ZYTIGA

1

עעבקנהזןולעטמרופ " רשואוקדבנונכותותואירבהדרשמי

םיחקורהתונקתיפלןכרצלןולע ) םירישכת ( משתה " ו - 1986

יפלעתקוושמהפורתה דבלבאפורםשרמ

םש הפורתה

הגיטייז 250 מ " תוילבטג

ליעפרמוח

הליכמהילבטלכ טאטצאןורטריבא 250 מ " ג – Abiraterone acetate 250 mg

רישכתבםיינגרלאוםיליעפיתלבםירמוח - האר / ףיעסי 6 " ףסונעדימ "

הפורתבשמתשתםרטבופוסדעןולעהתאןויעבארק . הפורתהלעיתיצמתעדימליכמהזןולע . ךלשיםא

תופסונתולאש , נפ ה חקורהלאואאפורהלא .

ךתלחמבלופיטלהמשרנוזהפורת . םירחאלהתואריבעתלא . איה יכךלהארנםאוליפאםהלקיזהלהלולע

המודםתלחמ .

1 . הפורתהתדעוימהמל ?

הגיטייז פורתהניה םשרמת ה טאטצאןורטריבאארקנהליעפרמוחהליכמ . ןוזינדרפםעדחיתנתינהגיטייז .

יתרורגתינומרעןטרסםעםירבגבלופיטלתשמשמהגיטייז חותינבלופיטלןתינאלש דימעו והלתופורתל תדר

וטסט ןורטס .

םישנבשומישלתדעוימהניאהגיטייז , םידלי םירגבתמוא .

תיטיופרתהצובק : םיזנאהלשיפיצפסבכעמ CYP17

2 . הפורתבשומישהינפל :

םארישכתבשמתשהלןיא :

תאםא ה שיגר ) תיגרלא ( הליכמרשאםיפסונהםיביכרמהמדחאלכלואטאטצאןורטריבאל

הפורתה . הםיביכרמהתמישרל ףיעסהארםיפסונ 6 " ףסונעדימ ."

ךנהםא ןוירהב . רבועבעוגפלהלולעהגיטייז .

הקינמךניהםא

הנגהאללהגיטייזבתעגלרוסאןוירהבתויהלתויושעואןוירהבןניהרשאםישנלע , ןהילע

תופפכתשיבלןוגכהנגהיעצמאבטוקנל , םא ןהילע הפורתבתעגל .

תבתורומחתויעבמלבוסהתאםא דבכהדוקפ

הפורתבשומישבתועגונהתודחוימתורהזא :

לופיטהינפל הגיטייזב , התאעדיילשי ךבצמלעאפור :

לבוסךניהםא בלתויעבמ , וא מרבעבתלבסםא םדהילכבתויעב .

הובגםדץחלמרבעבתלבסםא , בלתקיפסיאוא , ןגלשאלשתוכומנתומרוא

םדב .

2

ךניהםא כבתויעבמלבוס דב

הםא י ךנ תויעבלשהירוטסיהלעב היילכהתרתויתטולבב ) לנרדא ( ו\ תטולבבוא

חומהתרתוי ) pituitary (

ריהמבלבצקואליגראלבלבצקמלבוסךניה

המישנרצוקמלבוסךניהםא

תילעםא לקשמבתוריהמב

םיילגרתופכבתוחיפנךלשיםא , םיילגרואםיילוסרק

לוזנוקוטקרבעבתלטנםא תינומרעהןטרסבלופיטל

םדברכוסלשתוהובגתומרךלשיםא

תרחאתיאופרהייעבלכמלבוסךניהםא

וירהבתויהלתננכתמךניהםא ן , ףיעסיאר " רישכתבשמתשהלןיא "

תאםא ה חקול , הנורחאלתחקלוא , תורחאתופורת יפסותוםשרמאללתופורתללוכ

הנוזת , פס ר חקורלואאפורלךכלע .

טיז תוברתופורתםעביגהלהלוכיהגי ) בללתופורתללוכ , תופורתותועיגרמתופורת

תורחא ( ! תאואךלשאפורהתאעדיילידכלטונהתאשתופורתהלכלשהמישרןיכהליוצר

חקורה .

קיספהלואליחתהלןיא בשומיש הגיטייזךלםשרשאפורהםעתוצעייתהינפלהפורתםוש .

הפורתבשומיש וזמו ן

לעהגיטייזתחקלשי ק הקירהבי . לכואםעהגיטייזתחקלןיא . לכואםעהגיטייזתליטנ

ץוחנהמהפורתהלשרתויהלודגהגיפסלםורגלהלולע , יאוולתועפותלםורגללולעהרבד .

הגיטייזתליטנרחאלהעשתוחפלוהגיטייזתליטנינפלםייתעשתוחפלרבדלכאתלא .

הקנהוןוירה

גיטייז םישנבשומישלתדעוימהניאה .

קיזהלהלולעוזהפורת ןוירההךלהמבשמתשהלןיאןכלורבועל .

הקנהןמזבהפורתבשמתשהלןיא

לע זבתעגלרוסאןוירהבתויהלתויושעואןוירהבןניהרשאםישנ הנגהאללהגיטיי . ןהילע

הנגהיעצמאבטוקנל ןוגכ תשיבל תופפכ , תעגלתוכירצןהםא הפורתב .

רחאלעובשךשמבוךלהמבםודנוקבשמתשהלהרההשיאםעןימיסחיםייקמהרבגלע

הגיטייזםעלופיטה . םודנוקבשמתשהלןוירהלסנכיהלהיושעההשיאםעןימיסחיםייקמהרבגלע

בףסונבו רחאליעיהעינמיעצמא , הגיטייזםעלופיטהרחאלעובשךשמבוךלהמב .

אפורהםעץעייתה העינמיעצמאיבגלךלש .

ומישוהגיהנ ש תונוכמב

עיפשהלהיופצהניאהגיטייז תונוכמבשומישוהגיהנהתלוכילע .

הפורתהלשםיביכרמהמקלחלעבושחעדימ :

הגיטייז ליכמ ה זוטקל . ךלשייכךלעודיםא םימיוסמםירכוסלתוליבסרסוח , ךאפורלהנפ

הגיטייזתליטנתליחתינפל .

3

הילבטלכ הגיטייזלש הליכמ 198.6 מ " זוטקללשג

כהליכמהגיטייז - 27 מ " בןרתנג - 4 ימויהןונימהןניהשתוילבט . ןובשחבתאזתחקלשי

ןרתנתלבגהתטאידתחתרשאםילוחב .

