגישב לופיט וא העינמל - ןיציכלוק

תפחשב לופיטל הקיטויביטנא - ןיטובאפיר

יטוכיספיטנא - ןודיסרולו ןיפאיטווק

)ילרטנרפ ןתמב( םלוזאדימ :םיניפזאידוזנב

לימפרו ,ןיפידרקינ ,ןיפידפינ ,ןיפידולפ ,םזאיטליד :ןוגכ ןדיס תולעת ימסוח

יתאיר םד ץחל רתיב לופיטל - ןטנסוב

ןיטטסבוסור ,ןיטטסברוטא - לורטסלוכ תדרוהל תופורת

ןורדניתארונ וא טמיטסגרונ ,לוידרטסא ליניטא - )תולולג( ןויריה תעינמל תוילאנומרוה תופורת

סומילורקט ,סומילוריס ,ןירופסולקיצ - ןוסיח תכרעמ תואכדמ תופורת

)ףאשמב( לורטמלאס

ףאשמב וא ףאל סיסרתב דיאורטס - ןוזאקיטולפ

ןיצימורתירלק גוסמ םידילורקמה תחפשממ הקיטויביטנא

ןיפרונרפוב :םיידיאויפוא םיבאכ יככשמ

ליפאנדרו ,ליפלאדט ,ליפאנדליס - תונוא ןיאב לופיטל וא יתאיר יקרוע םד ץחל רתיב לופיטל תופורת :ןוזמו הפורתב שומיש .תוסומכה תא חותפל ןיא .ןוזמ םע התומלשב הפורתה תא לוטיל שי :הקנהו ןויריה

לפטמה אפורב יצעוויה .תורהל תננכתמ וא ןויריהב תא םא אפורל ירפס זאטאיירב לופיטה ינפל .ןויריהל סנכיהל תננכתמ ךנה םא וא ןויריהה ךלהמב זאטאייר תליטנ לע

תירוע הקבדמ ,תילניגו תעבט וא ימחר ךות ןקתה ,תוקירז ןוגכ םיילאנומרוה העינמ יעצמא ץעוויהל שי .זאטאייר םע לופיטה ךלהמב לועפל אל םילולע ןויריה תעינמל תולולגו ןויריה תעינמל .זאטאיירב לופיטה ךלהמב םהב שמתשהל ןתינש העינמ יעצמאל רשאב אפורב

.בוהצל ךפוה ויניע לש ןבלה קלחה וא ורוע ןווג םא אפורל רפסל שי ,דלוויי ךקוניתש רחאל היושע זאטאייר .ךקוניתל HIV-1 -ה ףיגנ תרבעהל ןוכיסה לשב זאטאייר תלטונ ךנה םא קינהל ןיא .ךקונית תא ליכאהל רתויב הבוטה ךרדה יבגל אפורב יצעוויה .םאה בלח ךרד קוניתל רובעל :תונוכמב שומישו הגיהנ .דימ ךלש אפורל תונפל שי ,תורוחרחסב שח ךנה םא :הפורתב םיביכרמהמ קלח לע בושח עדימ תליטנ ינפל אפורב ץעוויה םימיוסמ םירכוסל תוליבס יא ךלצא הנחבוא םא .זוטקל הליכמ זאטאייר .הפורתה ?הפורתב שמתשת דציכ .3 ךניא םא חקורה וא אפורה םע קודבל ךילע .אפורה תוארוהל םאתהב דימת רישכתב שמתשהל שי .רישכתב לופיטה ןפואו ןונימל עגונב חוטב .דבלב אפורה ידי לע ועבקי לופיטה ןפואו ןונימה .תורחא תוילאריוורטר-יטנא תופורת םע בולישב חקליהל תבייח זאטאייר םאתהב הפורתה תא לוטיל שי .אפורה ךל הרוהש יפכ םוי לכ עובק דעומב הפורתה תא לוטיל שי .אפורה ידי לע עבקנש ןמזה קרפו ןונימל .תצלמומה הנמה לע רובעל ןיא .תוסומכה תא חותפל ןיא .ןוזמ םע התומלשב הפורתה תא לוטיל שי יפכ לופיטב דימתהל שי .לפטמה אפורהמ הייחנה אלל ןונימ תונשל וא לופיט קיספהל ןיא .אפורה ידי לע ץלמוהש .זאטאיירב לופיטה תפוקת ךשמב לפטמה אפורה לש תילופיט תרגסמב תויהל בושח תליטנ לש הקספה .לזאת אל הפורתהש תנמ לע זאטאייר לש הקיפסמ תומכ ךל רומש דימת שוכרל לולע ףיגנה .םדב HIV-1-ה ףיגנ תמר תיילעל איבהל הלולע ,רצק ןמזל וליפא ,הפורתה .לופיטל רתוי השק ךופהי ךכמ האצותכו זאטאיירל תודימע האבה הנמה תא לוטילו תרכזנשכ דימ הנמ לוטיל שי ,שורדה ןמזב וז הפורת לוטיל תחכש םא .החכשנש הנמה םוקמב הלופכ הנמ לוטיל ןיא .ליגרה ןמזב תיב לש ןוימ רדחל וא אפורל דימ הנפ ,הפורתה ןמ דלי עלב תועטב םא וא רתי תנמ תלטנ םא .ךתיא הפורתה תזירא אבהו םילוח םא םייפקשמ בכרה .הפורת לטונ ךנהש םעפ לכב הנמהו תיוותה קודב !ךשוחב תופורת לוטיל ןיא .םהל קוקז ךנה

.חקורב וא אפורב ץעוויה ,הפורתב שומישל עגונב תופסונ תולאש ךל שי םא :יאוול תועפות .4 להבית לא .םישמתשמהמ קלחב יאוול תועפותל םורגל לולע זאטאיירב שומישה ,הפורת לכב ומכ .ןהמ תחא ףאמ לובסת אלו ןכתיי .יאוולה תועפות תמישר ארקמל :םיאבה םירקמב אפורל תונפל שי .תורומח יאוול תועפותל םורגל הלולע זאטאייר

היעב לע דיעהל לולע הז .תרוחרחס שיגרמ התאו הדימב דימ אפורל הנפ .בלה בצקב םייוניש .בלב

.הרומח תויהל םיתיעל הלוכי ךא ,זאטאייר םילטונה םילוחב החיכש רועב החירפ .תירוע החירפ תוולתהל הלוכי החירפ .לופיטב יוניש אלל םייעובש ךות תפלוח ללכ ךרדב תירוע החירפ .הרומח תויהל הלולעו םירחא םייניצר םינימסתל לופיטה תא קספה ,םיאבה םינימסתהמ דחא םע החירפ וא הרומח החירפ חתפמ התא םא !דימ אפורל הנפו זאטאיירב

תעפש ייומד םינימסת וא ילוח תשגרה

םוח

םיקרפמ וא םירירש יבאכ

(conjunctivitis( תוקלדומ וא תומודא םייניע

תויחופלש

הפב םיעצפ

םינפה לש תוחפנתה

רועל תחתמ םודא וא םח ,באוכ שוג

בורלו זאטאייר םילטונה םילוחב החיכש העפות הניה םייניעה לש ןבלה קלחב וא רועב בוהצ ןווג האצותכ םרגיהל הלוכי וז העפות .הרומח היעב לש ןימסת תווהל הלוכי םיתיעל ךא ,הקיזמ הניא ,דבכל הקיזמ הנניא וז העפותש תורמל .)דבכב רצונ ןיבוריליב( םדב ןיבוריליבה תמרב היילעמ קלחב וא רועב בוהצ ןווגב ןיחבמ התאו הדימב ידיימ ןפואב אפורל תונפל שי ,םייניעל וא ,רועל .םייניעה לש ןבלה

רימחהל תולולע ןה ,C וא B גוסמ דבכ תקלד ללוכ דבכב תויעבמ לבוס ךנה םא .דבכב תויעב דבכה ידוקפת תא קודבל תנמ לע םד תוקידב ךל עצבי ךלש אפורה .זאטאיירב לופיטה ךשמב ןתש :םיאבה םינימסתב שח ךנה םא דימ אפורל רפס .לופיטה ךלהמבו זאטאייר תליטנ םרט ,דרג ,הליחב ,הריהב האוצ ,בוהצל ךפוה ךיניע לש ןבלה קלחה וא ךרוע ןווג ,)הת עבצב( ההכ .הביקה רוזאב םיבאכ

תוקידב ךל עצבי ךלש אפורה .תוילכה דוקפת לע עיפשהל הלולע זאטאייר .תינורכ תוילכ תלחמ .לופיטה ךלהמבו זאטאייר תליטנ םרט ,תוילכה ידוקפת תא קודבל תנמ לע ןתשו םד

םילטונה םילפוטמהמ קלחב ורימחה וא וחווד )הימקילגרפיה( תוהובג רכוס תומר וא תרכוס לוטיל ליחתהל ושרדנ םילפוטמהמ קלח .זאטאייר ןוגכ זאטורפה יבכעמ תחפשממ תופורת .תרכוסב יתפורתה לופיטב יוניש ךורעל וא תרכוסב לופיטל תופורת

הווח התא םא ידיימ ןפואב אפורל חווד .זאטאיירב םילפוטמהמ קלחב וחווד תוילכב םינבא ,הנותחתה ןטבה רוזאב וא ןותחתה בגב באכ :לולכל םילולעה תוילכב םינבא לש םינימסת .ןתש ןתמ ןמזב באכ וא ,ןתשב םד תעפוה

הווח התא םא ידיימ ןפואב אפורל חווד .זאטאיירב םילפוטמהמ קלחב וחווד הרמה סיכב תויעב ,ןטבה לש ןוילע יעצמאה וא ינמיה קלחב באכ :לולכל םילולעה הרמה סיכב תויעב לש םינימסת .ןיעה לש ןבלה קלחה וא רועה תבהצה ,תואקהו תוליחב ,םוח

תחפשממ תופורתב לופיטה ךשמב םימומידב הילע לע וחוויד היליפומהב םילוח .היליפומה ילוח .זאטאייר ןוגכ תוזאטורפ יבכעמ

םייוניש .HIV-1 -ב לופיטל תופורת םילטונה םילפוטמב שחרתהל םילוכי ףוגב ןמושב םייוניש .ףוגה ףקיהבו ,הזחב ,ראווצהו בגה לש ןוילעה קלחב ןמושה תומכב הילע לולכל םילוכי הלא תיתואירבה העפשההו קיודמה םרוגה .םינפהו ,תועורזה ,םיילגרהמ ןמוש דוביא הווחתו ןכתיי .םיעודי םניא הלא םיבצמ לש חווטה תכורא

םילוחב חתפתהל לולע – )ןוסיחה תכרעמב םייוניש( immune reconstitution syndrome םחליהל ליחתהלו קזחתהל היושע ךלש ןוסיחה תכרעמ .HIV-1 -ל תופורתב לופיט םיליחתמש תליחת רחאל םישדח םינימסתב שח ךנה םא אפורל רפס .ףוגב םימדוק םימודר םימוהיזב .זאטאייר תליטנ :תוללוכ זאטאיירב לופיטה ןמזב תוחיכש יכה יאוולה תועפות ,תויתשוחתב הדירי - תומדרה תשוחת ,הניש יישק ,תואקה ,ןטבה רוזאב באכ ,שאר באכ ,הליחב ,ןואכיד ,לושלש ,םירירש יבאכ ,תרוחרחס ,םיילגרה תופכב וא םיידיב הפירש תשוחת וא ,ץוצקע .םוח וא ,תפלוח הנניא וא ,הרימחמ ,ךתוא הדירטמ יאוולה תועפותמ תחא םא ,יאוול תעפות העיפוה םא .אפורה םע ץעייתהל ךילע ,ןולעב הרכזוה אלש יאוול תעפותמ לבוס התא רשאכ לפטמה אפורל תונפל שי ,ףסונ עדימל .זאטאייר לש יאוולה תועפות לש האלמ המישר הנניא יהוז .חקורל וא יאוול תועפות לע חוויד" רושיקה לע הציחל תועצמאב תואירבה דרשמל יאוול תועפות לע חוודל ןתינ הנפמה (www.health.gov.il( תואירבה דרשמ רתא לש תיבה ףדב אצמנש "יתפורת לופיט בקע https://forms.gov.il/globaldata/ :רושיקל הסינכ י"ע וא ,יאוול תועפות לע חווידל ןווקמה ספוטל

getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

?הפורתה תא ןסחאל ךיא .5

חווטו םדי גשיהל ץוחמ רוגס םוקמב רומשל שי תרחא הפורת לכו וז הפורת !הלערה ענמ הארוה אלל האקהל םורגת לא .הלערה ענמת ךכ ידי לעו תוקונית וא/ו םידלי לש םתייאר !אפורמ תשרופמ

ךיראת .הזיראה יבג לע עיפומה )exp. date) הגופתה ךיראת ירחא הפורתב שמתשהל ןיא .שדוח ותוא לש ןורחאה םויל סחייתמ הגופתה

רחואי אל ךא ,םישדוח 6 ךות הפורתב שמתשהל ןתינ קובקבה לש הנושאר החיתפ רחאל .הזיראה יבג לע עיפומה הגופתה ךיראתמ

.רסח וא םוגפ קובקבה לש ימינפה םטאה םא שמתשהל ןיא

.קובקבה תא בטיה רוגסל שי .25ºC לע הלוע הניאש הרוטרפמטב ןסחאל שי

.שומישב ןניאש תופורת דימשהל דציכ חקורה תא לאש .הפשאל וא בויבל תופורת ךילשהל ןיא .הביבסה לע רומשל ורזעי ולא םיעצמא ףסונ עדימ .6 :םג הליכמ הפורתה ,ליעפה רמוחה לע ףסונ :םיליעפ יתלב םירמוח

Lactose monohydrate, crospovidone and magnesium stearate.

The hard gelatin capsule shells contain: gelatin, FD&C Blue No. 2, titanium dioxide.

The 300 mg capsule shells also contain: red iron oxide, black iron oxide, and

yellow iron oxide.

The capsules are imprinted with ink.

.זוטקל הליכמ הסומכה .טרדיהונומ זוטקל ג"מ 82.2 הליכמ הסומכ לכ - ג"מ 150 זאטאייר .טרדיהונומ זוטקל ג"מ 109.6 הליכמ הסומכ לכ - ג"מ 200 זאטאייר .טרדיהונומ זוטקל ג"מ 164.4 הליכמ הסומכ לכ - ג"מ 300 זאטאייר :הזיראה ןכות המו הפורתה תיארנ דציכ :ג"מ 150 זאטאייר תלכת עבצב הסומכה ףוגו םוטא לוחכ עבצב הסומכה שאר ,םיקלח ינש ,1# לדוגב ןיטל'ג תסומכ תולונרג הליכמ הסומכה ."3624" לוחכ בותיכו "BMS 150mg" ןבל בותיכ תללוכ הסומכה .םוטא .ריהב בוהצ דע ןבל עבצב .תוסומכ 60 הליכמ קובקבה תזירא :ג"מ 200 זאטאייר בותיכ תללוכ הסומכה .םוטא לוחכ עבצב הסומכה שארו ףוג ,םיקלח ינש ,0# לדוגב ןיטל'ג תסומכ .ריהב בוהצ דע ןבל עבצב תולונרג הליכמ הסומכה ."3631"-ו "BMS 200mg" ןבל .תוסומכ 60 הליכמ קובקבה תזירא :ג"מ 300 זאטאייר לוחכ עבצב הסומכה ףוגו םוטא םודא עבצב הסומכה שאר ,םיקלח ינש ,00# לדוגב ןיטל'ג תסומכ ןבל עבצב תולונרג הליכמ הסומכה ."3622"-ו "BMS 300mg" ןבל בותיכ תללוכ הסומכה .םוטא .ריהב בוהצ דע .תוסומכ 30 הליכמ קובקבה תזירא ,הירא תיירק ,18 טרב ןורהא 'חר ,מ"עב לארשי ביווקס סרייאמ-לוטסירב :ותבותכו םושירה לעב .לארשי ,4951448 הווקת חתפ .ב"הרא ,יזר'ג-וינ ,קיווסנוארב וינ ,ביווקס סרייאמ-לוטסירב תרבח :ותבותכו ןרציה :תואירבה דרשמב יתכלממה תופורתה סקנפב הפורתה םושיר רפסמ 140-78-30959-00 :ג"מ 150 זאטאייר 141-10-30960-06 :ג"מ 200 זאטאייר 146-78-33389-00 :ג"מ 300 זאטאייר דרשמ תוארוהל םאתהב ןכדועו 2016 רבוטקואב תואירבה דרשמ ידי לע רשואו קדבנ הז ןולע .2018 יאמב תואירבה ינבל תדעוימ הפורתה ,תאז ףא לע .רכז ןושלב חסונ הז ןולע ,האירקה תלקהלו תוטשפה םשל .םינימה ינש ۲٠۱۸ رايأ :خيرات يف ةحصلا ةرازو تاميلعت بجومب ةرشنلا هذه ىوتحم ثيدحت

مت ١٩٨٦ – )تارضحتسم( ةلديصلا ةمظنأ بجومب كلهتسملل ةرشن طقف بيبط ةفصو بجومب ءاودلا ق

وسي تلاوسبك غلم ١٥٠ زاتاير تلاوسبك غلم ٢٠٠ زاتاير تلاوسبك غلم ٣٠٠ زاتاير :اهتيمكو ةلاعفلا ةداملا Atazanavir (as sulfate) غلم ۱٥٠ )تافلوس لكش ىلع( ريڤانازاتأ :ىلع غلم ١٥٠ زاتاير نم ةلوسبك

ّ

لك يوتحت

150 mg

Atazanavir (as sulfate) غلم ۲٠٠ )تافلوس لكش ىلع( ريڤانازاتأ :ىلع غلم ٢٠٠ زاتاير نم ةلوسبك

ّ

لك يوتحت

200 mg

Atazanavir (as

sulfate)

غلم ٣٠٠ )تافلوس لكش ىلع( ريڤانازاتأ :ىلع غلم ٣٠٠ زاتاير نم ةلوسبك

ّ

لك يوتحت

300 mg

.زوتكلالا ىلع ةلوسبكلا يوتحت .٦ ةرقفلا رظنأ ،ةلاعفلا ريغ داوملا ةمئاقل اذإ .ءاودلا نع ةزجوم تامولعم ىلع ةرشنلا هذه يوتحت .ءاودلل كلامعتسإ لبق اهتياهن ىتح نعمتب ةرشنلا أرقإ .يلديصلا وأ بيبطلا عجار ،ةيفاضإ ةلئسأ كيدل ترفوت .كضرمل هباشم مهضرم نأ كل ادب ولو ىتح مه

رضي دق وهف .نيرخلآل هيطعت لا .كضرم جلاعل ءاودلا اذه فصو ةثلاث رمع نود ام عضرلل صصخم ريغ ءاودلا اذه .تاونس ٦ رمع قوف ام لافطلألو رابكلل صصخم زاتاير .رهشأ Human Immunodeficiency) HIV-1 سوريڤ دض ةيبط ةفصول جاتحي ءاود نع ةرابع وه زاتاير تاسوريڤلل ةداضم ىرخأ ةيودأ ةكراشمب ىطعي يذلا )۱ عون نم يرشبلا ةعانملا لشف سوريڤ – Virus-type 1 .HIV-1 ثولت ةجلاعمل ةصصخملا ةيعجرلا .)بستكملا ةعانملا لشف ةمزلاتم( زديلإا ضرمل ببسملا سوريڤلا نع ةرابع وه HIV-1 ىلع دعاس

ي نأ نكمم زاتاير نإف ،HIV-1 ثولت ةجلاعمل ةيعجرلا تاسوريڤلل ةداضم ىرخأ ةيودأ عم لمعتسي امدنع

CD4+

(T( عون نم مدلا ايلاخ ددع ةدايز ىلعو )يسوريڤلا ءبعلا ا

ضيأ ىمسي( مدلا يف HIV-1 سوريڤ ةيمك ضيفخت .ىرخلأا تاثولتلا ةبراحم ىلع دعاست يتلا ىلع دعاسي نأ هنأش نم CD4+ (T) عون نم مدلا ايلاخ ددع ةدايزو مدلا يف HIV-1 سوريڤ ةيمك ضيفخت نإ نوكي امدنع رهظت نأ نكمي يتلا تاثولت وأ ةافو لوصحل كيدل ةروطخلا نم ل

لقي نأ هنكميو ،يعانملا كزاهج نيسحت .(ةيزاهتنإ تاثولت( افيعض كيدل يعانملا زاهجلا لجأ نم كلذو HIV-1 ةيودأ لوانت ىلع صرحلا بجي .زديلإا نم يفشي لاو HIV-1 ثولت نم يفشي لا زاتاير .HIV ـب ةقلعتملا ىرخلأا ضارملأا نم ليلقتللو HIV-1 ثولت ىلع ةرطيسلا ؟ءاودلا صصخم ضرغ يلأ .١ لشف سوريڤ – Human Immunodeficiency Virus-type 1) HIV-1 سوريڤ ةجلاعمل صصخم زاتاير ةجلاعمل ةصصخملا ةيعجرلا تاسوريڤلل ةداضم ىرخأ ةيودأ ةكراشمب ىطعي يذلا )۱ عون نم يرشبلا ةعانملا .تاونس ٦ رمع قوف ام لافطلأاو رابكلا ىدل )Antiretroviral agents) HIV-1 .رهشأ ةثلاث رمع نود ام عضرلل صصخم ريغ زاتاير .زآيتورپلا تاطبثم نم :ةيجلاعلا ةليصفلا :ءاودلا لامعتسا لبق .٢ :اذإ ءاودلا لامعتسإ زوجي لا

رظنأ( ىرخلأا ءاودلا تابكرم نم دحاو لكل وأ )تافلوس ريڤانازاتأ( ةلاعفلا ةداملل )يجريلأ( ا

ساسح تنك .(٦ ةرقفلا

ببسي دق زاتاير .اهلمع ىلع رثؤي دق ةيلاتلا ةيودلأا عم زاتاير لوانت نإ .ةيلاتلا ةيودلأا نم دحاو لوانتت تنك :ةيلاتلا ةيودلأا عم لمعتسي امدنع ةافولا وأ ةايحلا ىلع ا

رطخ لكشت ،ةريطخ ةيبناج ضارعأ نيماتوچرإ ،نيماتوچرإ :لمشت توچرلإا ةليصف نم ةيودأ ؛ريڤيرپوزارچ/ريڤسابلإ ؛ديرپاسيس ؛نيسوزوفلأ /ريڤيرباكيلچ ؛نيڤونوچرإ ،نيڤونوچرإ ليثيم ،تلايسيم نيماتوچرإ ورديهيد ،نيماتوچرإ ورديهيد ،تارترات ؛نيتاتساڤول ؛)ريڤانوتير عم ا

يوس زاتاير ءاطعإ

مت لاح يف( نوديسارول ؛ناكيتونيريإ ؛زيڤاندنيإ ؛ريڤساتنربيپ طغض عافترا جلاعل ليفانيدليس ؛نيپمافير ؛ديزوميپ ؛نيپاريڤين ؛)ةئدهتلل مفلا قيرط نع ءاطعلإاب( ملاوزاديم .ملاوزايرت ؛)St. John’s wort( موتاروفريپ موكيريپيه ةتبن ؛نيتاتساڤميس ؛ينايرشلا يوئرلا مدلا .زاتاير عم هلاعأ ةنودملا ةيودلأا نم دحاو كلفط وأ تنأ لوانتت تنك اذإ ةريطخ لكاشم رهظت دق

.ةعضرم تنك :ءاودلا لامعتسإب قلعتت ةصاخ تاريذحت .هل فصو امع رياغم فدهل رضحتسملا لامعتسإ زوجي لا .ءاودلا لوانت لبق كلذ نع بيبطلا غلابإ كيلع ،ءاود

يلأ وأ ماعط يلأ ا

ساسح تنك اذإ .ءاودلا لوانت لبق بيبطلا رشتسإ – ةنيعم تايركسل لمحت مدع كيدل صخش اذإ .زوتكلا يوحي رضحتسملا :اذإ بيبطلا غلب زاتاير ـب جلاعلا لبق

