RISPERDAL CONSTA 25 MG

Israel - English - Ministry of Health

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Active ingredient:
RISPERIDONE
Available from:
J-C HEALTH CARE LTD
ATC code:
N05AX08
Pharmaceutical form:
POWDER FOR SUSPENSION FOR INJECTION
Composition:
RISPERIDONE 25 MG/VIAL
Administration route:
I.M
Prescription type:
Required
Manufactured by:
CILAG AG, SWITZERLAND
Therapeutic group:
RISPERIDONE
Therapeutic area:
RISPERIDONE
Therapeutic indications:
Risperdal consta is indicated for the treatment of schizophrenia and schizoaffective disorders.Risperdal consta is indicated as monotherapy for the maintenance treatment of bipolar I disorder to delay occurrence of mood episodes.Risperdal consta is indicated for adjunctive maintenance treatment to delay occurrence of mood episodes in patients with frequently relapsing bipolar disorder.
Authorization number:
127 28 30619 11
Authorization date:
2012-12-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

17-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

09-07-2019

דומע 1 ךותמ 7

עעבקנהזןולעטמרופ " לערשואוקדבנונכותותואירבהדרשמי ודי 5.12

םיחקורהתונקתיפלןכרצלןולע ) םירישכת ( משתה " ו -

) x ( אפורםשרמבתבייחוזהפורתה

הפורתבשמתשתםרטבופוסדעןולעהתאןויעבארק :

ותרוצורישכתהםש לדרפסיר הטסנוק ,

תירירשךותהקרזהלךשוממרורחשבףיחרת

בכרה ותומכוליעפהרמוחה :

הטסנוקלדרפסיר 25 מ " ליכמג : Risperidone 25mg

הטסנוקלדרפסיר 37.5 מ " ליכמג : Risperidone37.5mg

הטסנוקלדרפסיר 50 מ " ליכמג : Risperidone 50mg

תיטיופרתהצובק : םייטוכיספיטנא םייפיטא

תללוכהכרעה :

םעןוקובקב risperidone הקבאב , הקרזהלףיחרתתנכהל

ליכמהשומישלןכומקרזמ 2 מ " הפחרהללזונל .

טחמאללהפחרהלםאתמ

הקרזהלטחמ זוכעל

הקרזהלטחמ ל עורזהרירש

םיליעפיתלבםיביכרמ :

ןוקובקב : Polymer: 7525 DL JN1 (poly-d,1-lactide-co-glycolide)

הפחרהללזונ : Carmellose sodium 40 mPa.s, Sodiumchloride,Disodium hydrogen phosphatedihydrate, Citric

acid anhydrous, polysorbate 20, sodiumhydroxide, water for injection.

תיאופרתוליעפ הינרפוזיכסבלופיט , תיבטוקודהערפהבותויביטקפאוזיכסתוערפהב

רישכתבשמתשהלןיאיתמ ?

הפורתהיביכרממדחאלתושיגרהעודיםאשמתשהלןיא . החירפבלשמלאטבתהלהלוכיתושיגר , דרג , המישנרצוק םינפוא

תוחופנ . א תחאם מ השחרתההלאתועפות , אפורלתשגלשי .

לופיטהתלחתהינפלאפורבץעוויהלילבמהפורתבשמתשהלןיא

ךניהרשאכרישכתבישמתשתלא הקינמ . הזהרקמבאפורביצעוויה .

לבוסךניהםא / יוקילמרבעבתלבסואת דוקפתב :

בלה – תוצעוויהרחאלקרותוריהזבהטסנוקלדרפסירבשמתשהלשי אפורב , לבוסךניהםא / ת תויעבמ בלב , דוחיב

בלהבצקבתוערפהמ , הניקתיתלבתילמשחתוליעפמ בלב םאוא לטונךנה / ת תונשמרשאתופורת תילמשחהתוליעפהתא

בלב .

לבוסךניהםא / ת בלתלחממ םדילכוא , תרכוסמ , ןוסניקרפמ , ואיאוליפוגלהרושקההיצנמדמ היספליפאמ , עידוהלשי

אפור . לבקמךנהשןמזבתיאופרהחגשהבךרוצהיהיוןכתיי / ת הטסנוקלדרפסיר ואהנמהתמאתהבךרוצהיהישןכתייו

לופיטה .

הזיאודציכאפורבץעוויהלשייוקלידבכואיתיילכדוקפתילעבםילוחבוםישישקםילוחב ןונימ לוטיל .

ןוירהלסנכהלתננכתמואןוירהבךניהםא , בץעווהלשי הטסנוקלדרפסירבשמתשהלךלרתומםאהטילחירשאאפור .

דער , תושקונ םירירש ו / השלוחוא , תוינונשי , טקשרסוח , ואהמישניישק הנזהבישוק תולולע שחרתהל דלווב לש םא ש השמתשה

לשןורחאהשילשבהטסנוקלדרפסיר ןוירהה .

דומע 2 ךותמ 7

לולעךומנםדץחל רגיהל ם קלדרפסירלשינמזובשומישמ םדהץחלתדרוהלתופורתוהטסנו , לדרפסירבשמתשהלךילעםאןכל

םדהץחלתדרוהלתופורתםעדחיהטסנוק , ץעוויה / י אפורב .

ךלשםויםויהייחלעהפורתהעיפשתךיא ?

לעעיפשההלולעהפורתה ךתונרע א גוהנלךתלוכילעו . לץלמומןכל תונוכמליעפהלואגוהנלא , ינפל ירעיךאפורש תעפשהתאך

ךילעהפורתה .

הפורתהםעלופיטהתפוקתבםיפירחתואקשמואתונייתותשלןיא , תאריבגהלהלולעהפורתה לוהוכלאהתעפשה .

תורהזא :

תרחאןונימתרוצלכבלדרפסירתלטנאלםלועמםא , ליחתהלשי לדרפסירב חקלנה הפהךרד תלחתהינפל טה י לופ

הטסנוקלדרפסירב .

עלדרפסיר םורגללול ל היילע לקשמב , הסנ / תוניתמבלוכאלי .

רתויההובגתוחיכשבהרושקדימסורופםעואומצעשכללדרפסירתחיקלשוארההיצנמדמםילבוסהםישישקםילוחבםירקחמ

תוומירקמלש . לטונךנהםאאפורלרמולשי / ת דימסורופ , הובגםדץחלבלופיטלהפורת , ל ואבלבתומיוסמתויעב ל וקצב ת

ףוגב םילזונתורבטצהבקע .

היצנמדמםילבוסהםישישקםילוחב , ירקמוארנ םינפהלשלומינתשוחתואתימואתפהשלוחואילטנמהבצמבימואתפיוניש ,

תועורזה , רורבאלרובידירקמואףוגהלשדחאדצבדוחייבוםיילגרהוא . שירצקןמזקרפלוליפאוהרקהלאמדחאםא

הרזעלתונפל ר תיאופ דימ .

םא תא / ה אנאםדישירקמרבעבולבסואםילבוסךתחפשמינבמוהשימוא עדי אפורהתא . פצנםיילגרבותואירבםדישירק ו

הטסנוקלדרפסירולטנשםילפוטמב . םיינלטקתויהלםילולעתואירבםדישירק .

ךשוממשומישךלהמב , נפבתוינוצראלתותיוועלםורגללולעהטסנוקלדרפסיר םי . תשחרתמתאזהעפותוהדימב , שי תונפל

אפורל

תורידנםיתיעל , לובלבלשבצמ , הרכהבהדירי , תושקונואהובגםוח שחרתהללולעםירירש . תשחרתמתאזהעפותוהדימב ,

תאיכותואעדילואפורלתידיימתונפלשי / לטונה / הטסנוקלדרפסירת

תורידנםיתיעל , הטסנוקלדרפסירתליטנב , ןכתת םינבלםדיאתלשדאמהכומנהמר םימוהיזינפמהנגהלםישרדנה . אנא

עדי /י הריפסמרבעבתלבסםאאפורהתא םינבלםדיאתלשהכומנ ) רשא ןכתיי בקעהמרגנו תורחאתופורתבשומיש ( .

קידבךרוצלםדתוקידבעצבליושעאפורה ת םינבלהםדהיאתתמר

תורידנםיתיעל דאמ , ןכתיי ומרלשבצמ םדבתוהובגרכוסת . אנא הנפ /י םאאפורל תא / ה לבוס / ת ואמיצמ ן ןתשןתמוארבגומ

רבגומ

תויתפורתןיבתובוגת

םא ךנה לטונ / תפסונהפורתת , תרחאהפורתבלופיטהתעהזתרמגםאוא ןוזמיפסותוםשרמאללתופורתללוכ , ךילע חוודל

אפורל יאואםינוכיסעונמלידכלפטמה - ליעי ןיבתובוגתמםיעבונהתו תויתפורת .

דחוימב , תואבהתוצובקהמתופורתיבגל :

ךלשהבוגתהתלוכיתאתותיחפמהתופורתתעפשהריבגהלהלולעהטסנוקלדרפסיר ) תופורת העגרהל , םייטוקרנםיבאכיככשמ ,

היגרלאבלופיטלתומיוסמתופורת , ואכידידגונ ן םימיוסמ .( תופורתלוטילשי הידילעומשרנםאקרולא אפור .

תלחתהםאאפורהתאעדיילשיןכלעהטסנוקלדרפסירתעפשהתאתונשלתולולעתואבהתופורתה וא לוטילתקספה

הלאתופורת :

ןימפודלשםיטסינוגאומכןוסניקרפתלחמבלופיטלתופורת ) הפודובלהמגודל .(

לטונךנהםא / ת הובגםדץחלבלופיטלתופורת , ץחללםורגלהלולעהטסנוקלדרפסירםעדחיבןתלטינשםושמאפורבץעווהלשי

תדרלםדה הכומנהמרל ידמ .

דומע 3 ךותמ 7

תוליעפהתאתונשלתולולעשתופורתםילטונרשאכתוריהזבהטסנוקלדרפסירבשמתשהלשי לשמלומכבלהלשתילמשחה ) ךא

קראל ( הירלמבלופיטלתופורת , בצקתוערפהב בל , גרלאב תוי , תופורת תורחאתויטוכיספיטנא , ואכידידגונ ן , ואםינתשמםירישכת

םיחלמהתמרלעתועיפשמהתורחאתופורת ףוגב ) ןרתנ , ןגלשא , םויזנגמ ( .

ןיפזמברק , םינפבםיקזחבאכיפקתהבואהיספליפאבלופיטלרקיעבתשמשמההפורת ) trigeminal neuralgia ( תאדירוהלהלולע

לדרפסירתמר םדבהטסנוק .

וןואכידבלופיטלרקיעבתושמשמהןיטסקוראפוןיטסקואלפ ב הדרחתוערפהןווגמ , תולולע תולעהל םדבהטסנוקלדרפסירתמרתא .

ןכל , ותלחתהםאאפורלחוודלשי / ןיטסקוראפואןיטסקואלפלוטילתקספהוא .

לטונךנהםאאפורלרמולשי / ת דימסורופ , ) ףיעס – " הזא תור " (

הטסנוקלדרפסירתעפשהתאונשיתואבהתופורתהיכתוריבסה , הכומנ :

ןידיטנרוןידיטמיס , אלךאםדבהטסנוקלדרפסירתמרתאטעמתולעלתולולעהביקהתויצמוחתדרוהלתושמשמהתופורתיתש

התעפשהתאונשישריבס .

ןיצימורתיראל , מהקיטויביטנא תחפשמ םידילורקאמה , העפשהןיא םדבהטסנוקלדרפסירתמרלע .

טאמריפוטל , הנרגימוהיספליפאבלופיטלתשמשמה , םדבהטסנוקלדרפסירתמרלעתיתועמשמהעפשהןיא .

הטסנוקלדרפסירלעהעפשהןיאהיצנמדבלופיטלתושמשמהליפזנודוןימטנלגל .

התאהנשתהטסנוקלדרפסיריכתוריבסה תואבהתופורתהתעפש , הכומנ :

טאורפלווואםויתיללעהעפשהשישהארנאלהטסנוקלדרפסירל לעואהינאמבלופיטלתושמשמה ןיסקוגיד , תויעבבלופיטלהפורת

בל .

יאוולתועפות

הפורתהלשהיוצרהתוליעפלףסונב , עיפוהלתולולעהבשומישהןמזב תועפות יאוול . ולהתועפותהטמתומושר תורושקהיאו

הטסנוקלדרפסירבלופיטב . ץעוויהאנאועיפוהםיטרופמהםינימסתהדחאוהדימב אפורב :

רתויבתוצופנהיאוולהתועפות ) לעמ 1 ךותמ 10 םילפוטמ :(

תוננטצהינימסת

ישוק תומדריהב הפוצרהנישבישוקוא

ןואכיד , הדרח

באטבתמהםזינוסניקרפ : תיטיאואהיוקלתויתעונת , חת לשהשוחתףאםיתיעלוםירירשתוצווכתהואםירירשתושקונתשו

והעונתבןואפק בךרוצ תשדוחמהעונתתלחתה . םיילגרתרירג תיטיא , החונמבדער , לשרתיתשרפה וקור / הוא התרבג יר רו

דוביאו םינפבהעבה .