3 . הפורתבשמתשתדציכ :

אפורהתוארוהיפלשמתשהלשידימת .

חוטבךניאםאחקורהואאפורהםעקודבלךילע .

ימה דבלבאפורהידילעועבקילופיטהןפואוןונ .

אפורהידילעתלביקשתוארוהלםאתהבןוזינדרפםעהגיטייזתחקלשי .

לבוקמהןונימה ללכךרדב אוה 4 הגיטייזלשתוילבט םעפ םויב ) 1000 מ " ג םויב ( .

תצלמומההנמהלערובעלןיא

ךרוצהיפלעןונימהתאהנשיאפורהוןכתי .

עולבלשי תא תוילבט ה ןתומלשבהגיטייז .

תוילבטהתארובשלןיא .

םימםעהגיטייזתוילבטעולבלשי .

הקירהביקלעהגיטייזלוטילשי . לכואםעהגיטייזתחקלןיא . ינפלםייתעשתוחפלרבדלכאתלא

הגיטייזתליטנרחאלהעשתוחפלוהגיטייזתליטנ .

ןוזינדרפתארקנההפורתםעדחיתחקלנהגיטיז . שי ןוזינדרפהתאלוטיל אפורהתוארוהיפלע .

החיתפתוארוה :

םידליידילעהחיתפלדימעוניהשהסכמםעעיגמקיטסלפהקובקב . תוארוההיפלעהסכמהתאחותפלשי

תואבה :

עשהןוויכדגנכבוביסידכךותהטמיפלכקיטסלפהקקפלעץחל ןו

קקפהתארסה

ידילעםימרגנההלערההירקמרפסמתאתיתועמשמודירוהםידליידילעהחיתפלםידימעהםיקקפ

הנשלכבתופורת . םלוא , הזיראהתחיתפבהשקתמהתאםא , ריסהלהשקבבחקורלתונפלךתורשפאב

ליגרקקפלוכפהלוקקפהלשתוחיטבהןונגנמתא , החיתפללק .

בקעמותוקידב :

דבכידוקפיתקודבלתנמלעהגיטייזםעלופיטהךלהמבוינפלםדתוקידבעצביאפו .

רתויהובגןונימתועטבתלטנםא : םילוחהתיבלדימהנפואאפורהםעץעייתה

הפורתהןמדליעלבתועטבםא , ךתיאהפורתהתזיראאבהוםילוחתיבלשןוימרדחלואאפורלדימהנפ .

תחכשםא נמלוטיל ןוזינדרפואהגיטייזלשה , הנמהלעתוצפלתנמלעהלופכהנמלוטילןיא

החכשנש . ליגרהןמזבתרחמלהאבההנמהתאלוטילשי .

ןוזינדרפואהגיטייזלשתחאהנממרתוילוטילתחכשםא , דימאפורהםעץעוויה .

אפורהידילעץלמוהשיפכלופיטבדימתהלשי .

רבבצמברופישלחםאםג ךתואי , נדרפואהגיטייזתליטנקיספהלןיא י םעהליחתתוצעייתהאללןוז

אפורה .

ךשוחבתופורתלוטילןיא ! הנמהותיוותהקודב םעפלכב הפורתלטונךניהש . בכרה

םהלקוקזךניהםאםייפקשמ .

4

הפורתבשומישלעגונבתופסונתולאשךלשיםא , חקורבואאפורבץעוויה .

4 . יאוולתועפות

מכ הפורתלכלו , שומישה הגיטייזב םישמתשמהמקלחביאוולתועפותלםורגללולע . להביתלא י

יאוולהתועפותתמישרארקמל . סתאלוןכתי לוב ןהמתחאףאמ .

ורומחיאוולתועפותלםורגללולעהגיטייז ת ןהיניב :

הובגםדץחל , אוםדבןגלשאלשתוכומנתומר צ םילזונתרי ) תקצב .(

לוטילקספה םיאבהםימוטפמיסהמדחאבשיגרמהתאםאידיימןפואבאפורהתאעדיוהפורתהתא :

םירירשתשלוח , ותיווע ת בלתוקיפדואםירירש ) תויצטיפלפ .( תוכומנתומרלשםינמיסםהולאוןכתיי

םדבןגלשאלש .

אפורהתאעדיי תידיימ דחאבשיגרמהתאוהדימב רתויוא םיאבהםימוטפמיסהמ :

תרוחרחס

תוריהמבלתוקיפ

ןופליעתשוחת

שארבאכ

לובליב

םיילגרבבאכ

םיילגרהתופכבואםיילגרבתוחיפנ

הילכהתרתויתטולבבתויעב ןוזינדרפתחקלקיספמךניהםאשחרתהלםילולע , בהקולךנהםא ואםוהיז

ץחלתחתךניהש .

דבכבתויעב . ךלשדבכהתאקודבלתנמלעםדתוקידבעצביאפורה לופיטהךלהמבולופיטהתליחתינפל

הגיטייזםע .

תובורקםיתיעלתועיפומהיאוולתועפות :

םיקרפמבבאכואתוחיפנ

םירירשיבאכ

םוחילג

לושליש

ןתשהיכרדבםוהיז

לועיש

ליגראלבלבצק

ליגרהמהפוכתהנתשה

הלילתנתשה

תברצ

תעפשייומדםינימסת

תומצעבםירבש

השלוח

- םוחילג

5

- האקה

- הובגםדץחל

- המישנרצוק

- םדיפטש

םימודאםדיאתלשהכומנהמר ) הימנא (

ןגלשאלשהכומנהמר םדב

רכוסלשהובגהמר םדב

םידירצילגירטולורטסלוכלשתוהובגתומר םדב

םדתקידבבתורחאתוגירחתואצות

החירפ

ןתשבםד

לוכיעיישק

ללשכ יבב

הזחבבאכ

הרימחמיאוולהתועפותמתחאםא , ןולעבורכזוהאלשיאוולתועפותמלבוסהתארשאכוא , ץעייתהלךילע

אפורהםע .

5 . הפורתהתאןסחאלךיא ?

הלערהענמ ! לשםדיגשיהלץוחמרוגסםוקמברומשלשיתרחאהפורתלכווזהפורת

וםידלי / הלערהענמתךכידילעותוקוניתוא . א ורגתל ם תשרופמהארוהאללהאקהל

אפורהמ .

הגופתהךיראתירחאהפורתבשמתשהלןיא ) exp. Date ( הזיראהיבגלעעיפומה . ךיראת

שדוחותואלשןורחאהםוילסחייתמהגופתה .

שי הפורתהתאןסחאל לתחתמ - 30 סויזלצתולעמ .