.ءاود يلأ وأ ماعط يلأ اساسح تنك

.بلقلا يف لكاشم نم يناعت تنك

.C وأ B دبكلا باهتلإ سوريڤب ثولت كلذ يف امب دبكلا ةفيظو يف للخ نم يناعت تنك

.ةزليدلا تاجلاعل عضخت تنك

.يركسلا ءاد نم يناعت تنك

.روعانلا ضرم نم يناعت تنك

.ىرخأ ةيبط لكاشم نم يناعت تنك

لمحلا عنمل ةيدلج ةقصل ،ةيلبهم ةقلح وأ يمحر بلول ،نقح لثم ةينومره لمح عنم لئاسو نيلمعتست تنك عنم لئاسول ةبسنلاب بيبطلا ةراشتسا بجي .زاتاير ـب جلاعلا ةرتف للاخ لمعت لاأ نكمي يتلا لمحلا عنمل صارقأو .زاتاير ـب جلاعلا ةرتف للاخ اهلامعتسا نكمي يتلا لمحلا

."عاضرلإاو لمحلا" ةرقف يرظنأ ،لمحلل نيططخت وأ لمحلا ةرتف يف تنك

.رفصلأا ىلإ هينيع نم ضيبلأا مسقلا وأ هدلج نول ل

وحت اذإ بيبطلا غلابإ بجي ،كعيضر ةدلاو دعب :ةعباتملاو تاصوحفلا .جلاعلا للاخو زاتاير لوانت لبق ،دبكلا لمع فئاظو صحف لجأ نم مد تاصوحف كبيبط كل يرج

يس .جلاعلا للاخو زاتاير لوانت لبق ،ىلكلا لمع فئاظو صحف لجأ نم لوبو مد تاصوحف كبيبط كل يرج

يس

ِ

كحا ،ةيئاذغ تافاضإو ةيبط ةفصو نودب ةيودأ كلذ يف امب ىرخأ ةيودأ ،ا

ً

رخؤم تلوانت اذإ وأ ،لوانتت تنك اذإ تلاخدتلا نع ةجتانلا ةعاجنلا مدع وأ رطاخملا بنجتل كلذو كلذ نع يلديصلا وأ بيبطلل .ةيئاودلا بيبطلا رشتسإ .يلديصللو جلاعملا بيبطلل اهراهظلإ كلذو اهلوانتت يتلا ةيودلأا ةمئاق ظفحإ نود نم ديدج ءاود لوانت زوجي لا .زاتاير عم لخادتت يتلا ةيودلأا ةمئاق لوح يلديصلا وأ ناك اذإ اميف كدشري نأ جلاعملا بيبطلل نكمي .ا

ً

قبسم كب

ّ

صاخلا جلاعملا بيبطلا ةراشتسإ

نمآ وه زاتاير لوانت عم ةيوس ىرخأ ةيودأ لوانت ةيودلأا عم زاتاير لوانت نإ :ةيلاتلا ةيودلأا نم دحاو لوانتت تنك اذإ ءاودلا لامعتسإ زوجي لا ةايحلا ىلع ا

رطخ لكشت ،ةريطخ ةيبناج ضارعأ ىلإ زاتاير يدؤي دق .هلمع ىلع رثؤي دق ةيلاتلا :ةيلاتلا ةيودلأا عم لامعتسلااب ةافولا وأ :لمشت توچرلإا ةليصف نم ةيودأ ؛ريڤيرپوزارچ /ريڤسابلإ ؛ديرپاسيس ؛نيسوزوفلأ ليثيم ،تلايسيم نيماتوچرإورديهيد ،نيماتوچرإورديهيد ،تارترات نيماتوچرإ ،نيماتوچرإ يف( نوديسارول ؛ناكيتونيريإ ؛ريڤاندنيإ ؛ريڤساتنربيپ /ريڤيرباكيلچ ؛نيڤونوچرإ ؛نيڤونوچرإ مفلا قيرط نع ءاطعلإاب( ملاوزاديم ؛نيتاتساڤول ؛)ريڤانوتير عم ا

يوس زاتاير ءاطعإ

مت لاح ؛ينايرشلا يوئرلا مدلا طغض عافترا جلاعل ليفانيدليس ؛نيپمافير ؛ديزوميپ ؛نيپاريڤين ؛)ةئدهتلل .ملاوزايرت ؛)St. John’s wort( موتاروفريپ موكيريپيه ةتبن ؛نيتاتساڤميس .زاتاير عم هلاعأ ةنودملا ةيودلأا نم دحاو كلفط وأ تنأ لوانتت تنك اذإ ةريطخ لكاشم رهظت دق رييغت بلطتي )ريڤانوتير نودب وأ عم( زاتاير عم ةيوس ةيلاتلا ةيودلأا لامعتسا نأ زئاجلا نم ةراشتسإ بجي .هاندأ رهظت يتلا ةيودلأل وأ زاتاير ـل يئاودلا رادقملا ماظن وأ يئاودلا رادقملا :ةيلاتلا ةيودلأا نم رثكأ وأ دحاو لوانتت تنك اذإ جلاعملا بيبطلا

،زنريڤافيإ ،تاراموف لسكورپوزيد ريڤوفونيت ،نيزوناديد :لثم HIV جلاعل ةيودأ ريڤانوتير ،ريڤانيوكاس

C عون نم دبكلا باهتلإ جلاعل ريڤيرپلايسكوڤ ،ريڤساتاپليڤ ،ريڤوبسوفوس ،ريڤيرپيسوب

لوزارپيموأ ،نيديتوماف :لثم ةضومحلا زارفلإ ةطبثم ةيودأ ،ةضومحلل ةداضم ةيودأ

،)يزاهجلا ءاطعلإاب( نيئاكوديل ،ليديرپيب ،نورادويمأ :بلقلا مظن تابارطضإ جلاعل ةيودأ نيدينيوك

رثختلل داضم – نيرافراو

نودوزارت ،ةقلحلا ةيثلاث ةليصف نم :لثم بائتكلإا جلاعل ةيودأ

،لاتيبرابونيف ،نيئوتينيف ،نيپيزامابراك :لثم عرصلا جلاعل تاجلاتخلإل ةداضم ةيودأ نيجيرتوملا

لوزانوكيروڤ ،لوزانوكارتيإ ،لوزانوكوتيك :لثم تايرطفلل ةداضم

(Gout( سرقنلا جلاعل وأ عنمل – نيسيشلوك

لسلا جلاعل يويح داضم – نيتوبافير

ناهذلل تاداضم – نوديسارولو نيپايتيوك

نقح ءاطعلإاب( ملاوزاديم :تانيپيزايدوزنيب

ليماپاريڤ ،نيپيدراكين ،نيپيديفين ،نيپيدوليف ،مزايتليد :لثم مويسلاكلا تاونق تابجاح

يوئرلا مدلا طغض عافترإ جلاعل – ناتنيسوپ

نيتاتساڤوسور ،نيتاتساڤروتأ – لورتسلوكلا ضفخل ةيودأ

وأ تاميتسيجرون ،لويدارتسإ لينيثإ – )لمحلا عنم صارقأ( لمحلا عنمل ةينومروه ةيودأ نوردنيتإرون

سوميلوركات ،سوميلوريس ،نيروپسولكيس – يعانملا زاهجلل ةطبثم ةيودأ

)ةقشنمب( لوريتيملاس

ةقشنم وأ فنلأل خاخب نمض ديئوريتس – نوزاكيتولف

نيسيمورثيرلاك عون نم تاديلوركاملا ةليصف نم يويح داضم

نيفرونيرپوب :تانويفلأا ةليصف نم ملالآا تانكسم

،ليفانيدليس – يسنجلا زجعلا جلاعل وأ يوئرلا ينايرشلا مدلا طغض عافترا جلاعل ةيودأ ليفانيدراڤ ،ليفلاادات :ماعطلاو ءاودلا لامعتسإ .تلاوسبكلا حتف زوجي لا .ماعطلا عم لماكلا هلكشب ءاودلا لوانت بجي :عاضرلإاو لمحلا

يريشتسإ .لمحلل نيططخت وأ لمحلا ةرتف يف تنك اذإ بيبطلا يغلب زاتاير ـب جلاعلا لبق .لمحلل نيططخت تنك اذإ وأ لمحلا ةرتف للاخ زاتاير لوانت لوح جلاعملا بيبطلا

ةيدلج ةقصلا ،ة

يلبهم ةقلح وأ محرلا لخاد زاهج ،نقحلا لثم ة

ينومرهلا لمحلا عنم لئاسو ةراشتسا بجي .زاتاير ـب جلاعلا للاخ لمعت لا نأ نكمم ،لمحلا عنم بوبحو لمحلا عنمل .زاتاير ـب جلاعلا للاخ اهلامعتسا نكمي يتلا لمحلا عنم لئاسول ةبسنلاب بيبطلا

هينيع نم ضيبلأا مسقلا وأ هدلج نول لوحت اذإ بيبطلا غلابإ بجي ،كعيضر ةدلاو دعب .رفصلأا ىلإ ىلإ HIV-1 سوريڤ لقن ةروطخ ببسب كلذو زاتاير نيلوانتت تنك اذإ عاضرلإا زوجي لا ةقيرطلا لوح بيبطلا يريشتسإ .ملأا بيلح ربع عيضرلا ىلإ زاتاير لقتني نأ نكمم .كعيضر .كعيضر ماعطلإ لضفلأا :تانيكاملا لامعتسإو ةقايسلا .كبيبط ىلإ لاحلا يف هجوتلا بجي ،راودب رعشت تنك اذإ :ءاودلا تابكرم ضعب نع ةماه تامولعم بيبطلا رشتسإف ةنيعم تايركسل لمحت مدع كيدل صخش اذإ .زوتكلالا ىلع زاتاير يوتحي .ءاودلا لوانت لبق ؟ءاودلا لامعتسإ ةيفيك .٣ وأ بيبطلا نم حاضيتسلإا كيلع .بيبطلا تاميلعت بسح ا

مئاد رضحتسملا لامعتسا بجي .رضحتسملاب جلاعلا ةقيرطبو ةعرجلاب قلعتي اميف ا

قثاو نكت مل اذإ يلديصلا .طقف بيبطلا لبق نم ناددحي جلاعلا ةقيرطو يئاودلا رادقملا .ةيعجرلا تاسوريڤلل ةداضم ىرخأ ةيودأ ةكراشمب زاتاير لوانت متي نأ بجي بسحب ءاودلا لوانت بجي .بيبطلا تاميلعت بسحب موي لك ددحم دعوم يف ءاودلا لوانت بجي .بيبطلا اهددح يتلا ةينمزلا ةرتفلاو يئاودلا رادقملا .هب ىصوملا يئاودلا رادقملا زواجت زوجي لا .تلاوسبكلا حتف زوجي لا .ماعطلا عم لماكلا هلكشب ءاودلا لوانت بجي .جلاعملا بيبطلا نم تاداشرإ نود نم يئاودلا رادقملا رييغت وأ جلاعلا نع فقوتلا زوجي لا .بيبطلا ةيصوت بسحب جلاعلا يف رارمتسلاا بجي .زاتاير ـب جلاعلا ةرتف للاخ جلاعملا بيبطلا لبق نم يجلاع راطإ نمض نوكت نأ مهملا نم لوانت نع فقوتلا نإ .ءاودلا ذفني لا يكل كلذو زاتاير نم ةيفاك ةيمكب ا

مئاد ظفتحت نأ بجي سوريڤلا بستكي دق .مدلا يف HIV-1 سوريڤ ةبسن عافترلإ يدؤي دق ،ريصق تقول ولو ،ءاودلا .جلاعلل ةبوعص رثكأ حبصي كلذل ةجيتنو زاتاير ـل ةمواقم تقولا يف ةمداقلا ةعرجلا لوانتو كركذت لاح ةعرج لوانت بجي ،بولطملا تقولا يف ءاودلا اذه لوانت تيسن اذإ .ةيسنملا ةعرجلا نع اضوع ةفعاضم ةعرج لوانت زوجي لا .يدايتعلإا كعم رضحأو ىفشتسملل وأ بيبطلا ىلإ لاحلا يف هجوت ،ءاودلا نم أطخلاب لفط علب اذإو ةطرفم ةعرج تلوانت اذإ .ءاودلا ةبلع اهيف لوانتت ةرم لك يف يئاودلا رادقملا نم دكأتلاو ءاودلا عباط صيخشت بجي !ةمتعلا يف ةيودلأا لوانت زوجي لا .كلذ رملأا مزل اذإ ةيبطلا تاراظنلا عض .ءاود .يلديصلا وأ بيبطلا رشتسإ ،ءاودلا لامعتسإ لوح ةيفاضإ ةلئسأ كيدل ترفوت اذإ :ةيبناجلا ضارعلأا .٤ ضارعلأا ةمئاق نم شهدنت لا .نيلمعتسملا ضعب دنع ةيبناج ا

ضارعأ ببسي دق زاتاير لامعتسإ نإ ،ءاود لكب امك .اهنم ا

يأ يناعت لاأ زئاجلا نم .ةيبناجلا :ةيلاتلا تلااحلا يف بيبطلا ىلإ هجوتلا بجي .ةريطخ ةيبناج ضارعأ زاتاير ببسي دق

.بلقلا يف ةلكشم ىلع لدت نأ نكمي هذه .راودب رعشت تنك اذإ بيبطلا ىلإ لاحلا يف هجوت .بلقلا مظن يف تاريغت

ضعب يف ريطخ نوكي نأ نكمي هنكل ،زاتاير نولوانتي نيذلا ىضرملا ىدل عئاش يدلجلا حفطلا .يدلج حفط حفطلا قفارتي نأ نكمي .جلاعلا يف رييغت ءارجإ نود نم نيعوبسأ للاخ يدلجلا حفطلا ةداع لوزي .نايحلأا .ريطخ نوكي دق وهو ىرخأ ةي

دج ضارعأب لاحلا يف هجوتو زاتاير ـب جلاعلا نع فقوت ،ةيلاتلا ضارعلأا ىدحإ عم حفط وأ ريطخ حفط كيدل روطت اذإ !بيبطلا ىلإ

ازنولفنلإا هبشت ضارعأ وأ ةكعوب روعشلا

ةنوخس

لصافملا وأ تلاضعلا يف ملاآ

)ةمحتلملا باهتلإ( نينيعلا باهتلا وأ رارمحإ

تلاصيوح

مفلا يف تاحرقت

هجولا خافتنإ

دلجلا تحت نم ءارمح وأ ةنخاس ،ةملؤم ةلتك

راض ريغ وهو زاتاير نولوانتي نيذلا ىضرملا ىدل عئاش ضرع وه نينيعلا نم ضيبلأا مسقلا وأ دلجلا رارفصإ ةبسن عافترإ ةجيتن ضرعلا اذه ثدحي نأ نكمي .ةريطخ ةلكشمل ضرع انايحأ لكشي نأ نكمي هنكل ،بلغلأا ىلع ،دلجلل ،دبكلل راض ريغ ضرعلا اذه نأ نم مغرلا ىلع .)دبكلا يف نيبوريليبلا جاتنإ متي( مدلا يف نيبوريليبلا .نينيعلا نم ضيبلأا مسقلا وأ دلجلا رارفصإ ظحلات تنك اذإ يروف لكشب بيبطلا ىلإ هجوتلا بجي ،نينيعلل وأ

مقافتت دق اهنإف ،C وأ B عون نم دبك باهتلا كلذ يف امب دبكلا يف لكاشم نم يناعت تنك اذإ .دبكلا يف لكاشم للاخو زاتاير لوانت لبق دبكلا فئاظو صحفل كلذو كل مدلا صوحف ءارجإب كبيبط موقي .زيتايرب جلاعلا للاخ كدلج نول لوحت ،)ياشلا نولب( نكاد لوب :ةيلاتلا ضارعلأاب رعشت تنك اذإ لاحلا يف بيبطلا غلب .جلاعلا ةرتف .ةدعملا ةقطنم يف ملاآ ،ةكح ،نايثغ ،حتاف زارب ،رفصلأا ىلإ كينيع نم ضيبلأا مسقلا وأ

نم لوبو مد تاصوحف كبيبط كل يرج

يس .ىلكلا لمع فئاظو ىلع رثؤي نأ نكمم زاتاير .ةنمز

م ىلك ضارمأ .جلاعلا للاخو زاتاير لوانت لبق ،ىلكلا فئاظو صحف لجأ

ةليصف نم ةيودأ نولوانتي نيذلا نيجلاعتملا ضعب ىدل تمقافت وأ اهنع غيلبتلا

مت ،ركسلا بسن عافترإ وأ يركس رييغت ءارجإ وأ يركسلا جلاعل ةيودأ لوانت يف ءدبلا نيجلاعت

ملا ضعب نم بل

ط .زاتاير لثم زآيتورپلا تاطبثم .يركسلل يئاودلا جلاعلا يف

نم يناعت تنك اذإ يروف لكشب بيبطلا غلب .زاتاير ـب نيجلاعتملا ضعب ىدل ىلكلا يف ىصح لكشت نع غلب يف مد روهظ ،نطبلا لفسأ ةقطنم يف وأ رهظلا لفسأ يف ملأ :لمشت نأ نكمم يتلا ىلكلا يف ىصحل ضارعأ .لوبتلا ءانثأ ملأ وأ ،لوبلا

ضارعأب ترعش اذإ يروف لكشب بيبطلا غلب .زاتاير ـب نيجلاعتملا ضعب ىدل ةرارملا يف لكاشم ثودح نع غلب ،تاؤيقتو نايثغ ،ةنوخس ،نطبلا نم يولعلا طسوتملا وأ نميلأا مسقلا يف ملأ :لمشت نأ نكمم يتلا ةرارملا لكاشم .نيعلا نم ضيبلأا مسقلا وأ دلجلا رارفصإ

ةليصف نم ةيودأب جلاعلا ةرتف يف ةفزنلأا يف عافترا نع اوغلب روعانلا ىضرم .)ايليفوميهلا( روعانلا ىضرم .زاتاير لثم زآيتورپلا تاطبثم

نأ نكمي تاريغتلا هذه .HIV-1 جلاعل ةيودأ نولوانتي نيجلاعتم ىدل ثدحت نأ نكمي مسجلا موحش يف تاريغت نأ زئاجلا نم .مسجلا طيحم يفو ،ردصلا يف ،قنعلاو رهظلا نم يولعلا مسقلا يف موحشلا ةيمك ةدايز لمشت ديعب يحصلا ريثأتلاو قيقدلا ببسلا وه ام ا

فورعم سيل .هجولاو ،نيعارذلا ،نيلجرلا نم موحشلا نادقفب رمت .تلااحلا هذهل ىدملا

نيذلا ىضرملا ىدل روطتي دق – )ةعانملا زاهج يف تاريغت( immune reconstitution syndrome ةقباس ةلماخ تاثولت ةبراحمب أدبي نأو ىوقأ حبصي نأ كتعانم زاهج نأش نم .HIV-1 ـل ةيودأب ا

جلاع نوأدبي .زاتاير لوانت ءدب دعب ةديدج ضارعأب رعشت تنك اذإ بيبطلا غلب .مسجلا يف :لمشت زاتاير ـب جلاعلا ةرتف للاخ ا

عويش رثكلأا ةيبناجلا ضارعلأا روعشلا وأ ،زخو ،سحلا يندت – ردخب روعشلا ،مونلا يف تابوعص ،تاؤيقت ،نطبلا ةقطنم يف ملأ ،عادص ،نايثغ .ةنوخس ،بائتكإ ،لاهسإ ،تلاضعلا يف ملاآ ،راود ،نيمدقلا يف وأ نيديلا يف قرحب ضرع نم يناعت امدنع وأ ،لوزت لا وأ مقافتت ،كجعزت ةيبناجلا ضارعلأا ىدحإ تناك اذإ ،

يبناج ضرع رهظ اذإ .بيبطلا ةراشتسإ كيلع ،ةرشنلا هذه يف ركذي مل يبناج وأ جلاعملا بيبطلا ةعجارم بجي ،ةيفاضإ تامولعمل .زاتاير ـل ةيبناجلا ضارعلأل ةلماكلا ةمئاقلا تسيل هذه .يلديصلا بقع ةيبناج ضارعأ نع غيلبت" طبارلا ىلع طغضلا ةطساوب ةحصلا ةرازول ةيبناج ضارعأ نع غيلبتلا ناكملإاب ىلإ كهجوي يذلا )www.health.gov.il( ةحصلا ةرازو عقومل ةيسيئرلا ةحفصلا ىلع دوجوملا "يئاود جلاع :طبارلا لوخد قيرط نع وأ ،ةيبناج ضارعأ نع غيلبتلل رشابملا جذومنلا

h t t p s : / / f o r m s . g o v . i l / g l o b a l d a t a / g e t s e q u e n c e / g e t s e q u e n c e .

aspx?formType=AdversEffectMedic@moh.gov.il

؟ءاودلا نيزخت ةيفيك .٥

وأ/و لافطلأا ةيؤر لاجمو يديأ لوانتم نع ا

ديعب قلغم ناكم يف ءاود لكو ءاودلا اذه ظفح بجي !ممستلا بنجت !بيبطلا نم ةحيرص تاميلعت نودب ؤيقتلا ببست لا .ممستلاب مهتباصإ بنجتت كلذبو ،عضرلا

خيرات ريشي .ةبلعلا ىلع رهظي يذلا )exp. date) ةيحلاصلا خيرات ءاضقنا دعب ءاودلا لامعتسإ زوجي لا .رهشلا سفن نم ريخلأا مويلا ىلإ ةيحلاصلا

ةيحلاصلا ءاضقنإ خيرات زواجتي لا امب نكلو ،رهشأ ٦ للاخ ءاودلا لامعتسإ ناكملإاب ةرم لولأ ةنينقلا حتف دعب .ةبلعلا ىلع رهظي يذلا

صقان وأ ا

بوطعم يلخادلا ةنينقلا متخ ناك اذإ لامعتسلإا زوجي لا

ديج ةنينقلا قلاغإ بجي .ةيوئم ةجرد ٢٥ نع ديزت لا ةرارح ةجردب نيزختلا بجي

.لامعتسلإا ديق دعت مل ةيودأ نم صلختلا ةيفيك نع يلديصلا لأسإ .ةمامقلل وأ يراجملا ىلإ ةيودلأا يمر زوجي لا .ةئيبلا ىلع ظافحلا يف لئاسولا هذه دعاست :ةيفاضإ تامولعم .٦

ً

ضيأ ةلاعفلا ةداملل ةفاضلإاب ءاودلا يوتحي :ةلاعفلا ريغ داوملا

Lactose monohydrate, crospovidone and magnesium stearate.

The hard gelatin capsule shells contain: gelatin, FD&C Blue No. 2, titanium

dioxide.

The 300 mg capsule shells also contain: red iron oxide, black iron oxide, and

yellow iron oxide.

The capsules are imprinted with ink.