שארבאכ

תוצופניאוולתועפות ) מרתוי - 1 ךותמ 100 מתוחפךאםילפוטמ - 1 תמ ךו 10 םילפוטמ :(

תואירתקלד , תונופמיסתקלד ) סיטיכנורב ( , םיסוניסבםוהיז , םוהיז ןתשהיכרדב , תיומדהלחמ תעפש .

הימנא

לורפןומרוההתומרתאתולעהללולעהטסנוקלדרפסיר םדתוקידבבתולגלןתינשיפכןיטק , רשא תולוכי , ךא חרכהבאל ,

םינימסתתעפוהלםורגל . תומרלשםינימסת םיללוכןיטקלורפלשתוהובג : םירבגלצא - םיידשהלשתוחפנתה , ישוק עיגהל

הילערומשלואהפקזל וא לכ היעב תרחא ינימהדוקפתב . םישנלצא – רסוחתשוחת בתוחונ םיידש , תשרפה המבלח םיידש ,

ישדוחהרוזחמהלשתורחאתוערפהואתסוורדעה .

תוהובגרכוסתומר םדב , היילע לקשמב , בהדירי לקשמ , ןובאתבהיילעואהדירי

הנישתויעב , תונבצע , ינימהקשחבהדירי , החונמרסוח , תוינונשיתשוחת וא תונרע הכומנ

הינוטסיד – העפות תברעמה תוצווכתה םירירש תכשוממואתיטיא ינוצראלו ת לש םירירשה . תורמל ברעלהלוכיוזהעפותש

קלחלכ ףוגב ) לוכיו ה הניקתאלהביציבאטבתהל ( , םינפהירירשועפשויללכךרדב . לשתוניקתאלתועונתתללוכהעפותה

םייניעה , ה הפ , ה ואןושל ה תסל .

תרוחרחס

היזניקסיד – לולכלהלולעשתינוצראלםירירשתעונת תורזוחתועונת , תויולתפתהואתויתיווע .

דער

דומע 4 ךותמ 7

הייארשוטשט

מבלבצק ריה

ךומנםדץחל , הובגםדץחל

המישנרצוק , ןורגבאכ , לועיש , ףאבשדוגו

תוחוניאואןטבבאכ ןטבב , האקה , לוכיעהתכרעמבםוהז , תוריצע , לושלש , לוכיעתויעב , םיינישיבאכוהפבשבוי

החירפ

םירירשתויוצווכתה , תומצעואםירירשיבאכ , בגבאכ , באכ מ םיקרפ

ןתשתפילד ) הלתלוכירסוח קפאת (

תויעב הפקזב

רדעה תסו

דשהמבלחתפילד םי

ףוגבתוחיפנ , ב ואםיידי ב םיילגר , םוח , הזחבתוחוניא , השלוח , תופייע

באכ

הקרזההרוזאבהבוגת , דרגתללוכה , תוחיפנואבאכ

םדבדבכימיזנאתומרבהיילע

תוליפנ

תוצופנןניאשיאוולתועפות ) מרתוי - 1 ךותמ 1,000 ךאםילפוטמ מתוחפ - 1 ךותמ 0 10 םילפוטמ :(

המישנהיכרדבםוהיז , ןתשהתיחופלשבםוהיז , םיינזואםוהיז , םייניעםוהיז , םידקשתקלד , ינרופיצביתיירטפםוהיז םי , םוהיז

רועב , ףוגהמקלחבוארועבםיוסמרוזאללבגומהםוהיז , ילאריוםוהיז , רועבתקלד האצותכ מ להפישח תידרק , הסרומ

סצבא ( רועהתחת

םינבלםדיאתתריפסבהדירי , בהדירי תמר תויסט ) בםיעייסמהםדיאת תריצע םומיד ( , םימודאםדיאתתריפסבהדירי

תיגרלאהבוגת

ןתשברכוסתואצמה , תרכוסלשהרמחהואתרכוס

שןובאתןדבוא ליבוהללולע לקשמבהדיריוהנוזתתתל

וםידירצילגירטתומרבהיילע / לורטסלוכוא ) םינמוש ( םדב

חורבצמ םמורמ ) מ א הינ ( , לובלב , העגהבישוק המזגרואל , םיטויס

תרחואמהעונתתערפה ) Tardive dyskinesia ( – ותועונת / וא תותיווע אל םינפהלשתוטלשנ , ה ואןושל םירחאםיקלח

ףוגב . הדימב תא / ה הווח תועונת ינוצריתלב ו יבצקות ו ןושלהלשת , ה והפ ה םינפ הנפ / י תידיימ אפורל . ןכתי הרויאפורהו

הטסנוקלדרפסירבלופיטהתאקיספהל

חומלםדתמירזלשתימואתפהקספה ) ינימואץבש - ץבש (

הרכהןדבוא , םיסוכרפ , תופלעתה

םימיוסמףוגיקלחעינהלטלשניתלבףחד , תוערפה לקשמיוושב , היצנידרואוק הניקתאל , לרבעמבתרוחרחס בצמ הדימע ,

התמושתבהערפה בל , רובידבתויעב , םעטהשוחבתויעבואןדבוא , עגמובאכלרועהתושיגרבהדירי , ואץוצקעתשוחת

רועהלשלולמנ

םייניעתקלד , ןיעהתימחלבתקלד , םייניעבשבוי , וביר י תועמד , םייניעבתוימומדא .

רורחסתשוחת ) וגיטרו ( , םיינזואבםילוצלצ , םיינזואבאכ

ירודזורפרופרפ ם ) בלבצק רידסאל ( , בלהלשןותחתהקלחלןוילעהקלחהןיבשהכלוהבהערפה , הניקתאלתילמשחהכלוה

בלהלש , חוורמתכראה QT בלהלש , יטיאבלבצק , בלבילמשחהחתמהלשהניקתאלהקידב ) רגוידרקורטקלא ם / ECG ( ,

תוניקתאלבלתומיעפלתועדומ ) תויצטיפלפ (

רבעמבךומנםדץחל הדימעל ) ךכמהאצותכ , השלוחשוחלםילולעהטסנוקלדרפסירםילטונהםימיוסמםישנא , ואתרוחרחס

ימואתפןפואבהבישיואהדימעבצמלרבעמבףלעתהלםילולע (

תיחטשוהריהמהמישנ , שדוג המישניכרדב , םיפוצפצ , ףאהםמד

דומע 5 ךותמ 7

הטילשרסוח ) קפאתהלתלוכירסוח ( האוצןתמב , העילבבישוק , רבגה לוכיעהתכרעמבםיזגלשה

דוריג , רעישןדבוא , המזקא , רועבשבוי , רועבתוימומדא , רועהעבציוניש , הנקא , םישקשק

תומרבהיילע CPK ) זאניקופסופןיטארק ( םדב , רירשבקזנואהעיגפמהאצותכררחתשמהםיזנא

םיקרפמןוישק , םיקרפמתוחפנתה , םירירשתשלוח , ראווצבאכ

ןתשןתמבתופיכת , ןתשתתלתלוכירסוח , ןתשןתמבםיבאכ

תוערפה ערזתטילפב

תסווברוחיא , ישדוחהרוזחמלהרושקהתרחאהערפהלכואתסוורדעה

םירבגבםיידשתוחתפתה , ינימדוקפתרסוח , םיידשבתוחוניא , קיתרנהמהשרפה

םינפהתוחפנתה , הפה , םייתפשהואםייניעה

תורומרמצ , ףוגהתרוטרפמטבהיילע

הכילההתרוצביוניש

אמצתשוחת , וחת הבוטאלתיללכהש , דוריחורבצמ

רועהתושקתה

םדבדבכימיזנאתומרבהיילע

לופיטתלבקןמזבבאכ

תורידניאוולתועפות ) ב מרתוי - 1 ךותמ 10,000 מתוחפךאםילפוטמ - 1 ךותמ 0 0 1,0 םילפוטמ :(

מןגהלםייארחאשםדבםינבלהםיאתהתומרבהדירי םימוהיזינפ

ןתשהחפנתאתסוומהןומרוהלשהניקתאלהשרפה

םדבתוכומנרכוסתומר

םימלשהבורמהייתש

שגררדעה

הריאממתיטפלוריונתנומסת ) Neuroleptic malignantsyndrome :( לובלב , הרכהבהדיריואדוביא , תושקונוהובגםוח

הרומחםירירש

הרכהתמר / הכומנתועדומ

שארהלשדער

םייניעהתעונתבהערפה , םייניעלוגלג , רתיתושיגר םייניעהלש רואל

ןיקתאלבלבצק

םיילגרבםדישירק , תואירבםדישירק

המישניישק ) םושנלתלוכירסוח ( הנישןמזב

ןוזמתפיאשמהאצותכתואירתקלד , תואירבשדוג ,

תואירהמםיציפנתולוק , לוקבתויעב , המישנהיכרדבתויעב

תקלד בלבלב , םייעמתמיסח

לעהחירפ רועה הפורתבשומישלהרושקה , תדפרס ) רועבתיגרלאהבוגת .( רועהתובעתה , רועבתויעב , רועבתורובח

םירירשיבאכורירשהיביסקוריפ

הביציבתויעב

םיידשתלדגה , םיידשהמהשרפה

ףוגהתרוטרפמטבהדירי , תוחוניאתשוחת

ורועהלשהבהצה םייניעה ) תבהצ (

דואמתורידניאוולתועפות ) תוחפ מ - 1 ךותמ 0 0 10,0 םילפוטמ :(

םייחינכסמםיכוביס האצותכ תרכוסמ תנזואמאל

המישניישקלליבוהלוןורגהתאברעלהלוכירשאתוחיפנבהוולמהרומחתיגרלאהבוגת

העודייתלבתורידתתולעביאוולתועפות :

דומע 6 ךותמ 7

יאתרפסמבתנכוסמהדירי שרדנהגוסהמםינבלםד הנגהל מ םימוהיזינפ

םוחבתנייפואמההפירחתיגרלאהבוגת , הפבתוחיפנ , םינפב , ןושלבואםייתפשב , המישנרצוק , דוריג , רועהלעהחירפ

םדהץחלבהדיריםימעפלו

ףוגהתאתנכסמהרתויבתמזגומםימתייתש

םדבןילוסניאהתמרבהיילע ) התומרתאתסוומהןומרוה ףוגברכוס (

חומבםדהילכבהיעב

יוריגלהבוגתרסוח

תמדרת האצותכ תרכוסמ תנזואמאל

ימואתפןורוועואהייארןדבוא

המוקואלג ) רבגומיניעךותץחל ( , םייפעפעהילושבםורקתורצווה

הדימעבצמלרבעמבתורבגומבלתומיעפ

הקמסה , ןושלהתוחפנתה

דאמהשקהאוצ

תוקודסםייתפש

ממהפקז תוברעתהשורדלהלולערשאתכשו כ תיגרורי

הזחבתוטולבהלשתוחיפנ

םיידיבוםיילגרברוקתשוחת

תופורתמהלימגלשםינימסת

םייעמתקלד

רתיןונימ – רשאמתוקירזבתוחפריבסרתיןונימ תחיקלב העילבבלדרפסיר ). םירודכבןוגכ , הסימת (

תועפותהמרתויואתחאתורקלתולולערתיןונימב תואבה : הרכהבהדירי , םונמנ , תוינונשי , רבגומדער , תרבגומםירירשתושקונ , בצק

ךומנםדץחלוריהמבל . בלבהניקתאלתילמשחהכלוהלשםירקמוחווד ) תכראה עטקמ QT ( םיסוכרפו .

לדרפסירםעדחיבתורחאתופורתםילטונםאתורקללוכירתיןונימ . הלעמםימושרהםינימסתבתשגרהםא , אפורלתונפלשי .

תועפות יאוול תוסחייתהתובייחמה תדחוימ :

ךשוממשומישךלהמב , םינפבתוינוצראלתותיוועלםורגללולעהטסנוקלדרפסיר . תשחרתמתאזהעפותוהדימב , תונפלשי

אפורל

תורידנםיתיעל , לובלבלשבצמ , הרכהבהדירי , שחרתהללולעםישקונםירירשואהובגםוח . הדימב תשחרתמתאזהעפותו ,

תאיכותואעדילואפורלתידיימתונפלשי / לטונה / הטסנוקלדרפסירת

םדבההובגרכוסתמרלעחוודםירידנםירקמב . שיגרמךנהםאאפורלחוודלשי / ה ןוגכםינימסת ואמיצ ן וארבגומ הנתשה תרבגומ .

ירקמוארנהיצנמדמםילבוסהםישישקםילוחב צמבימואתפיוניש םינפהלשלומינתשוחתואתימואתפהשלוחואילטנמהב ,

תועורזה , רורבאלרובידירקמואףוגהלשדחאדצבדוחייבוםיילגרהוא . הרזעלתונפלשירצקןמזקרפלוליפאוהרקהלאמדחאםא

תיאופר דימ .

ב ובשהרקמלכ ךנה שיגרמ / אלשיאוולתועפותה וניוצ הזןולעב , ביונישלחםאוא ךתשגרה תיללכה אפורהםעץעייתהלךילע

דימ .

הארוהרדעהבלבוקמןונימ תרחא מ אפורה :

ךותהקירזבתנתינהטסנוקלדרפסיר תירירש ל זוכע רירשלאוא עורזה יאופרתווצשיאידילעםייעובשלכ . קירזהלשי םעפןיפולחל

לאמשדצבםעפוןימידצ ףוגהלש . ירוהךרדקירזהלןיא ד .