הנושארהחיתפרחאלףדמייח : 30 םוי .

ייזתוילבטתאןסחאלשי תירוקמההזיראבהגיט .

6 . ףסונעדימ

םגהליכמהפורתהליעפהרמוחהלעףסונ :

Lactose Monohydrate, MicrocrystallineCellulose, Croscarmellose sodium,

Povidone, Sodium lauryl sulfate,,Magnesium Stearate and silica,Colloidal

anhydrous,.

יביכרמ םינגרלאם : מהפורתה זוטקלהליכ .

הליכמהילבטלכ 198.6 מ " זוטקללשג טרדיהונומ

כהליכמהגיטייז - 27 מ " בןרתנג - 4 ימויהןונימהןניהשתוילבט

הזיראהןכותהמוהפורתהתיארנדציכ :

ןווגבןבלדעןבלעבצבןניההגיטייזתוילבט םרק ) off white ( , לאבואהרוצתולעב תי , םע

6

בותיכה “AA250” דחאדצב .

וילבטה קובקבבתועיגמת קיטסלפהסכמםעקיטסלפ .

קובקבלכ ליכמ 120 תוילבט . קובקבליכמןוטרקלכ דחא .

ותבותכוםושירהלעב : ג ' תלהיסיי ' עברק " מ , םייפשץוביק , 60990 .

ותבותכוןרציהםש : ןסנאי - גליס SPA , הניטל , הילטיא

קדבנהזןולע ערשואו " ךיראתבתואירבהדרשמי : יאמ 2013

תואירבהדרשמביתכלממהתופורתהסקנפבהפורתהםושיררפסמ : 148-03-33481-00

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Zytiga_SPC_FEB_2016

"רשואו קדבנ ונכותו תואירבה דרשמ י"ע עבקנ הז ןולע טמרופ"

Prescribing Information

ZYTIGA

Abiraterone acetate 250 mg tablets

1

INDICATIONS AND USAGE

ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of

patients with metastatic castration-resistant prostate cancer.

2

DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dose of ZYTIGA is 1,000 mg (four 250mg tablets) administered orally

once daily in combination with prednisone 5 mg administered orally twice daily. ZYTIGA must be

taken on an empty stomach. No food should be consumed for at least two hours

before the dose of ZYTIGA is taken and for at least one hour after the dose of

ZYTIGA is taken [see Clinical pharmacology (12.3)]. The tablets should be

swallowed whole with water.

Do not crush or chew tablets

Serum transaminases should be measured prior to starting treatment with ZYTIGA, every two weeks for

the first three months of treatment and monthly thereafter. Blood pressure, serum potassium and fluid

retention should be monitored monthly. However, patients with a significant risk for congestive heart

failure should be monitored every 2 weeks for the first three months of treatment and monthly thereafter.

In patients with pre-existing hypokalaemia or those that develop hypokalaemia whilst being treated

with ZYTIGA, consider maintaining the patient’s potassium level at ≥ 4.0 mM.

For patients who develop Grade ≥ 3 toxicities including hypertension, hypokalaemia, oedema and

other non-mineralocorticoid toxicities, treatment should be withheld and appropriate medical

management should be instituted. Treatment with ZYTIGA should not be reinitiated until symptoms

of the toxicity have resolved to Grade 1 or baseline.

In the event of a missed daily dose of either ZYTIGA or prednisone, treatment should be resumed the

following day with the usual daily dose.

2.2 Dose Modification Guidelines

Hepatic Impairment

In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce

the recommended dose of ZYTIGA to 250 mg once daily. A once daily dose of

250 mg in patients with moderate hepatic impairment is predicted to result in an area

under the concentration curve (AUC) similar to the AUC seen in patients with normal

hepatic function receiving 1,000 mg once daily. However, there are no clinical data at

the dose of 250 mg once daily in patients with moderate hepatic impairment and

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Zytiga_SPC_May_2016 USPI May 16

caution is advised. In patients with moderate hepatic impairment monitor ALT, AST,

and bilirubin prior to the start of treatment, every week for the first month, every two

weeks for the following two months of treatment and monthly thereafter. If elevations

in ALT and/or AST greater than 5X upper limit of normal (ULN) or total bilirubin

greater than 3X ULN occur in patients with baseline moderate hepatic impairment, discontinue

ZYTIGA and do not re-treat patients with ZYTIGA [see Use in Specific Populations (8.6) and Clinical

Pharmacology (12.3)].

ZYTIGA should be used with caution in patients with moderate hepatic impairment, only if the benefit

clearly outweighs the possible risk.

Do not use ZYTIGA in patients with severe hepatic impairment (Child-Pugh Class C).

Hepatotoxicity

For patients who develop hepatotoxicity during treatment with ZYTIGA (ALT and/or

AST greater than 5X ULN or total bilirubin greater than 3X ULN), interrupt treatment

with ZYTIGA [see Warnings and Precautions (5.3)].

Treatment may be restarted at a reduced dose of 750 mg once daily following return of liver function

tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total

bilirubin less than or equal to 1.5X ULN. For patients who resume treatment, monitor

serum transaminases and bilirubin at a minimum of every two weeks for three months

and monthly thereafter.

If hepatotoxicity recurs at the dose of 750 mg once daily, re-treatment may be

restarted at a reduced dose of 500 mg once daily following return of liver function

tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN

and total bilirubin less than or equal to 1.5X ULN.

If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue

treatment with ZYTIGA.

If patients develop severe hepatotoxicity (ALT or AST 20 times the upper limit of normal) anytime while

on therapy, ZYTIGA should be discontinued and patients should not be re-treated with ZYTIGA.

Renal impairment

No dosage adjustment is necessary for patients with renal impairment . However, there

is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is

advised in these patients.

2.3 Dose Modification Guidelines for strong CYP3A4 inducers

Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin,

rifabutin, rifapentine, phenobarbital) during ZYTIGA treatment. Although there are no

clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers,

because of the potential for an interaction, if a strong CYP3A4 inducer must be

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co-administered, increase the ZYTIGA dosing frequency to twice a day only during the

co-administration period (e.g., from 1,000 mg once daily to 1,000 mg twice a day). Reduce

the dose back to the previous dose and frequency, if the concomitant strong CYP3A4 inducer

is discontinued [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

3

DOSAGE FORMS AND STRENGTHS

ZYTIGA (abiraterone acetate) 250 mg tablets are white to off-white, oval-shaped

tablets debossed with AA250 on one side.