.زوتكلالا ىلع صرقلا يوتحي .تارديهونوم زوتكلا غلم ۸۲٫۲ ىلع ةلوسبك لك يوتحت – غلم ۱٥٠ زاتاير .تارديهونوم زوتكلا غلم ۱٠٩٫٦ ىلع ةلوسبك لك يوتحت – غلم ۲٠٠ زاتاير .تارديهونوم زوتكلا غلم ۱٦٤٫٤ ىلع ةلوسبك لك يوتحت – غلم ٣٠٠ زاتاير :ةبلعلا ىوتحم وه امو ءاودلا ودبي فيك :غلم ١٥٠ زاتاير .متاع يوامس هنول ةلوسبكلا مسجو متاع قرزأ هنول ةلوسبكلا سأر ،نيمسق نم ،#1 مجح تاذ نيتلايجلا نم ةلوسبك تابيبح ىلع ةلوسبكلا يوتحت .قرزأ نولب "3624" ةباتكلاو ضيبأ نولب "BMS 150mg" ةباتكلا ةلوسبكلا لمشت .حتاف رفصأ ىتح ضيبأ نول تاذ .ةلوسبك ٦٠ ىلع ةنينقلا ةوبع يوتحت :غلم ٢٠٠ زاتير ةباتكلا ةلوسبكلا لمشت .متاع قرزأ نولب ةلوسبكلا سأرو مسج ،نيمسق نم ،#0 مجح تاذ نيتلايجلا نم ةلوسبك .حتاف رفصأ ىتح ضيبأ نول تاذ تابيبح ىلع ةلوسبكلا يوتحت .ضيبأ نولب "3631" -و "BMS 200mg" .ةلوسبك ٦٠ ىلع ةنينقلا ةوبع يوتحت :غلم ٣٠٠ زاتاير قرزأ هنول ةلوسبكلا مسجو متاع رمحأ هنول ةلوسبكلا سأر ،نيمسق نم ،#00 مجح تاذ نيتلايجلا نم ةلوسبك نول تاذ تابيبح ىلع ةلوسبكلا يوتحت .ضيبأ نولب "3622" -و "BMS 300mg" ةباتكلا ةلوسبكلا لمشت .متاع .حتاف رفصأ ىتح ضيبأ .ةلوسبك ٣٠ ىلع ةنينقلا ةوبع يوتحت ،هيرأ تايرك ،۱۸ تريب نورهأ عراش ،.ض.م ليئارسإ بيوكس سريام – لوتسيرب :هناونعو ليجستلا بحاص .ليئارسإ ،٤٩٥۱٤٤۸ اڤكت - حتيپ .ةدحتملا تايلاولا ،يسريج وين ،كيوسنورب وين ،بيوكس سريام – لوتسيرب ةكرش :هناونعو جتنملا :ةحصلا ةرازو يف يموكحلا ةيودلأا لجس يف ءاودلا لجس مقر ۱٤٠-٧۸-٣٠٩٥٩-٠٠ :غلم ۱٥٠ زاتاير ۱٤۱-۱٠-٣٠٩٦٠-٠٦ :غلم ۲٠٠ زاتاير ۱٤٦-٧۸-٣٣٣۸٩-٠٠ :غلم ٣٠٠ زاتاير بجومب اهثيدحت

متو ۲٠۱٦ لولأا نيرشت يف صخ

رو صح

ف اهاوتحمو ةرشنلا هذه ةغيص ةحصلا ةرازو ترقأ .۲٠۱۸ رايأ يف ةحصلا ةرازو تاميلعت صصخم ءاودلا نإف ،كلذ نم مغرلا ىلع .ركذملا ةغيصب ةرشنلا هذه ةغايص تمت ،ةءارقلا نيوهتو ةلوهس لجأ نم .نيسنجلا لاكل

The content of this leaflet was updated according to the guidelines of the

Ministry of Health in May 2018

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only

REYATAZ 150 mg capsules

REYATAZ 200 mg capsules

REYATAZ 300 mg capsules

The active ingredient and its quantity:

Each capsule of REYATAZ 150 mg contains: atazanavir (as sulfate) 150 mg

Each capsule of REYATAZ 200 mg contains: atazanavir (as sulfate) 200 mg

Each capsule of REYATAZ 300 mg contains: atazanavir (as sulfate) 300 mg

The capsule contains lactose.

For the list of inactive ingredients, please see section 6.

Read this leaflet carefully in its entirety before using the medicine. This

leaflet contains concise information about the medicine. If you have further

questions, refer to the doctor or pharmacist.

This medicine has been prescribed to treat your ailment. Do not pass it on to

others. It may harm them even if it seems to you that their ailment is similar.

REYATAZ is intended for adults and children above 6 years of age. This

medicine is not intended for infants under 3 months of age.

REYATAZ is an HIV-1 )Human Immunodeficiency Virus-type 1( prescription

medicine given in combination with other antiretroviral medicines intended to

treat HIV-1 infections.

HIV-1 is the virus that causes AIDS (Acquired Immunodeficiency Syndrome).

When used with other antiretroviral medicines to treat HIV-1 infection, REYATAZ

may help reduce the amount of HIV-1 in the blood )also called viral load) and

to increase the number of CD4+ (T) cells in your blood that help fight off other

infections.

Reducing the amount of HIV-1 and increasing the CD4+ )T( cells in your blood

may help to improve your immune system and may reduce your risk of death or

of infections that can occur when your immune system is weak (opportunistic

infections).

REYATAZ does not cure HIV-1 infection and does not cure AIDS. Be sure

to take the HIV-1 medicines to control HIV-1 infection and decrease other HIV-

related illnesses.

1.

WHAT IS THE MEDICINE INTENDED FOR?

REYATAZ is intended for treatment of HIV-1 )Human Immunodeficiency Virus-

type 1) and is given in combination with other antiretroviral medicines intended

to treat HIV-1 )antiretroviral agents( in adults and children over 6 years of age.

REYATAZ is not intended for infants under 3 months of age.

Therapeutic group: protease inhibitors.

2.

BEFORE USING THE MEDICINE:

Do not use the medicine if:

you are sensitive (allergic) to the active ingredient (atazanavir sulfate) or to

any of the other ingredients of the medicine (see section 6).

you are taking any of the following medicines. Taking REYATAZ with the

following medicines may affect its activity. REYATAZ may cause serious life-

threatening side effects or death when used with the following medicines:

Alfuzosin;

cisapride;

elbasvir/grazoprevir;

ergot

medicines

including:

ergotamine, ergotamine tartrate, dihydroergotamine, dihydroergotamine

mesylate, methylergonovine, ergonovine; glecaprevir/pibrentasvir; indinavir;

irinotecan; lurasidone )if REYATAZ is given with ritonavir(; lovastatin;

midazolam )when taken by mouth for sedation(; nevirapine; pimozide;

rifampin; sildenafil for the treatment of pulmonary arterial hypertension;

simvastatin; Hypericum perforatum )St. John’s wort(; triazolam.

Serious problems may occur if you or your child take any of the medicines

listed above with REYATAZ.

you are breastfeeding.

Special warnings regarding use of the medicine:

Do not use the medicine for any purpose other than for which it was prescribed.

If you are sensitive to any food or medicine, inform the doctor before taking the

medicine.

This

preparation

contains

lactose.

have

been

diagnosed

with

intolerance to certain sugars - consult the doctor before taking the medicine.

Before treatment with REYATAZ, tell the doctor if:

you are sensitive to any food or medicine.

you have heart problems.

you have impaired liver function, including hepatitis B or C virus infection.

you are undergoing dialysis treatment.

you have diabetes.

you have hemophilia.

you have other medical problems.

you are using hormonal forms of birth control, such as injections, an intrauterine

device or vaginal ring, a dermal contraceptive patch and birth control pills that

may not work during treatment with REYATAZ. Consult the doctor about forms

of birth control that may be used during treatment with REYATAZ.

pregnant

planning

pregnancy;

“Pregnancy

breastfeeding” section.

After your baby is born, tell the doctor if his skin or the white part of his eyes

turns yellow.

Tests and follow up:

Your doctor will do blood tests to check your liver function before you start

REYATAZ and during treatment.

Your doctor will do blood and urine tests to check your kidney function before you

start REYATAZ and during treatment.

If you are taking, or have recently taken, other medicines including non-

prescription medicines and nutritional supplements, tell the doctor or

pharmacist, in order to prevent hazards or lack of efficacy resulting from

drug interactions.

Keep the list of medicines you are taking in order to present it to the

attending doctor and pharmacist. Consult the doctor or pharmacist regarding

the list of medicines that interact with REYATAZ. Do not take a new medicine

without first consulting your attending doctor. The attending doctor can

advise you whether taking other medicines with REYATAZ is safe.

Do not use the medicine if you are taking any of the following medicines. Taking

REYATAZ with the following medicines may affect its activity. REYATAZ may

cause serious life-threatening side effects or death when used with the following

medicines:

Alfuzosin; cisapride; elbasvir/grazoprevir; ergot medicines including: ergotamine,

ergotamine

tartrate,

dihydroergotamine,

dihydroergotamine

mesylate,

methylergonovine,

ergonovine;

glecaprevir/pibrentasvir;

indinavir;

irinotecan;

lurasidone )if REYATAZ is used with ritonavir(; lovastatin; midazolam )when

taken by mouth for sedation(; nevirapine; pimozide; rifampin; sildenafil for the

treatment of pulmonary arterial hypertension; simvastatin; Hypericum perforatum

)St. John’s wort(; triazolam.

Serious problems may occur if you or your child take any of the medicines listed

above with REYATAZ.

Use of the following medicines with REYATAZ (with or without ritonavir) may

require an adjustment in the dosage or dosing regimen of REYATAZ or of the

medicines listed below. Consult the attending doctor if you are taking one or

more of the following medicines:

Medicines to treat HIV such as: didanosine, tenofovir disoproxil fumarate,

efavirenz, saquinavir, ritonavir

Boceprevir, sofosbuvir, velpatasvir, voxilaprevir to treat hepatitis C

Antacids, buffered medications such as: famotidine, omeprazole

Medicines to treat heart rate disturbances: amiodarone, bepridil, lidocaine

)systemically administered(, quinidine

Warfarin - anticoagulant

Antidepressants such as: tricyclic antidepressants, trazodone

Anticonvulsants

treat

epilepsy

such

carbamazepine,

phenytoin,

phenobarbital, lamotrigine

Antifungals such as: ketoconazole, itraconazole, voriconazole

Colchicine - to prevent or treat gout

Rifabutin - an antibiotic to treat tuberculosis

Quetiapine and lurasidone - antipsychotics

Benzodiazepines: midazolam (parenterally administered)

Calcium channel blockers such as: diltiazem, felodipine, nifedipine, nicardipine,

verapamil

Bosentan - to treat pulmonary hypertension

Medicines to lower cholesterol - atorvastatin, rosuvastatin

Hormonal contraceptives )oral contraceptives( - ethinyl estradiol, norgestimate

or norethindrone

Medicines that depress the immune system - ciclosporin, sirolimus, tacrolimus

Salmeterol (inhaled)

Fluticasone - a nasal spray or inhaled steroid

Clarithromycin - a macrolide antibiotic

Opioid analgesics: buprenorphine

Medicines to treat pulmonary arterial hypertension or to treat impotence -

sildenafil, tadalafil, vardenafil

Use of the medicine and food:

Take the medicine whole with food. Do not open the capsules.

Pregnancy and breastfeeding:

Before treatment with REYATAZ, tell the doctor if you are pregnant or planning

to become pregnant. Consult the attending doctor about taking REYATAZ

during pregnancy or if you are planning a pregnancy.

Hormonal forms of birth control, such as injections, an intrauterine device

or vaginal ring, a dermal contraceptive patch, and birth control pills may not

work during treatment with REYATAZ. Consult the doctor about forms of birth

control that may be used during treatment with REYATAZ.

After your baby is born, tell the doctor if his skin or the white part of his eyes

turns yellow.

Do not breastfeed if you are taking REYATAZ, due to risk of transmitting HIV-1 to

your baby. REYATAZ may pass to the baby through the breast milk. Consult the

doctor regarding the best way to feed your baby.

Driving and using machinery:

If you feel dizzy, refer to your doctor immediately.

Important information about some of the medicine’s ingredients:

REYATAZ contains lactose. If you have been diagnosed with an intolerance to

certain sugars, consult the doctor before taking the medicine.

3.

HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor’s instructions. Check with the doctor or

pharmacist if you are not sure about the dosage and the treatment regimen of

this product.

The dosage and treatment regimen will be determined by the doctor only.

REYATAZ must be taken in combination with other antiretroviral medicines.

Take the medicine at a set time every day, as instructed by the doctor. Take the

medicine according to the dosage and time period determined by the doctor.

Do not exceed the recommended dose.

Take the medicine whole with food. Do not open the capsules.

Do not stop treatment or change the dosage unless the attending doctor

tells you to. Adhere to the treatment regimen as recommended by the doctor.

It is important to be under the attending doctor’s care throughout the period of

treatment with REYATAZ.

Always be sure to have an adequate amount of REYATAZ with you so that

the medicine does not run out. Stopping treatment with the medicine, even for

a short time, may lead to increased HIV-1 levels in the blood. The virus may

become resistant to REYATAZ and as a result, become more difficult to treat.

If you forget to take this medicine at the required time, take a dose as soon

as you remember and take the next dose at the usual time. Do not take a double

dose instead of the forgotten dose.

If you took an overdose, or if a child has accidentally swallowed the medicine,

refer immediately to a doctor or to a hospital emergency room, and bring the

package of the medicine with you.

Do not take medicines in the dark! Check the label and dose each time you take

the medicine. Wear glasses if you need them.

If you have further questions regarding use of the medicine, consult the doctor

or pharmacist.

4.

SIDE EFFECTS:

As with any medicine, use of REYATAZ may cause side effects in some users.

Do not be alarmed when reading the list of side effects. You may not suffer from

any of them.

REYATAZ can cause serious side effects. Refer to a doctor in the following cases:

Changes in the heart rhythm. Refer to a doctor immediately if you feel dizzy.

This could indicate a heart problem.

Skin rash. Skin rash is common in patients taking REYATAZ, but can sometimes

be severe. Skin rash usually goes away within 2 weeks without any change in

treatment. Rash may be accompanied by other serious symptoms and could

be severe.

If you develop a severe rash or a rash with any of the following symptoms, stop

treatment with REYATAZ and refer to the doctor immediately!

General feeling of sickness or flu-like symptoms

Fever

Muscle or joint aches

Red or inflamed eyes (conjunctivitis)

Blisters

Mouth sores

Swelling of the face

Painful, warm or red lump under the skin

Yellowing of the skin or the white part of the eyes is a common effect in

patients taking REYATAZ and is usually not harmful, but could sometimes be

a symptom of a serious problem. This effect may be due to an increase in

bilirubin levels in the blood (bilirubin is made by the liver). Although this effect

does not damage the liver, skin, or eyes, refer to a doctor immediately if you

notice yellowing of the skin or the white part of the eyes.

Liver problems. If you have liver problems, including hepatitis B or C, they

may get worse during the course of treatment with REYATAZ. Your doctor will

perform blood tests to check your liver function before taking REYATAZ and

during the treatment. Tell the doctor immediately if you experience any of the

following symptoms: dark )tea-colored( urine, your skin or the white part of your

eyes turns yellow, light-colored stools, nausea, itching, stomach-area pain.

Chronic kidney disease. REYATAZ may affect your kidneys function. Your

doctor will do blood and urine tests to check your kidneys function before you

start REYATAZ and during treatment.

Diabetes or high sugar levels (hyperglycemia) have been reported or have

worsened in some patients taking protease inhibitor medicines such as

REYATAZ. Some patients had to start taking medicines to treat diabetes or

have had to change the diabetes medicinal treatment.

Kidney stones have been reported in some patients taking REYATAZ. Tell your

doctor immediately if you experience symptoms of kidney stones which may include:

pain in the low back or low stomach area, blood in the urine, or pain when urinating.

Gallbladder problems have been reported in some patients taking REYATAZ.

Tell your doctor immediately if you experience symptoms of gallbladder

problems which may include: pain in the right or middle upper stomach area,

fever, nausea and vomiting, yellowing of the skin or the white part of the eye.

Hemophilia patients. Hemophilia patients reported increased bleeding during

the course of treatment with protease inhibitors such as REYATAZ.

Changes in body fat can happen in patients taking HIV-1 medicines. These

changes can include an increased amount of fat in the upper back and neck,

breast, and around the body trunk. You may experience loss of fat from the

legs, arms, and face. The exact cause and long-term health effect of these

conditions are not known.

Immune reconstitution syndrome (changes in the immune system( - may develop

in patients starting treatment with HIV-1 medicines. Your immune system may

get stronger and begin to fight previously dormant infections in your body. Tell

the doctor if you experience new symptoms after starting to take REYATAZ.

The most common side effects during treatment with REYATAZ include:

Nausea, headache, stomach-area pain, vomiting, trouble sleeping, numbness,

tingling or burning sensation in the hands or feet, dizziness, muscle pain,

diarrhea, depression, fever.

If you experience side effect, if any of the side effects bothers you, worsens, or

does not go away, or if you suffer from a side effect not mentioned in the leaflet,

consult with the doctor.

This is not a full list of side effects of REYATAZ. For further information, refer to

the attending doctor or pharmacist.

Side effects can be reported to the Ministry of Health by clicking on the link

“Report Side Effects of Drug Treatment” found on the Ministry of Health

homepage (www.health.gov.il) that directs you to the online form for reporting

side effects, or by entering the link:

h t t p s : / / f o r m s . g o v . i l / g l o b a l d a t a / g e t s e q u e n c e / g e t s e q u e n c e .

aspx?formType=AdversEffectMedic@moh.gov.il

5.

HOW SHOULD THIS MEDICINE BE STORED?

Avoid poisoning! This medicine and any other medicine must be stored in a safe

place out of the reach and sight of children and/or infants to avoid poisoning. Do

not induce vomiting unless explicitly instructed to do so by a doctor!

Do not use the medicine after the expiry date (exp. date) that appears on the

package. The expiry date refers to the last day of that month.

The medicine can be used within 6 months after first opening the bottle, but no

later than the expiry date that appears on the package.

Do not use if the inner seal of the bottle is damaged or missing.

Store at a temperature that does not exceed 25°C. Keep the bottle tightly closed.

Do not dispose of medicines via wastewater or waste bin. Ask the pharmacist

how to dispose of medicines no longer in use. These measures will help to

protect the environment.

6.

FURTHER INFORMATION:

In addition to the active ingredient, the medicine also contains:

Inactive ingredients:

Lactose monohydrate, crospovidone, and magnesium stearate.

The hard gelatin capsule shells contain: gelatin, FD&C Blue No. 2, titanium dioxide.

The 300 mg capsule shells also contain: red iron oxide, black iron oxide, and

yellow iron oxide.

The capsules are imprinted with ink.

The capsule contains lactose.

REYATAZ 150 mg - each capsule contains 82.2 mg lactose monohydrate.

REYATAZ 200 mg - each capsule contains 109.6 mg lactose monohydrate.

REYATAZ 300 mg - each capsule contains 164.4 mg lactose monohydrate.

What the medicine looks like and the contents of the package:

REYATAZ 150 mg:

A size #1 gelatin capsule with two parts, the top of the capsule is opaque blue

and the body of the capsule is opaque light blue. The capsule includes “BMS

150mg” written on it in white and “3624” written in blue. The capsule contains

white to light yellow granules.

The bottle pack contains 60 capsules.

REYATAZ 200 mg:

A size #0 gelatin capsule with two parts, the body and the top of the capsule

are opaque blue. The capsule includes “BMS 200mg” and “3631” written on it in

white. The capsule contains white to light yellow granules.

The bottle pack contains 60 capsules.

REYATAZ 300 mg:

A size #00 gelatin capsule with two parts, the top of the capsule is opaque red and

the body of the capsule is opaque blue. The capsule includes “BMS 300mg” and

“3622” written on it in white. The capsule contains white to light yellow granules.

The bottle pack contains 30 capsules.

License holder and address: Bristol-Myers Squibb Israel Ltd., 18 Aharon Bart

St., Kiryat Aryeh, Petach Tikva 4951448, Israel.

Manufacturer and address: Bristol-Myers Squibb Company, New Brunswick,

New Jersey, USA.

Registration number of the medicine in the National Drug Registry of the

Ministry of Health:

REYATAZ 150 mg: 140-78-30959-00

REYATAZ 200 mg: 141-10-30960-06

REYATAZ 300 mg: 146-78-33389-00

This leaflet was checked and approved by the Ministry of Health in October 2016,

and updated according to the guidelines of the Ministry of Health in May 2018.

DOR-Rey-PIL-0718-07

DOR-Rey-PIL-0718-07

The content of this leaflet was updated according to the guidelines of the Ministry of Health in May 2018

Prescribing Information

REYATAZ

150 mg

REYATAZ

200 mg

REYATAZ

300 mg

(ATAZANAVIR SULFATE) CAPSULES

1

INDICATIONS AND USAGE

REYATAZ

(atazanavir sulfate) is indicated in combination with other antiretroviral agents for

the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV-1 RNA

levels and CD4+ cell counts from controlled studies of 96 weeks duration in antiretroviral-naive

and 48 weeks duration in antiretroviral-treatment-experienced adult and pediatric patients at least

6 years of age.

The following points should be considered when initiating therapy with REYATAZ:

In Study AI424-045, REYATAZ/ritonavir and lopinavir/ritonavir were similar for the

primary efficacy outcome measure of time-averaged difference in change from baseline

in HIV RNA level. This study was not large enough to reach a definitive conclusion that

REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy

outcome measure of proportions below the HIV RNA lower limit of detection [see

Clinical Studies (14.2)

.

The number of baseline primary protease inhibitor mutations affects the virologic response to

REYATAZ/ritonavir [see

Clinical Pharmacology (12.4)

2

DOSAGE AND ADMINISTRATION

General Dosing Recommendations:

REYATAZ Capsules must be taken with food.

Do not open the capsules.

The recommended oral dosage of REYATAZ depends on the treatment history of the

patient and the use of other coadministered drugs. When coadministered with H

-receptor

antagonists or proton-pump inhibitors, dose separation may be required [see

Dosage and

Administration (2.1)

When

coadministered

with

didanosine

buffered

enteric-coated

formulations,

REYATAZ should be given (with food) 2 hours before or 1 hour after didanosine.

REYATAZ without ritonavir is not recommended for treatment-experienced adult or

pediatric patients with prior virologic failure [see

Clinical Studies (14)

Efficacy and safety of REYATAZ with ritonavir in doses greater than 100 mg once daily

have not been established. The use of higher ritonavir doses might alter the safety profile

of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended.

Prescribers should consult the complete prescribing information for ritonavir when using

this agent.

2.1

Testing Prior to Initiation and During Treatment with REYATAZ

Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and

continued during treatment with REYATAZ. Renal laboratory testing should include serum

creatinine, estimated creatinine clearance, and urinalysis with microscopic examination

see

Warnings and Precautions (5.5, 5.6)].

Hepatic laboratory testing should be performed in patients with underlying liver disease prior to

initiation of REYATAZ and continued during treatment with REYATAZ

[see Warnings and

Precautions (5.4)].

2.2

Recommended Adult Dosage

Table 1 summarizes the recommended REYATAZ dosing regimen in adults. All REYATAZ

dosing regimens are to be administered as a single dose with food.

Table 1:

REYATAZ Dosing Regimens

Treatment-Naive Patients

REYATAZ 300 mg with ritonavir 100 mg once daily

If unable to tolerate ritonavir

REYATAZ 400 mg once daily

When combined with any of the following:

Tenofovir

-receptor antagonist

Proton-pump inhibitor

REYATAZ 300 mg with ritonavir 100 mg once daily

The H

-receptor antagonist dose should not exceed a dose comparable to famotidine 40 mg twice

daily. Administer REYATAZ and ritonavir simultaneously with, and/or at least 10 hours after the

-receptor antagonist.

If unable to tolerate ritonavir, administer REYATAZ 400 mg once daily at least 2 hours before

and at least 10 hours after the H

-receptor antagonist. No single dose of the H

-receptor antagonist

should exceed a dose comparable to famotidine 20 mg and the total daily dose should not exceed a

dose comparable to famotidine 40 mg.

Table 1:

REYATAZ Dosing Regimens

The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg daily

and must be taken approximately 12 hours prior to REYATAZ and ritonavir.

When combined with efavirenz

REYATAZ 400 mg with ritonavir 100 mg once daily

Efavirenz should be administered on an empty stomach, preferably at bedtime.

Treatment-Experienced Patients

REYATAZ 300 mg with ritonavir 100 mg once daily

Do not coadminister with proton-pump inhibitors or efavirenz in treatment-experienced patients.

When given with an H

-receptor antagonist

REYATAZ 300 mg with ritonavir 100 mg once daily

The H

-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice

daily. Administer REYATAZ and ritonavir simultaneously with, and/or at least 10 hours after the

-receptor antagonist.

When given with both tenofovir

and

an H

receptor antagonist

REYATAZ 400 mg with ritonavir 100 mg once daily

The H

-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice

daily. Administer REYATAZ and ritonavir simultaneously with, and/or at least 10 hours after the

-receptor antagonist.