דבלבאפורהתארוהיפלןונימ .

תצלמומההנמהלערובעלןיא .

שיבוצקןמזבוזהפורתלוטילתחכשםא עייתהל ץ הבהאפרמבתוחאהואאפורהםע תא / לפוטמה / ת .

הלופכהנמתועטבתלטנםא ץעייתה / י ואאפורב הנפ / י לשןוימהרדחל םילוחהתיב .

קםייוסינבקדבנאלהטסנוקלדרפסיר ליגלתחתמםירגבתמוםידליבםייניל 18 .

דומע 7 ךותמ 7

לכותדציכ / לופיטהתחלצהלעייסלי

לךילע דימתה ב לעץלמוהשלופיט - אפורהידי .

הפורתבלופיטהקיספהלןיאךתואירבבצמברופישלחםאםג אלא ב םעתוצעייתה ה אפור ןפואבו

רקובמ .

ענמ / י הלערה !

ברומשלשיתרחאהפורתלכווזהפורת רוגסםוקמ וםידלילשםדיגשיהלץוחמ / ידילעותוקוניתוא -

ךכ ענמת / י הלערה .

הפורתהןמדליעלבתועטבםאוארתיתנמתלטנםא , הנפ /י תיבלןוימרדחלדימ - םילוח אבהו / י תזירא

ךתאהפורתה . םורגלןיא האקהל אפורמתשרופמהארוהאלל !

ךלהמשרנוזהפורת , ךתלחמבלופיטל . םישנאב םירחא הפורתה קיזהלהלולע . לא ןתית / י הפורת ךיבורקלוז ,

ךירכמואךינכש .

ךשוחבתופורתלוטילןיא !

קודבלשי הנמהותיוותה םעפלכב ךניהש לטונ / ת הפורת . ביכרהלשי ךניהםאםייפקשמ קוקז / ה םהל .

הנסחא :

) x ( רוריקבןסחאלשי : 2°C-8°C° .

םג הזיראהיאנתיפל / םיצלמומההנסחא , דבלבתלבגומהפוקתלתורמשנתופורת .

רישכתהלשהגופתהךיראתלבלםישלאנ ! קפסלשהרקמלכב , תאךלקפיסשחקורבץעוויהלךילע

הפורתה . הזיראהתואבתונושתופורתןסחאלןיא .

סמ ' הפורתהםושיר :

הטסנוקלדרפסיר 25 מ " ג – , -11, -12 127 2830619

הטסנוקלדרפסיר 37.5 מ " ג – , -11,-12 12729 30620

הטסנוקלדרפסיר 50 מ " ג – , -11, -12 127 3030621

ןרצי : עבגליס " מ , ץיוושןזואהפש

םושירהלעב : ג ' תלהיסיי ' רק , ץוביק םייפש 60990 , לארשי .

Page

1

41

RISPERDAL

®

CONSTA

®

25mg, 37.5 mg and 50 mg

Powder and Solvent for Prolonged Release Suspension for Intramuscular Injection

1

Therapeutic indication

1.1

SCHIZOPHRENIA

RISPERDAL

CONSTA

(risperidone) is indicated for the treatment of schizophrenia and

schizoaffective disorders.(see Clinical studies (14))

1.2

Bipolar disorder

Risperdal consta is indicated as monotherapy for the maintenance treatment of bipolar I disorder to

delay

occurrence of mood episodes.

Risperdal consta is indicated for adjunctive maintenance treatment to delay occurrence of mood

episodes in

patients with frequently relapsing bipolar disorder.

2

DOSAGE AND ADMINISTRATION

For patients who have never taken oral RISPERDAL

, it is recommended to establish tolerability with oral

RISPERDAL

prior to initiating treatment with RISPERDAL

CONSTA

RISPERDAL

CONSTA

should be administered every 2 weeks by deep intramuscular (IM) deltoid or gluteal

injection. Each injection should be administered by a health care professional using the appropriate enclosed safety

needle

[see Dosage and Administration

(2.8)

]

. For deltoid administration, use the 1-inch needle alternating

injections between the two arms. For gluteal administration, use the 2-inch needle alternating injections between

the two buttocks. Do not administer intravenously.

2.1

Schizophrenia

The recommended dose for the treatment of schizophrenia is 25 mg IM every 2 weeks. Although dose response for

effectiveness has not been established for RISPERDAL

CONSTA

, some patients not responding to 25 mg may

benefit from a higher dose of 37.5 mg or 50 mg. The maximum dose should not exceed 50 mg RISPERDAL

CONSTA

every 2 weeks. No additional benefit was observed with dosages greater than 50 mg RISPERDAL

CONSTA

; however, a higher incidence of adverse effects was observed.

The efficacy of RISPERDAL

CONSTA

in the treatment of schizophrenia has not been evaluated in controlled

clinical trials for longer than 12 weeks. Although controlled studies have not been conducted to answer the

question

long

patients

with

schizophrenia

should

treated

with

RISPERDAL

CONSTA

oral

risperidone has been shown to be effective in delaying time to relapse in longer term use. It is recommended that

responding patients be continued on treatment with RISPERDAL

CONSTA

at the lowest dose needed. The

physician who elects to use RISPERDAL

CONSTA

for extended periods should periodically re-evaluate the

long-term risks and benefits of the drug for the individual patient.

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-

RELATED

PSYCHOSIS

ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS TREATED WITH

ANTIPSYCHOTIC DRUGS ARE AT AN INCREASED RISK OF DEATH.. RISPERDAL

®

CONSTA

®

(RISPERIDONE) IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH

DEMENTIA-RELATED PSYCHOSIS. [SEE WARNINGS AND PRECAUTIONS (5.1)]

Page

2

41

2.2

Bipolar Disorder

The recommended dose for monotherapy or adjunctive therapy to lithium or valproate for the maintenance

treatment of Bipolar I Disorder is 25 mg IM every 2 weeks. Some patients may benefit from a higher dose of 37.5

mg or 50 mg. Dosages above 50 mg have not been studied in this population. The physician who elects to use

RISPERDAL

CONSTA

for extended periods should periodically re-evaluate the long-term risks and benefits of

the drug for the individual patient.

2.3

General Dosing Information

A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in

patients

with

hepatic

renal

impairment,

certain

drug

interactions

that

increase

risperidone

plasma

concentrations [see DRUG INTERACTIONS (7.11)] or in patients who have a history of poor tolerability to

psychotropic medications. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.

Oral

RISPERDAL

another

antipsychotic

medication)

should

given

with

first

injection

RISPERDAL

CONSTA

and continued for 3 weeks (and then discontinued) to ensure that adequate therapeutic

plasma concentrations are maintained prior to the main release phase of risperidone from the injection site

[see

Clinical Pharmacology (12.3)]

Upward dose adjustment should not be made more frequently than every 4 weeks. The clinical effects of this dose

adjustment should not be anticipated earlier than 3 weeks after the first injection with the higher dose.

In patients with clinical factors such as hepatic or renal impairment or certain drug interactions that increase

risperidone plasma concentrations [see DRUG INTERACTIONS (7.11)], dose reduction as low as 12.5 mg may

be appropriate. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.

Do not combine two different dose strengths of RISPERDAL

CONSTA

in a single administration.

2.4

Dosage in Special Populations

Elderly

For elderly patients treated with RISPERDAL

CONSTA

, the recommended dosage is 25 mg IM every 2 weeks.

Oral

RISPERDAL

another

antipsychotic

medication)

should

given

with

first

injection

RISPERDAL

CONSTA

and should be continued for 3 weeks to ensure that adequate therapeutic plasma

concentrations are maintained prior to the main release phase of risperidone from the injection site

[see Clinical

Pharmacology (12.3)]

Renal or Hepatic Impairment

Patients with renal or hepatic impairment should be treated with titrated doses of oral RISPERDAL

prior to

initiating treatment with RISPERDAL

CONSTA

. The recommended starting dose is 0.5 mg oral RISPERDAL

twice daily during the first week, which can be increased to 1 mg twice daily or 2 mg once daily during the second

week. If a total daily dose of at least 2 mg oral RISPERDAL

is well tolerated, an injection of 25 mg

RISPERDAL

CONSTA

can be administered every 2 weeks. Oral supplementation should be continued for 3

weeks after the

first injection until the main release of risperidone from the injection site has begun. In some

patients, slower

titration may be medically appropriate. Alternatively, a starting dose of RISPERDAL®

CONSTA® of 12.5 mg

may be appropriate. The efficacy of the 12.5 mg dose has not been investigated in clinical

trials.

Patients with renal impairment may have less ability to eliminate risperidone than normal adults. Patients with

impaired hepatic function may have an increase in the free fraction of t h e risperidone, possibly resulting in

enhanced effect

[see Clinical Pharmacology (12.3)]

. Elderly patients and patients with a predisposition to

hypotensive

reactions

whom

such

reactions

would

pose

particular

risk

should

instructed

nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the

Page

3

41

edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated

position). These patients should avoid sodium depletion or dehydration, and circumstances

that accentuate

hypotension (alcohol intake, high ambient temperature, etc.). Monitoring of orthostatic vital signs should be

considered

[see Warnings and Precautions (5.7)]

2.5

Reinitiation of Treatment in Patients Previously Discontinued

There are no data to specifically address reinitiation of treatment. When restarting patients who have had an

interval off treatment

with

RISPERDAL

CONSTA

, supplementation

with oral RISPERDAL

another

antipsychotic medication) should be administered.

2.6

Switching from Other Antipsychotics

There are no systematically collected data to specifically address switching patients from other antipsychotics to

RISPERDAL

CONSTA

concerning

concomitant

administration

with

other

antipsychotics.

Previous

antipsychotics should be continued for 3 weeks after the first injection of RISPERDAL

CONSTA

to ensure that

therapeutic concentrations are maintained until the main release phase of risperidone from the injection site has

begun

[see

Clinical

Pharmacology

(12.3)]

patients

have

never

taken

oral

RISPERDAL

recommended to establish tolerability with oral RISPERDAL

prior to initiating treatment with RISPERDAL

CONSTA

recommended

with

other

antipsychotic

medications,

need

continuing

existing

medication should be re evaluated periodically.

2.7

Co-Administration of RISPERDAL® CONSTA® with Certain Other Medications

Co-administration

carbamazepine

other

enzyme

inducers

(e.g.,

phenytoin,

rifampin,

phenobarbital) with risperidone would be expected to cause decreases in the plasma concentrations of the sum of

risperidone

9-hydroxyrisperidone

combined,

which

could

lead

decreased

efficacy

RISPERDAL

CONSTA

treatment. The dose of risperidone needs to be titrated accordingly for patients receiving these enzyme

inducers, especially during initiation or discontinuation of therapy with these inducers

[see Drug Interactions

(7.11)]

. At the initiation of therapy with carbamazepine or other known CYP 3A4 hepatic enzyme inducers,

patients should be closely monitored during the first 4-8 weeks, since the dose of RISPERDAL

CONSTA

need

adjusted.

dose

increase,

additional

oral

RISPERDAL

need

considered.

discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL

CONSTA

should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of

RISPERDAL

CONSTA

between 2 to 4 weeks before the planned discontinuation of carbamazepine or other

inducers

adjust

expected

increase

plasma

concentrations

risperidone

plus

hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RISPERDAL

CONSTA

discontinuing from carbamazepine or other CYP3A4 enzyme inducers, it is recommended to continue treatment

with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5

mg or necessitates interruption of RISPERDAL® CONSTA® treatment. The efficacy of the 12.5 mg dose has not

been investigated in clinical trials.

Fluoxetine

and paroxetine, CYP 2D6 inhibitors, have been

shown to increase the plasma concentration

risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-

hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The dose of

risperidone needs to be titrated accordingly when fluoxetine or paroxetine is co-administered. When either

concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of

RISPERDAL

CONSTA

. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a

lower dose of RISPERDAL

CONSTA

between 2 to 4 weeks before the planned start of fluoxetine or paroxetine

therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine

is initiated in patients receiving the recommended dose of 25 mg RISPERDAL

CONSTA

, it is recommended to

continue

treatment with

the 25 mg

dose unless

clinical judgment necessitates

lowering

the RISPERDAL®

CONSTA®

dose

12.5

necessitates

interruption

RISPERDAL®

CONSTA®

treatment.

When

RISPERDAL® CONSTA® is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of

Page

4

41

12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. The

effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone

and 9-hydroxyrisperidone have not been studied.

[see Drug Interactions (7.11)]

2.8 Instructions for Use

For deltoid or gluteal intramuscular injection only

Important Information

RISPERDAL

CONSTA

requires close attention to these step-by-step ‘Instructions for Use to help ensure

successful administration.

Use components provided

The components in this dose pack are specifically designed for use with RISPERDAL CONSTA.

RISPERDAL

CONSTA

must be reconstituted

only

in the diluent supplied in the dose pack.

Do not

substitute ANY components of the dose pack.

Do not store suspension after reconstitution.

Administer dose as soon as possible after reconstitution to avoid settling.

Proper dosing

The entire contents of the vial must be administered to ensure intended dose of RISPERDAL CONSTA is

delivered.

Do not reuse

. Medical devices require specific material characteristics to perform as intended.

These characteristics have been verified for single use only. Any attempt to re-process the

device for subsequent re-use may

adversely affect the integrity

of the device or lead to

deterioration in performance.