4

CONTRAINDICATIONS

4.1 Pregnancy

ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated

for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug

is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the

patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in

Specific Populations (8.1)].

4.2 Hypersensitivity to the active substance or to any of the excipients listed in section 11.

4.3 Severe hepatic impairment [Child-Pugh Class C)

5

WARNINGS AND PRECAUTIONS

5.1 Hypertension, Hypokalemia and Fluid Retention Due to

Mineralocorticoid Excess

ZYTIGA may cause hypertension, hypokalaemia and fluid retention as a consequence of increased

mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1 ).

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting

in a reduction in incidence and severity of these adverse reactions. Caution is required in treating

patients whose underlying medical conditions might be compromised by increases in blood pressure,

hypokalaemia (e.g., those on cardiac glycosides), or fluid retention (e.g., those with heart failure),

severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and those

with severe renal impairment.

ZYTIGA should be used with caution in patients with a history of cardiovascular disease. The phase 3

studies conducted with ZYTIGA excluded patients with uncontrolled hypertension, clinically

significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the

past 6 months, severe or unstable angina, or New York Heart Association Class (NYHA) III or IV

heart failure (study 301) or Class II to IV heart failure (study 302) or cardiac ejection fraction

measurement of < 50%. In study 302 patients with atrial fibrillation, or other cardiac arrhythmia

requiring medical therapy were excluded. Safety in patients with left ventricular ejection fraction

(LVEF) < 50% or NYHA Class III or IV heart failure (in study 301) or NYHA Class II to IV heart

failure (in study 302) was not established .

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Before treating patients with a significant risk for congestive heart failure (e.g.a history of cardiac

failure, uncontrolled hypertension, or cardiac events such as ischaemic heart disease), consider

obtaining an assessment of cardiac function (e.g. echocardiogram). Before treatment with ZYTIGA,

cardiac failure should be treated and cardiac function optimised. Hypertension, hypokalaemia and

fluid retention should be corrected and controlled. During treatment, blood pressure, serum potassium,

fluid retention (weight gain, peripheral oedema), and other signs and symptoms of congestive heart

failure should be monitored every 2 weeks for 3 months, then monthly thereafter and abnormalities

corrected. QT prolongation has been observed in patients experiencing hypokalaemia in association

with ZYTIGA treatment. Assess cardiac function as clinically indicated, institute appropriate

management and consider discontinuation of ZYTIGA treatment if there is a clinically significant

decrease in cardiac function .

5.2 Adrenocortical Insufficiency

Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking

ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients

receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with

concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical

insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions,

or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by

adverse reactions associated with mineralocorticoid excess seen in patients treated with

ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis

of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated

before, during and after stressful situations [see Warnings and Precautions (5.1)].

5.3 Hepatotoxicity

In postmarketing experience, there have been ZYTIGA-associated severe hepatic toxicity, including

fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions (6.2)].

In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in

4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment.

Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation

than those beginning with normal values. Treatment discontinuation due to liver enzyme increases

occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to

hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment

with ZYTIGA, every two weeks for the first three months of treatment and

monthly thereafter. In patients with baseline moderate hepatic impairment

receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin

prior to the start of treatment, every week for the first month, every two weeks for the

following two months of treatment and monthly thereafter. Promptly measure serum

total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of

hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's

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baseline should prompt more frequent monitoring. If at any time AST or ALT rise

above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment

and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return

of liver function tests to the patient’s baseline or to AST and ALT less than or equal

to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2)].

If patients develop severe hepatotoxicity (ALT or AST 20 times the upper limit of normal) anytime

while on therapy, ZYTIGA should be discontinued and patients should not be re-treated with ZYTIGA.

ZYTIGA should be used with caution in patients with moderate hepatic impairment, only if the benefit

clearly outweighs the possible risk. ZYTIGA should not be used in patients with severe hepatic

impairment .

5.4 Bone density

Decreased bone density may occur in men with metastatic advanced prostate cancer (castration

resistant prostate cancer). The use of ZYTIGA in combination with a glucocorticoid could increase

this effect.

5.5Prior use of ketoconazole

Lower rates of response might be expected in patients previously treated with ketoconazole for

prostate cancer.

5.6 Hyperglycaemia

The use of glucocorticoids could increase hyperglycaemia, therefore blood sugar should be measured

frequently in patients with diabetes.

5.7 Use with chemotherapy

The safety and efficacy of concomitant use of ZYTIGA with cytotoxic chemotherapy has not been

established .

5.8 Intolerance to excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose

intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this

medicine. This medicinal product also contains more than 1 mmol (or 27.2 mg) sodium per dose of

four tablets. To be taken into consideration by patients on a controlled sodium diet.

5.9 Potential risks

Anaemia and sexual dysfunction may occur in men with metastatic castration resistant prostate cancer

including those undergoing treatment with ZYTIGA.

5.10 Skeletal Muscle Effects

Cases of myopathy have been reported in patients treated with ZYTIGA. Some patients had

rhabdomyolysis with renal failure. Most cases developed within the first month of treatment and

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recovered after ZYTIGA withdrawal. Caution is recommended in patients concomitantly treated with

drugs known to be associated with myopathy/rhabdomyolysis.

5.11 Interactions with other medicinal products

Strong inducers of CYP3A4 during treatment are to be avoided unless there is no therapeutic

alternative, due to risk of decreased exposure to ZYTIGA (see section 7).

6 ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling:

Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess

[seeWarnings and Precautions (5.1)].

Adrenocortical insufficiency [see Warnings and Precautions (5.2)].

Hepatotoxicity [see Warnings and Precautions (5.3)].

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

clinical practice.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic

castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH)

agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was

administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active

treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that

occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or

discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection

and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that

occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline

phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST,

hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy

Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy.

Patients were not eligible if AST and/or ALT ≥ 2.5 XULN in the absence of liver metastases. Patients

with liver metastases were excluded if AST and/or ALT > 5X ULN.

Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute

increase in frequency compared to placebo or were events of special interest. The median duration of

treatment with ZYTIGA was 8 months.