[For

these

drugs

other

antiretroviral

agents

which

dosing

modification

appropriate, see

Drug Interactions (7)

2.3

Recommended

Pediatric Dosage

The recommended daily dosage of REYATAZ for pediatric patients (6 to less than 18 years of

age) is based on body weight and should not exceed the recommended adult dosage. REYATAZ

Capsules must be taken with food. The data are insufficient to recommend dosing of REYATAZ

for any of the following: (1) patients less than 6 years of age, (2) without ritonavir in any

pediatric patient less than 13 years of age, and (3) patients less than 40 kg receiving concomitant

tenofovir, H

-receptor antagonists, or proton-pump inhibitors.

The recommended dosage of REYATAZ with ritonavir in pediatric patients at least 6 years of

age is shown in Table 2.

Table 2:

Dosage for Pediatric Patients (6 to less than 18 years of age) for

REYATAZ Capsules with ritonavir

a

Body Weight

REYATAZ dose

ritonavir dose

15 kg to less than 20 kg

150 mg

100 mg

20 kg to less than 40 kg

200 mg

100 mg

at least 40 kg

300 mg

100 mg

The REYATAZ and ritonavir dose should be taken together once daily with food.

For treatment-naive patients at least 13 years of age and at least 40 kg, who are unable to tolerate

ritonavir, the recommended dose is REYATAZ 400 mg (without ritonavir) once daily with food.

For patients at least 13 years of age and at least 40 kg receiving concomitant tenofovir,

-receptor antagonists, or proton-pump inhibitors, REYATAZ should not be administered

without ritonavir.

Pregnancy Dosing During and the Postpartum Period:

REYATAZ should not be administered without ritonavir.

REYATAZ should only be administered to pregnant women with HIV-1 strains susceptible

to atazanavir.

For pregnant patients, no dose adjustment is required for REYATAZ with the following

exceptions:

For treatment-experienced pregnant women during the second or third trimester, when

REYATAZ

coadministered

with

either

-receptor

antagonist

or

tenofovir,

REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are

insufficient data to recommend a REYATAZ dose for use with both an H

-receptor

antagonist

and

tenofovir in treatment-experienced pregnant women.

No dose adjustment is required for postpartum patients. However, patients should be closely

monitored for adverse events because atazanavir exposures could be higher during the first

2 months after delivery. [See

Use in Specific Populations (8.1)

Clinical Pharmacology

(12.3)

2.4

Renal Impairment

For patients with renal impairment, including those with severe renal impairment who are not

managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive

patients with end stage renal disease managed with hemodialysis should receive REYATAZ

300 mg with ritonavir 100 mg. REYATAZ should not be administered to HIV-treatment-

experienced patients with end stage renal disease managed with hemodialysis. [See

Use in

Specific Populations (8.7)

2.5

Hepatic Impairment

REYATAZ should be used with caution in patients with mild-to-moderate hepatic impairment.

For patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced

prior virologic failure, a dose reduction to 300 mg once daily should be considered. REYATAZ

should

used

patients

with

severe

hepatic

impairment

(Child-Pugh

Class

REYATAZ/ritonavir has not been studied in subjects with hepatic impairment and is not

recommended. [See

Warnings and Precautions (5.5)

Use in Specific Populations (8.8)

3

DOSAGE FORMS AND STRENGTHS

REYATAZ Capsules:

150 mg capsule with blue cap and powder blue body, printed with white ink “BMS 150 mg”

on the cap and with blue ink “3624” on the body.

200 mg capsule with blue cap and blue body, printed with white ink “BMS 200 mg” on the

cap and with white ink “3631” on the body.

300 mg capsule with red cap and blue body, printed with white ink “BMS 300 mg” on the

cap and with white ink “3622” on the body.

4

CONTRAINDICATIONS

REYATAZ is contraindicated:

in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-

Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components

of REYATAZ capsules

[see Warnings and Precautions (5.2)]

when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for

clearance,

which

elevated

plasma

concentrations

interacting

drugs

associated with serious and/or life-threatening events (see Table 6).

when coadministered with drugs that strongly induce CYP3A and may lead to lower

exposure and loss of efficacy of REYATAZ (see Table 6).

Table 6 displays drugs that are contraindicated with REYATAZ.

Table 6:

Drugs that are Contraindicated with REYATAZ (Information in the table

applies to REYATAZ with or without ritonavir, unless otherwise

indicated)

Drug Class

Drugs within class that are

contraindicated with REYATAZ

Clinical Comment

Alpha 1-

Adrenoreceptor

Antagonist

Alfuzosin

Potential for increased alfuzosin concentrations, which can

result in hypotension.

Antimycobacterials

Rifampin

Rifampin substantially decreases plasma concentrations of

atazanavir, which may result in loss of therapeutic effect

and development of resistance.

Antineoplastics

Irinotecan

Atazanavir inhibits UGT1A1 and may interfere with the

metabolism of irinotecan, resulting in increased irinotecan

toxicities.

Antipsychotics

Lurasidone

Potential for serious and/or life-threatening reactions if REYATAZ is

coadministered with ritonavir.

Table 6:

Drugs that are Contraindicated with REYATAZ (Information in the table

applies to REYATAZ with or without ritonavir, unless otherwise

indicated)

Drug Class

Drugs within class that are

contraindicated with REYATAZ

Clinical Comment

Pimozide

Potential for serious and/or life-threatening reactions such as cardiac

arrhythmias.

Benzodiazepines

Triazolam, orally administered

midazolam

Triazolam and orally administered midazolam are

extensively metabolized by CYP3A4. Coadministration of

triazolam or orally administered midazolam with

REYATAZ may cause large increases in the concentration

of these benzodiazepines. Potential for serious and/or life-

threatening events such as prolonged or increased sedation

or respiratory depression.

Ergot Derivatives

Dihydroergotamine, ergotamine,

ergonovine, methylergonovine

Potential for serious and/or life-threatening events such as

acute ergot toxicity characterized by peripheral vasospasm

and ischemia of the extremities and other tissues.

GI Motility Agent

Cisapride

Potential for serious and/or life-threatening reactions such

as cardiac arrhythmias.

Hepatitis C Direct-

Acting Antivirals

Elbasvir/grazoprevir

May increase the risk of ALT elevations due to a

significant increase in grazoprevir plasma concentrations.

Herbal Products

Glecaprevir/pibrentasvir

St. John’s wort (

Hypericum

perforatum

May increase the risk of ALT elevations due to an increase

in glecaprevir and pibrentasvir concentrations.

Coadministration of St. John’s wort and REYATAZ may

result in loss of therapeutic effect and development of

resistance.

HMG-CoA Reductase

Inhibitors

Lovastatin, simvastatin

Potential for serious reactions such as myopathy, including

rhabdomyolysis.

PDE5 Inhibitor

Sildenafil

when dosed for the

treatment of pulmonary arterial

hypertension

Potential for sildenafil-associated adverse events (which

include visual disturbances, hypotension, priapism, and

syncope).

Protease Inhibitors

Indinavir

Both REYATAZ and indinavir are associated with indirect

(unconjugated) hyperbilirubinemia.

Non-nucleoside

Reverse Transcriptase

Inhibitors

Nevirapine

Nevirapine substantially decreases atazanavir exposure

which may result in loss of therapeutic effect and

development of resistance. Potential risk for nevirapine-

associated adverse reactions due to increased nevirapine

exposures.

Drug Interactions, Table 16 (7)

for parenterally administered midazolam.

Drug Interactions, Table 16 (7)

for sildenafil* when dosed for erectile dysfunction.

5

WARNINGS AND PRECAUTIONS

5.1

Cardiac Conduction Abnormalities

REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some patients.

In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were

asymptomatic and generally limited to first-degree AV block. There have been reports of second-

degree

block

other

conduction

abnormalities

[see

Adverse

Reactions

(6.2)

and

Overdosage (10)]

. In clinical trials that included electrocardiograms, asymptomatic first-degree

block

observed

5.9%

atazanavir-treated

patients

(n=920),

5.2%

lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and

3.0% of efavirenz-treated patients (n=329). In Study AI424-045, asymptomatic first-degree AV

block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of

lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because

of limited clinical experience in patients with preexisting conduction system disease (eg, marked

first-degree AV block or second- or third-degree AV block). ECG monitoring should be

considered in these patients

[see Clinical Pharmacology (12.2)]

5.2

Severe Skin Reactions

In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately

20% of patients treated with REYATAZ. The median time to onset of rash in clinical studies was

7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-

moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or

severe rash (occurring at a rate of

2%) are presented for the individual clinical studies

[see

Adverse Reactions (6.1)]

. Dosing with REYATAZ was often continued without interruption in

patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases

of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug

rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients

receiving REYATAZ

[see

Contraindications (4) and Adverse Reactions (6.1)]

. REYATAZ

should be discontinued if severe rash develops.

5.4

Hepatotoxicity

Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases

before treatment may be at increased risk for developing further transaminase elevations or

hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to

initiating therapy with REYATAZ and during treatment

[see Dosage and Administration (2.2),

Adverse Reactions (6.1), and Use in Specific Populations (8.8)]

5.5

Chronic Kidney Disease

Chronic

kidney

disease

HIV-infected

patients

treated

with

atazanavir,

with

without

ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven

cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug

crystals in the renal parenchyma. Consider alternatives to REYATAZ in patients at high risk for

renal disease or with preexisting renal disease. Renal laboratory testing (including serum

creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should

be conducted in all patients prior to initiating therapy with REYATAZ and continued during

treatment with REYATAZ. Expert consultation is advised for patients who have confirmed renal

laboratory abnormalities while taking REYATAZ. In patients with progressive kidney disease,

discontinuation of REYATAZ may be considered

[see Dosage and Administration (2.1 and 2.4)

and Adverse Reactions (6.2)]

5.6

Nephrolithiasis and Cholelithiasis

Cases

nephrolithiasis

and/or

cholelithiasis

have

been

reported

during

postmarketing

surveillance in HIV-infected patients receiving REYATAZ therapy. Some patients required

hospitalization for additional management and some had complications. Because these events

were reported voluntarily during clinical practice, estimates of frequency cannot be made. If

signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or

discontinuation of therapy may be considered

[see

Adverse Reactions (6.2)]

5.7

Risk of Serious Adverse Reactions Due to Drug Interactions

Initiation of REYATAZ with ritonavir, a CYP3A inhibitor, in patients receiving medications

metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already

receiving

REYATAZ

with

ritonavir,

increase

plasma

concentrations

medications

metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or

decrease concentrations of REYATAZ with ritonavir, respectively. These interactions may lead

clinically significant adverse reactions potentially leading to severe, life threatening, or fatal

events from greater exposures of concomitant medications.

clinically significant adverse reactions from greater exposures of REYATAZ with ritonavir.

loss

therapeutic

effect

REYATAZ

with

ritonavir

possible

development

resistance.

See Table 16 for steps to prevent or manage these possible and known significant drug

interactions,

including

dosing

recommendations

[see

Drug

Interactions

(7)]

Consider

potential

drug

interactions

prior

during

REYATAZ/ritonavir

therapy;

review

concomitant medications during REYATAZ/ritonavir therapy; and monitor for the adverse

reactions associated with the concomitant medications

[see Contraindications (4) and Drug

Interactions (7)]

5.8

Hyperbilirubinemia

Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated)

bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia

is reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occur

with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data

are available for patients experiencing persistent elevations in total bilirubin >5 times the upper

limit of normal (ULN). Alternative antiretroviral therapy to REYATAZ may be considered if

jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for

patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced

doses has not been established

[see Adverse Reactions (6.1)]

5.9

Diabetes Mellitus/Hyperglycemia

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia

have

been

reported

during

postmarketing

surveillance

HIV-infected

patients

receiving

protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin

or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis

has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia

persisted in some cases. Because these events have been reported voluntarily during clinical

practice, estimates of frequency cannot be made and a causal relationship between protease

inhibitor therapy and these events has not been established

[see

Adverse Reactions (6.2)]

5.10

Immune Reconstitution Syndrome

Immune

reconstitution

syndrome

been

reported

patients

treated

with

combination

antiretroviral

therapy,

including

REYATAZ.

During

initial

phase

combination

antiretroviral treatment, patients whose immune system responds may develop an inflammatory

response

indolent

residual

opportunistic

infections

(such

Mycobacterium

avium

infection,

cytomegalovirus,

Pneumocystis

jiroveci

pneumonia,

tuberculosis),

which

necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome)

have also been reported to occur in the setting of immune reconstitution; however, the time to

onset is more variable, and can occur many months after initiation of treatment.

5.11

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement

(buffalo

hump),

peripheral

wasting,

facial

wasting,

breast

enlargement,

“cushingoid

appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and

long-term consequences of these events are currently unknown. A causal relationship has not

been established.

5.12

Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and

hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some

patients additional factor VIII was given. In more than half of the reported cases, treatment with

protease inhibitors was continued or reintroduced. A causal relationship between protease

inhibitor therapy and these events has not been established.

5.13

Resistance/Cross-Resistance

Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to

atazanavir may not preclude the subsequent use of other protease inhibitors

[see Microbiology

(12.4)]

6

ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

cardiac conduction abnormalities

[see Warnings and Precautions (5.1)]

rash

[see

Warnings and Precautions (5.2)]

hyperbilirubinemia

[see

Warnings and Precautions (5.8)]

chronic kidney disease

[see Warnings and Precautions (5.5)]

nephrolithiasis and cholelithiasis

[see Warnings and Precautions (5.6)]

6.1

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates

observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials

of another drug and may not reflect the rates observed in practice.

Adverse Reactions in Treatment-Naive Adult Patients

The safety profile of REYATAZ in treatment-naive adults is based on 1625 HIV-1 infected

patients in clinical trials. 536 patients received REYATAZ 300 mg with ritonavir 100 mg and

1089 patients received REYATAZ 400 mg or higher (without ritonavir).

The most common adverse reactions were nausea, jaundice/scleral icterus, and rash.

Selected clinical adverse reactions of moderate or severe intensity reported in

2% of treatment-

naive patients receiving combination therapy including REYATAZ

300 mg with ritonavir

100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively.

Table 7:

Selected Adverse Reactions

a

of Moderate or Severe Intensity

Reported in

2% of Adult Treatment-Naive Patients,

b

Study AI424-

138

weeks

c

REYATAZ 300 mg with ritonavir

100 mg (once daily) and tenofovir

DF with emtricitabine

d

(n=441)

weeks

c

lopinavir 400 mg with ritonavir

100 mg (twice daily) and tenofovir

DF with emtricitabine

d

(n=437)

Digestive System

Nausea

Jaundice/scleral icterus

Diarrhea

Skin and Appendages

Rash

None reported in this treatment arm.

Includes events of possible, probable, certain, or unknown relationship to treatment regimen.

Based on the regimen containing REYATAZ.

Median time on therapy.

As a fixed-dose combination: 300 mg tenofovir DF, 200 mg emtricitabine once daily.

Table 8:

Selected Adverse Reactions

a

of Moderate or Severe Intensity Reported in

≥2% of Adult Treatment-Naive Patients,

b

Studies AI424-034, AI424-007,

and AI424-008

Study AI424-034

Studies AI424-007, -008

64 weeks

c

REYATAZ

400 mg once daily +

lamivudine +

zidovudine

e

64 weeks

c

efavirenz

600 mg once daily

+ lamivudine +

zidovudine

e

120 weeks

c,d

REYATAZ

400 mg once daily +

stavudine +

lamivudine or

didanosine

73 weeks

c,d

nelfinavir

750 mg TID or

1250 mg BID +

stavudine +

lamivudine or

didanosine

(n=404)

(n=401)

(n=279)

(n=191)

Body as a Whole

Headache

Digestive System

Nausea

Jaundice/scleral icterus

Vomiting

Abdominal pain

Diarrhea

Nervous System

Insomnia

<1%

Dizziness

<1%

Peripheral neurologic

symptoms

<1%

Skin and Appendages

Rash

None reported in this treatment arm.

Includes events of possible, probable, certain, or unknown relationship to treatment regimen.

Based on regimens containing REYATAZ.

Median time on therapy.

Includes long-term follow-up.

As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.

Adverse Reactions in Treatment-Experienced Adult Patients

The safety profile of REYATAZ in treatment-experienced adults is based on 119 HIV-1 infected

patients in clinical trials.

The most common adverse reactions are jaundice/scleral icterus and myalgia.

Selected clinical adverse reactions of moderate or severe intensity reported in

2% of treatment-

experienced patients receiving REYATAZ/ritonavir are presented in Table 9.

Table 9: Selected Adverse Reactions

a

of Moderate or Severe Intensity

Reported in

2% of Adult Treatment-Experienced Patients,

b

Study

AI424-045

48 weeks

c

REYATAZ/ritonavir 300/100 mg

once daily + tenofovir DF + NRTI

(n=119)

48 weeks

c

lopinavir/ritonavir 400/100 mg

twice daily

d

+ tenofovir DF +

NRTI

(n=118)

Body as a Whole

Fever

Digestive System

Jaundice/scleral icterus

Diarrhea

Nausea

Nervous System

Table 9: Selected Adverse Reactions

a

of Moderate or Severe Intensity

Reported in

2% of Adult Treatment-Experienced Patients,

b

Study

AI424-045

48 weeks

c

REYATAZ/ritonavir 300/100 mg

once daily + tenofovir DF + NRTI

(n=119)

48 weeks

c

lopinavir/ritonavir 400/100 mg

twice daily

d

+ tenofovir DF +

NRTI

(n=118)

Depression

<1%

Musculoskeletal System

Myalgia

None reported in this treatment arm.

Includes events of possible, probable, certain, or unknown relationship to treatment regimen.

Based on the regimen containing REYATAZ.

Median time on therapy.

As a fixed-dose combination.

Laboratory Abnormalities in Treatment-Naive Patients

The percentages of adult treatment-naive patients treated with combination therapy including

REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) with

Grade 3–4 laboratory abnormalities are presented in Tables 10 and 11, respectively.

Table 10:

Grade 3–4 Laboratory Abnormalities Reported in

2% of Adult

Treatment-Naive Patients,

a

Study AI424-138

96 weeks

96 weeks

REYATAZ 300 mg

with ritonavir 100 mg

(once daily) and tenofovir DF

with emtricitabine

lopinavir 400 mg

with ritonavir 100 mg

(twice daily) and tenofovir

DF

with emtricitabine

Variable

Limit

(n=441)

(n=437)

Chemistry

High

SGOT/AST

SGPT/ALT

Total Bilirubin

<1%

Lipase

Creatine Kinase

Total Cholesterol

240 mg/dL

Hematology

Table 10:

Grade 3–4 Laboratory Abnormalities Reported in

2% of Adult

Treatment-Naive Patients,

a

Study AI424-138

96 weeks

96 weeks

REYATAZ 300 mg

with ritonavir 100 mg

(once daily) and tenofovir DF

with emtricitabine

lopinavir 400 mg

with ritonavir 100 mg

(twice daily) and tenofovir

DF

with emtricitabine

Variable

Limit

(n=441)

(n=437)

Neutrophils

<750 cells/mm

Based on the regimen containing REYATAZ.

Median time on therapy.

As a fixed-dose combination: 300 mg tenofovir DF, 200 mg emtricitabine once daily.

ULN = upper limit of normal.

Table 11:

Grade 3–4 Laboratory Abnormalities Reported in

2% of Adult

Treatment-Naive Patients,

a

Studies AI424-034, AI424-007, and AI424-

008

Study AI424-034

Studies AI424-007, -008

64 weeks

b

64 weeks

b

120 weeks

b,c

73 weeks

b,c

REYATAZ

400 mg

once daily

+ lamivudine

+ zidovudine

e

efavirenz

600 mg

once daily

+ lamivudine

+ zidovudine

e

REYATAZ

400 mg

once daily

+ stavudine

+ lamivudine or

+ stavudine

+ didanosine

nelfinavir

750 mg TID or

1250 mg BID

+ stavudine

+ lamivudine or

+ stavudine

+ didanosine

Variable

Limit

d

(n=404)

(n=401)

(n=279)

(n=191)

Chemistry

High

SGOT/AST

SGPT/ALT

Total Bilirubin

<1%

Amylase

Lipase

<1%

Creatine

Kinase

Total

Cholesterol

240 mg/dL

Triglycerides

751 mg/dL

<1%

Hematology

Hemoglobin

<8.0 g/dL

<1%

Table 11:

Grade 3–4 Laboratory Abnormalities Reported in

2% of Adult

Treatment-Naive Patients,

a

Studies AI424-034, AI424-007, and AI424-

008

Study AI424-034

Studies AI424-007, -008

64 weeks

b

64 weeks

b

120 weeks

b,c

73 weeks

b,c

REYATAZ

400 mg

once daily

+ lamivudine

+ zidovudine

e

efavirenz

600 mg

once daily

+ lamivudine

+ zidovudine

e

REYATAZ

400 mg

once daily

+ stavudine

+ lamivudine or

+ stavudine

+ didanosine

nelfinavir

750 mg TID or

1250 mg BID

+ stavudine

+ lamivudine or

+ stavudine

+ didanosine

Variable

Limit

d

(n=404)

(n=401)

(n=279)

(n=191)

Neutrophils

<750 cells/mm

* None reported in this treatment arm.

a Based on regimen(s) containing REYATAZ.

b Median time on therapy.

c Includes long-term follow-up.

d ULN = upper limit of normal.

e As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine

twice daily.

Change in Lipids from Baseline in Treatment-Naive Patients

For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-

cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively.

Table 12:

Lipid Values, Mean Change from Baseline, Study AI424-138

REYATAZ/ritonavir

lopinavir/ritonavir

Baseline

Week 48

Week 96

Baseline

Week 48

Week 96

mg/dL

mg/dL

Change

mg/dL

Change

mg/dL

mg/dL

Change

mg/dL

Change

(n=428

)

(n=372

)

(n=372

)

(n=342

)

(n=342

)

(n=424

)

(n=335

)

(n=335

)

(n=291

)

(n=291

)

LDL-Cholesterol

+14%

+14%

+19%

+17%

HDL-Cholesterol

+29%

+21%

+37%

+29%

Total Cholesterol

+13%

+13%

+25%

+25%

Triglycerides

+15%

+13%

+52%

+50%

REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose combination: 300 mg tenofovir DF, 200

mg emtricitabine once daily.

Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline,

serum

lipid-reducing

agents

were

used

lopinavir/ritonavir

treatment

REYATAZ/ritonavir

Through

Week

serum

lipid-reducing

agents

were

used

lopinavir/ritonavir treatment arm and 2% in the REYATAZ/ritonavir arm. Through Week 96, serum lipid-

reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ/ritonavir

arm.

Lopinavir 400 mg with ritonavir 100 mg twice daily with the fixed-dose combination 300 mg tenofovir DF, 200

mg emtricitabine once daily.

The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and

Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values,

respectively.

Number of patients with LDL-cholesterol measured.

Fasting.

Table 13:

Lipid Values, Mean Change from Baseline, Study AI424-034

REYATAZ

a,b

efavirenz

b,c

Baseline

mg/dL

(n=383

e

)

Week 48

mg/dL

(n=283

e

)

Week 48

Change

d

(n=272

e

)

Baseline

mg/dL

(n=378

e

)

Week 48

mg/dL

(n=264

e

)

Week 48

Change

d

(n=253

e

)

LDL-Cholesterol

+18%

HDL-Cholesterol

+13%

+24%

Total Cholesterol

+21%

Triglycerides

−9%

+23%

REYATAZ 400 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice

daily.

Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline,

serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the REYATAZ arm.

Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the

REYATAZ arm.

Efavirenz 600 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice

daily.

The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and

Week 48 values and is not a simple difference of the baseline and Week 48 mean values.

Number of patients with LDL-cholesterol measured.

Fasting.

Laboratory Abnormalities in Treatment-Experienced Patients

percentages

adult

treatment-experienced

patients

treated

with

combination

therapy

including

REYATAZ/ritonavir

with

Grade

3–4

laboratory

abnormalities

presented

Table 14.