SINGLE-USE DEVICE

Page

5

41

Dose pack contents

Take out dose pack

Connect vial adapter to vial

Step 1

Assemble components

Page

6

41

Connect prefilled syringe to vial adapter

Remove sterile blister

Keep vial vertical to

prevent leakage. Hold

base of vial and pull up

on the sterile blister to

remove.

Do not

shake.

Use proper grip

Hold

white

collar at the tip of

the syringe.

Do

not

hold

syringe by the glass

barrel

during

assembly.

Remove cap

Holding the white collar,

snap off the white cap.

Do not

twist or cut off

the white cap.

Do not

touch syringe tip.

This will result in

contamination.

Connect

syringe

to vial adapter

Hold vial adapter

by skirt to keep

stationary.

Hold syringe by

white collar

then

insert tip into the

luer opening of the

vial adapter.

Do not

hold the

glass syringe

barrel. This may

Page

7

41

Do not

touch exposed

luer opening on vial

adapter. This will result

in contamination.

broken-off cap can

discarded.

cause the white

collar to loosen or

detach.

Attach the syringe

to the vial adapter

with a firm

clockwise twisting

motion

until it

feels snug.

Do not

over-

tighten. Over-

tightening may

cause the syringe

tip to break.

Step 2

Reconstitute microspheres

Inject diluent

Inject entire amount of

diluent from syringe

into the vial.

Suspend microspheres

in diluent

Continuing to hold

down the plunger rod,

shake vigorously for

at least 10 seconds

, as

shown.

Check the suspension.

When properly mixed,

the suspension appears

uniform, thick and

milky in color.

Microspheres will be

visible in the liquid.

Immediately proceed

to the next step so

suspension does not

settle.

Transfer suspension

to syringe

Invert vial

completely. Slowly

pull plunger rod

down to withdraw

entire contents from

the vial into the

syringe.

Remove vial

adapter

Hold white collar on

the syringe and

unscrew from vial

adapter.

Tear section of the

vial label at the

perforation. Apply

detached label to

the syringe for

identification

purposes.

Discard both vial

and vial adapter

appropriately.

Page

8

41

Step 3

Attach needle

Select appropriate needle

Attach needle

Choose needle based on

Peel blister pouch open part

injection location (gluteal or

way and use to grasp the base

deltoid).

of the needle, as shown.

Holding the white collar on

the syringe

, attach syringe to

needle luer connection with a

firm

clockwise twisting

motion

until snug.

Do

not

touch

needle

luer

opening. This will result in

contamination.

Resuspend microspheres

Fully remove the blister

pouch.

Just before injection, shake

syringe vigorously again, as

some settling will have

occurred.

Page

9

41

Step 4

Inject dose

Remove

transparent

needle

protector

Move the needle

safety device

back towards

the syringe, as

shown. Then

hold white

collar on

syringe and

carefully pull

the transparent

needle protector

straight off.

Do not

twist

transparent

needle

protector, as the

luer connection

may loosen.

Remove air

bubbles

Hold needle

upright and tap

gently to make

any air bubbles

rise to the top.

Slowly and

carefully press

plunger rod

upward to

remove air.

Inject

Immediately

inject entire

contents of

syringe

intramuscularly

(IM) into the

gluteal or deltoid

muscle of the

patient.

Gluteal injection

should be made

into the upper-

outer quadrant of

the gluteal area.

Do not

administer

intravenously.

Secure needle in

safety device

Using one hand,

place needle safety

device at a 45

degree angle on a

hard, flat surface.

Press down with a

firm, quick motion

until needle is

fully engaged in

safety device.

Avoid needle

stick injury:

Do not

use two

hands.

Do not

intentionally

disengage or

mishandle the

needle safety

device.

Do not

attempt to

straighten the

needle or engage

the safety device if

the needle is bent

or damaged.

Properly

dispose of

needles

Check to

confirm needle

safety device is

fully engaged.

Discard in an

approved sharps

container.

Also discard the

unused needle

provided in the

dose pack.

Page

10

41

3

DOSAGE FORMS AND STRENGTHS

RISPERDAL

CONSTA

is available in dosage strengths of 25 mg, 37.5 mg, and 50 mg risperidone. It is

provided as a dose pack, consisting of a vial containing the risperidone microspheres, a pre-filled syringe

containing 2 mL of diluent for RISPERDAL CONSTA®, a vial Adapter®, and two Terumo

SurGuard® 3

Needles for intramuscular injection (a 21 G UTW 1-inch needle with needle protection device for

deltoid

administration and a 20 G TW 2-inch needle with needle protection device for gluteal administration).

4

CONTRAINDICATIONS

RISPERDAL

CONSTA

is contraindicated in patients with a known hypersensitivity to either risperidone or

paliperidone, or to any of the excipients in the RISPERDAL CONSTA® formulation listed in section

Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients

treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.

5

WARNINGS AND PRECAUTIONS

5.1

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk

of

death.

Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical

antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-

treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about

4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths

appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs

may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed

to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

RISPERDAL

®

CONSTA

®

(risperidone) is not approved for the treatment of dementia-related

psychosis

(see Boxed Warning).

5.2

Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related

Psychosis

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in

patients (mean age 85 years; range 73-97) in trials of oral risperidone in elderly patients with dementia related

psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse

events in patients

treated

with oral

risperidone

compared

to patients

treated

with

placebo.

RISPERDAL

CONSTA

is not approved for the treatment of patients with dementia related psychosis

[See also Boxed Warning

and Warnings and Precautions (5.1)]

5.3

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been

reported

association with antipsychotic

drugs.

Clinical manifestations

hyperpyrexia, muscle

rigidity,

altered

mental

status,

evidence

autonomic

instability

(irregular

pulse

blood

pressure,

tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase,

myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important

Page

11

41

to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic

infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important

considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and

primary central nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs

not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment

Page

12

41

of any concomitant serious medical problems for which specific treatments are available. There is no general

agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug

therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have

been reported.

5.4

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with

antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially

elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic

treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their

potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to

increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the

patient increase. However, the syndrome can develop, although much less commonly, after relatively brief

treatment periods at low doses.

syndrome

remit,

partially or completely, if antipsychotic treatment is withdrawn.

Antipsychotic

treatment, itself, however, may

suppress (or partially suppress) the signs and symptoms of the syndrome and

thereby may possibly mask the

underlying process. The effect that symptomatic suppression has upon the long-

term course of the syndrome is

unknown.

Given these considerations, RISPERDAL

CONSTA

should be prescribed in a manner that is most likely to

minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for

patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom

alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients

who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory

clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL

CONSTA

, drug

discontinuation

should

considered.

However,

some

patients

require

treatment

with

RISPERDAL

CONSTA

despite the presence of the syndrome.

5.5

Metabolic changes

Atypical

antipsychotic

drugs

have

been

associated

with

metabolic

changes

that

increase

cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body

weight gain. While all the drugs in the class have been shown to produce some metabolic changes, each drug has

its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated

with ketoacidosis or hyperosmolar

coma or death, have been reported in patients treated with atypical

antipsychotics including RISPERDAL

Assessment of the relationship between atypical antipsychotic use and

glucose abnormalities is complicated by

the possibility of an increased background risk of diabetes mellitus in

patients with schizophrenia and the

increasing incidence of diabetes mellitus in the general population. Given

Page

13

41

these confounders, the relationship between atypical antipsychotic use and hyperglycemia related adverse events is

not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent

hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for

hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including

RISPERDAL, should be monitored regularly for worsening of glucose control. Patients with risk factors for

diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics,

including

RISPERDAL

should

undergo

fasting

blood

glucose

testing

beginning

treatment

periodically during treatment. Any patient treated with atypical antipsychotics including RISPERDAL should be

monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who

develop symptoms of hyperglycemia during treatment with atypical antipsychotics including RISPERDAL, should

undergo

fasting

blood

glucose

testing.

some

cases,

hyperglycemia

resolved

when

atypical

antipsychotic, including RISPERDAL was discontinued; however, some patients required continuation of anti-

diabetic treatment despite discontinuation of RISPERDAL.

Pooled data from 3 double-blind, placebo-controlled studies in subjects with schizophrenia and 4 double-blind,

placebo-controlled monotherapy studies in subjects with bipolar mania with oral risperidone are presented in Table

In longer-term, controlled and uncontrolled studies in adult subjects, RISPEDAL

was associated with a mean

change in glucose of +2.8 mg/dL at Week 24(n=151) and +4.1 mg/dL at Week 48 (n=50)

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from 7 placebo-controlled, 3-to 8-week, fixed- or flexible-dose studies in adult subjects with

schizophrenia or bipolar mania are presented in Table 2.

Page

14

41

In longer-term, controlled and uncontrolled studies, RISPERDAL®was associated with a mean change in (a) non-

fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and +5.5 mg/dL at Week 48 (n=86): and (b) non-fasting

triglycerides of +19.9 mg/dL at Week 24 (n=52)

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data from a placebo-controlled, 12-week, fixed-dose study in adult subjects with schizophrenia are presented in

Table 3.

In an uncontrolled, longer-term, open-label study, RISPERDAL® CONSTA® was associated with a mean change

in weight of +2.1 kg at Week 24(n=268) and +2.8 kg at Week 50(n=199)

5.6

Hyperprolactinemia

As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation

persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than

other antipsychotic agents.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion.

This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male

patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving

Page

15

41

prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead

decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent

in

vitro

factor of potential

importance

prescription of these

drugs is contemplated

in a

patient

with

previously detected breast cancer.

An increase in pituitary gland,

mammary gland, and pancreatic islet cell

neoplasia

(mammary

adenocarcinomas,

pituitary

pancreatic

adenomas) was

observed

risperidone

carcinogenicity studies conducted in mice and rats

[see Nonclinical Toxicology (13.1)]

. Neither clinical studies nor

epidemiologic studies conducted to date have shown an association between chronic administration of this class of

drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

5.7

Orthostatic Hypotension

RISPERDAL

CONSTA

may induce orthostatic hypotension associated with dizziness, tachycardia, and in some

patients, syncope, especially during the initial dose-titration period with oral risperidone, probably reflecting its

alpha adrenergic antagonistic properties. Syncope was reported in 0.8% (12/1499 patients) of patients treated with

RISPERDAL

CONSTA

multiple-dose

studies.

Patients

should

instructed

nonpharmacologic

interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for

several minutes before attempting to stand in the morning and slowly rising from a seated position).

RISPERDAL

CONSTA

should

used

with particular

caution in (1)

patients

with known cardiovascular

disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular

disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and

(2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be

considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically

significant hypotension has

been observed

with concomitant

of oral RISPERDAL

antihypertensive

medication.

5.8

Falls

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics,

including RISPERDAL CONSTA

, which may lead to falls and, consequently, fractures or other fall-related

injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these

effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term

antipsychotic therapy.

5.9

Leukopenia, Neutropenia, and Agranulocytosis

Class

Effect:

clinical

trial

and/or

postmarketing

experience,

events

of leukopenia/neutropenia

have

been

reported temporally related to antipsychotic agents, including RISPERDAL

CONSTA

. Agranulocytosis has also

been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and a

history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a

drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during

the first few months of therapy and discontinuation of RISPERDAL

CONSTA

should be considered at the first

sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs

of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute

neutrophil count <1000/mm

) should discontinue RISPERDAL

CONSTA

and have their WBC followed until

recovery.

Page

16

41

5.10

Potential for Cognitive and Motor Impairment

Somnolence was reported by 5% of patients treated with RISPERDAL

CONSTA

in multiple-dose trials. Since

risperidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about

operating hazardous machinery, including automobiles, until they are reasonably certain that treatment with

RISPERDAL

CONSTA

does not affect them adversely.

5.11

Seizures

During premarketing testing, seizures occurred in 0.3% (5/1499 patients) of patients treated with RISPERDAL

CONSTA

. Therefore, RISPERDAL

CONSTA

should be used cautiously in patients with a history of seizures.

5.12

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is

a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. RISPERDAL

CONSTA

and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

[see also Boxed Warning and Warnings and Precautions (5.1)]

5.13

Priapism

Priapism has been reported during postmarketing surveillance

[see Adverse Reactions (6.8)]

Severe priapism may

require surgical intervention.

5.14

Thrombotic Thrombocytopenic Purpura (TTP)

A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL

in a large, open

premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but

eventually recovered after receiving plasmapheresis. The relationship to RISPERDAL

therapy is unknown.

5.15

Body Temperature Regulation

Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and

hypothermia have been reported in association with oral RISPERDAL

or RISPERDAL

CONSTA

use. Caution

is advised when prescribing RISPERDAL

CONSTA

for patients who will be exposed to temperature extremes.

5.16

Administration

RISPERDAL

CONSTA

should be injected into the deltoid or gluteal muscle, and care must be taken to avoid

inadvertent injection into a blood vessel.

[see Dosage and Administration (2) and Adverse Reactions ( 6.7)]

5.17

Antiemetic Effect

Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may mask signs and

symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye’s syndrome, and

brain tumor.

5.18

Use in Patients with Concomitant Illness

Clinical experience

with RISPERDAL

CONSTA

in patients

with certain concomitant systemic illnesses is

limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive antipsychotics, including

RISPERDAL

CONSTA

reported

have

increased

sensitivity

antipsychotic

medications.

Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural

instability

Page

17

41

with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic

malignant

syndrome.