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Table 1: Adverse Reactions due to ZYTIGA in

Study 1

ZYTIGA with Prednisone

(N=791)

Placebo with Prednisone

(N=394)

System/Organ Class

Adverse reaction

All Grades

Grade 3-4

All Grades

Grade 3-4

Musculoskeletal and connective

Tissue disorders

Joint swelling/ discomfort

29.5

23.4

Muscle discomfort

26.2

23.1

General disorders

Edema

26.7

18.3

Vascular disorders

Hot flush

19.0

16.8

Hypertension

Gastrointestinal disorders

Diarrhea

17.6

13.5

Dyspepsia

Infections and infestations

Urinary tract infection

11.5

Upper respiratory tract

Respiratory, thoracic and

Mediastinal disorders

Cough

10.6

Renal and urinary disorders

Urinary frequency

Nocturia

Injury, poisoning and

procedural complications

Fractures

5.9 1.4 2.3 0

Cardiac disorders

Arrhythmia

Chest pain or chest

discomfort

Cardiac failure

1 Adverse events graded according to CTCAE version 3.0

2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness,

3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and

Musculoskeletal stiffness

4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalised edema

5 Includes all fractures with exception of pathological fracture

6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia,

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Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete,

Conduction disorder, and Bradyarrhythmia.

7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia

occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction,

Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus

(7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1

Abiraterone (N=791)

Placebo (N=394)

Laboratory

Abnormality

All Grades

Grade 3-4

All Grades

Grade 3-4

Hypertriglyceridemia

62.5

53.0

High AST

30.6

36.3

Hypokalemia

28.3

19.8

Hypophosphatemia

23.8

15.7

High ALT

11.1

10.4

High Total Bilirubin

Study 2: Metastatic CRPC Prior to Chemotherapy

Study

enrolled

1088

patients

with

metastatic

CRPC

received

prior

cytotoxic

chemotherapy. Patients were ineligible if AST and/or ALT ≥ 2.5X ULN and patients were excluded if

they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥ 2% absolute

increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8

months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2

ZYTIGA with Prednisone

(N=542)

Placebo with Prednisone

(N=540)

System/Organ Class

Adverse reaction

All Grades

Grade 3-4

All Grades

Grade 3-4

General disorders

Fatigue

39.1

34.3

Edema

25.1

20.7

Pyrexia

Musculoskeletal and connective

tissue disorder

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Joint swelling/discomfort

30.3

25.2

Groin pain

Gastrointestinal disorders

Constipation

23.1

19.1

Diarrhea

21.6

17.8

Dyspepsia

11.1

Vascular disorders

Hot flush

22.3

18.1

Hypertension

21.6

13.1

Respiratory, thoracic and

Mediastinal disorders

Cough

17.3

13.5

Dyspena

11.8

Psychiatric disorders

Insomnia

13.5

11.3

Injury, poisoning and

procedural complications

Constusion

13.3

Falls

Infections and infestations

Upper respiratory tract

infection

12.7 0.0 8.0 0.0

Nasopharyngitis 10.7 0.0 8.1 0.0

Renal and urinary disorders

Hematuria

10.3

Skin and subcutaneous tissue disorders

Rash

Adverse events graded according to CTCAE version 3.0

Includes terms Edema peripheral, Pitting edema, and Generalized edema

Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more

frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%),

hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the

ZYTIGA arm.

Table 4 : Laboratory Abnormalities in > 15% of Patients in the ZYTIGA Arm of Study 2

Abiraterone (N=542)

Placebo (N=540)

Laboratory

Grades 1-4

Grade 3-4

Grades 1-4

Grade 3-4

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Abnormality

Hematology

Lymphopenia

38.2

31.7

Chemistry

Hyperglycemia

56.6

50.9

High ALT

41.9

29.1

High AST

37.3

28.7

Hypernatremia

32.8

25.0

Hypokalemia

17.2

10.2

1

Based on non-fasting blood draws

Cardiovascular Adverse Reactions:

In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated

with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure

occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths.

Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment

discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with

arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms.

There were 7 (0.5 %) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3 %) deaths

in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the

placebo arms and 2 deaths in the ZYTIGA arms.

6.2 Post Marketing Experience

The following additional adverse reactions have been identified during post approval use of ZYTIGA.

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

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

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

Hepatobiliary Disorders: fulminant hepatitis, including acute hepatic failure and death.

Additional adverse event identified in clinical trials and post marketing:

Frequency categories are defined as follows: common (≥ 1/100 to < 1/10);

uncommon (≥ 1/1,000 to

< 1/100);

rare (≥1/10,000 to <1/1,000):

Infections and infestations:

common: sepsis

Respiratory, thoracic and mediastinal disorders:

rare: allergic alveolitis

a Spontaneous reports from post-marketing experience

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Cardiac disorders

Not known: myocardial infraction, QT prolongation

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@moh.gov.il

7

DRUG INTERACTIONS

7.1 Effect of food on abiraterone acetate

Administration with food significantly increases the absorption of abiraterone acetate. The efficacy

and safety when given with food have not been established therefore this medicinal product must not

be taken with food.

7.2 Drugs that Inhibit or Induce CYP3A4 Enzymes

Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4

inducer, decreased exposure of abiraterone by 55%.

Avoid concomitant strong CYP3A4 inducers (phenytoin, carbamazepine, rifampicin, rifabutin,

rifapentine, phenobarbital, St John's wort [Hypericum perforatum]) during ZYTIGA treatment. If a

strong CYP3A4 inducer must be co-administered,increase the ZYTIGA dosing frequency [see Dosage

and Administration (2.3) and Clinical Pharmacology (12.3)].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of

CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see

Clinical Pharmacology (12.3)].

7.3 Effects of Abiraterone on Drug Metabolizing Enzymes

ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6 and CYP2C8. In a CYP2D6

drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate)

were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with

abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily.

Avoid coadministration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic

index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and

consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical

Pharmacology (12.3)].

Examples of medicinal products metabolised by CYP2D6 include metoprolol,

propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine,

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oxycodone and tramadol (the latter three products requiring CYP2D6 to form their active analgesic

metabolites).

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8

substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000

mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to

a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical

Pharmacology (12.3)].

7.4 Use with products known to prolong QT interval

Since androgen deprivation treatment may prolong the QT interval, caution is advised when

administering ZYTIGA with medicinal products known to prolong the QT interval or medicinal

products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III

(e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone,

moxifloxacin, antipsychotics, etc.

8

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X [see Contraindications (4.1)].

ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of

action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in

pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal

CYP17

inhibitor

could

affect

development

fetus.

Abiraterone

acetate

caused

developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the

recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while

receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while

taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for

pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment

with ZYTIGA.

In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental

toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of

organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post

implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay

(skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased

fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses

≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures

(AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

8.2 Nursing Mothers

ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human

milk. Because many drugs are excreted in human milk, and because of the potential for serious

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adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue

nursing, or discontinue the drug taking into account the importance of the drug to the mother.