Table 14:

Grade 3–4 Laboratory Abnormalities Reported in

2% of Adult

Treatment-Experienced Patients, Study AI424-045

a

48 weeks

b

48 weeks

b

REYATAZ/ritonavir

300/100 mg once daily +

tenofovir DF + NRTI

lopinavir/ritonavir

400/100 mg twice daily

d

+

tenofovir DF+ NRTI

Variable

Limit

c

(n=119)

(n=118)

Chemistry

High

SGOT/AST

SGPT/ALT

Total Bilirubin

<1%

Lipase

Creatine Kinase

Total Cholesterol

240 mg/dL

Triglycerides

751 mg/dL

Glucose

251 mg/dL

<1%

Hematology

Platelets

<50,000 cells/mm

Neutrophils

<750 cells/mm

Based on regimen(s) containing REYATAZ.

Median time on therapy.

ULN = upper limit of normal.

As a fixed-dose combination.

Change in Lipids from Baseline in Treatment-Experienced Patients

Study

AI424-045,

changes

from

baseline

LDL-cholesterol,

HDL-cholesterol,

total

cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia

was less with REYATAZ/ritonavir than with lopinavir/ritonavir. However, the clinical impact of

such findings has not been demonstrated.

Table 15:

Lipid Values, Mean Change from Baseline, Study AI424-045

REYATAZ/ritonavir

a,b

lopinavir/ritonavir

b,c

Baseline

mg/dL

(n=111

e

)

Week 48

mg/dL

(n=75

e

)

Week 48

Change

d

(n=74

e

)

Baseline

mg/dL

(n=108

e

)

Week 48

mg/dL

(n=76

e

)

Week 48

Change

d

(n=73

e

)

LDL-Cholesterol

−10%

HDL-Cholesterol

−7%

Total Cholesterol

−8%

Triglycerides

−4%

+30%

REYATAZ 300 mg once daily + ritonavir + tenofovir DF + 1 NRTI.

Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline,

serum

lipid-reducing

agents

were

used

lopinavir/ritonavir

treatment

REYATAZ/ritonavir

arm.

Through

Week

serum

lipid-reducing

agents

were

used

lopinavir/ritonavir treatment arm and 8% in the REYATAZ/ritonavir arm.

Lopinavir/ritonavir (400/100 mg) BID + tenofovir DF + 1 NRTI.

The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and

Week 48 values and is not a simple difference of the baseline and Week 48 mean values.

Number of patients with LDL-cholesterol measured.

Fasting.

Adverse Reactions in Pediatric Patients: REYATAZ Capsules

The safety and tolerability of REYATAZ Capsules with and without ritonavir have been

established in pediatric patients at least 6 years of age from the open-label, multicenter clinical

trial PACTG 1020A.

The safety profile of REYATAZ in pediatric patients (6 to less than 18 years of age) taking the

capsule formulation was generally similar to that observed in clinical studies of REYATAZ in

adults. The most common Grade 2–4 adverse events (

5%, regardless of causality) reported in

pediatric patients were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%),

vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%),

nasal

congestion

(6%),

oropharyngeal

pain

(6%),

wheezing

(6%),

rhinorrhea

(6%).

Asymptomatic second-degree atrioventricular block was reported in <2% of patients. The most

common Grade 3–4 laboratory abnormalities occurring in pediatric patients taking the capsule

formulation

were

elevation

total

bilirubin

mg/dL,

58%),

neutropenia

(9%),

hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of

less than 3%.

Adverse Reactions in Patients Co-Infected with Hepatitis B and/or Hepatitis C Virus

In Study AI424-138, 60 patients treated with REYATAZ/ritonavir 300 mg/100 mg once daily,

and 51 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, each with fixed dose

tenofovir DF-emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels

>5 times

developed

(6/60)

REYATAZ/ritonavir-treated

patients

8% (4/50) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in

(6/60)

REYATAZ/ritonavir-treated

patients

none

(0/50)

lopinavir/ritonavir-treated patients

.

In Study AI424-045, 20 patients treated with REYATAZ/ritonavir 300 mg/100 mg once daily,

and 18 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, were seropositive for

hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the

REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients.

AST levels >5 times ULN developed in 10% (2/20) of the REYATAZ/ritonavir-treated patients

and 6% (1/18) of the lopinavir/ritonavir-treated patients

.

In Studies AI424-008 and AI424-034, 74 patients treated with 400 mg of REYATAZ once daily,

58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B

and/or C at study entry. ALT levels >5 times ULN developed in 15% of the REYATAZ-treated

patients, 14% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. AST

levels >5 times ULN developed in 9% of the REYATAZ-treated patients, 5% of the efavirenz-

treated patients, and 17% of the nelfinavir-treated patients. Within REYATAZ and control

regimens, no difference in frequency of bilirubin elevations was noted between seropositive and

seronegative patients

[see Warnings and Precautions (5.8)]

6.2

Postmarketing Experience

The following events have been identified during postmarketing use of REYATAZ. Because

these reactions are reported voluntarily from a population of unknown size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole:

edema

Cardiovascular System:

second-degree AV block, third-degree AV block, left bundle branch

block, QTc prolongation

[see Warnings and Precautions (5.1)]

Gastrointestinal System:

pancreatitis

Hepatic System:

hepatic function abnormalities

Hepatobiliary Disorders:

cholelithiasis

[see Warnings and Precautions (5.6)]

, cholecystitis,

cholestasis

Metabolic System and Nutrition Disorders:

diabetes mellitus, hyperglycemia

[see Warnings and

Precautions (5.9)]

Musculoskeletal System:

arthralgia

Renal

System:

nephrolithiasis

[see

Warnings

and

Precautions

(5.6)]

interstitial

nephritis,

granulomatous interstitial nephritis, chronic kidney disease

[see Warnings and Precautions

(5.5)]

Skin and Appendages:

alopecia, maculopapular rash

[see Contraindications (4) and

Warnings

and Precautions (5.2)]

, pruritus, angioedema

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

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

oh.gov.il

7

DRUG INTERACTIONS

7.1

Potential for REYATAZ to Affect Other Drugs

Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs

primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of

the other drug that could increase or prolong its therapeutic and adverse effects.

Atazanavir

weak

inhibitor

CYP2C8.

REYATAZ

without

ritonavir

recommended when coadministered with drugs highly dependent on CYP2C8 with narrow

therapeutic

indices

(eg,

paclitaxel,

repaglinide).

When

REYATAZ

with

ritonavir

coadministered with substrates of CYP2C8, clinically significant interactions are not expected

[see

Clinical Pharmacology, Table 22 (12.3)].

The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when

REYATAZ is coadministered with ritonavir. See

the complete prescribing information for

ritonavir for information on drug interactions with ritonavir.

7.2

Potential for Other Drugs to Affect REYATAZ

Atazanavir

CYP3A4

substrate;

therefore,

drugs

that

induce

CYP3A4

decrease

atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect.

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir

expected

proton-pump

inhibitors,

antacids,

buffered

medications,

-receptor

antagonists are administered with REYATAZ

[see Dosage and Administration]

7.3

Established and Other Potentially Significant Drug Interactions

Table 16 provides dosing recommendations in adults as a result of drug interactions with

REYATAZ. These recommendations are based on either drug interaction studies or predicted

interactions due to the expected magnitude of interaction and potential for serious events or loss

of efficacy.

Table 16:

Established and Other Potentially Significant Drug Interactions:

Alteration in Dose or Regimen May Be Recommended Based on

Drug Interaction Studies

a

or Predicted Interactions (Information in

the table applies to REYATAZ with or without ritonavir, unless

otherwise indicated)

Concomitant Drug Class:

Specific Drugs

Effect on

Concentration of

Atazanavir or

Concomitant Drug

Clinical Comment

HIV Antiviral Agents

Nucleoside Reverse

Transcriptase Inhibitors

(NRTIs):

didanosine buffered

formulations

enteric-coated (EC) capsules

atazanavir

didanosine

Coadministration of REYATAZ with didanosine buffered tablets resulted in a

marked decrease in atazanavir exposure. It is recommended that REYATAZ be

given (with food) 2 h before or 1 h after didanosine buffered formulations.

Simultaneous administration of didanosine EC and REYATAZ with food

results in a decrease in didanosine exposure. Thus, REYATAZ and

didanosine EC should be administered at different times.

Nucleotide Reverse

Transcriptase Inhibitors:

tenofovir disoproxil fumarate

(DF)

atazanavir

tenofovir

Tenofovir DF may decrease the AUC and C

of atazanavir. When

coadministered with tenofovir DF in adults, it is recommended that REYATAZ

300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single

daily dose with food). REYATAZ increases tenofovir concentrations. The

mechanism of this interaction is unknown. Higher tenofovir concentrations

could potentiate tenofovir -associated adverse reactions, including renal

disorders. Patients receiving REYATAZ and tenofovir DF should be monitored

for tenofovir-associated adverse reactions. For pregnant women taking

REYATAZ with ritonavir

and

tenofovir DF, see

Dosage and Administration

(2.3)

Non-nucleoside Reverse

Transcriptase Inhibitors

(NNRTIs):

efavirenz

atazanavir

Efavirenz decreases atazanavir exposure.

In treatment-naive adult patients:

If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg

capsules) should be administered with ritonavir 100 mg simultaneously once

daily with food, and efavirenz 600 mg should be administered once daily on an

empty stomach, preferably at bedtime.

In treatment-experienced adult patients:

Coadministration of REYATAZ with efavirenz in treatment-experienced

patients is not recommended due to decreased atazanavir exposure.

Protease Inhibitors:

saquinavir (soft gelatin

capsules)

saquinavir

Appropriate dosing recommendations for this combination, with or without

ritonavir, with respect to efficacy and safety have not been established. In a

clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and

tenofovir DF 300 mg (all given once daily) plus nucleoside analogue reverse

transcriptase inhibitors did not provide adequate efficacy

[see

Clinical Studies

(14.2)]

Ritonavir

atazanavir

If REYATAZ is coadministered with ritonavir, it is recommended that

REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with

food in adults. See the complete prescribing information for ritonavir for

information on drug interactions with ritonavir.

Others

other protease

inhibitor

Although not studied, the coadministration of REYATAZ/ritonavir and an

additional protease inhibitor would be expected to increase exposure to the

other protease inhibitor. Such coadministration is not recommended.

HCV Antiviral Agents

Protease Inhibitors:

boceprevir

atazanavir

ritonavir

Concomitant administration of boceprevir and atazanavir/ritonavir resulted in

reduced steady-state exposures to atazanavir and ritonavir. Coadministration of

REYATAZ/ritonavir and boceprevir is not recommended.

sofosbuvir, velpatasvir,

voxilaprevir

voxilaprevir

Coadministration with REYATAZ is not recommended.

Other Agents

Table 16:

Established and Other Potentially Significant Drug Interactions:

Alteration in Dose or Regimen May Be Recommended Based on

Drug Interaction Studies

a

or Predicted Interactions (Information in

the table applies to REYATAZ with or without ritonavir, unless

otherwise indicated)

Concomitant Drug Class:

Specific Drugs

Effect on

Concentration of

Atazanavir or

Concomitant Drug

Clinical Comment

Antacids and buffered

medications

atazanavir

Reduced plasma concentrations of atazanavir are expected if antacids, including

buffered medications, are administered with REYATAZ. REYATAZ should be

administered 2 hours before or 1 hour after these medications.

Antiarrhythmics:

amiodarone,

bepridil, lidocaine (systemic),

quinidine

amiodarone,

bepridil, lidocaine

(systemic), quinidine

Coadministration with REYATAZ has the potential to produce serious and/or

life-threatening adverse events and has not been studied. Caution is warranted

and therapeutic concentration monitoring of these drugs is recommended if they

are used concomitantly with REYATAZ.

Anticoagulants:

warfarin

warfarin

Coadministration with REYATAZ has the potential to produce serious and/or

life-threatening bleeding and has not been studied. It is recommended that

International Normalized Ratio (INR) be monitored.

Antidepressants:

tricyclic

antidepressants

tricyclic

antidepressants

Coadministration with REYATAZ has the potential to produce serious and/or

life-threatening adverse events and has not been studied. Concentration

monitoring of these drugs is recommended if they are used concomitantly with

REYATAZ.

Trazodone

trazodone

Concomitant use of trazodone and REYATAZ with or without ritonavir may

increase plasma concentrations of trazodone. Nausea, dizziness, hypotension,

and syncope have been observed following coadministration of trazodone and

ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the

combination should be used with caution and a lower dose of trazodone should

be considered.

Antiepileptics:

carbamazepine

atazanavir

carbamazepine

Plasma concentrations of atazanavir may be decreased when carbamazepine is

administered with REYATAZ without ritonavir. Coadministration of

carbamazepine and REYATAZ without ritonavir is not recommended.

Ritonavir may increase plasma levels of carbamazepine. If patients beginning

treatment with REYATAZ/ritonavir have been titrated to a stable dose of

carbamazepine, a dose reduction for carbamazepine may be necessary.

phenytoin, phenobarbital

atazanavir

phenytoin

phenobarbital

Plasma concentrations of atazanavir may be decreased when phenytoin or

phenobarbital is administered with REYATAZ without ritonavir.

Coadministration of phenytoin or phenobarbital and REYATAZ without

ritonavir is not recommended. Ritonavir may decrease plasma levels of

phenytoin and phenobarbital. When REYATAZ with ritonavir is

coadministered with either phenytoin or phenobarbital, a dose adjustment of

phenytoin or phenobarbital may be required.

Lamotrigine

lamotrigine

Coadministration of lamotrigine and REYATAZ

with

ritonavir may decrease

lamotrigine plasma concentrations. Dose adjustment of lamotrigine may be

required when coadministered with REYATAZ and ritonavir. Coadministration

of lamotrigine and REYATAZ

without

ritonavir is not expected to decrease

lamotrigine plasma concentrations. No dose adjustment of lamotrigine is

required when coadministered with REYATAZ without ritonavir.

Antifungals:

ketoconazole, itraconazole

REYATAZ/ritonavir:

ketoconazole

itraconazole

Coadministration of ketoconazole has only been studied with REYATAZ

without ritonavir (negligible increase in atazanavir AUC and C

). Due to the

effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole

(>200 mg/day) should be used cautiously with REYATAZ/ritonavir.

Table 16:

Established and Other Potentially Significant Drug Interactions:

Alteration in Dose or Regimen May Be Recommended Based on

Drug Interaction Studies

a

or Predicted Interactions (Information in

the table applies to REYATAZ with or without ritonavir, unless

otherwise indicated)

Concomitant Drug Class:

Specific Drugs

Effect on

Concentration of

Atazanavir or

Concomitant Drug

Clinical Comment

Voriconazole

REYATAZ/ritonavir

in subjects with a

functional CYP2C19

allele:

voriconazole

atazanavir

REYATAZ/ritonavir

in subjects without a

functional CYP2C19

allele:

voriconazole

atazanavir

The use of voriconazole in patients receiving REYATAZ/ritonavir is not

recommended unless an assessment of the benefit/risk to the patient justifies the

use of voriconazole. Patients should be carefully monitored for voriconazole-

associated adverse reactions and loss of either voriconazole or atazanavir

efficacy during the coadministration of voriconazole and REYATAZ/ritonavir.

Coadministration of voriconazole with REYATAZ (without ritonavir) may

affect atazanavir concentrations; however, no data are available.

Antigout:

colchicine

colchicine

The coadministration of REYATAZ with colchicine in patients with renal or

hepatic impairment is not recommended.

Recommended adult dosage of colchicine when administered with

REYATAZ:

Treatment of gout flares:

0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not

to be repeated before 3 days.

Prophylaxis of gout flares:

If the original regimen was 0.6 mg

twice

a day, the regimen should be

adjusted to 0.3 mg

once a day

If the original regimen was 0.6 mg

once

a day, the regimen should be

adjusted to 0.3 mg

once every other day

Treatment of familial Mediterranean fever (FMF):

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Antimycobacterials:

rifabutin

rifabutin

A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times

per week) is recommended. Increased monitoring for rifabutin-associated

adverse reactions including neutropenia is warranted.

Table 16:

Established and Other Potentially Significant Drug Interactions:

Alteration in Dose or Regimen May Be Recommended Based on

Drug Interaction Studies

a

or Predicted Interactions (Information in

the table applies to REYATAZ with or without ritonavir, unless

otherwise indicated)

Concomitant Drug Class:

Specific Drugs

Effect on

Concentration of

Atazanavir or

Concomitant Drug

Clinical Comment

Antipsychotics:

quetiapine and

lurasidone

quetiapine

REYATAZ

lurasidone

REYATAZ/ritonavir

lurasidone

Initiation of REYATAZ with ritonavir in patients taking quetiapine:

Consider alternative antiretroviral therapy to avoid increases in quetiapine

exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of

the current dose and monitor for quetiapine-associated adverse reactions. Refer

to the quetiapine prescribing information for recommendations on adverse

reaction monitoring.

Initiation of quetiapine in patients taking REYATAZ with ritonavir:

Refer to the quetiapine prescribing information for initial dosing and titration of

quetiapine.

REYATAZ without ritonavir

If coadministration is necessary, reduce the lurasidone dose. Refer to the

lurasidone prescribing information for concomitant use with moderate CYP3A4

inhibitors.

REYATAZ/ritonavir

Use of lurasidone is contraindicated.

Benzodiazepines:

parenterally administered

midazolam

midazolam

Concomitant use of parenteral midazolam with REYATAZ may increase

plasma concentrations of midazolam. Coadministration should be done in a

setting which ensures close clinical monitoring and appropriate medical

management in case of respiratory depression and/or prolonged sedation.

Dosage reduction for midazolam should be considered, especially if more than a

single dose of midazolam is administered. Coadministration of oral midazolam

with REYATAZ is CONTRAINDICATED.

Calcium channel blockers:

diltiazem

diltiazem and

desacetyl-diltiazem

Caution is warranted. A dose reduction of diltiazem by 50% should be

considered. ECG monitoring is recommended. Coadministration of

REYATAZ/ritonavir with diltiazem has not been studied.

felodipine, nifedipine,

nicardipine, and verapamil

calcium channel

blocker

Caution is warranted. Dose titration of the calcium channel blocker should be

considered. ECG monitoring is recommended.

Endothelin receptor

antagonists:

Bosentan

atazanavir

bosentan

Plasma concentrations of atazanavir may be decreased when bosentan is

administered with REYATAZ without ritonavir. Coadministration of bosentan

and REYATAZ without ritonavir is not recommended.

Coadministration of bosentan in

adult

patients on REYATAZ/ritonavir:

For patients who have been receiving REYATAZ/ritonavir for at least

10 days, start bosentan at 62.5 mg once daily or every other day based on

individual tolerability.

Coadministration of REYATAZ/ritonavir in adult patients on bosentan:

Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir.

At least 10 days after starting REYATAZ/ritonavir, resume bosentan at

62.5 mg once daily or every other day based on individual tolerability.

HMG-CoA reductase

inhibitors:

atorvastatin,

rosuvastatin

atorvastatin

rosuvastatin

Titrate atorvastatin dose carefully and use the lowest necessary dose.

Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy,

including rhabdomyolysis, may be increased when HIV protease inhibitors,

including REYATAZ, are used in combination with these drugs.

Table 16:

Established and Other Potentially Significant Drug Interactions:

Alteration in Dose or Regimen May Be Recommended Based on

Drug Interaction Studies

a

or Predicted Interactions (Information in

the table applies to REYATAZ with or without ritonavir, unless

otherwise indicated)

Concomitant Drug Class:

Specific Drugs

Effect on

Concentration of

Atazanavir or

Concomitant Drug

Clinical Comment

H

-Receptor antagonists

atazanavir

Plasma concentrations of atazanavir were substantially decreased when

REYATAZ 400 mg once daily was administered simultaneously with

famotidine 40 mg twice daily in adults, which may result in loss of therapeutic

effect and development of resistance.

In treatment-naive adult patients:

REYATAZ 300 mg with ritonavir 100 mg once daily with food should be

administered simultaneously with, and/or at least 10 hours after, a dose of the

-receptor antagonist (H2RA). An H2RA dose comparable to famotidine

20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can

be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive

patients.

For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with

food should be administered at least 2 hours before and at least 10 hours after a

dose of the H2RA. No single dose of the H2RA should exceed a dose

comparable to famotidine 20 mg, and the total daily dose should not exceed a

dose comparable to famotidine 40 mg. The use of REYATAZ without ritonavir

in pregnant women is not recommended.

In treatment-experienced adult patients:

Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir,

the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice

daily, and the REYATAZ and ritonavir doses should be administered

simultaneously with, and/or at least 10 hours after, the dose of the H2RA.

REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose

with food) if taken with an H2RA.

REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose

with food) if taken with both tenofovir DF and an H2RA.

REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose

with food) if taken with either tenofovir DF or an H2RA for pregnant

women during the second and third trimester. REYATAZ is not

recommended for pregnant women during the second and third trimester

taking REYATAZ with both tenofovir DF and an H2RA.

Hormonal contraceptives:

ethinyl estradiol and

norgestimate or norethindrone

ethinyl estradiol

norgestimate

ethinyl estradiol

norethindrone

Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir

with oral contraceptives is considered. If an oral contraceptive is administered

with REYATAZ plus ritonavir, it is recommended that the oral contraceptive

contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered

without ritonavir, the oral contraceptive should contain no more than 30 mcg of

ethinyl estradiol.

Potential safety risks include substantial increases in progesterone exposure.

The long-term effects of increases in concentration of the progestational agent

are unknown and could increase the risk of insulin resistance, dyslipidemia, and

acne.

Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal

contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable

contraceptives) or oral contraceptives containing progestogens other than

norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not

been studied; therefore, alternative methods of contraception are recommended.

Immunosuppressants:

cyclosporine, sirolimus,

tacrolimus

immunosuppressants

Therapeutic concentration monitoring is recommended for these

immunosuppressants when coadministered with REYATAZ.

Table 16:

Established and Other Potentially Significant Drug Interactions:

Alteration in Dose or Regimen May Be Recommended Based on

Drug Interaction Studies

a

or Predicted Interactions (Information in

the table applies to REYATAZ with or without ritonavir, unless

otherwise indicated)

Concomitant Drug Class:

Specific Drugs

Effect on

Concentration of

Atazanavir or

Concomitant Drug

Clinical Comment

Inhaled beta agonist:

Salmeterol

salmeterol

Coadministration of salmeterol with REYATAZ is not recommended.

Concomitant use of salmeterol and REYATAZ may result in increased risk of

cardiovascular adverse reactions associated with salmeterol, including QT

prolongation, palpitations, and sinus tachycardia.

Inhaled/nasal steroid:

fluticasone

REYATAZ

fluticasone

Concomitant use of fluticasone propionate and REYATAZ (without ritonavir)

may increase plasma concentrations of fluticasone propionate. Use with

caution. Consider alternatives to fluticasone propionate, particularly for long-

term use.

REYATAZ/ritonavir

fluticasone

Concomitant use of fluticasone propionate and REYATAZ/ritonavir may

increase plasma concentrations of fluticasone propionate, resulting in

significantly reduced serum cortisol concentrations. Systemic corticosteroid

effects, including Cushing’s syndrome and adrenal suppression, have been

reported during postmarketing use in patients receiving ritonavir and inhaled or

intranasally administered fluticasone propionate. Coadministration of

fluticasone propionate and REYATAZ/ritonavir is not recommended unless the

potential benefit to the patient outweighs the risk of systemic corticosteroid side

effects

[see

Warnings and Precautions (5.1)]

Macrolide antibiotics:

clarithromycin

clarithromycin

14-OH

clarithromycin

atazanavir

Increased concentrations of clarithromycin may cause QTc prolongations;

therefore, a dose reduction of clarithromycin by 50% should be considered

when it is coadministered with REYATAZ. In addition, concentrations of the

active metabolite 14-OH clarithromycin are significantly reduced; consider

alternative therapy for indications other than infections due to

Mycobacterium

avium

complex. Coadministration of REYATAZ/ritonavir with clarithromycin

has not been studied.

Opioids:

Buprenorphine

buprenorphine

norbuprenorphine

Coadministration of buprenorphine and REYATAZ with or without ritonavir

increases the plasma concentration of buprenorphine and norbuprenorphine.

Coadministration of REYATAZ plus ritonavir with buprenorphine warrants

clinical monitoring for sedation and cognitive effects. A dose reduction of

buprenorphine may be considered. Coadministration of buprenorphine and

REYATAZ with ritonavir is not expected to decrease atazanavir plasma

concentrations. Coadministration of buprenorphine and REYATAZ without

ritonavir may decrease atazanavir plasma concentrations. The coadministration

of REYATAZ and buprenorphine without ritonavir is not recommended.