Caution is advisable when using RISPERDAL

CONSTA

in patients with diseases or conditions that could

affect metabolism or hemodynamic responses. RISPERDAL

CONSTA

has not been evaluated or used to any

appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with

these diagnoses were excluded from clinical studies during the product’s premarket testing.

Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renal

impairment (creatinine clearance <30 mL/min/1.73 m

) treated with oral RISPERDAL

; an increase in the free

fraction of risperidone is also seen in patients with severe hepatic impairment. Patients with renal or hepatic

impairment should be carefully titrated on oral RISPERDAL

before treatment with RISPERDAL

CONSTA

initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose

adjustment, such as in patients with renal or hepatic impairment

[see Dosage and Administration

(2.4)

]

5.19

Osteodystrophy and Tumors in Animals

RISPERDAL

CONSTA

produced osteodystrophy in male and female rats in a 1 year toxicity study and a 2-year

carcinogenicity study at a dose of 40 mg/kg administered IM every 2 weeks.

RISPERDAL

CONSTA

produced

renal

tubular

tumors

(adenoma,

adenocarcinoma)

adrenomedullary

pheochromocytomas in male rats in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks.

addition, RISPERDAL

CONSTA

produced an increase in a marker of cellular proliferation in renal tissue in

males

in the 1-year toxicity study and in renal tumor-bearing males in the 2-year carcinogenicity study at 40 mg/kg

administered IM every 2 weeks. (Cellular proliferation was not measured at the low dose or in females in either

study.)

The effect dose for osteodystrophy and the tumor findings is 8 times the IM maximum recommended human dose

(MRHD) (50 mg) on a mg/m

basis and is associated with a plasma exposure (AUC) 2 times the expected plasma

exposure (AUC) at the IM MRHD. The no-effect dose for these findings was 5 mg/kg (equal to the IM MRHD on

mg/m

basis). Plasma exposure (AUC) at the no-effect dose was one third the expected plasma exposure (AUC)

the IM MRHD.

Neither the renal or adrenal tumors, nor osteodystrophy, were seen in studies of orally administered

risperidone.

Osteodystrophy was not observed in dogs at doses up to 14 times (based on AUC) the IM MRHD in

1 year toxicity study.

The renal tubular and adrenomedullary tumors in male rats and other tumor findings are described in more detail

Section 13.1 (Carcinogenicity, Mutagenesis, Impairment of Fertility).

The relevance of these findings to human risk is unknown.

6

ADVERSE REACTIONS

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

Increased mortality in elderly patients with dementia-related psychosis

[see Boxed Warning and

Warnings and Precaution (5.1)]

Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis

[see Warnings and Precautions (5.2)]

Page

18

41

Neuroleptic malignant syndrome

[see Warnings and Precautions (5.3)]

Tardive dyskinesia

[see Warnings and Precautions (5.4)]

Metabolic changes {see Warnings and Precautions (5.5)}

Hyperprolactinemia

[see Warnings and Precautions (5.6)]

Orthostatic hypotension

[see Warnings and Precautions (5.7)]

Falls [see Warnings and Precautions (5.8)]

Leukopenia/Neutropenia and Agranulocytosis

[see Warnings and Precautions (5.9)]

Potential for cognitive and motor impairment

[see Warnings and Precautions (5.10)]

Seizures

[see Warnings and Precautions (5.11)]

Dysphagia

[see Warnings and Precautions (5.12)]

Priapism

[see Warnings and Precautions (5.13)]

Thrombotic Thrombocytopenic Purpura (TTP)

[see Warnings and Precautions (5.14)]

Disruption of body temperature regulation

[see Warnings and Precautions (5.15)]

Avoidance of inadvertent injection into a blood vessel

[see Warnings and Precautions (5.16)]

Antiemetic effect

[see Warnings and Precautions (5.17)]

Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies

[see

Warnings and Precautions (5.18)]

Diseases or conditions that could affect metabolism or hemodynamic responses

[see Warnings and

Precautions (5.18)]

Osteodystrophy and tumors in animals

[see Warnings and Precautions (5. 19)]

The most common adverse reactions in clinical trials in patients with schizophrenia

(≥5%) were: headache,

parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increased, pain in extremity,

dry mouth. The most common adverse reactions in the double-blind, placebo-controlled periods of the bipolar

disorder

trials were weight increased (5% in the monotherapy trial) and tremor and parkinsonism (≥10% in the

adjunctive

treatment trial).

The most common adverse reactions that were associated with discontinuation from the 12 week double-blind,

placebo-controlled trial in patients with schizophrenia (causing discontinuation in ≥ 1% of patients) were agitation,

depression, anxiety, and akathisia. Adverse reactions that were associated with discontinuation from the double-

blind, placebo-controlled periods of the bipolar disorder trials were hyperglycemia (one patient in the

monotherapy

trial) and hypokinesia and tardive dyskinesia (one patient each in the adjunctive treatment trial).

The data described in this section are derived from a clinical trial database consisting of 2392 patients exposed to

one or more doses of RISPERDAL

CONSTA

for the treatment of schizophrenia. Of these 2392 patients, 332

were patients who received RISPERDAL

CONSTA

while participating in a 12-week double-blind, placebo-

controlled trial. Two hundred and two (202) of the 332 were schizophrenia patients who received 25 mg or 50 mg

RISPERDAL

CONSTA

. The conditions and duration of treatment with RISPERDAL

CONSTA

in the other

clinical trials varied greatly and included (in overlapping categories) double blind, fixed- and flexible-dose,

placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term

(up to 12 weeks) and longer term (up to 4 years) exposures. Safety was assessed by collecting adverse events and

performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.

Page

19

41

In addition to the studies in patients with schizophrenia, safety data are presented from a trial assessing the

efficacy and safety of RISPERDAL

CONSTA

when administered as monotherapy for maintenance treatment in

patients with bipolar I disorder. The subjects in this multi-center, double-blind, placebo-controlled study were

adult patients who met DSM-IV criteria for Bipolar Disorder Type I and who were stable on risperidone (oral or

long-acting injection), were stable on other antipsychotics or mood stabilizers, or were experiencing an acute

episode. After a 3-week period of treatment with open-label oral risperidone (n=440), subjects who demonstrated

initial response to oral risperidone in this period and those who were stable on risperidone (oral or long-acting

injection) at study entry entered into a 26-week stabilization period of open-label RISPERDAL

CONSTA

(n=501). Subjects who demonstrated a maintained response during this period were then randomized into a 24-

month

double-blind,

placebo-controlled

period

which

they

received

RISPERDAL

CONSTA

(n=154)

placebo (n=149) as monotherapy. Subjects who relapsed or who completed the double-blind period could choose

enter an 8-week open-label RISPERDAL

CONSTA

extension period (n=160).

Safety data are also presented from a trial assessing the efficacy and safety of RISPERDAL

CONSTA

when

administered as adjunctive maintenance treatment in patients with bipolar disorder. The subjects in this multi-

center, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria for Bipolar Disorder

Type

I or Type

II and

who experienced

least 4 episodes of mood

disorder

requiring psychiatric/clinical

intervention in the previous 12 months, including at least 2 episodes in the 6 months prior to the start of the study.

the start of this study, all patients (n=275) entered into a 16-week open-label treatment phase in which they

received

RISPERDAL

CONSTA

in addition to continuing their treatment as usual, which consisted of various

mood

stabilizers (primarily lithium and valproate), antidepressants, and/or anxiolytics. Patients who reached

remission

at the end of this 16-week open-label treatment phase (n=139) were then randomized into a 52-week

double-blind,

placebo-controlled phase in which they received RISPERDAL

CONSTA

(n=72) or placebo (n =

67) as adjunctive treatment in addition to continuing their treatment as usual. Patients who did not reach remission

the end of the 16-week open-label treatment phase could choose to continue to receive RISPERDAL

CONSTA

adjunctive therapy in an open-label manner, in addition to continuing their treatment as usual, for up

to an additional

36 weeks as clinically indicated for a total period of up to 52 weeks; these patients (n=70) were

also included in the

evaluation of safety.

Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical

investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of

individuals

experiencing

adverse

events,

events

were

grouped

standardized

categories

using

MedDRA

terminology.

Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered

to be reasonably associated with the use of RISPERDAL

CONSTA

(adverse drug reactions) based on the

comprehensive assessment of the available adverse event information. A causal association for RISPERDAL

CONSTA

often cannot be reliably established in individual cases. Further, 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.

The majority of all adverse reactions were mild to moderate in severity.

6.1

Commonly-Observed

Adverse

Reactions

in

Double-Blind,

Placebo-Controlled

Clinical

Trials

Schizophrenia

Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL

CONSTA

-treated patients with

schizophrenia in one 12-week double-blind, placebo-controlled trial.

Page

20

41

Table 4. Adverse Reactions in ≥ 2% of RISPERDAL

®

CONSTA

®

-Treated Patients with Schizophrenia in a

12-Week Double-Blind, Placebo-Controlled Trial

Percentage of Patients Reporting Event

RISPERDAL

®

CONSTA

®

Placebo

System /Organ Class

25 mg

50 mg

Adverse Reaction

(N=99)

(N=103)

(N=98)

Eye disorders

Vision blurred

Gastrointestinal disorders

Constipation

Dry mouth

Dyspepsia

Nausea

Toothache

Salivary hypersecretion

General disorders and administration site

conditions

Fatigue*

Edema peripheral

Pain

Pyrexia

Infections and infestations

Upper respiratory tract infection

Investigations

Weight increased

Weight decreased

Musculoskeletal and connective tissue

disorders

Pain in extremity

Nervous system disorders

Headache

Parkinsonism*

Dizziness

Page

21

41

Akathisia*

Sedation*

Tremor

Syncope

Hypoesthesia

Respiratory, thoracic and mediastinal

disorders

Cough

Sinus congestion

Skin and subcutaneous tissue disorders

Acne

Dry skin

* Fatigue includes fatigue and asthenia. Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness,

muscle rigidity, and bradykinesia. Akathisia includes akathisia and restlessness. Sedation includes sedation and

somnolence.

6.2

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials –

Bipolar Disorder

Table 5 lists the treatment-emergent adverse reactions reported in 2% or more of RISPERDAL

CONSTA

treated patients in the 24-month double-blind, placebo-controlled treatment period of the trial assessing the

efficacy and safety of RISPERDAL

CONSTA

when administered as monotherapy for maintenance treatment in

patients with Bipolar I Disorder.

Table 5

Adverse Reactions in ≥ 2% of Patients with Bipolar I Disorder Treated with RISPERDAL

®

CONSTA

®

as Monotherapy in a 24-Month Double-Blind, Placebo-Controlled Trial

Percentage of Patients Reporting Event

System/Organ Class

RISPERDAL

®

CONSTA

®

Placebo

Adverse Reaction

(N=154)

(N=149)

Investigations

Weight increased

Nervous system disorders

Dizziness

Vascular disorders

Hypertension

Table 6 lists the treatment-emergent adverse reactions reported in 4% or more of patients in the 52-week double-

blind, placebo-controlled treatment phase of a trial assessing the efficacy and safety of RISPERDAL

CONSTA

when administered as adjunctive maintenance treatment in patients with bipolar disorder.

Page

22

41

Table 6. Adverse Reactions in ≥ 4% of Patients with Bipolar Disorder Treated with RISPERDAL

®

CONSTA

®

as Adjunctive Therapy in a 52-Week Double-Blind, Placebo-Controlled Trial

Percentage of Patients Reporting Event

RISPERDAL

®

CONSTA

®

Placebo

System/Organ Class

Treatment as Usual

Treatment as Usual

Adverse Reaction

(N=72)

(N=67)

General disorders and administration site conditions

Gait abnormal

Infections and infestations

Upper respiratory tract infection

Investigations

Weight increased

Metabolism and nutrition disorders

Decreased appetite

Increased appetite

Musculoskeletal and connective tissue disorders

Arthralgia

Nervous system disorders

Tremor

Parkinsonism

Dyskinesia

Sedation

Disturbance in attention

Reproductive system and breast disorders

Amenorrhea

Respiratory, thoracic and mediastinal disorders

Cough

Page

23

41

Patients received double-blind RISPERDAL® CONSTA® or placebo in addition to continuing their treatment

as usual, which included mood stabilizers, antidepressants, and/or anxiolytics.

Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and bradykinesia. Dyskinesia includes

muscle twitching and dyskinesia

Sedation includes sedation and somnolence.

6.3

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone

The following additional adverse reactions occurred in <2% of the RISPERDAL

CONSTA

-treated patients in

the above schizophrenia double-blind, placebo-controlled trial dataset, in <2% of the RISPERDAL® CONSTA®-

treated patients in the above double-blind, placebo-controlled period of the monotherapy bipolar disorder trial

dataset, or in <4% of the RISPERDAL

CONSTA

-treated patients in the above double-blind, placebo-controlled

period of the adjunctive treatment bipolar disorder trial dataset. The following also includes additional adverse

reactions reported at any frequency in RISPERDAL

CONSTA

-treated patients who participated in the open-

label phases of the above bipolar disorder studies and in other studies, including double-blind, active controlled

and open-label studies in schizophrenia and bipolar disorder.