8.3 Pediatric Use

Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

8.4 Geriatric Use

Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and

over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed

between these elderly patients and younger patients. Other reported clinical experience has not

identified differences in responses between the elderly and younger patients, but greater sensitivity of

some older individuals cannot be ruled out.

8.5 Patients with Hepatic Impairment

The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate

(n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects

with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000

mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6 fold in subjects with mild and

moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic

function.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe

(n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic

function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the

fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to

subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with

baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of

ZYTIGA to 250 mg once daily.

Do not use ZYTIGA in patients with baseline severe hepatic

impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN

occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see

Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage

adjustment may be required [see Dosage and Administration (2.2), Warnings and Precautions (5.3),

and Clinical Pharmacology (12.3)].

8.6 Patients with Renal Impairment

In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy

subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on

hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary

for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology

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Zytiga_SPC_May_2016 USPI May 16

(12.3)].

8.7 Effects on ability to drive and use machines

ZYTIGA has no or negligible influence on the ability to drive or use machines.

10

OVERDOSAGE

Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive

measures, including monitoring for arrhythmias , hypokalemia, signs and symptoms of fluid retention

and cardiac failure and assess liver function.

11

DESCRIPTION

Abiraterone acetate, the active ingredient of ZYTIGA is the acetyl ester of abiraterone. Abiraterone is

an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of

abiraterone acetate. Abiraterone acetate is designated chemically as (3β)- 17-(3-pyridinyl)androsta-

5,16-dien-3-yl acetate and its structure is:

Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Its molecular formula

is C

and it has a molecular weight of 391.55. Abiraterone acetate is a lipophilic compound

with an octanol-water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa

of the aromatic nitrogen is 5.19.

Inactive ingredients in the tablets are lactose monohydrate, microcrystalline cellulose, croscarmellose

sodium, povidone, sodium lauryl sulfate, magnesium stearate, and silica, colloidal anhydrous .

12

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor,

that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal,

and prostatic tumor tissues and is required for androgen biosynthesis.

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CYP17 catalyzes two sequential reactions:

the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives

by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and

androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens

and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased

mineralocorticoid production by the adrenals (see Warnings and Precautions [5.1]).

Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen

levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy,

decrease androgen production in the testes but do not affect androgen production by the adrenals or

in the tumor.

ZYTIGA decreased serum testosterone and other androgens in patients in the placebo-controlled

phase 3 clinical trial. It is not necessary to monitor the effect of ZYTIGA on serum testosterone levels.

Changes in serum prostate specific antigen (PSA) levels may be observed but have

not been shown to correlate with clinical benefit in individual patients.

12.3 Pharmacokinetics

Following administration of abiraterone acetate, the pharmacokinetics of abiraterone

and abiraterone acetate have been studied in healthy subjects and in patients with

metastatic castration-resistant prostate cancer (CRPC). In vivo, abiraterone acetate is converted to

abiraterone. In clinical studies, abiraterone acetate plasma concentrations

were below detectable levels (< 0.2 ng/mL) in > 99% of the analyzed samples.

Absorption

Following oral administration of abiraterone acetate to patients with metastatic CRPC,

the median time to reach maximum plasma abiraterone concentrations is 2 hours.

Abiraterone accumulation is observed at steady-state, with a 2-fold higher exposure

(steady-state AUC) compared to a single 1,000 mg dose of abiraterone acetate.

At the dose of 1,000 mg daily in patients with metastatic CRPC, steady-state values

(mean ±SD) of C

were 226 ± 178 ng/mL and of AUC were 993 ± 639

ng.hr/mL.

No major deviation from dose proportionality was observed in the dose range of

250 mg to 1,000 mg. However, the exposure was not significantly increased when the dose was

doubled from 1,000 to 2,000 mg (8% increase in the mean AUC).

Systemic exposure of abiraterone is increased when abiraterone acetate is administered

with food. In healthy subjects abiraterone C

and AUC

0-∞

were approximately 7-and 5-

fold higher, respectively, when a single dose of abiraterone acetate was administered

with a low-fat meal (7% fat, 300 calories) and approximately 17-and 10-fold higher,

respectively, when a single dose of abiraterone acetate was administered with a high-fat

(57% fat, 825 calories) meal compared to overnight fasting. Abiraterone AUC

0-∞

approximately 7-fold or 1.6-fold higher, respectively, when a single dose of abiraterone

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acetate was administered 2 hours after or 1 hour before a medium fat meal (25% fat, 491

calories) compared to overnight fasting.

Systemic exposures of abiraterone in patients with metastatic CRPC, after repeated

dosing of abiraterone acetate were similar when abiraterone acetate was taken with low-

fat meals for 7 days and increased approximately 2-fold when taken with high-fat meals

for 7 days compared to when taken at least 2 hours after a meal and at least 1 hour

before a meal for 7 days.

Given the normal variation in the content and composition of meals, taking ZYTIGA with

meals has the potential to result in increased and highly variable exposures. Therefore,

no food should be consumed for at least two hours before the dose of ZYTIGA is taken

and for at least one hour after the dose of ZYTIGA is taken. The tablets should be

swallowed whole with water [see Dosage and Administration (2.1)].

Distribution and Protein Binding

Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and

alpha-1 acid glycoprotein. The apparent steady-state volume of distribution (mean ± SD)

is 19,669 ± 13,358 L. In vitro studies show that at clinically relevant concentrations, abiraterone

acetate and abiraterone are not substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an

inhibitor of P-gp.

Metabolism

Following oral administration of

C-abiraterone acetate as capsules, abiraterone

acetate is hydrolyzed to abiraterone (active metabolite). The conversion is likely

through esterase activity (the esterases have not been identified) and is not CYP

mediated. The two main circulating metabolites of abiraterone in human plasma are abiraterone

sulphate (inactive) and N-oxide abiraterone sulphate (inactive), which

account for about 43% of exposure each. CYP3A4 and SULT2A1 are the enzymes

involved in the formation of N-oxide abiraterone sulphate and SULT2A1 is

involved in the formation of abiraterone sulphate.

Excretion

In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma

(mean ± SD) is 12 ± 5 hours. Following oral administration of

C-abiraterone acetate,

approximately 88% of the radioactive dose is recovered in feces and approximately 5%

in urine. The major compounds present in feces are unchanged abiraterone acetate and

abiraterone (approximately 55% and 22% of the administered dose, respectively).

Patients with Hepatic Impairment

The pharmacokinetics of abiraterone was examined in subjects with baseline mild

(n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B,

respectively) and in 8 healthy control subjects with normal hepatic function.