Table 16:

Established and Other Potentially Significant Drug Interactions:

Alteration in Dose or Regimen May Be Recommended Based on

Drug Interaction Studies

a

or Predicted Interactions (Information in

the table applies to REYATAZ with or without ritonavir, unless

otherwise indicated)

Concomitant Drug Class:

Specific Drugs

Effect on

Concentration of

Atazanavir or

Concomitant Drug

Clinical Comment

PDE5 inhibitors:

sildenafil,

tadalafil, vardenafil

sildenafil

tadalafil

vardenafil

Coadministration with REYATAZ has not been studied but may result in an

increase in PDE5 inhibitor-associated adverse reactions, including hypotension,

syncope, visual disturbances, and priapism.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Use of sildenafil* for the treatment of pulmonary hypertension (PAH) is

contraindicated with REYATAZ

[see

Contraindications (4)]

The following dose adjustments are recommended for the use of tadalafil*

with REYATAZ:

Coadministration of tadalafil* in patients on REYATAZ (with or without

ritonavir):

For patients receiving REYATAZ (with or without ritonavir) for at

least one week, start tadalafil* at 20 mg once daily. Increase to 40 mg

once daily based on individual tolerability.

Coadministration of REYATAZ (with or without ritonavir) in patients on

tadalafil*:

Avoid the use of tadalafil* when starting REYATAZ (with or without

ritonavir). Stop tadalafil* at least 24 hours before starting REYATAZ

(with or without ritonavir). At least one week after starting

REYATAZ (with or without ritonavir), resume tadalafil* at 20 mg

once daily. Increase to 40 mg once daily based on individual

tolerability.

Use of PDE5 inhibitors for erectile dysfunction:

Use (sildenafil*) with caution at reduced doses of 25 mg every 48

hours with increased monitoring for adverse events.

Use (tadalafil*) with caution at reduced doses of 10 mg every

72 hours

with increased monitoring for adverse events.

REYATAZ/ritonavir:

Use vardenafil with caution at reduced doses of no

more than 2.5 mg every 72 hours with increased monitoring for adverse

reactions.

REYATAZ:

Use vardenafil with caution at reduced doses of no more than

2.5 mg every 24 hours with increased monitoring for adverse reactions.

Proton-pump inhibitors:

omeprazole

atazanavir

Plasma concentrations of atazanavir were substantially decreased when

REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was

administered with omeprazole 40 mg once daily in adults, which may result in

loss of therapeutic effect and development of resistance.

In treatment-naive adult patients:

The proton-pump inhibitor (PPI) dose should not exceed a dose comparable to

omeprazole 20 mg and must be taken approximately 12 hours prior to the

REYATAZ 300 mg with ritonavir 100 mg dose.

In treatment-experienced adult patients:

The use of PPIs in treatment-experienced patients receiving REYATAZ is not

recommended.

For magnitude of interactions see

Clinical Pharmacology, Tables 21

22 (12.3)

Contraindications (4), Table 6

for orally administered midazolam.

In combination with atazanavir 300 mg and ritonavir 100 mg once daily.

In combination with atazanavir 400 mg once daily.

7.4

Drugs with No Observed Interactions with REYATAZ

No clinically significant drug interactions were observed when REYATAZ was coadministered

with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase

inhibitors lamivudine or zidovudine

[see Clinical Pharmacology, Tables

and

(12.3)].

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to

REYATAZ during pregnancy.

Risk Summary

Atazanavir has been evaluated in a limited number of women during pregnancy. Available

human and animal data suggest that atazanavir does not increase the risk of major birth defects

overall compared to the background rate

[see Data].

In the U.S. general population, the

estimated background risk of major birth defects and miscarriage in clinically recognized

pregnancies

2-4%

15-20%,

respectively.

treatment-related

malformations

were

observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at

the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When

atazanavir was administered to rats during pregnancy

and throughout lactation, reversible

neonatal growth retardation was observed

[see Data]

Clinical Considerations

Dose Adjustments during Pregnancy and the Postpartum Period

REYATAZ must be administered with ritonavir in pregnant women.

For pregnant patients, no dosage adjustment is required for REYATAZ with the following

exceptions:

For treatment-experienced pregnant women during the second or third trimester, when

REYATAZ is coadministered with either an H

-receptor antagonist

or

tenofovir DF,

REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are

insufficient data to recommend a REYATAZ dose for use with both an H

-receptor

antagonist

and

tenofovir DF in treatment-experienced pregnant women.

No dosage adjustment is required for postpartum patients. However, patients should be

closely monitored for adverse events because atazanavir exposures could be higher during

first

2 months

after

delivery

[see

Dosage

and

Administration

(2.3)

and

Clinical

Pharmacology (12.3)]

Maternal Adverse Reactions

Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have

occurred in pregnant women using REYATAZ in combination with nucleoside analogues, which

are associated with an increased risk of lactic acidosis syndrome.

Hyperbilirubinemia occurs frequently in patients who take REYATAZ

[see Warnings and

Precautions (5.8)]

, including pregnant women

[see Data]

Advise

pregnant

women

potential

risks

lactic

acidosis

syndrome

hyperbilirubinemia.

Fetal/Neonatal Adverse Reactions

All infants, including neonates exposed to REYATAZ

in utero

, should be monitored for the

development of severe hyperbilirubinemia during the first few days of life

[see Data].

Data

Human Data

In clinical trial AI424-182, REYATAZ/ritonavir (300/100 mg or 400/100 mg) in combination

with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the

second or third trimester. Among the 39 women who completed the study, 38 women achieved

less

than

copies/mL

time

delivery.

of 20

(30%)

women

REYATAZ/ritonavir

300/100

(62%)

women

REYATAZ/ritonavir

400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times

ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182.

Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of

maternal concentrations. Among the 40 infants born to 40 HIV-infected pregnant women, all had

test results that were negative for HIV-1 DNA at the time of delivery and/or during the first

6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing

zidovudine.

evidence

severe

hyperbilirubinemia

(total

bilirubin

levels

greater

than

20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this

study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less

than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.

Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants

were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than

Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as

women who had a previous infant who developed hemolytic disease and/or had neonatal

pathologic jaundice (requiring phototherapy).

Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had

adequately collected serum glucose samples with values of less than 40 mg/dL that could not be

attributed to maternal glucose intolerance, difficult delivery, or sepsis.

Based on prospective reports from the APR of approximately 1600 live births following

exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the

first trimester and 569 exposed in second/third trimesters), there was no difference between

atazanavir and overall birth defects compared with the background birth defect rate. In the U.S.

general population, the estimated background risk of major birth defects in clinically recognized

pregnancies is 2-4%.

Animal Data

In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring

born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times

those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day

ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused neonatal

growth retardation during lactation that reversed after weaning. Maternal drug exposure at this

dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal

toxicity occurred at this exposure level.

8.2

Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not

breastfeed their infants to avoid risking postnatal transmission of HIV-1. Atazanavir has been

detected in human milk. No data are available regarding atazanavir effects on milk production.

Atazanavir was present in the milk of lactating rats and was associated with neonatal growth

retardation that reversed after weaning.

Because of both the potential for HIV-1 transmission and the potential for serious adverse

reactions in breastfed infants, advise women not to breastfeed.

8.4

Pediatric Use

REYATAZ is indicated in combination with other antiretroviral agents for the treatment of

HIV-1 infection in pediatric patients 6 years of age and older. REYATAZ is not recommended

for use in pediatric patients below the age of 3 months due to the risk of kernicterus

[see

Indications and Usage (1)]

. All REYATAZ contraindications, warnings, and precautions apply

to pediatric patients

[see Contraindications (4) and Warnings and Precautions (5)].

The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at

least 3 months of age and older weighing at least 5 kg were established in three open-label,

multicenter

clinical

trials:

PACTG

1020A,

AI424-451,

AI424-397

[see

Clinical

Pharmacology (12.3) and

Clinical Studies (14.3)]

. The safety profile in pediatric patients was

generally similar to that observed in adults

[see

Adverse Reactions (6.1)]

. See

Dosage and

Administration (2.2)

for dosing recommendations for the use of REYATAZ capsules in pediatric

patients.

8.5

Geriatric Use

Clinical studies of REYATAZ did not include sufficient numbers of patients aged 65 and over to

determine whether they respond differently from younger patients. Based on a comparison of

mean single-dose pharmacokinetic values for C

and AUC, a dose adjustment based upon age

is not recommended. In general, appropriate caution should be exercised in the administration

and monitoring of REYATAZ in elderly patients reflecting the greater frequency of decreased

hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6

Age/Gender

A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18-40 years) and

elderly (n=30;

65 years) healthy subjects. There were no clinically significant pharmacokinetic

differences observed due to age or gender.

8.7

Impaired Renal Function

REYATAZ is not recommended for use in HIV-treatment-experienced patients with end stage

renal disease managed with hemodialysis

[see

Dosage and Administration (2.4) and Clinical

Pharmacology (12.3)]

8.8

Impaired Hepatic Function

REYATAZ

recommended

patients

with

severe

hepatic

impairment.

REYATAZ/ritonavir is not recommended in patients with any degree of hepatic impairment

[see

Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]

10

OVERDOSAGE

Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg

(three times the 400 mg maximum recommended dose) have been taken by healthy volunteers

without

symptomatic

untoward

effects.

single

self-administered

overdose

29.2

REYATAZ in an HIV-infected patient (73 times the 400-mg recommended dose) was associated

with asymptomatic bifascicular block and PR interval prolongation. These events resolved

spontaneously. At REYATAZ doses resulting in high atazanavir exposures, jaundice due to

indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR

interval prolongation may be observed

[see Warnings and Precautions (5.1, 5.8) and Clinical

Pharmacology (12.2)].

Treatment of overdosage with REYATAZ should consist of general supportive measures,

including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If

indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage.

Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There

is no specific antidote for overdose with REYATAZ. Since atazanavir is extensively metabolized

by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant

removal of this medicine.

11

DESCRIPTION

The active ingredient in REYATAZ capsules is atazanavir sulfate, which is an HIV-1 protease

inhibitor.

chemical

name

atazanavir

sulfate

S

S

S

S

)-3,12-Bis(1,1-dimethylethyl)-8-

hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-

pentaazatetradecanedioic

acid

dimethyl

ester,

sulfate

(1:1).

molecular

formula

, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The

free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula:

Atazanavir sulfate is a white to pale-yellow crystalline powder. It is slightly soluble in water

(4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about

1.9 at 24

REYATAZ Capsules are available for oral administration in strengths of 150 mg, 200 mg, or

300 mg of atazanavir, which are equivalent to 170.8 mg, 227.8 mg, or 341.69 mg of atazanavir

sulfate, respectively. The capsules also contain the following inactive ingredients: crospovidone,

lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive

ingredients: gelatin, FD&C Blue No. 2, titanium dioxide, black iron oxide, red iron oxide, and

yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C

Blue

isopropyl

alcohol,

ammonium

hydroxide,

propylene

glycol,

n-butyl

alcohol,

simethicone, and dehydrated alcohol.

12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

Atazanavir is an HIV-1 antiretroviral drug

[see

Microbiology (12.4)]

12.2

Pharmacodynamics

Cardiac Electrophysiology

Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has

been

observed

healthy

volunteers

receiving

atazanavir.

placebo-controlled

study

(AI424-076), the mean (±SD) maximum change in PR interval from the predose value was

24 (±15)

msec

following

oral

dosing

with

atazanavir

(n=65)

compared

13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study

were asymptomatic. There is limited information on the potential for a pharmacodynamic

interaction in humans between atazanavir and other drugs that prolong the PR interval of the

electrocardiogram

[see Warnings and Precautions (5.1)]

Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of

72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice

the maximum recommended dosage) were compared with placebo; there was no concentration-

dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 HIV-

infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the

atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected

patient in clinical trials had a QTc interval >500 msec

[see Warnings and Precautions (5.1)]

12.3

Pharmacokinetics

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-

infected patients after administration of REYATAZ 400 mg once daily and after administration

of REYATAZ 300 mg with ritonavir 100 mg once daily (see Table 17).

Table 17:

Steady-State Pharmacokinetics of Atazanavir in Healthy Subjects

or HIV-Infected Patients in the Fed State

400 mg once daily

300 mg with ritonavir

100 mg once daily

Parameter

Healthy

Subjects

(n=14)

HIV-Infected

Patients

(n=13)

Healthy

Subjects

(n=28)

HIV-Infected

Patients

(n=10)

(ng/mL)

Geometric mean (CV%)

5199 (26)

2298 (71)

6129 (31)

4422 (58)

Mean (SD)

5358 (1371)

3152 (2231)

6450 (2031)

5233 (3033)

Median

AUC (ngh/mL)

Geometric mean (CV%)

28132 (28)

14874 (91)

57039 (37)

46073 (66)

Mean (SD)

29303 (8263)

22262 (20159)

61435 (22911)

53761 (35294)

T-half (h)

Mean (SD)

7.9 (2.9)

6.5 (2.6)

18.1 (6.2)

8.6 (2.3)

(ng/mL)

Geometric mean (CV%)

159 (88)

120 (109)

1227 (53)

636 (97)

Mean (SD)

218 (191)

273 (298)

1441 (757)

862 (838)

n=26.

n=12.

Figure 1 displays the mean plasma concentrations of atazanavir at steady state after REYATAZ

400 mg once daily (as two 200-mg capsules) with a light meal and after REYATAZ 300 mg (as

two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in HIV-infected adult

patients.

Figure 1:

Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg

(n=13) and 300 mg with Ritonavir (n=10) for HIV-Infected Adult

Patients

Absorption

Atazanavir is rapidly absorbed with a T

of approximately 2.5 hours. Atazanavir demonstrates

nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and C

values over the dose range of 200 to 800 mg once daily. Steady state is achieved between

Days 4 and 8, with an accumulation of approximately 2.3 fold.

Food Effect

Administration of REYATAZ with food enhances bioavailability and reduces pharmacokinetic

variability. Administration of a single 400-mg dose of REYATAZ with a light meal (357 kcal,

8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in C

relative to

the fasting state. Administration of a single 400-mg dose of REYATAZ with a high-fat meal

(721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change

in C

relative to the fasting state. Administration of REYATAZ with either a light meal or

high-fat meal decreased the coefficient of variation of AUC and C

by approximately one-half

compared to the fasting state.

Coadministration of a single 300-mg dose of REYATAZ and a 100-mg dose of ritonavir with a

light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a

40% increase in both the C

and the 24-hour concentration of atazanavir relative to the fasting

state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect

the AUC of atazanavir relative to fasting conditions and the C

was within 11% of fasting

values. The 24-hour concentration following a high-fat meal was increased by approximately

delayed

absorption;

median

increased

from

hours.

Coadministration of REYATAZ with ritonavir with either a light or a high-fat meal decreased

the coefficient of variation of AUC and C

by approximately 25% compared to the fasting

state.

Distribution

Atazanavir is 86% bound to human serum proteins and protein binding is independent of

concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a

similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients

dosed with REYATAZ 400 mg once daily with a light meal for 12 weeks, atazanavir was

detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir

(n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between

0.11 and 4.42.

Metabolism

Atazanavir is extensively metabolized in humans. The major biotransformation pathways of

atazanavir

humans

consisted

monooxygenation

dioxygenation.

Other

minor

biotransformation

pathways

atazanavir

metabolites

consisted

glucuronidation,

N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of

atazanavir in plasma have been characterized. Neither metabolite demonstrated

in vitro

antiviral

activity.

In vitro

studies using human liver microsomes suggested that atazanavir is metabolized

by CYP3A.

Elimination

Following a single 400-mg dose of

C-atazanavir, 79% and 13% of the total radioactivity was

recovered in the feces and urine, respectively. Unchanged drug accounted for approximately

20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination

half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was

approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.

Specific Populations

Renal Impairment

In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the

administered dose. REYATAZ has been studied in adult subjects with severe renal impairment

(n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean

atazanavir C

was 9% lower, AUC was 19% higher, and C

was 96% higher in subjects with

severe

renal

impairment

undergoing

hemodialysis

(n=10),

than

age-,

weight-,

gender-matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the

administered dose was removed. When atazanavir was administered either prior to, or following

hemodialysis (n=10), the geometric means for C

, AUC, and C

were approximately 25% to

43% lower compared to subjects with normal renal function. The mechanism of this decrease is

unknown. REYATAZ is not recommended for use in HIV-treatment-experienced patients with

end stage renal disease managed with hemodialysis

[see Dosage and Administration (2.4)]

Hepatic Impairment

REYATAZ has been studied in adult subjects with moderate-to-severe hepatic impairment (14

Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC

42% greater in subjects with impaired hepatic function than in healthy volunteers. The mean

half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in

healthy volunteers. A dose reduction to 300 mg is recommended for patients with moderate

hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as

increased concentrations of atazanavir are expected. REYATAZ is not recommended for use in

patients with severe hepatic impairment. The pharmacokinetics of REYATAZ in combination

with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of

REYATAZ with ritonavir is not recommended for use in patients with any degree of hepatic

impairment

[see Dosage and Administration (2.5)]

Pediatrics

pharmacokinetic

parameters

atazanavir

steady

state

pediatric

patients

were

predicted by a population pharmacokinetic model and are summarized in Table 19 by weight

ranges that correspond to the recommended doses [see

Dosage and Administration (2.3)

Table 19:

Predicted Steady-State Pharmacokinetics of Atazanavir (capsule

formulation) with Ritonavir in HIV-Infected Pediatric Patients

Body Weight

(range in kg)

atazanavir/ritonavir

Dose (mg)

C

max

ng/mL

Geometric Mean

(CV%)

AUC ngh/mL

Geometric Mean

(CV%)

C

min

ng/mL

Geometric Mean

(CV%)

15 to <35

200/100

3303 (86%)

37235 (84%)

538 (99%)

300/100

2980 (82%)

37643 (83%)

653 (89%)

Pregnancy

The pharmacokinetic data from HIV-infected pregnant women receiving REYATAZ Capsules

with ritonavir are presented in Table 20.

Table 20:

Steady-State Pharmacokinetics of Atazanavir with Ritonavir in

HIV-Infected Pregnant Women in the Fed State

Pharmacokinetic Parameter

Atazanavir 300 mg with ritonavir 100 mg

2nd Trimester

(n=5

a

)

3rd Trimester

(n=20)

Postpartum

b

(n=34)

ng/mL

Geometric mean (CV%)

3078.85

(50)

3291.46

(48)

5721.21

(31)

AUC ngh/mL

Geometric mean (CV%)

27657.1

(43)

34251.5

(43)

61990.4

(32)

ng/mL

Geometric mean (CV%)

538.70

(46)

668.48

(50)

1462.59

(45)

Available data during the 2nd trimester are limited.

Atazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the

postpartum

period

(4-12

weeks)

than

those

observed

historically

HIV-infected,

non-pregnant

patients.

Atazanavir plasma trough concentrations were approximately 2.2-fold higher during the postpartum period when

compared to those observed historically in HIV-infected, non-pregnant patients.

is concentration 24 hours post-dose.

Drug Interaction Data

Atazanavir is a metabolism-dependent CYP3A inhibitor, with a K

inact

value of 0.05 to 0.06 min

−1

and K

value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (K

=1.9 µM)

and CYP2C8 (K

=2.1 µM).

Atazanavir has been shown

in vivo

not to induce its own metabolism nor to increase the

biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, REYATAZ

decreased the urinary ratio of endogenous 6

-OH cortisol to cortisol versus baseline, indicating

that CYP3A production was not induced.

Clinically

significant

interactions

expected

between

atazanavir

substrates

CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant

interactions are not expected between atazanavir when administered with ritonavir and substrates

of CYP2C8. See

the complete prescribing information for ritonavir for information on other

potential drug interactions with ritonavir.

Based on known metabolic profiles, clinically significant drug interactions are not expected

between

REYATAZ

dapsone,

trimethoprim/sulfamethoxazole,

azithromycin,

erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline,

desipramine, metoprolol).

Drug

interaction

studies

were

performed

with

REYATAZ

other

drugs

likely

coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The

effects of coadministration of REYATAZ on the AUC, C

, and C

are summarized in Tables

21 and 22. Neither didanosine EC nor diltiazem had a significant effect on atazanavir exposures

(see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). REYATAZ did

not have a significant effect on the exposures of didanosine (when administered as the buffered

tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see

Drug

Interactions (7)

Table 21:

Drug Interactions: Pharmacokinetic Parameters for Atazanavir in

the Presence of Coadministered Drugs

a

Coadministered

Drug

Coadministered Drug

Dose/Schedule

REYATAZ

Dose/Schedule

Ratio (90% Confidence Interval) of Atazanavir

Pharmacokinetic Parameters with/without

Coadministered Drug;

No Effect = 1.00

C

max

AUC

C

min

atenolol

50 mg QD, d 7–11

(n=19) and d 19–23

400 mg QD, d 1–11

(n=19)

1.00

(0.89, 1.12)

0.93

(0.85, 1.01)

0.74

(0.65, 0.86)

boceprevir

800 mg TID,

d 1–6, 25–31

300 mg QD/ritonavir

100 mg QD, d 10–31

atazanavir: 0.75

(0.64-0.88)

ritonavir: 0.73

(0.64-0.83)

atazanavir: 0.65

(0.55-0.78)

ritonavir: 0.64

(0.58-0.72)

atazanavir: 0.51

(0.44-0.61)

ritonavir: 0.55

(0.45-0.67)

clarithromycin

500 mg BID, d 7–10

(n=29) and d 18–21

400 mg QD, d 1–10

(n=29)

1.06

(0.93, 1.20)

1.28

(1.16, 1.43)

1.91

(1.66, 2.21)

didanosine (ddI)

(buffered tablets)

plus stavudine

(d4T)

ddI: 200 mg

1 dose,

d4T: 40 mg

1 dose

(n=31)

400 mg

1 dose

simultaneously with

ddI and d4T

(n=31)

0.11

(0.06, 0.18)

0.13

(0.08, 0.21)

0.16

(0.10, 0.27)

Table 21:

Drug Interactions: Pharmacokinetic Parameters for Atazanavir in

the Presence of Coadministered Drugs

a

Coadministered

Drug

Coadministered Drug

Dose/Schedule

REYATAZ

Dose/Schedule

Ratio (90% Confidence Interval) of Atazanavir

Pharmacokinetic Parameters with/without

Coadministered Drug;

No Effect = 1.00

C

max

AUC

C

min

ddI: 200 mg

1 dose,

d4T: 40 mg

1 dose

(n=32)

400 mg

1 dose

1 h after ddI + d4T

(n=32)

1.12

(0.67, 1.18)

1.03

(0.64, 1.67)

1.03

(0.61, 1.73)

efavirenz

600 mg QD, d 7–20

(n=27)

400 mg QD, d 1–20

(n=27)

0.41

(0.33, 0.51)

0.26

(0.22, 0.32)

0.07

(0.05, 0.10)

600 mg QD, d 7–20

(n=13)

400 mg QD, d 1–6 (n=23)

then 300 mg/ritonavir

100 mg QD, 2 h before

efavirenz, d 7–20 (n=13)

1.14

(0.83, 1.58)

1.39

(1.02, 1.88)

1.48

(1.24, 1.76)

600 mg QD,

d 11–24 (pm)

(n=14)

300 mg QD/ritonavir

100 mg QD, d 1–10 (pm)

(n=22), then 400 mg

QD/ritonavir 100 mg QD,

d 11–24 (pm),

(simultaneously with

efavirenz)

(n=14)

1.17

(1.08, 1.27)

1.00

(0.91, 1.10)

0.58

(0.49, 0.69)

famotidine

40 mg BID, d 7–12

(n=15)

400 mg QD, d 1–6 (n=45),

d 7–12 (simultaneous

administration)

(n=15)

0.53

(0.34, 0.82)

0.59

(0.40, 0.87)

0.58

(0.37, 0.89)

40 mg BID, d 7–12

(n=14)

400 mg QD (pm), d 1–6

(n=14), d 7–12 (10 h after,

2 h before famotidine)

(n=14)