Blood and lymphatic system disorders

: anemia, neutropenia

Cardiac disorders

: tachycardia, atrioventricular block first degree, palpitations, sinus bradycardia, bundle branch

block left, bradycardia, sinus tachycardia, bundle branch block right

Ear and labyrinth disorders

: ear pain, vertigo

Endocrine disorders

: hyperprolactinemia

Eye disorders

: conjunctivitis, visual acuity reduced

Gastrointestinal disorders

: diarrhea, vomiting, abdominal pain upper, abdominal pain, stomach discomfort,

gastritis

General disorders and administration site conditions

: injection site pain, chest discomfort, chest pain, influenza

like illness, sluggishness, malaise, induration, injection site induration, injection site swelling, injection site

reaction, face edema

Immune system disorders

: hypersensitivity

Infections and infestations

: nasopharyngitis, influenza, bronchitis, urinary tract infection, rhinitis, respiratory

tract infection, ear infection, pneumonia, lower respiratory tract infection, pharyngitis, sinusitis, viral infection,

infection, localized infection, cystitis, gastroenteritis, subcutaneous abscess

Injury and poisoning

: fall, procedural pain

Investigations

blood

prolactin

increased,

alanine

aminotransferase

increased,

electrocardiogram

abnormal,

gamma-glutamyl

transferase

increased,

blood

glucose

increased,

hepatic

enzyme

increased,

aspartate

aminotransferase increased, electrocardiogram QT prolonged, glucose urine present

Page

24

41

Metabolism and nutritional disorders

: anorexia, hyperglycemia

Musculoskeletal, connective tissue and bone disorders

: posture abnormal, myalgia, back pain, buttock pain,

muscular weakness, neck pain, musculoskeletal chest pain

Nervous system disorders

: coordination abnormal, dystonia, tardive dyskinesia, drooling, paresthesia, dizziness

postural, convulsion, akinesia, hypokinesia, dysarthria

Psychiatric disorders

: insomnia, agitation, anxiety, sleep disorder, depression, initial insomnia, libido decreased,

nervousness

Renal and urinary disorders

: urinary incontinence

Reproductive

system

and

breast

disorders

galactorrhea,

oligomenorrhea,

erectile

dysfunction,

sexual

dysfunction, ejaculation disorder, gynecomastia, breast discomfort, menstruation irregular, menstruation delayed,

menstrual disorder, ejaculation delayed

Respiratory, thoracic and mediastinal disorders

: nasal congestion, pharyngolaryngeal pain, dyspnea, rhinorrhea

Skin and subcutaneous tissue disorders

: rash, eczema, pruritus generalized, pruritus

Vascular disorders

: hypotension, orthostatic hypotension

Additional adverse Reactions Reported with Oral RISPERDAL®

The following is a list of additional adverse reactions that have been reported during the clinical trial evaluation of

oral RISPERDAL®, regardless of frequency of occurrence:

Blood and Lymphatic Disorders

: granulocytopenia

Cardiac Disorders

: atrioventricular block

Ear and Labyrinth Disorders

: tinnitus

Eye Disorders

: ocular hyperemia, eye discharge, eye rolling, eyelid edema, eye swelling, eyelid margin crusting,

dry eye, lacrimation increased, photophobia, glaucoma

Gastrointestinal Disorders

: abdominal pain upper, dysphagia, fecaloma, abdominal discomfort, fecal

incontinence, lip swelling, cheilitis, aptyalism

General Disorders

: thirst, feeling abnormal, gait disturbance, pitting edema, edema, chills, discomfort,

generalized edema, drug withdrawal syndrome, peripheral coldness

Immune System Disorders

: drug hypersensitivity

Infections and Infestations

: tonsillitis, eye infection, cellulitis, otitis media, onychomycosis, acarodermatitis,

bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic

Investigations

: body

temperature increased, heart rate increased, eosinophil count increased, white blood cell

count decreased,

hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body

temperature

decreased, blood pressure decreased, transaminases increased

Metabolism and Nutrition Disorders

polydipsia

Musculoskeletal, Connective Tissue, and Bone Disorders

: joint swelling, joint stiffness, rhabdomyolysis,

torticollis

Page

25

41

Nervous System Disorders

: hypertonia, balance disorder, dysarthria, unresponsive to stimuli, depressed level of

consciousness, movement disorder, hypokinesia, parkinsonian rest tremor, transient ischemic attack,

cerebrovascular accident, masked facies, speech disorder, loss of consciousness, muscle contractions involuntary,

akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head

titubation

Psychiatric Disorders:

blunted affect, confusional state, middle insomnia, listlessness, anorgasmia

Renal and Urinary Disorders:

enuresis, dysuria, pollakiuria

Reproductive System and Breast Disorders:

vaginal discharge, retrograde ejaculation, ejaculation disorder,

ejaculation failure, breast enlargement

Respiratory, Thoracic, and Mediastinal Disorders:

epistaxis, wheezing, pneumonia aspiration, dysphonia,

productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation,

nasal edema

Skin and Subcutaneous Tissue Disorders:

erythema, skin discoloration, skin lesion, skin disorder, rash

erythematous, rash papular, hyperkeratosis, dandruff, seborrheic dermatitis, rash generalised, rash maculopapular

Vascular Disorders:

flushing

6.4

Discontinuations Due to Adverse Reactions

Schizophrenia

Approximately 11% (22/202) of RISPERDAL

CONSTA

-treated patients in the 12-week double-blind, placebo-

controlled schizophrenia trial discontinued treatment due to an adverse event, compared with 13% (13/98) who

received placebo. The adverse reactions associated with discontinuation in two or more RISPERDAL

CONSTA

-treated patients were: agitation (3%), depression (2%), anxiety (1%), and akathisia (1%).

Bipolar Disorder

In the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of

RISPERDAL

CONSTA

when administered as monotherapy for maintenance treatment in patients with bipolar I

disorder, 1 (0.6%) of 154 RISPERDAL

CONSTA

-treated patients discontinued due to an adverse reaction

(hyperglycemia).

In the 52-week double-blind phase of the placebo-controlled trial in which RISPERDAL

CONSTA

administered as adjunctive therapy to patients with bipolar disorder in addition to continuing with their treatment

as usual, approximately 4% (3/72) of RISPERDAL

CONSTA

-treated patients discontinued treatment due to an

adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adverse reactions associated with

discontinuation in RISPERDAL

CONSTA

-treated patients were: hypokinesia (one patient) and tardive

dyskinesia (one patient).

6.5

Dose Dependency of Adverse Reactions in Clinical Trials

Extrapyramidal Symptoms:

Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week double-blind, placebo

controlled trial comparing three doses of RISPERDAL

CONSTA

(25 mg, 50 mg, and 75 mg) with placebo in

patients with schizophrenia, including: (1) the incidence of spontaneous reports of EPS symptoms; and (2) the

change from baseline to endpoint on the total score (sum of the subscale scores for parkinsonism, dystonia, and

dyskinesia) of the Extrapyramidal Symptom Rating Scale (ESRS).

As shown in Table 1, the overall incidence of EPS-related adverse reactions (akathisia, dystonia, parkinsonism,

and tremor) in patients treated with 25 mg RISPERDAL

CONSTA

was comparable to that of patients treated

with placebo; the incidence of EPS related adverse reactions was higher in patients treated with 50 mg

RISPERDAL

CONSTA

Page

26

41

The median change from baseline to endpoint in total ESRS score showed no worsening in patients treated with

RISPERDAL

CONSTA

compared with patients treated with placebo: 0 (placebo group);

-1 (25 mg group, significantly less than the placebo group); and 0 (50 mg group).

Dystonia

Class Effect:

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible

individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles,

sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of

the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity

with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is

observed in males and younger age groups.

6.6

Changes in ECG

The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg RISPERDAL

CONSTA

98 schizophrenic patients treated with placebo in the 12 week double blind, placebo controlled trial were

evaluated.

Compared with placebo, there were no statistically significant differences in QTc intervals (using

Fridericia’s

and linear correction factors) during treatment with RISPERDAL

CONSTA

The electrocardiograms of 227 patients with Bipolar I Disorder were evaluated in the 24-month double-blind,

placebo-controlled period. There were no clinically relevant differences in QTc intervals (using Fridericia’s and

linear correction factors) during treatment with RISPERDAL

CONSTA

compared to placebo.

The electrocardiograms of 85 patients with bipolar disorder were evaluated in the 52-week double-blind, placebo-

controlled trial. There were no statistically significant differences in QTc intervals (using Fridericia’s and linear

correction factors) during treatment with RISPERDAL

CONSTA

25 mg, 37.5 mg, or 50 mg when administered

as adjunctive treatment in addition to continuing treatment as usual compared to placebo.

6.7

Pain Assessment and Local Injection Site Reactions

The mean intensity of injection pain reported by patients with schizophrenia using a visual analog scale (0 = no

pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo:

16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings

indicated that 1% of patients treated with 25 mg or 50 mg RISPERDAL

CONSTA

experienced redness,

swelling, or induration at the injection site.

In a separate study to observe local-site tolerability in which RISPERDAL

CONSTA

was administered into the

deltoid muscle every 2 weeks over a period of 8 weeks, no patient discontinued treatment due to local injection

site pain or reaction. Clinician ratings indicated that only mild redness, swelling, or induration at the injection site

were observed in subjects treated with 37.5 mg or 50 mg RISPERDAL

CONSTA

at 2 hours after deltoid

injection. All ratings returned to baseline at the predose assessment of the next injection 2 weeks later. No

moderate or severe reactions were observed in any subject.

6.8 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of risperidone; because these

reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their

frequency:

agranulocytosis, alopecia,

anaphylactic

reaction, angioedema, atrial

fibrillation, blood cholesterol

increased, blood triglycerides increased, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose

metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, ileus,

Page

27

41

inappropriate

Page

28

41

antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation,

sleep apnea syndrome, thrombocytopenia, urinary retention, a n d water intoxication, . In addition, the following

adverse reactions have been observed during postapproval use

of RISPERDAL

CONSTA

: cerebrovascular

disorders, including cerebrovascular accidents, and diabetes

mellitus aggravated.

Retinal artery occlusion after injection of RISPERDAL

CONSTA

has been reported during postmarketing

surveillance. This has been reported in the presence of abnormal arteriovenous anastomosis.

Serious injection site reactions including abscess, cellulitis, cyst, hematoma, necrosis, nodule, and ulcer have been

reported

with

RISPERDAL

CONSTA

during

postmarketing

surveillance. Isolated cases required surgical

intervention

Very rarely, cases of anaphylactic reaction after injection with RISPERDAL® CONSTA® have been reported

during postmarketing experience in patients who have previously tolerated oral risperidone.

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.

7

DRUG INTERACTIONS

The interactions of RISPERDAL

CONSTA

with coadministration of other drugs have not been systematically

evaluated. The drug interaction data provided in this section are based on studies with oral RISPERDAL

7.1

Centrally-Acting Drugs and Alcohol

Given

the primary

CNS effects

risperidone, caution should be used when

RISPERDAL

CONSTA

administered in combination with other centrally acting drugs

alcohol.

7.2

Drugs with Hypotensive Effects

Because of its potential for inducing hypotension, RISPERDAL

CONSTA

may enhance the hypotensive effects

of other therapeutic agents with this potential.

7.3

Levodopa and Dopamine Agonists

RISPERDAL

CONSTA

may antagonize the effects of levodopa and dopamine agonists.

7.4

Amitriptyline

Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9-hydroxyrisperidone

combined following concomitant administration with oral RISPERDAL

7.5

Cimetidine and Ranitidine

Page

29

41

Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively.

However,

cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas

ranitidine increased

the AUC of risperidone and 9-hydroxyrisperidone combined by 20%.

7.6

Clozapine

Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

7.7

Lithium

Repeated doses of oral RISPERDAL

(3 mg twice daily) did not affect the exposure (AUC) or peak plasma

concentrations (C

) of lithium (n=13).

7.8

Valproate

Repeated

doses

oral

RISPERDAL

once

daily)

affect

pre-dose

average

plasma

concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo

(n=21). However, there was a 20% increase in valproate peak plasma concentration (C

) after concomitant

administration of oral RISPERDAL

7.9

Digoxin

Oral RISPERDAL

(0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of

digoxin.

7.10

Topiramate

Oral RISPERDAL

administered at doses from 1-6 mg/day concomitantly with topiramate 400 mg/day resulted in

a 23% decrease in risperidone Cmax and a 33% decrease in risperidone AUC

0-12 hour

at steady state. Minimal

reductions

exposure

risperidone

9-hydroxyrisperidone

combined,

change

hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no

clinically relevant effect of oral RISPERDAL

on the pharmacokinetics of topiramate.

7.11

Drugs That Inhibit CYP 2D6 and Other CYP Isozymes

Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the

population

and that can be inhibited by a variety of psychotropic and other drugs

[see Clinical Pharmacology

(12.3)]

Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the

plasma

concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical

studies involving a modest number of poor metabolizers (n

70 patients) does not suggest that poor and extensive

metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been

made.

In vitro

studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4,

are only weak inhibitors of risperidone metabolism.

Fluoxetine and Paroxetine

Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), CYP 2D6 inhibitors, have been shown to

increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect

the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone

by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should

re-evaluate the dose of RISPERDAL

CONSTA

. When initiation of fluoxetine or paroxetine is considered,

patients may be placed on a lower dose of RISPERDAL

CONSTA

between 2 to 4 weeks before the planned

Page

30

41

start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of

risperidone.