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Systemic exposure to abiraterone after a single oral 1,000 mg dose given under

fasting conditions increased approximately 1.1-fold and 3.6-fold in subjects with

mild and moderate baseline hepatic impairment, respectively. The mean half-life of abiraterone is

prolonged to approximately 18 hours in subjects with mild hepatic

impairment and to approximately 19 hours in subjects with moderate hepatic

impairment.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe

(n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic

function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold in subjects

with severe baseline hepatic impairment compared to subjects with normal hepatic function. In

addition, the mean protein binding was found to be lower in the severe hepatic impairment group

compared to the normal hepatic function group, which resulted in a two-fold increase in the fraction of

free drug in patients with severe hepatic impairment.[see Dosage and Administration (2.2) and Use in

Specific Populations (8.6)].

Patients with Renal Impairment

The pharmacokinetics of abiraterone were examined in patients with end-stage renal

disease (ESRD) on a stable hemodialysis schedule (N=8) and in matched control

subjects with normal renal function (N=8). In the ESRD cohort of the trial, a single

1,000 mg ZYTIGA dose was given under fasting conditions 1 hour after dialysis,

and samples for pharmacokinetic analysis were collected up to 96 hours post dose.

Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in

subjects with end-stage renal disease on dialysis, compared to subjects with normal

renal function [see Use in Specific Populations (8.7)].

Drug Interactions

In vitro studies with human hepatic microsomes showed that abiraterone

has a potential to inhibit CYP1A2, CYP2D6 ,CYP2C8 and and to a lesser extent CYP2C9, CYP2C19

and CYP3A4/5.

In an in vivo drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6

substrate) were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was

given with abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily). The AUC

for dextrorphan, the active metabolite of dextromethorphan, increased approximately

1.3 fold [see Drug Interactions (7.2)].

In a clinical study to determine the effects of abiraterone acetate 1,000 mg daily (plus

prednisone 5 mg twice daily) on a single 100 mg dose of the CYP1A2 substrate

theophylline, no increase in systemic exposure of theophylline was observed.

Abiraterone is a substrate of CYP3A4, in vitro. In a clinical pharmacokinetic interaction

study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampin, 600 mg daily

for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma

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AUC∞ of abiraterone was decreased by 55% [see Drug Interactions (7.1)].

In a separate clinical pharmacokinetic interaction study of healthy subjects,

co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically

meaningful effect on the pharmacokinetics of abiraterone [see Drug Interactions (7.1)].

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by

46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate [see

Drug Interactions (7.2)].

In vitro, abiraterone and its major metabolites were shown to inhibit the hepatic uptake transporter

OATP1B1. There are no clinical data available to confirm transporter based interaction.

12.4 QT Prolongation

In a multi-center, open-label, single-arm trial, 33 patients with metastatic CRPC received ZYTIGA

orally at a dose of 1,000 mg once daily at least 1 hour before or 2 hours after a meal in combination

with prednisone 5 mg orally twice daily. Assessments up to Cycle 2 Day 2 showed no large changes in

the QTc interval (i.e., >20 ms) from baseline. However, small increases in the QTc interval

(i.e., <10 ms) due to abiraterone acetate cannot be excluded due to study design limitations.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and

50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the

combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested.

This finding is considered to be related to the pharmacological activity of abiraterone. Rats are

regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone

acetate was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical

exposure based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the

transgenic (Tg.rasH2) mouse.

Abiraterone acetate and abiraterone did not induce mutations in the microbial mutagenesis (Ames)

assay and was not clastogenic in both the in vitro cytogenetic assay using primary human

lymphocytes and in the in vivo rat micronucleus assay.

ZYTIGA has the potential to impair reproductive function and fertility in humans based on findings in

animals. In repeat-dose toxicity studies in male rats (13- and 26-weeks) and monkeys (39-weeks),

atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥ 50

mg/kg/day in rats and ≥ 250 mg/kg/day in monkeys and were consistent with the antiandrogenic

pharmacological activity of abiraterone [see Nonclinical Toxicology (13.2.)]. These effects were

observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately

0.6 times the AUC in humans.

In fertility studies in rats, reduced organ weights of the reproductive system, sperm counts, sperm

motility, altered sperm morphology and decreased fertility were observed in males dosed for 4 weeks

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at ≥ 30 mg/kg/day. Mating of untreated females with males that received 30 mg/kg/day abiraterone

acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an

increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from

the last abiraterone acetate administration. Female rats dosed for 2 weeks until day 7 of pregnancy at

≥ 30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre-

implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters

in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks

from the last abiraterone acetate administration. The dose of 30 mg/kg/day in rats is approximately 0.3

times the recommended dose of 1000 mg/day based on body surface area.

13.2 Animal Toxicology and/or Pharmacology

In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating

testosterone levels occurred with abiraterone acetate at approximately one half the human clinical

exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the

male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary

glands. The changes in the reproductive organs are consistent with the antiandrogenic harmacological

activity of abiraterone acetate. A dose dependent increase in cataracts was observed in rats at 26

weeks starting at ≥50 mg/kg/day (similar to the human clinical exposure based on AUC).

In the 39-week monkey study, no cataracts were observed at higher doses (2 times greater than the

clinical exposure based on AUC). All other toxicities associated with abiraterone acetate reversed or

were partially resolved after a 4-week recovery period.

14

CLINICAL STUDIES

The efficacy and safety of ZYTIGA in patients with metastatic castration-resistant prostate cancer

(CRPC) that has progressed on androgen deprivation therapy was demonstrated in two randomized,

placebo-controlled, multicenter phase 3 clinical trials. Patients with prior ketoconazole treatment for

prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials.

Concurrent use of spironolactone was not allowed during the study period

Study 1 (301)

Patients with metastatic CRPC who had received prior docetaxel chemotherapy

:

A total of 1195 patients were randomized 2:1 to receive either ZYTIGA orally

at a dose of 1,000 mg once daily in combination with prednisone 5 mg orally twice

daily (N=797) or placebo once daily plus prednisone 5 mg orally twice daily (N=398). Patients

randomized to either arm were to continue treatment until disease progression (defined as a 25%

increase in PSA over the patient’s baseline/nadir together with protocol-defined radiographic

progression and symptomatic or clinical progression), initiation of new treatment, unacceptable toxicity

or withdrawal.