1.08

(0.82, 1.41)

0.95

(0.74, 1.21)

0.79

(0.60, 1.04)

40 mg BID, d 11–20

(n=14)

300 mg QD/ritonavir

100 mg QD, d 1–10 (n=46),

d 11–20

(simultaneous

administration)

(n=14)

0.86

(0.79, 0.94)

0.82

(0.75, 0.89)

0.72

(0.64, 0.81)

20 mg BID, d 11–17

(n=18)

300 mg QD/ritonavir

100 mg QD/tenofovir DF

300 mg QD, d 1–10 (am)

(n=39), d 11–17 (am)

(simultaneous

administration with am

famotidine) (n=18)

0.91

(0.84, 0.99)

0.90

(0.82, 0.98)

0.81

(0.69, 0.94)

40 mg QD (pm),

d 18–24

(n=20)

300 mg QD/ritonavir

100 mg QD/tenofovir DF

300 mg QD, d 1–10 (am)

(n=39), d 18–24 (am) (12 h

after pm famotidine)

(n=20)

0.89

(0.81, 0.97)

0.88

(0.80, 0.96)

0.77

(0.63, 0.93)

Table 21:

Drug Interactions: Pharmacokinetic Parameters for Atazanavir in

the Presence of Coadministered Drugs

a

Coadministered

Drug

Coadministered Drug

Dose/Schedule

REYATAZ

Dose/Schedule

Ratio (90% Confidence Interval) of Atazanavir

Pharmacokinetic Parameters with/without

Coadministered Drug;

No Effect = 1.00

C

max

AUC

C

min

40 mg BID, d 18–24

(n=18)

300 mg QD/ritonavir

100 mg QD/tenofovir DF

300 mg QD, d 1–10 (am)

(n=39), d 18–24 (am) (10 h

after pm famotidine and 2 h

before am famotidine)

(n=18)

0.74

(0.66, 0.84)

0.79

(0.70, 0.88)

0.72

(0.63, 0.83)

40 mg BID, d 11–20

(n=15)

300 mg QD/ritonavir

100 mg QD, d 1–10 (am)

(n=46), then 400 mg

QD/ritonavir 100 mg QD,

d 11–20 (am) (n=15)

1.02

(0.87, 1.18)

1.03

(0.86, 1.22)

0.86

(0.68, 1.08)

grazoprevir/

elbasvir

grazoprevir 200 mg QD

d 1 - 35

(n = 11)

300 mg QD/ritonavir 100

mg QD, d 1- 35

(n = 11)

1.12

(1.01, 1.24)

1.43

(1.30, 1.57)

1.23

(1.13, 1.34)

elbasvir 50 mg QD

d 1 - 35

(n = 8)

300 mg QD/ritonavir 100

mg QD, d 1 - 35

(n = 8)

1.02

(0.96, 1.08)

1.07

(0.98,1.17)

1.15

(1.02, 1.29)

ketoconazole

200 mg QD, d 7–13

(n=14)

400 mg QD, d 1–13

(n=14)

0.99

(0.77, 1.28)

1.10

(0.89, 1.37)

1.03

(0.53, 2.01)

nevirapine

200 mg BID,

d 1–23

(n=23)

300 mg QD/ritonavir

100 mg QD, d 4–13, then

400 mg QD/ritonavir

100 mg QD, d 14–23

(n=23)

0.72

(0.60, 0.86)

1.02

(0.85, 1.24)

0.58

(0.48, 0.71)

0.81

(0.65, 1.02)

0.28

(0.20, 0.40)

0.41

(0.27, 0.60)

omeprazole

40 mg QD, d 7–12

(n=16)

400 mg QD, d 1–6 (n=48),

d 7–12 (n=16)

0.04

(0.04, 0.05)

0.06

(0.05, 0.07)

0.05

(0.03, 0.07)

40 mg QD, d 11–20

(n=15)

300 mg QD/ritonavir

100 mg QD, d 1–20 (n=15)

0.28

(0.24, 0.32)

0.24

(0.21, 0.27)

0.22

(0.19, 0.26)

20 mg QD, d 17–23

(am)

(n=13)

300 mg QD/ritonavir

100 mg QD, d 7–16 (pm)

(n=27), d 17–23 (pm)

(n=13)

0.61

(0.46, 0.81)

0.58

(0.44, 0.75)

0.54

(0.41, 0.71)

20 mg QD, d 17–23

(am) (n=14)

300 mg QD/ritonavir

100 mg QD, d 7–16 (am)

(n=27), then 400 mg

QD/ritonavir 100 mg QD,

d 17–23 (am) (n=14)

0.69

(0.58, 0.83)

0.70

(0.57, 0.86)

0.69

(0.54, 0.88)

pitavastatin

4 mg QD

for 5 days

300 mg QD

for 5 days

1.13

(0.96, 1.32)

1.06

(0.90, 1.26)

rifabutin

150 mg QD, d 15–28

(n=7)

400 mg QD, d 1–28

(n=7)

1.34

(1.14, 1.59)

1.15

(0.98, 1.34)

1.13

(0.68, 1.87)

Table 21:

Drug Interactions: Pharmacokinetic Parameters for Atazanavir in

the Presence of Coadministered Drugs

a

Coadministered

Drug

Coadministered Drug

Dose/Schedule

REYATAZ

Dose/Schedule

Ratio (90% Confidence Interval) of Atazanavir

Pharmacokinetic Parameters with/without

Coadministered Drug;

No Effect = 1.00

C

max

AUC

C

min

rifampin

600 mg QD, d 17–26

(n=16)

300 mg QD/ritonavir

100 mg QD, d 7–16 (n=48),

d 17–26 (n=16)

0.47

(0.41, 0.53)

0.28

(0.25, 0.32)

0.02

(0.02, 0.03)

ritonavir

100 mg QD, d 11–20

(n=28)

300 mg QD, d 1–20

(n=28)

1.86

(1.69, 2.05)

3.38

(3.13, 3.63)

11.89

(10.23, 13.82)

tenofovir DF

300 mg QD, d 9–16

(n=34)

400 mg QD, d 2–16

(n=34)

0.79

(0.73, 0.86)

0.75

(0.70, 0.81)

0.60

(0.52, 0.68)

300 mg QD, d 15–42

(n=10)

300 mg/ritonavir 100 mg

QD, d 1–42

(n=10)

0.72

(0.50, 1.05)

0.75

(0.58, 0.97)

0.77

(0.54, 1.10)

voriconazole

(Subjects with at

least one

functional

CYP2C19 allele)

200 mg BID,

d 2–3, 22–30;

400 mg BID, d 1, 21

(n=20)

300 mg/ritonavir 100 mg

QD, d 11–30

(n=20)

0.87

(0.80, 0.96)

0.88

(0.82, 0.95)

0.80

(0.72, 0.90)

voriconazole

(Subjects without

a functional

CYP2C19 allele)

50 mg BID,

d 2–3, 22–30;

100 mg BID, d 1, 21

(n=8)

300 mg/ritonavir 100 mg

QD, d 11–30

(n=8)

0.81

(0.66, 1.00)

0.80

(0.65, 0.97)

0.69

(0.54, 0.87)

Data provided are under fed conditions unless otherwise noted.

All drugs were given under fasted conditions.

REYATAZ 300 mg plus ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir

geometric mean C

that was similar and AUC and C

values that were 1.79- and 4.46-fold higher relative to REYATAZ

400 mg once daily alone.

Similar results were noted when famotidine 20 mg BID was administered 2 hours after and 10 hours before atazanavir 300 mg

and ritonavir 100 mg plus tenofovir DF 300 mg.

Atazanavir/ritonavir/tenofovir DF was administered after a light meal.

Study was conducted in HIV-infected individuals.

Compared with atazanavir 400 mg historical data without nevirapine (n=13), the ratio of geometric means (90% confidence

intervals) for C

, AUC, and C

were 1.42 (0.98, 2.05), 1.64 (1.11, 2.42), and 1.25 (0.66, 2.36), respectively, for

atazanavir/ritonavir

300/100

2.02

(1.42,

2.87),

2.28

(1.54,

3.38),

1.80

(0.94,

3.45),

respectively,

atazanavir/ritonavir 400/100 mg.

Parallel group design; n=23 for atazanavir/ritonavir plus nevirapine, n=22 for atazanavir 300 mg/ritonavir 100 mg without

nevirapine. Subjects were treated with nevirapine prior to study entry.

Omeprazole 40 mg was administered on an empty stomach 2 hours before REYATAZ.

Omeprazole 20 mg was administered 30 minutes prior to a light meal in the morning and REYATAZ 300 mg plus ritonavir

100 mg in the evening after a light meal, separated by 12 hours from omeprazole.

REYATAZ 300 mg plus ritonavir 100 mg once daily separated by 12 hours from omeprazole 20 mg daily resulted in increases

in atazanavir geometric mean AUC (10%) and C

(2.4-fold), with a decrease in C

(29%) relative to REYATAZ 400 mg

once daily in the absence of omeprazole (study days 1

Omeprazole 20 mg was given 30 minutes prior to a light meal in the morning and REYATAZ 400 mg plus ritonavir 100 mg

once daily after a light meal, 1 hour after omeprazole. Effects on atazanavir concentrations were similar when REYATAZ

400 mg plus ritonavir 100 mg was separated from omeprazole 20 mg by 12 hours.

REYATAZ 400 mg plus ritonavir 100 mg once daily administered with omeprazole 20 mg once daily resulted in increases in

atazanavir geometric mean AUC (32%) and C

(3.3-fold), with a decrease in C

(26%) relative to REYATAZ 400 mg once

daily in the absence of omeprazole (study days 1

Compared with atazanavir 400 mg QD historical data, administration of atazanavir/ritonavir 300/100 mg QD increased the

atazanavir geometric mean values of C

, AUC, and C

by 18%, 103%, and 671%, respectively.

Note that similar results were observed in studies where administration of tenofovir DF and REYATAZ was separated by

12 hours.

Ratio of atazanavir plus ritonavir plus tenofovir DF to atazanavir plus ritonavir. Atazanavir 300 mg plus ritonavir 100 mg

results in higher atazanavir exposure than atazanavir 400 mg (see footnote

). The geometric mean values of atazanavir

pharmacokinetic

parameters

when

coadministered

with

ritonavir

tenofovir

were:

3190

ng/mL,

AUC = 34459 ng

h/mL, and C

= 491 ng/mL. Study was conducted in HIV-infected individuals.

NA = not available.

Table 22:

Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs

in the Presence of REYATAZ

a

Coadministered

Drug

Coadministered

Drug

Dose/Schedule

REYATAZ

Dose/Schedule

Ratio (90% Confidence Interval) of Coadministered Drug

Pharmacokinetic Parameters with/without REYATAZ;

No Effect = 1.00

C

max

AUC

C

min

acetaminophen

1 gm BID, d 1–20

(n=10)

300 mg QD/ritonavir

100 mg QD, d 11–20

(n=10)

0.87

(0.77, 0.99)

0.97

(0.91, 1.03)

1.26

(1.08, 1.46)

atenolol

50 mg QD, d 7–11

(n=19) and d 19–23

400 mg QD, d 1–11

(n=19)

1.34

(1.26, 1.42)

1.25

(1.16, 1.34)

1.02

(0.88, 1.19)

boceprevir

800 mg TID,

d 1–6, 25–31

300 mg QD/ritonavir

100 mg QD,

d 10–31

0.93

(0.80, 1.08)

0.95

(0.87, 1.05)

0.82

(0.68, 0.98)

clarithromycin

500 mg BID,

d 7–10 (n=21) and

d 18–21

400 mg QD, d 1–10

(n=21)

1.50

(1.32, 1.71)

OH-clarithromycin:

0.28

(0.24, 0.33)

1.94

(1.75, 2.16)

OH-clarithromycin:

0.30

(0.26, 0.34)

2.60

(2.35, 2.88)

clarithromycin:

0.38

(0.34, 0.42)

ddI (enteric-

coated [EC]

capsules)b

400 mg d 1 (fasted),

d 8 (fed)

(n=34)

400 mg QD, d 2–8

(n=34)

0.64

(0.55, 0.74)

0.66

(0.60, 0.74)

1.13

(0.91, 1.41)

400 mg d 1 (fasted),

d 19 (fed)

(n=31)

300 mg QD/ritonavir

100 mg QD, d 9–19

(n=31)

0.62

(0.52, 0.74)

0.66

(0.59, 0.73)

1.25

(0.92, 1.69)

diltiazem

180 mg QD, d 7–11

(n=28) and d 19–23

400 mg QD, d 1–11

(n=28)

1.98

(1.78, 2.19)

desacetyl-diltiazem:

2.72

(2.44, 3.03)

2.25

(2.09, 2.16)

desacetyl-diltiazem:

2.65

(2.45, 2.87)

2.42

(2.14, 2.73)

desacetyl-

diltiazem:

2.21

(2.02, 2.42)

ethinyl estradiol

& norethindrone

0.035 mg ethinyl

estradiol and

0.5/0.75/1 mg

norethindrone

tablets*

d 1–29

(n=19)

400 mg QD,

d 16–29

(n=19)

ethinyl estradiol: 1.15

(0.99, 1.32)

norethindrone: 1.67

(1.42, 1.96)

ethinyl estradiol: 1.48

(1.31, 1.68)

norethindrone: 2.10

(1.68, 2.62)

ethinyl estradiol:

1.91

(1.57, 2.33)

norethindrone:

3.62

(2.57, 5.09)

ethinyl estradiol

& norgestimate

0.035mg ethinyl

estradiol and

0.180/0.215/0.250

mg norgestimate *

QD, d 1–28 (n=18),

then 0.025mg

ethinyl estradiol and

0.180/0.215/0.250

mg norgestimate

*QD,

d 29–42

(n=14)

300 mg QD/ritonavir

100 mg QD,

d 29–42

(n=14)

ethinyl estradiol:

0.84

(0.74, 0.95)

17-deacetyl

norgestimate:

1.68

(1.51, 1.88)

ethinyl estradiol:

0.81

(0.75, 0.87)

17-deacetyl

norgestimate:

1.85

(1.67, 2.05)

ethinyl

estradiol:

0.63

(0.55, 0.71)

17-deacetyl

norgestima

2.02

(1.77, 2.31)

glecaprevir/

pibrentasvir

300 mg glecaprevir

(n=12)

300 mg QD/ritonavir

100 mg QD

(n=12)

≥4.06

(3.15, 5.23)

≥6.53

(5.24, 8.14)

≥14.3

(9.85, 20.7)

120 mg pibrentasvir

(n=12)

300 mg QD/ritonavir

100 mg QD

(n=12)

≥1.29

(1.15, 1.45)

≥1.64

(1.48, 1.82)

≥2.29

(1.95, 2.68)

grazoprevir/

elbasvir

grazoprevir 200 mg

d 1 - 35

(n = 12)

300 mg QD/ritonavir

100 mg QD

d 1 - 35

(n=12)

6.24

(4.42, 8.81)

10.58

(7.78, 14.39)

11.64

(7.96, 17.02)

elbasvir 50 mg QD

d 1 - 35

(n = 10)

300 mg QD/ritonavir

100 mg QD

d 1 - 35

(n=10)

4.15

(3.46, 4.97)

4.76

(4.07, 5.56)

6.45

(5.51 7.54)

methadone

Stable maintenance

dose, d 1–15

(n=16)

400 mg QD, d 2–15

(n=16)

(R)-methadone

0.91

(0.84, 1.0)

total: 0.85

(0.78, 0.93)

(R)-methadone

1.03

(0.95, 1.10)

total: 0.94

(0.87, 1.02)

(R)-methadone

1.11

(1.02, 1.20)

total: 1.02

(0.93, 1.12)

nevirapine

,i,j

200 mg BID,

d 1–23

(n=23)

300 mg QD/

ritonavir 100 mg QD, d

4–13, then

400 mg QD/

ritonavir 100 mg QD, d

14–23

(n=23)

1.17

(1.09, 1.25)

1.21

(1.11, 1.32)

1.25

(1.17, 1.34)

1.26

(1.17, 1.36)

1.32

(1.22, 1.43)

1.35

(1.25, 1.47)

omeprazole

40 mg single dose,

d 7 and d 20

(n=16)

400 mg QD, d 1–12

(n=16)

1.24

(1.04, 1.47)

1.45

(1.20, 1.76)

rifabutin

300 mg QD, d 1–10

then 150 mg QD,

d 11–20

(n=3)

600 mg QD,

d 11–20

(n=3)

1.18

(0.94, 1.48)

25-O-desacetyl-

rifabutin: 8.20

(5.90, 11.40)

2.10

(1.57, 2.79)

25-O-desacetyl-

rifabutin: 22.01

(15.97, 30.34)

3.43

(1.98, 5.96)

25-O-desacetyl-

rifabutin: 75.6

(30.1, 190.0)

150 mg twice

weekly, d 1–15

(n=7)

300 mg QD/

ritonavir 100 mg

QD, d 1–17 (n=7)

2.49

(2.03, 3.06)

25-O-desacetyl-

rifabutin: 7.77

(6.13, 9.83)

1.48

(1.19, 1.84)

25-O-desacetyl-

rifabutin: 10.90

(8.14, 14.61)

1.40

(1.05, 1.87)

25-O-desacetyl-

rifabutin: 11.45

(8.15, 16.10)

pitavastatin

4 mg QD

for 5 days

300 mg QD

for 5 days

1.60

(1.39, 1.85)

1.31

(1.23, 1.39)

rosiglitazone

4 mg single dose,

d 1, 7, 17

(n=14)

400 mg QD,

d 2–7, then

300 mg QD/

ritonavir 100 mg QD, d

8–17

(n=14)

1.08

(1.03, 1.13)

0.97

(0.91, 1.04)

1.35

(1.26, 1.44)

0.83

(0.77, 0.89)

rosuvastatin

10 mg

single dose

300 mg QD/

ritonavir 100 mg

QD for 7 days

7-fold

3-fold

saquinavir

(soft

gelatin capsules)

1200 mg QD,

d 1–13

(n=7)

400 mg QD, d 7–13

(n=7)

4.39

(3.24, 5.95)

5.49

(4.04, 7.47)

6.86

(5.29, 8.91)

sofosbuvir/

velpatasvir/

voxilaprevir

400 mg sofosbuvir

single dose

(n=15)

300 mg/100 mg ritonavir

single dose

(n=15)

1.29

(1.09, 1.52)

sofosbuvir metabolite

GS-331007

1.05

(0.99, 1.12)

1.40

(1.25, 1.57)

sofosbuvir metabolite

GS-331007

1.25

(1.16, 1.36)

100 mg velpatasvir

single dose

(n=15)

300 mg/100 mg ritonavir

single dose

(n=15)

1.29

(1.07, 1.56)

1.93

(1.58, 2.36)

100 mg voxilaprevir

single dose

(n=15)

300 mg/100 mg ritonavir

single dose

(n=15)

4.42

(3.65, 5.35)

4.31

(3.76, 4.93)

Tenofovir DF

300 mg QD, d 9–16

(n=33) and d 24–30

(n=33)

400 mg QD, d 2–16

(n=33)

1.14

(1.08, 1.20)

1.24

(1.21, 1.28)

1.22

(1.15, 1.30)

300 mg QD, d 1–7

(pm) (n=14)

d 25–34 (pm)

(n=12)

300 mg QD/ritonavir

100 mg QD, d 25–34

(am) (n=12)

1.34

(1.20, 1.51)

1.37

(1.30, 1.45)

1.29

(1.21, 1.36)

voriconazole

(Subjects with at least

one functional

CYP2C19 allele)

200 mg BID,

d 2–3, 22–30;

400 mg BID,

d 1, 21

(n=20)

300 mg/ritonavir 100 mg

QD, d 11–30

(n=20)

0.90

(0.78, 1.04)

0.67

(0.58, 0.78)

0.61

(0.51, 0.72)

voriconazole

(Subjects without a

functional CYP2C19

allele)

50 mg BID,

d 2–3, 22–30;

100 mg BID,

d 1, 21

(n=8)

300 mg/ritonavir 100 mg

QD, d 11–30

(n=8)

4.38

(3.55, 5.39)

5.61

(4.51, 6.99)

7.65

(5.71, 10.2)

lamivudine +

zidovudine

150 mg lamivudine

+ 300 mg

zidovudine BID,

d 1–12

(n=19)

400 mg QD, d 7–12

(n=19)

lamivudine: 1.04

(0.92, 1.16)

zidovudine: 1.05

(0.88, 1.24)

zidovudine

glucuronide: 0.95

(0.88, 1.02)

lamivudine: 1.03

(0.98, 1.08)

zidovudine: 1.05

(0.96, 1.14)

zidovudine glucuronide:

1.00

(0.97, 1.03)

lamivudine: 1.12

(1.04, 1.21)

zidovudine: 0.69

(0.57, 0.84)

zidovudine

glucuronide: 0.82

(0.62, 1.08)

Data provided are under fed conditions unless otherwise noted.

400 mg ddI EC and REYATAZ were administered together with food on Days 8 and 19.

Upon further dose normalization of ethinyl estradiol 25 mcg with atazanavir relative to ethinyl estradiol 35 mcg without

atazanavir, the ratio of geometric means (90% confidence intervals) for C

, AUC, and C

were 0.82 (0.73, 0.92),

1.06 (0.95, 1.17), and 1.35 (1.11, 1.63), respectively.

Upon further dose normalization of ethinyl estradiol 35 mcg with atazanavir/ritonavir relative to ethinyl estradiol 25 mcg

without atazanavir/ritonavir, the ratio of geometric means (90% confidence intervals) for C

, AUC, and C

were

1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1.00), respectively.

All subjects were on a 28 day lead-in period; one full cycle of Ortho Tri-Cyclen

. Ortho Tri-Cyclen

contains 35 mcg of

ethinyl estradiol. Ortho Tri-Cyclen

LO contains 25 mcg of ethinyl estradiol. Results were dose normalized to an ethinyl

estradiol dose of 35 mcg.

17-deacetyl norgestimate is the active component of norgestimate.

Effect of atazanavir and ritonavir on the first dose of glecaprevir and pibrentasvir is reported.

(R)-methadone is the active isomer of methadone.

Study was conducted in HIV-infected individuals.

Subjects were treated with nevirapine prior to study entry.

Omeprazole was used as a metabolic probe for CYP2C19. Omeprazole was given 2 hours after REYATAZ on Day 7; and was

given alone 2 hours after a light meal on Day 20.

Not the recommended therapeutic dose of atazanavir.

When compared to rifabutin 150 mg QD alone d1

10 (n=14). Total of rifabutin + 25-O-desacetyl-rifabutin: AUC 2.19 (1.78,

2.69).

Rosiglitazone used as a probe substrate for CYP2C8.

Mean ratio (with/without coadministered drug).

indicates an increase in rosuvastatin exposure.

The combination of atazanavir and saquinavir 1200 mg QD produced daily saquinavir exposures similar to the values

produced by the standard therapeutic dosing of saquinavir at 1200 mg TID. However, the C

is about 79% higher than that

for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID.

Note that similar results were observed in a study where administration of tenofovir DF and REYATAZ was separated by

12 hours.

Administration of tenofovir DF and REYATAZ was temporally separated by 12 hours.

NA = not available.

12.4

Microbiology

Mechanism of Action

Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively

inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected

cells, thus preventing formation of mature virions.

Antiviral Activity in Cell Culture

Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC

) in the

absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates

grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells.

ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J

isolates in cell culture. ATV has variable activity against HIV-2 isolates (1.9-32 nM), with EC

values above the EC

values of failure isolates. Two-drug combination antiviral activity studies

with ATV showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir,

nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs

(abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the

HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis,

adefovir and ribavirin, without enhanced cytotoxicity.

Resistance

In Cell Culture:

HIV-1 isolates with a decreased susceptibility to ATV have been selected in cell

culture and obtained from patients treated with ATV or atazanavir/ritonavir (ATV/RTV). HIV-1

isolates with 93- to 183-fold reduced susceptibility to ATV from three different viral strains were

selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to

ATV resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the

protease cleavage sites following drug selection. Recombinant viruses containing the I50L

substitution without other major PI substitutions were growth impaired and displayed increased

susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir,

and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and

amprenavir, respectively, and did not appear to be cross-resistant.