When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg

RISPERDAL

CONSTA

, it is recommended to continue treatment with the 25 mg dose unless clinical judgment

necessitates

lowering

RISPERDAL®

CONSTA®

dose

12.5

necessitates

interruption

RISPERDAL®

CONSTA® treatment. When RISPERDAL® CONSTA® is initiated in patients already receiving

fluoxetine or

paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not

been investigated

clinical

trials.

[see

also

DOSAGE

AND

ADMINISTRATION

(2.5)]

effects

discontinuation

concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-

hydroxyrisperidone

have not been studied.

Erythromycin

There were no significant interactions between oral RISPERDAL

and erythromycin.

7.12

Carbamazepine and Other CYP 3A4 Enzyme Inducers

Carbamazepine co-administration with oral RISPERDAL

decreased the steady-state plasma concentrations of

risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be

affected.

Co-administration

other

known

enzyme

inducers

(e.g.,

phenytoin,

rifampin,

phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone

and 9-hydroxyrisperidone, which could lead to decreased efficacy of RISPERDAL

CONSTA

treatment. At the

initiation of therapy with carbamazepine or other known hepatic enzyme inducers, patients should be closely

monitored during the first 4 - 8 weeks, since the dose of RISPERDAL

CONSTA

may need to be adjusted. A

dose increase, or additional oral RISPERDAL

, may need to be considered. On discontinuation of carbamazepine

or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL

CONSTA

should be re-evaluated and,

if necessary, decreased. Patients may be placed on a lower dose of RISPERDAL

CONSTA

between 2 to 4

weeks before the planned discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for the

expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the

recommended dose of 25 mg RISPERDAL

CONSTA

and discontinuing from carbamazepine or other CYP 3A4

enzyme inducers, it is recommended to continue treatment with the 25 mg dose unless clinical judgment

necessitates

lowering

RISPERDAL®

CONSTA®

dose

12.5

necessitates

interruption

RISPERDAL®

CONSTA® treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials.

[see also

DOSAGE AND ADMINSTRATION (2.5)]

7.13

Drugs Metabolized by CYP 2D6

In vitro

studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, RISPERDAL

CONSTA

is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic

pathway. In drug interaction studies, oral RISPERDAL

did not significantly affect the pharmacokinetics of

donepezil and galantamine, which are metabolized by CYP 2D6.

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Pregnancy

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal

and/or withdrawal symptoms following delivery

(see Clinical Considerations)

. Overall, available data from

published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated

risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

(see Data).

There are risks to the

mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including

RISPERDAL CONSTA

, during pregnancy

(see Clinical Considerations)

. Risperidone has been detected in plasma

in adult subjects up to 8 weeks after a single-dose administration of RISPERDAL CONSTA

[see Clinical

Pharmacology (12.3)]

. The clinical significance of RISPERDAL CONSTA

administered before pregnancy or

anytime during pregnancy is not known.

Page

31

41

Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum

recommended human dose (MRHD) with maternal toxicity observed at 4-times the MRHD based on mg/m

body

surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m

body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to

pregnant rats at 1.5-times the MRHD based on mg/m

body surface area. Learning was impaired in offspring of rats

when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the

MRHD based on mg/m

body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All

pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population,

the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4%

and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse,

hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal

outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence,

respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs,

including RISPERDAL CONSTA

, during the third trimester of pregnancy. These symptoms have varied in

severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics

during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective

observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A

retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy

did not indicate an overall increased risk for major birth defects. There was a small increase in the risk major of

birth defects (RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in a

subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no

mechanism of action to explain the difference in malformation rates.

Animal Data

Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which

is 3 times the MRHD of 16 mg/day based on mg/m

body surface area; maternal toxicity occurred at 4 times the

MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3

to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m

body surface area.

Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the

MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2

mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m

body surface area; postnatal development and

growth of the offspring were also delayed.

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout

gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day based on mg/m

body surface

area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the

dams:

A no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5

times the MRHD based on mg/m

body surface area.

In a rat cross-

fostering study the number of live

offspring was decreased, the number of stillbirths increased

and the birth weight was decreased in offspring of drug-

treated pregnant rats. In addition, the number of deaths

increased by Day 1 among offspring of drug-treated

pregnant rats, regardless of whether or not the offspring

were cross fostered. Risperidone also appeared to impair maternal

behavior in that offspring body weight gain

and survival (from Day 1 to 4 of lactation) were reduced in offspring born to

control but reared by drug-treated

dams. All of these effects occurred at 5

mg/kg which is 3 times the MRHD based on mg/m

and the only dose tested

in the study.

8.2

Lactation

Risk Summary

Limited data from published literature reports the presence of risperidone and its metabolite, 9-

hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3% and 4.7% of the maternal

weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms

(tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical

Page

32

41

Considerations). Risperidone has been detected in plasma in adult subjects up to 8 weeks after a single-dose

administration of RISPERDAL CONSTA® [see Clinical Pharmacology (12.3)], and the clinical significance on

the breastfed infant is not known. There is no information on the effects of risperidone on milk production. The

developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need

for RISPERDAL CONSTA® and any potential adverse effects on the breastfed child from

RISPERDAL CONSTA® or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to RISPERDAL CONSTA® through breastmilk should be monitored for excess sedation,

failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

8.3

Females and Males of Reproductive Potential

Infertility

Females

Based on the pharmacologic action of risperidone (D2 receptor antagonism), treatment with RISPERDAL

CONSTA

may result in an increase in serum prolactin levels, which may lead to a reversible reduction in

fertility in females of reproductive potential

[see Warnings and Precautions (5.6)].

8.4

Pediatric Use

Safety and effectiveness of RISPERDAL

CONSTA

in pediatric patients have not been

established.

However, juvenile animal toxicology studies have been conducted with oral

risperidone.

Juvenile Animal Studies Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to

the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day

which are 1.2, 3.4

and 13.5 times the MRHD of 6 mg/day for children, based on mg/m

body surface area. Bone

length and density

were decreased, with a no-effect dose of 0.31 mg/kg/day: this dose produced plasma AUC

of risperidone plus its

active metabolite paliperidone (9-hydroxy-risperidone) that were similar to those in

children and adolescents

receiving the MRHD of 6mg/day. In addition, sexual maturation was delayed at all doses in both males and females.

The above effects showed little or no

reversibility in females after a 12 week drug-free recovery period.

Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy

through adolescence in humans) showed impaired learning and memory performance (reversible only in females),

with a no-effect dose of 0.63 mg/kg/day,

which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m

body surface area.. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure

observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development

were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of

risperidone

plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/day for

children.

8.5 Geriatric Use

In an open-label study, 57 clinically stable, elderly patients (≥65 years old) with schizophrenia or schizoaffective

disorder received RISPERDAL

CONSTA

every 2 weeks for up to 12 months. In general, no differences in the

tolerability of RISPERDAL

CONSTA

were observed between otherwise healthy elderly and nonelderly

patients.

Therefore, dosing recommendations for otherwise healthy elderly patients are the same as for nonelderly

patients. Because elderly patients exhibit a greater tendency to orthostatic hypotension than nonelderly patients,

elderly patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of

orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the

morning and slowly rising from a seated position). In addition, monitoring of orthostatic vital signs should be

considered in elderly patients for whom orthostatic hypotension is of concern

[see Warnings and Precautions

(5.7)]

Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis

Page

33

41

In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of

mortality was observed in patients treated with furosemide plus oral risperidone when compared to patients treated

with oral risperidone alone or with oral placebo plus furosemide. No pathological mechanism has been identified

to explain this finding, and no consistent pattern for cause of death was observed. An increase of mortality in

elderly

patients

with

dementia-related

psychosis

seen

with

oral

risperidone

regardless

concomitant use with furosemide. RISPERDAL

CONSTA

is not approved for the treatment of patients with

dementia-related psychosis.

[see Boxed Warning and Warnings and Precautions (5.1)]

9

DRUG ABUSE AND DEPENDENCE

9.1

Controlled Substance

RISPERDAL

CONSTA

(risperidone) is not a controlled substance.

9.2

Abuse

RISPERDAL

CONSTA

has not been systematically studied in animals or humans for its potential for abuse.

Because RISPERDAL

CONSTA

is to be administered by health care professionals, the potential for misuse or

abuse by patients is low.

9.3

Dependence

RISPERDAL

CONSTA

has not been systematically studied in animals or humans for its potential for tolerance

or physical dependence.

10

OVERDOSAGE

10.1

Human Experience

cases

overdose

were

reported

premarketing

studies

with

RISPERDAL

CONSTA

Because

RISPERDAL

CONSTA

is to be administered by health care professionals, the potential for overdosage by

patients is low.

In premarketing experience with oral RISPERDAL

, there were eight reports of acute RISPERDAL

overdosage,

with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were

those resulting from an exaggeration of the drug’s known pharmacological effects, i.e., drowsiness and sedation,

tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240

mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving

an estimated overdose of 36 mg, was associated with a seizure.

Postmarketing experience with oral RISPERDAL

includes reports of acute overdose, with estimated doses of up

to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration

drug’s

known

pharmacological

effects,

i.e.,

drowsiness,

sedation,

tachycardia,

hypotension,

extrapyramidal

symptoms.

Other

adverse

reactions

reported

since

market

introduction

related

oral

RISPERDAL

overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in

association with combined overdose of oral RISPERDAL

and paroxetine.

10.2

Management of Overdosage

In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation.

Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic

monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide,

Page

34

41

and quinidine carry a theoretical hazard of QT prolonging effects that might be additive to those of risperidone.

Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of

risperidone, resulting in problematic hypotension.

There is no specific antidote to risperidone. Therefore, appropriate supportive measures should be instituted. The

possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be

treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and

dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced

alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

Close medical supervision and monitoring should continue until the patient recovers.

11

DESCRIPTION

RISPERDAL CONSTA

contains risperidone, an atypical antipsychotic belonging to the chemical class

benzisoxazole

derivatives.

chemical

designation

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-

piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-

pyrido[1,2-a]pyrimidin-4-one.

molecular

formula

and its molecular weight is 410.49. The

structural formula is:

Risperidone is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1

N HCl.

RISPERDAL

CONSTA

(risperidone) Long-Acting Injection is a combination of extended-release microspheres

for injection and diluent for parenteral use.

The extended-release microspheres formulation is a white to off-white, free-flowing powder that is available in

dosage strengths of 25 mg, 37.5 mg, or 50 mg risperidone per vial. Risperidone is micro encapsulated in 7525

polylactide-co-glycolide (PLG) at a concentration of 381 mg risperidone per gram of microspheres.

diluent

parenteral

clear,

colorless

solution.

Composition

diluent

includes

sodium

carboxymethyl cellulose

, sodium chloride

,disodium

hydrogen

phosphate

dihydrate

citric

acid

anhydrous, , polysorbate 20,

sodium hydroxide, and water for injection. The microspheres are suspended in

the diluent prior to injection.

RISPERDAL

CONSTA

is provided as a dose pack, consisting of a vial containing the microspheres, a pre-filled

syringe containing the diluent, a vial Adapter®, and two Terumo SurGuard® 3 Needles (a 21 G UTW 1-inch

needle with needle protection device for deltoid administration and a

20 G TW 2-inch needle with needle protection

device for gluteal administration).

12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

The mechanism of action of risperidone in schizophreniais

unclear. The drug’s therapeutic activity in

schizophrenia could be mediated through

a combination of dopamine Type 2 (D

) and serotonin Type 2 (5HT

receptor antagonism.

The clinical effect from risperidone results from the combined concentrations of risperidone

and its major active metabolite, 9-hydroxyrisperidone (paliperidone)

[see Clinical Pharmacology (12.3)]

Page

35

41

Antagonism at receptors other than D

and 5HT

may explain some of the other effects of risperidone

[see

Clinical Pharmacology (12.1)]

12.2

Pharmacodynamics

Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin

Type 2

(5HT

), dopamine Type 2 (D2), α1 and α2 adrenergic, and H

histaminergic receptors.

Risperdone showed low to

moderate affinity (Ki of 47

to 253 nM) for the serotonin 5HT

, 5HT

, and 5HT

receptors, weak affinity (Ki

of 620 to 800 nM) for the

dopamine D

and haloperidol-sensitive sigma site, and no affinity (when tested at

concentrations >10

M) for

cholinergic muscarinic or β1 and β2 adrenergic receptors.

12.3

Pharmacokinetics

Absorption

After a single intramuscular (gluteal) injection of RISPERDAL

CONSTA

, there is a small initial release of the

drug (< 1% of the dose), followed by a lag time of 3 weeks. The main release of the drug starts from 3 weeks

onward, is maintained from 4 to 6 weeks, and subsides by 7 weeks following the intramuscular (IM) injection.

Therefore, oral antipsychotic

supplementation should be given during the

first 3

weeks of treatment

with

RISPERDAL

CONSTA

to maintain therapeutic levels until the main release of risperidone from the injection

site has begun

[see Dosage and Administration (2)]

. Following single doses of RISPERDAL

CONSTA

, the

pharmacokinetics

risperidone,

9-hydroxyrisperidone

(the

major

metabolite),

risperidone

plus

hydroxyrisperidone were linear in the dosing range of 12.5 mg to 50 mg.