The following patient demographics and baseline disease characteristics were balanced

between the treatment arms. The median age was 69 years (range 39-95) and the racial distribution

was 93.3% Caucasian, 3.6% Black, 1.7% Asian, and 1.6% Other. Eighty-nine percent of patients

enrolled had an ECOG performance status score of 0-1 and 45% had a Brief Pain Inventory score of ≥

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4 (patient’s reported worst pain over the previous 24 hours). Ninety percent of patients had

metastases in bone and 30% had visceral involvement. Seventy percent of patients had radiographic

evidence of disease progression and 30% had PSA-only progression. Seventy percent of patients had

previously received one cytotoxic chemotherapy regimen and 30% received two regimens.

The protocol pre-specified interim analysis was conducted after 552 deaths and showed a statistically

significant improvement in overall survival (OS) in patients treated with ZYTIGA compared to patients

in the placebo arm (Table 5 and Figure 1). An updated survival analysis was conducted when

775 deaths (97% of the planned number of deaths for final analysis) were observed.

Results from this analysis were consistent with those from the interim analysis (Table 3).

Table 5: Overall Survival of Patients Treated with Either ZYTIGA or Placebo in

Combination with Prednisone in Study 1 (Intent-to-Treat Analysis)

ZYTIGA (N=797)

Placebo (N=398)

Primary Survival Analysis

Deaths (%)

333 (42%)

219 (55%)

Median survival (months)

(95% CI)

14.8 (14.1, 15.4)

10.9 (10.2, 12.0)

p value

<0.0001

Hazard ratio (95% CI)

0.646 (0.543, 0.768)

Updated Survival Analysis

Deaths (%)

501 (63%)

274 (69%)

Median survival (months)

(95% CI)

15.8 (14.8, 17.0)

11.2 (10.4, 13.1)

Hazard ratio (95% CI)

0.740 (0.638, 0.859)

P-value is derived from a log-rank test stratified by ECOG performance status score (0-1 vs. 2),

pain score (absent vs. present), number of prior chemotherapy regimens (1 vs. 2), and type of

disease progression (PSA only vs. radiographic).

Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors ZYTIGA

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Study 2 (302)

Patients with metastatic CRPC who had not received prior cytotoxic chemotherapy

In Study 2, 1088 patients were randomized 1:1 to receive either ZYTIGA at a dose of 1,000mg once

daily (N=546) or Placebo once daily (N=542). Both arms were given concomitant prednisone 5mg

twice

daily.

Patients

continued

treatment

until

radiographic

clinical

(cytotoxic

chemotherapy,

radiation or surgical treatment for cancer, pain requiring chronic opioids, or ECOG performance status

decline to 3 or more) disease progression, unacceptable toxicity or withdrawal. Patients with moderate

or severe pain, opiate use for cancer pain, or visceral organ metastases were excluded.

Patient demographics were balanced between the treatment arms. The median age was 70 years.

The racial distribution of patients treated with ZYTIGA was 95.4% Caucasian, 2.8% Black, 0.7% Asian

and 1.1% Other. The ECOG performance status was 0 for 76% of patients, and 1 for 24% of patients.

Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS).

Baseline pain assessment was 0-1 (asymptomatic) in 66% of patients and 2-3 (mildly symptomatic) in

26% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours).

Radiographic progression-free survival was assessed with the use of sequential imaging studies and

was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate

Cancer Working Group 2 criteria) and/or modified Response Evaluation Criteria In Solid Tumors

(RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally-reviewed

radiographic assessment of progression.

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The planned final analysis for OS, conducted after 741 deaths (median follow up of 49 months)

demonstrated a statistically significant OS improvement in patients treated with ZYTIGA compared to

those treated with placebo (Table 6 and Figure 2). Sixty-five percent of patients on the ZYTIGA arm

and 78% of patients on the placebo arm used subsequent therapies that may prolong OS in metastatic

CRPC. ZYTIGA was used as a subsequent therapy in 13% of patients on the ZYTIGA arm and 44% of

patients on the placebo arm.

Table 6: Overall Survival of Patients Treated with Either ZYTIGA or Placebo in Combination with

Prednisone in Study 2 (Intent-to-Treat Analysis)

Overall Survival

Zytiga

(N=546)

Placebo

(N=542)

Deaths

354 (65%)

387 (71%)

Median survival (months) (95% CI)

34.7 (32.7, 36.8)

30.3 (28.7, 33.3)

p-value

0.0033

Hazard ratio

(95% CI)

0.81 (0.70 ,0.93)

p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1).

Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors ZYTIGA

Figure 2: Kaplan Meier Overall Survival Curves in Study 2

At the pre-specified rPFS analysis, 150 (28%) patients treated with ZYTIGA and 251 (46%) patients

treated with placebo had radiographic progression. A significant difference in rPFS between treatment

groups was observed (Table 7 and Figure 3).

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Table 7: Radiographic Progression-free Survival of Patients Treated with Either ZYTIGA or

Placebo in Combination with Prednisone in Study 2 (Intent-to-Treat Analysis)

Radiographic Progression-free

Survival

Zytiga

(N=546)

Placebo

(N=542)

Progression of deaths

150 (28%)

251 (46%)

Median rPFS (months)

(95% CI)

(11.66, NR)

8.28

(8.12, 8.54)

p-value

<0.0001

Hazard ratio

(95% CI)

0.425 (0.347,0.522)

NR= Not reached

P-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1).

Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors ZYTIGA

Figure 3– Kaplan Meier Curves of Radiographic Progression-free Survival in Study 2

(Intent-to-Treat analysis)

The primary efficacy analyses are supported by the following prospectively defined

endpoints. The median time to initiation of cytotoxic chemotherapy was 25.2 months for

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patients receiving ZYTIGA and 16.8 months for patients receiving placebo (HR=0.580;

95% CI: [0.487, 0.691], p < 0.0001).

The median time to opiate use for prostate cancer pain was not reached for patients

receiving ZYTIGA and was 23.7 months for patients receiving placebo (HR=0.686; 95%

CI: [0.566, 0.833], p=0.0001). The time to opiate use result was supported by a delay in

patient reported pain progression favoring the ZYTIGA arm.

16

HOW SUPPLIED/STORAGE AND HANDLING

ZYTIGA (abiraterone acetate) 250 mg tablets are white to off-white, oval tablets debossed with AA250

on one side. ZYTIGA 250 mg tablets are available in high-density polyethylene bottles of 120 tablets.

Storage and Handling

Store below 30°C.

Shelf life after first opening: 30days.

Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA

without protection, e.g., gloves [see Use in Specific Populations (8.1)].

Manufacturer :

Janssen Cilag S.P.A, Latina, Italy

License Holder:

J-C Health Care Ltd, Kibbutz Shefayim 6099000, Israel