Clinical Studies of Treatment-Naive Patients: Comparison of Ritonavir-Boosted REYATAZ vs.

Unboosted REYATAZ:

Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir

100 mg vs. REYATAZ 400 mg once daily when administered with lamivudine and extended-

release stavudine in HIV-infected treatment-naive patients

.

A summary

of the number of

virologic failures and virologic failure isolates with ATV resistance in each arm is shown in

Table 23.

Table 23:

Summary of Virologic Failures

a

at Week 96 in Study AI424-089:

Comparison of Ritonavir Boosted REYATAZ vs. Unboosted

REYATAZ: Randomized Patients

REYATAZ 300 mg

+

ritonavir 100 mg

(n=95)

REYATAZ 400 mg

(n=105)

Virologic Failure (

50 copies/mL) at Week 96

15 (16%)

34 (32%)

Virologic Failure with Genotypes and

Phenotypes Data

Virologic Failure Isolates with ATV-resistance

at Week 96

0/5 (0%)

4/17 (24%)

Virologic Failure Isolates with I50L Emergence

at Week 96

0/5 (0%)

2/17 (12%)

Virologic Failure Isolates with Lamivudine

Resistance at Week 96

2/5 (40%)

11/17 (65%)

Virologic failure includes patients who were never suppressed through Week 96 and on study at Week 96, had

virologic rebound or discontinued due to insufficient viral load response.

Percentage of Virologic Failure Isolates with genotypic and phenotypic data.

Mixture of I50I/L emerged in 2 other ATV 400 mg-treated patients. Neither isolate was phenotypically resistant

to ATV.

Clinical

Studies

of

Treatment-Naive

Patients

Receiving

REYATAZ

300

mg

with

Ritonavir

100 mg:

In Phase III Study AI424-138, an as-treated genotypic and phenotypic analysis was

conducted

samples

from

patients

experienced

virologic

failure

(HIV-1

400 copies/mL) or discontinued before achieving suppression on ATV/RTV (n=39; 9%) and

LPV/RTV (n=39; 9%) through 96 weeks of treatment. In the ATV/RTV arm, one of the

virologic failure isolates had a 56-fold decrease in ATV susceptibility emerge on therapy with

the development of PI resistance-associated substitutions L10F, V32I, K43T, M46I, A71I, G73S,

I85I/V,

L90M.

NRTI

resistance-associated

substitution

M184V

also

emerged

treatment in this isolate conferring emtricitabine resistance.

Two ATV/RTV-virologic failure

isolates had baseline phenotypic ATV resistance and IAS-defined major PI resistance-associated

substitutions at baseline.

The I50L substitution emerged on study in one of these failure isolates

and was associated with a 17-fold decrease in ATV susceptibility from baseline and the other

failure isolate with baseline ATV resistance and PI substitutions (M46M/I and I84I/V) had

additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on ATV treatment

associated with a 3-fold decrease in ATV susceptibility from baseline. Five of the treatment

failure isolates in the ATV/RTV arm developed phenotypic emtricitabine resistance with the

emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none

developed phenotypic tenofovir disoproxil resistance. In the LPV/RTV arm, one of the virologic

failure patient isolates had a 69-fold decrease in LPV susceptibility emerge on therapy with the

development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI

substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six LPV/RTV

virologic

failure

isolates

developed

M184V

substitution

phenotypic

emtricitabine

resistance and two developed phenotypic tenofovir disoproxil resistance.

Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 400 mg without Ritonavir:

ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure

on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an

average of 50 weeks of ATV therapy), often in combination with an A71V substitution, but also

developed one or more other PI substitutions (eg, V32I, L33F, G73S, V82A, I85V, or N88S)

with or without the I50L substitution. In treatment-naive patients, viral isolates that developed

the I50L substitution, without other major PI substitutions, showed phenotypic resistance to ATV

but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir,

ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect

of the I50L substitution on the efficacy of subsequently administered PIs.

Clinical Studies of Treatment-Experienced Patients:

In studies of treatment-experienced patients

treated with ATV or ATV/RTV, most ATV-resistant isolates from patients who experienced

virologic failure developed substitutions that were associated with resistance to multiple PIs and

displayed decreased susceptibility to multiple PIs. The most common protease substitutions to

develop in the viral isolates of patients who failed treatment with ATV 300 mg once daily and

RTV 100 mg once daily (together with tenofovir DF and an NRTI) included V32I, L33F/V/I,

E35D/G,

M46I/L,

I50L,

F53L/V,

I54V,

A71V/T/I,

G73S/T/C,

V82A/T/L,

I85V,

L89V/Q/M/T. Other substitutions that developed on ATV/RTV treatment including E34K/A/Q,

G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if

multiple PI resistance substitutions were present in the HIV-1 virus of the patient at baseline,

ATV resistance developed through substitutions associated with resistance to other PIs and could

include the development of the I50L substitution. The I50L substitution has been detected in

treatment-experienced patients experiencing virologic failure after long-term treatment. Protease

cleavage site changes also emerged on ATV treatment but their presence did not correlate with

the level of ATV resistance.

Clinical Studies of Pediatric Subjects in AI424-397 (PRINCE I) and AI424-451 (PRINCE II):

Treatment-emergent

ATV/RTV

resistance-associated

amino

acid

substitution

M36I

protease was detected in the virus of one subject among treatment failures in AI424-397. In

addition, three known resistance-associated substitutions for other PIs arose in the viruses from

one subject each (L19I/R, H69K/R, and I72I/V). Reduced susceptibility to ATV, RTV, or

ATV/RTV was not seen with these viruses. In AI424-451, ATV/RTV resistance-associated

substitutions G16E, V82A/I/T, I84V, and/or L90M arose in the viruses of two subjects. The virus

population

harboring

M46M/V,

V82V/I,

I84I/V,

L90L/M

substitutions

acquired

phenotypic resistance to RTV (RTV phenotypic fold-change of 3.5, with a RTV cutoff of 2.5-

fold change). However, these substitutions did not result in phenotypic resistance to ATV (ATV

phenotypic

fold-change

<1.8,

with

cutoff

2.2-fold

change).

Secondary

resistance-associated amino acid substitutions also arose in the viruses of one subject each,

including V11V/I, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61E/G emerged

in the viruses of two subjects who failed treatment with ATV/RTV. Viruses from nine subjects in

the two studies developed NRTI resistance-associated substitutions: K65K/R (n=1), M184V

(n=7), and T215I (n=1).

Cross-Resistance

Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of

clinical isolates from ATV clinical trials of PI-experienced patients showed that isolates cross-

resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with

substitutions that included I84V or G48V were resistant to ATV. Greater than 60% of isolates

containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV,

and 38% of isolates containing a D30N substitution in addition to other changes were resistant to

ATV. Isolates resistant to ATV were also cross-resistant to other PIs with >90% of the isolates

resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to

amprenavir. In treatment-experienced patients, PI-resistant viral isolates that developed the I50L

substitution in addition to other PI resistance-associated substitution were also cross-resistant to

other PIs.

Baseline Genotype/Phenotype and Virologic Outcome Analyses

Genotypic

and/or

phenotypic

analysis

baseline

virus

determining

susceptibility before initiation of ATV/RTV therapy. An association between virologic response

at 48 weeks and the number and type of primary PI resistance-associated substitutions detected

in baseline HIV-1 isolates from antiretroviral-experienced patients receiving ATV/RTV once

daily or lopinavir (LPV)/RTV twice daily in Study AI424-045 is shown in Table 24.

Overall, both the number and type of baseline PI substitutions affected response rates in

treatment-experienced patients. In the ATV/RTV group, patients had lower response rates when

3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were

present compared to patients with 1–2 PI substitutions, including one of these substitutions.

Table 24:

HIV RNA Response by Number and Type of Baseline PI

Substitution, Antiretroviral-Experienced Patients in Study AI424-

045, As-Treated Analysis

Virologic Response = HIV RNA <400 copies/mL

b

Number and Type of Baseline PI

Substitutions

a

ATV/RTV

(n=110)

LPV/RTV

(n=113)

3 or more primary PI substitutions including

c

:

D30N

75% (6/8)

50% (3/6)

M36I/V

19% (3/16)

33% (6/18)

M46I/L/T

24% (4/17)

23% (5/22)

I54V/L/T/M/A

31% (5/16)

31% (5/16)

A71V/T/I/G

34% (10/29)

39% (12/31)

G73S/A/C/T

14% (1/7)

38% (3/8)

V77I

47% (7/15)

44% (7/16)

V82A/F/T/S/I

29% (6/21)

27% (7/26)

I84V/A

11% (1/9)

33% (2/6)

N88D

63% (5/8)

67% (4/6)

L90M

10% (2/21)

44% (11/25)

Table 24:

HIV RNA Response by Number and Type of Baseline PI

Substitution, Antiretroviral-Experienced Patients in Study AI424-

045, As-Treated Analysis

Virologic Response = HIV RNA <400 copies/mL

b

Number and Type of Baseline PI

Substitutions

a

ATV/RTV

(n=110)

LPV/RTV

(n=113)

Number of baseline primary PI substitutions

a

All patients, as-treated

58% (64/110)

59% (67/113)

0–2 PI substitutions

75% (50/67)

75% (50/67)

3–4 PI substitutions

41% (14/34)

43% (12/28)

5 or more PI substitutions

0% (0/9)

28% (5/18)

Primary substitutions include any change at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84,

N88, and L90.

Results should be interpreted with caution because the subgroups were small.

There were insufficient data (n<3) for PI substitutions V32I, I47V, G48V, I50V, and F53L.

The response rates of antiretroviral-experienced patients in Study AI424-045 were analyzed by

baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The

analyses are based on a select patient population with 62% of patients receiving an NNRTI-based

regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are

needed to determine clinically relevant break points for REYATAZ.

Table 25:

Baseline Phenotype by Outcome, Antiretroviral-Experienced

Patients in Study AI424-045, As-Treated Analysis

Baseline Phenotype

a

Virologic Response = HIV RNA <400 copies/mL

b

ATV/RTV

(n=111)

LPV/RTV

(n=111)

0–2

71% (55/78)

70% (56/80)

>2–5

53% (8/15)

44% (4/9)

>5–10

13% (1/8)

33% (3/9)

>10

10% (1/10)

23% (3/13)

Fold change susceptibility in cell culture relative to the wild-type reference.

Results should be interpreted with caution because the subgroups were small.

13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two

years. In the mouse study, drug-related increases in hepatocellular adenomas were found in

females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable

adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was

2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with

100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor

incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or

3.9 (females) times those measured in humans at the clinical dose.

Mutagenesis

Atazanavir tested positive in an

in vitro

clastogenicity test using primary human lymphocytes, in

the absence and presence of metabolic activation. Atazanavir tested negative in the

in vitro

Ames

reverse-mutation assay,

in vivo

micronucleus and DNA repair tests in rats, and

in vivo

damage test in rat duodenum (comet assay).

Impairment of Fertility

At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that

human

clinical

dose,

(300

mg/day

atazanavir

boosted

with

mg/day

ritonavir)

significant effects on mating, fertility, or early embryonic development were not observed.

14

CLINICAL STUDIES

14.1

Adult Patients without Prior Antiretroviral Therapy

Study

AI424-138:

a

96-week

study

comparing

the

antiviral

efficacy

and

safety

of

REYATAZ/ritonavir with lopinavir/ritonavir, each in combination with fixed-dose tenofovirDF-

emtricitabine in HIV-1 infected treatment-naive subjects.

Study AI424-138 was a 96-week,

open-label, randomized, multicenter study, comparing REYATAZ (300 mg once daily) with

ritonavir (100 mg once daily) to lopinavir with ritonavir (400/100 mg twice daily), each in

combination with fixed-dose tenofovir DF with emtricitabine (300/200 mg once daily), in

878 antiretroviral treatment-naive treated patients. Patients had a mean age of 36 years (range:

19-72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and

68% were male. The median baseline plasma CD4+ cell count was 204 cells/mm

(range: 2 to

810 cells/mm

) and the mean baseline plasma HIV-1 RNA level was 4.94 log

copies/mL

(range: 2.60 to 5.88 log

copies/mL). Treatment response and outcomes through Week 96 are

presented in Table 26.

Table 26:

Outcomes of Treatment Through Week 96 in Treatment-Naive

Adults (Study AI424-138)

REYATAZ

300 mg + ritonavir 100 mg

(once daily) with tenofovir

DF/emtricitabine

(once daily)

a

(n=441)

lopinavir

400 mg + ritonavir 100 mg

(twice daily) with tenofovir

DF/emtricitabine

(once daily)

a

(n=437)

Outcome

96 Weeks

96 Weeks

Responder

b,c,d

Virologic failure

Rebound

Never suppressed through Week 96

Death

Discontinued due to adverse event

Discontinued for other reasons

As a fixed-dose combination: 300 mg tenofovir DF, 200 mg emtricitabine once daily.

Patients achieved HIV RNA <50 copies/mL at Week 96. Roche Amplicor

, v1.5 ultra-sensitive assay.

Pre-specified ITT analysis at Week 48 using as-randomized cohort: ATV/RTV 78% and LPV/RTV 76%

(difference estimate: 1.7% [95% confidence interval: −3.8%, 7.1%]).

Pre-specified ITT analysis at Week 96 using as-randomized cohort: ATV/RTV 74% and LPV/RTV 68%

(difference estimate: 6.1% [95% confidence interval: 0.3%, 12.0%]).

Includes viral rebound and failure to achieve confirmed HIV RNA <50 copies/mL through Week 96.

Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.

Through 96 weeks of therapy, the proportion of responders among patients with high viral loads

(ie, baseline HIV RNA

100,000 copies/mL) was comparable for the REYATAZ/ritonavir

(165 of 223 patients, 74%) and lopinavir/ritonavir (148 of 222 patients, 67%) arms. At 96 weeks,

median

increase

from

baseline

CD4+

cell

count

cells/mm

REYATAZ/ritonavir arm and 273 cells/mm

for the lopinavir/ritonavir arm.

Study AI424-034: REYATAZ once daily compared to efavirenz once daily, each in combination

with fixed-dose lamivudine + zidovudine twice daily.

Study AI424-034 was a randomized,

double-blind, multicenter trial comparing REYATAZ (400 mg once daily) to efavirenz (600 mg

once daily), each in combination with a fixed-dose combination of lamivudine (3TC) (150 mg)

and zidovudine (ZDV) (300 mg) given twice daily, in 810 antiretroviral treatment-naive patients.

Patients had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian,

and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm

(range: 64 to

1424 cells/mm

) and the mean baseline plasma HIV-1 RNA level was 4.8 log

copies/mL

(range: 2.2 to 5.9 log

copies/mL). Treatment response and outcomes through Week 48 are

presented in Table 27.

Table 27:

Outcomes of Randomized Treatment Through Week 48 in Treatment-

Naive Adults (Study AI424-034)

Outcome

REYATAZ

400 mg once daily

+ lamivudine

+ zidovudine

d

(n=405)

efavirenz

600 mg once daily

+ lamivudine

+ zidovudine

d

(n=405)

Responder

67% (32%)

62% (37%)

Virologic failure

Rebound

Never suppressed through Week 48

Death

<1%

Discontinued due to adverse event

Discontinued for other reasons

Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.

Roche Amplicor

HIV-1 Monitor

Assay, test version 1.0 or 1.5 as geographically appropriate.

Includes viral rebound and failure to achieve confirmed HIV RNA <400 copies/mL through Week 48.

Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.

As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.

Through 48 weeks of therapy, the proportion of responders among patients with high viral loads

(ie, baseline HIV RNA

100,000 copies/mL) was comparable for the REYATAZ and efavirenz

arms.

mean

increase

from

baseline

CD4+

cell

count

cells/mm

REYATAZ arm and 160 cells/mm

for the efavirenz arm.

Study AI424-008: REYATAZ 400 mg once daily compared to REYATAZ 600 mg once daily, and

compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine

twice daily.

Study AI424-008 was a 48-week, randomized, multicenter trial, blinded to dose of

REYATAZ, comparing REYATAZ at two dose levels (400 mg and 600 mg once daily) to

nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine

(150 mg) given twice daily, in 467 antiretroviral treatment-naive patients. Patients had a mean

age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male. The mean baseline

CD4+ cell count was 295 cells/mm

(range: 4 to 1003 cells/mm

) and the mean baseline plasma

HIV-1 RNA level was 4.7 log

copies/mL (range: 1.8 to 5.9 log

copies/mL). Treatment

response and outcomes through Week 48 are presented in Table 28.

Table 28:

Outcomes of Randomized Treatment Through Week 48 in

Treatment-Naive Adults (Study AI424-008)

Outcome

REYATAZ

400 mg once daily +

lamivudine + stavudine

(n=181)

nelfinavir

1250 mg twice daily +

lamivudine + stavudine

(n=91)

Responder

67% (33%)

59% (38%)

Virologic failure

Rebound

Never suppressed through Week 48

Death

<1%

Discontinued due to adverse event

Discontinued for other reasons

Patients achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.

Roche Amplicor

HIV-1 Monitor

Assay, test version 1.0 or 1.5 as geographically appropriate.

Includes viral rebound and failure to achieve confirmed HIV RNA <400 copies/mL through Week 48.

Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation, and other reasons.

Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was

234 cells/mm

for the REYATAZ 400-mg arm and 211 cells/mm

for the nelfinavir arm.

14.2

Adult Patients with Prior Antiretroviral Therapy

Study AI424-045: REYATAZ once daily + ritonavir once daily compared to REYATAZ once daily

+ saquinavir (soft gelatin capsules) once daily, and compared to lopinavir + ritonavir twice

daily, each in combination with tenofovir DF+ one NRTI.

Study AI424-045 was a randomized,

multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily)

to REYATAZ (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily),

and to lopinavir + ritonavir (400/100 mg twice daily), each in combination with tenofovir DF and

one NRTI, in 347 (of 358 randomized) patients who experienced virologic failure on HAART

regimens

containing

PIs,

NNRTIs,

NRTIs.

mean

time

prior

exposure

antiretrovirals was 139 weeks for PIs, 85 weeks for NNRTIs, and 283 weeks for NRTIs. The

mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean

baseline CD4+ cell count was 338 cells/mm

(range: 14 to 1543 cells/mm

) and the mean

baseline plasma HIV-1 RNA level was 4.4 log

copies/mL (range: 2.6 to 5.88 log

copies/mL).

Treatment outcomes through Week 48 for the REYATAZ/ritonavir and lopinavir/ritonavir

treatment arms are presented in Table 29. REYATAZ/ritonavir and lopinavir/ritonavir were

similar for the primary efficacy outcome measure of time-averaged difference in change from

baseline in HIV RNA level. Study AI424-045 was not large enough to reach a definitive

conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary

efficacy outcome measure of proportions below the HIV RNA lower limit of quantification

[see

Microbiology, Tables 24 and

25 (12.4)]

Table 29:

Outcomes of Treatment Through Week 48 in Study AI424-045

(Patients with Prior Antiretroviral Experience)

Outcome

REYATAZ 300 mg +

ritonavir 100 mg once

daily + tenofovir DF+

1 NRTI

(n=119)

lopinavir/ritonavir

(400/100 mg) twice

daily + tenofovir DF +

1 NRTI

(n=118)

Difference

a

(REYATAZ-

lopinavir/ritonavir)

(CI)

HIV RNA Change from Baseline

(log

copies/mL)

−1.58

−1.70

+0.12

(−0.17, 0.41)

CD4+ Change from Baseline

(cells/mm

−7

(−67, 52)

Percent of Patients Responding

HIV RNA <400 copies/mL

−2.2%

(−14.8%, 10.5%)

HIV RNA <50 copies/mL

−7.1%

(−19.6%, 5.4%)

Time-averaged difference through Week 48 for HIV RNA; Week 48 difference in HIV RNA percentages and

CD4+ mean changes, REYATAZ/ritonavir vs lopinavir/ritonavir; CI = 97.5% confidence interval for change in

HIV RNA; 95% confidence interval otherwise.

Roche Amplicor

HIV-1 Monitor

Assay, test version 1.5.

Protocol-defined primary efficacy outcome measure.

Based on patients with baseline and Week 48 CD4+ cell count measurements (REYATAZ/ritonavir, n=85;

lopinavir/ritonavir, n=93).

Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48.

No patients in the REYATAZ/ritonavir treatment arm and three patients in the lopinavir/ritonavir

treatment arm experienced a new-onset CDC Category C event during the study.

In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for REYATAZ

400 mg with saquinavir (n=115) was

1.55 log

copies/mL, and the time-averaged difference in

change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33. The corresponding mean

increase in CD4+ cell count was 72 cells/mm

. Through 48 weeks of treatment, the proportion of

patients in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%).

In this study, coadministration of REYATAZ and saquinavir did not provide adequate efficacy

[see Drug Interactions (7)]

Study AI424-045 also compared changes from baseline in lipid values.

[See Adverse Reactions

(6.1).]

Study AI424-043:

Study AI424-043 was a randomized, open-label, multicenter trial comparing

REYATAZ (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily), each in

combination with two NRTIs, in 300 patients who experienced virologic failure to only one prior

PI-containing regimen. Through 48 weeks, the proportion of patients with plasma HIV-1 RNA

<400 (<50) copies/mL was 49% (35%) for patients randomized to REYATAZ (n=144) and

69% (53%) for patients randomized to lopinavir/ritonavir (n=146). The mean change from

baseline was

1.59 log

copies/mL in the REYATAZ treatment arm and

2.02 log

copies/mL

in the lopinavir/ritonavir arm. Based on the results of this study, REYATAZ without ritonavir

was inferior to lopinavir/ritonavir in PI-experienced patients with prior virologic failure and is

not recommended for such patients.

14.3

Pediatric Patients

Pediatric Trials with REYATAZ Capsules

Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ

capsules was based on data from the open-label, multicenter clinical trial PACTG 1020A which

included patients from 6 years to 21 years of age. In this study, 105 patients (43 antiretroviral-

naive and 62 antiretroviral-experienced) received once daily REYATAZ capsule formulation,

with or without ritonavir, in combination with two NRTIs.

One-hundred five (105) patients (6 to less than 18 years of age) treated with the REYATAZ

capsule formulation, with or without ritonavir, were evaluated. Using an ITT analysis, the overall

proportions of antiretroviral-naive and -experienced patients with HIV RNA <400 copies/mL at

Week

were

(22/43)

(21/62),

respectively.

overall

proportions

antiretroviral-naive and -experienced patients with HIV RNA <50 copies/mL at Week 96 were

47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4

count

weeks

therapy

335 cells/mm

antiretroviral-naive

patients

220 cells/mm

in antiretroviral-experienced patients.

16

HOW SUPPLIED/STORAGE AND HANDLING

REYATAZ Capsules

REYATAZ

(atazanavir) capsules are available in the following strengths

and configurations of

plastic bottles with child-resistant closures.

Product

Strength*

Capsule Shell Color

(cap/body)

Markings on Capsule

(ink color)

Capsules per

Bottle

cap

body

150 mg

blue/powder blue

BMS 150 mg

(white)

3624

(blue)

200 mg

blue/blue

BMS 200 mg

(white)

3631

(white)

300 mg

red/blue

BMS 300 mg

(white)

3622

(white)

REYATAZ (atazanavir sulfate) Capsules should be stored below 25ºC.

After first opening, use within 6 months.

*150 mg atazanavir equivalent to 170.8 mg atazanavir sulfate.

200 mg atazanavir equivalent to 227.8 mg atazanavir sulfate.

300 mg atazanavir equivalent to 341.7 mg atazanavir sulfate.

REGISTRATION NUMBERS

Reyataz 150 mg: 140 78 30959 00

Reyataz 200 mg: 141 10 30960 06

Reyetaz 300 mg: 146 78 33389 00

MANUFACTURER

BRISTOL-MYERS SQUIBB Company

1 SQUIBB DRIVE, NEW BRUNSWICK, NJ 08903 USA

LICENSE HOLDER

Bristol-Myers Squibb Israel Ltd.

18 Aharon Bart St., Kiryat Arye, Petah-Tikva 4951448, Israel

The format of this leaflet was determined by the Ministry of Health and its content was checked

and approved by it in June 2016

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