The combination of the release profile and the dosage regimen (IM injections every 2 weeks) of RISPERDAL

CONSTA

results in sustained therapeutic concentrations. Steady-state plasma concentrations are reached after 4

injections and are maintained for 4 to 6 weeks after the last injection. Following multiple doses of 25 mg and 50

mg RISPERDAL

CONSTA

, plasma concentrations of risperidone, 9-hydroxyrisperidone, and risperidone plus

9-hydroxyrisperidone were linear.

Deltoid and gluteal intramuscular injections at the same doses are bioequivalent and, therefore, interchangeable.

Distribution

Once absorbed, risperidone is rapidly distributed. The volume of distribution is 1 - 2 L/kg. In plasma, risperidone

is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%,

and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone

displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL),

warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of

risperidone at 10 ng/mL and of 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.

Metabolism and Drug Interactions

Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of

risperidone

to 9-hydroxyrisperidone by

the enzyme, CYP 2D6. A minor metabolic pathway

through

dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone.

Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-

hydroxyrisperidone.

CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics,

antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-8% of

Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to

inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers

Page

36

41

convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more

slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations

than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and

multiple doses, are similar in extensive and poor metabolizers.

The interactions of RISPERDAL

CONSTA

with coadministration of other drugs have not been systematically

evaluated in human subjects. Drug interactions are based primarily on experience with oral RISPERDAL

Risperidone could be subject to two kinds of drug drug interactions. First, inhibitors of CYP 2D6 interfere with

conversion of risperidone to 9-hydroxyrisperidone

[see Drug Interactions (7.11)]

. This occurs with quinidine,

giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic

benefits and adverse effects of RISPERDAL

in patients receiving quinidine have not been evaluated, but

observations in a modest number (n

70) of poor metabolizers given oral RISPERDAL

do not suggest important

differences between poor and extensive metabolizers. Second, co-administration of carbamazepine and other

known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with oral RISPERDAL

cause a decrease

in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone

[see Drug Interactions (7.12)]

. It

would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6.

Relatively weak binding of risperidone to the enzyme suggests this is unlikely

[see Drug Interactions (7.11)]

Excretion

Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As

illustrated by a mass balance study of a single 1 mg oral dose of

C risperidone administered as solution to three

healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in

the feces.

apparent

half-life

risperidone

plus

9-hydroxyrisperidone

following

RISPERDAL

CONSTA

administration

days,

associated

with

monoexponential

decline

plasma

concentrations. This half-life of 3-6 days is related to the erosion of the microspheres and subsequent absorption of

risperidone. The clearance of risperidone and risperidone plus 9-hydroxyrisperidone was 13.7 L/h and 5.0 L/h in

extensive CYP 2D6 metabolizers, and 3.3 L/h and 3.2 L/h in poor CYP 2D6 metabolizers, respectively. No

accumulation of risperidone was observed during long-term use (up to 12 months) in patients treated every 2

weeks with 25 mg or 50 mg RISPERDAL

CONSTA

. The elimination phase is complete approximately 7 to 8

weeks after the last injection.

Renal Impairment

In patients with moderate to severe renal disease treated with oral RISPERDAL

, clearance of the sum of

risperidone and its active metabolite decreased by 60% compared with young healthy subjects. Although patients

with renal impairment were not studied with RISPERDAL

CONSTA

, it is recommended that patients with renal

impairment be carefully titrated on oral RISPERDAL

before treatment with RISPERDAL

CONSTA

initiated

at a dose of 25 mg. A lower initial dose of 12. 5 mg may be appropriate when clinical factors warrant

dose

adjustment, such as in patients with renal impairment

[see Dosage and Administration (2.4)]

Hepatic Impairment

While the pharmacokinetics of oral RISPERDAL

in subjects with liver disease were comparable to those in

young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the

diminished concentration of both albumin and α1-acid glycoprotein. Although patients with hepatic impairment

were not studied with RISPERDAL

CONSTA

, it is recommended that patients with hepatic impairment be

carefully titrated on oral RISPERDAL® before treatment with RISPERDAL® CONSTA® is initiated at a dose of

25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as

in patients with hepatic impairment [see Dosage and Administration

(2.4)]

Page

37

41

Elderly

In an open label trial, steady state concentrations of risperidone plus 9-hydroxyrisperidone in otherwise healthy

elderly patients (≥65 years old) treated with RISPERDAL

CONSTA

for up to 12 months fell within the range of

values observed in otherwise healthy nonelderly patients. Dosing recommendations are the same for otherwise

healthy elderly patients and nonelderly patients

[see Dosage and Administration (2)]

Race and Gender Effects

No specific pharmacokinetic study was

conducted to investigate race and gender effects, but a population

pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender

(whether or not corrected for body weight) or race.

13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis - Oral

Risperidone was administered in the

diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for

25 months to rats. These doses are

equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and

6 times (rats) the MRHD of 16 mg/day, based on mg/m

body surface area. A maximum tolerated dose was not

achieved

male

mice. There

significant increase in pituitary gland adenomas

, endocrine pancreatic

adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on

mg/m

(mg/kg) basis at which these tumors occurred.

Multiples of Maximum Human

Dose in mg/m

2

(mg/kg)

Tumor Type

Species

Sex

Lowest

Effect

Level

Highest No-

Effect Level

Pituitary adenomas

mouse

Female

0.75 (9.4)

0.2 (2.4)

Endocrine pancreas adenomas

Male

1.5 (9.4)

0.4 (2.4)

Mammary gland adenocarcinomas

mouse

Female

0.2 (2.4)

none

Female

0.4 (2.4)

none

Male

6.0 (37.5)

1.5 (9.4)

Mammary gland neoplasm, Total

Male

1.5 (9.4)

0.4 (2.4)

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels

were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic

toxicity studies showed that risperidone elevated serum prolactin levels 5-6 fold in mice and rats at the same doses

used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has

been found in rodents after chronic administration of other antipsychotic drugs and is considered to be

prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in

rodents is unclear

[see Warnings and Precautions (5.6)]

Carcinogenesis - Intramuscular

Risperidone

was evaluated in a 24 month carcinogenicity study in which SPF Wistar rats were

treated every

2 weeks with intramuscular (IM) injections of either 5 mg/kg or 40 mg/kg of risperidone. These

doses are 1 and

8 times the MRHD (50 mg) on a mg/m

basis. A control group received injections of 0.9% NaCl,

and a vehicle

control group was injected with placebo microspheres. There was a significant increase in pituitary

gland

adenomas, endocrine pancreas adenomas, and adrenomedullary pheochromocytomas at 8 times the IM

MRHD

on a mg/m

basis. The incidence of mammary gland adenocarcinomas was significantly increased in

female

Page

38

41

rats at both doses (1 and 8 times the IM MRHD on a mg/m

basis). A significant increase in renal tubular

tumors

(adenoma, adenocarcinomas) was observed in male rats at 8 times the IM MRHD on a mg/m

basis.

Plasma

exposures (AUC) in rats were 0.3 and 2 times (at 5 and 40 mg/kg, respectively) the expected plasma

exposure

(AUC) at the IM MRHD.

Dopamine D

receptor antagonists have been shown to chronically elevate prolactin levels in rodents. Serum

prolactin levels were not measured during the carcinogenicity studies of oral risperidone; however, measurements

taken during subchronic toxicity studies showed that oral risperidone elevated serum prolactin levels 5- to 6-fold

in mice and rats at the same doses used in the oral carcinogenicity studies. Serum prolactin levels increased in a

dose dependent manner up to 6- and 1.5-fold in male and female rats, respectively, at the end of the 24-month

treatment with

risperidone

every 2 weeks IM. Increases in the incidence of pituitary gland, endocrine

pancreas,

and mammary gland neoplasms have been found in rodents after chronic administration of other

antipsychotic

drugs and may be prolactin-mediated.

The relevance for human risk of the findings of prolactin mediated endocrine tumors in rodents is unknown

[see

Warnings and Precautions (5.6)]

Mutagenesis

No evidence of mutagenic or clastogenic potential for risperidone was found in the

in vitro

tests

Ames gene

mutation , the mouse lymphoma assay, rat hepatocyte DNA repair assay, the chromosomal aberration test in human

lymphocytes, Chinese hamster ovary cells, or in the

in vivo

micronucleus test in mice, and the

sex linked recessive

lethal test in

Drosophila

addition,

no evidence

of mutagenic

potential was

found in

in

vitro

Ames

reverse mutation

test

RISPERDAL

CONSTA

Impairment of Fertility

Oral risperidone (0.16 to 5

mg/kg) impaired mating, but not fertility, in rat

reproductive studies at doses 0.1 to 3

times the oral

maximum recommended human dose MRHD o f 16 mg/day) b a s e d on a mg/m

body surface

area. The effect appeared to be in

females, since impaired mating behavior was not noted in the male fertility

study. In a subchronic study in Beagle dogs in which oral risperidone was administered at doses of 0.31 to 5

mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the oral MRHD on a mg/m

basis. Dose related decreases were also noted in serum testosterone at the same doses. Serum testosterone and

sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose

could not be determined in either rat or dog.

14

CLINICAL STUDIES

14.1

Schizophrenia

The effectiveness of RISPERDAL

CONSTA

in the treatment of schizophrenia was established, in part, on the

basis of extrapolation from the established effectiveness of the oral formulation of risperidone. In addition, the

effectiveness of RISPERDAL

CONSTA

in the treatment of schizophrenia was established in a 12-week,

placebo-controlled

trial

adult

psychotic

inpatients

outpatients

criteria

schizophrenia.

Efficacy data were obtained from 400 patients with schizophrenia who were randomized to receive injections of

25 mg, 50 mg, or 75 mg RISPERDAL

CONSTA

or placebo every 2 weeks. During a 1 week run in period,

patients were discontinued from other antipsychotics and were titrated to a dose of 4 mg oral RISPERDAL

Patients who received RISPERDAL

CONSTA

were given doses of oral RISPERDAL

(2 mg for patients in the

25-mg group, 4 mg for patients in the 50 mg group, and 6 mg for patients in the 75 mg group) for the 3 weeks after

Page

39

41

the first injection to provide therapeutic plasma concentrations until the main release phase of risperidone from the

injection site had begun. Patients who received placebo injections were given placebo tablets.

Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated, multi-item

inventory, composed of five subscales to evaluate positive symptoms, negative symptoms, disorganized thoughts,

uncontrolled hostility/excitement, and anxiety/depression.

The primary efficacy variable in this trial was change from baseline to endpoint in the total PANSS score. The

mean total PANSS score at baseline for schizophrenic patients in this study was 81.5.

Total PANSS scores showed significant improvement in the change from baseline to endpoint in schizophrenic

patients treated with each dose of RISPERDAL

CONSTA

(25 mg, 50 mg, or 75 mg) compared with patients

treated with placebo. While there were no statistically significant differences between the treatment effects for the

three dose groups, the effect size for the 75 mg dose group was actually numerically less than that observed for the

50 mg dose group.

Subgroup analyses did not indicate any differences in treatment outcome as a function of age, race, or gender.

14.2

Bipolar Disorder - Monotherapy

The effectiveness of RISPERDAL

CONSTA

for the maintenance treatment of Bipolar I Disorder was

established

in a multicenter, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria for

Bipolar

Disorder Type I, who were stable on medications or experiencing an acute manic or mixed episode.

A total of 501 patients were treated during a 26-week open-label period with RISPERDAL

CONSTA

(starting

dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50 mg; in patients not tolerating the 25

mg dose, the dose could be reduced to 12.5 mg). In the open-label phase, 303 (60%) patients were judged to be

stable and were randomized to double-blind treatment with either the same dose of RISPERDAL

CONSTA

placebo and monitored for relapse. The primary endpoint was time to relapse to any mood episode (depression,

mania, hypomania, or mixed).

Time

to relapse was

delayed in

patients

receiving RISPERDAL

CONSTA

monotherapy

compared to

placebo. The majority of relapses were due to manic rather than depressive symptoms. Based on their bipolar

disorder history, subjects entering this study had had, on average, more manic episodes than depressive episodes.

14.3

Bipolar Disorder - Adjunctive Therapy

The effectiveness of RISPERDAL

CONSTA

as an adjunct to treatment with lithium or valproate for the

maintenance treatment of Bipolar Disorder was established in a multi-center, randomized, double-blind, placebo-

controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I and who experienced at

least 4 episodes of mood disorder requiring psychiatric/clinical intervention in the previous 12 months, including

at least 2 episodes in the 6 months prior to the start of the study.

A total of 240 patients were treated during a 16-week open-label period with RISPERDAL

CONSTA

(starting

dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50 mg), as adjunctive therapy in addition

to continuing their treatment as usual for their bipolar disorder, which consisted of mood stabilizers (primarily

lithium and valproate), antidepressants, and/or anxiolytics. All oral antipsychotics were discontinued after the first

three weeks of the initial RISPERDAL

CONSTA

injection. In the open-label phase, 124 (51.7%) were judged

to be stable for at least the last 4 weeks and were randomized to double-blind treatment with either the same dose

of RISPERDAL

CONSTA

or placebo in addition to continuing their treatment as usual and monitored for

relapse during a 52-week period. The primary endpoint was time to relapse to any new mood episode (depression,

mania, hypomania, or mixed).

Time to relapse was delayed in patients receiving adjunctive therapy with RISPERDAL

CONSTA

as compared

Page

40

41

to placebo. The relapse types were about half depressive and half manic or mixed episodes.

15

HOW SUPPLIED/STORAGE AND HANDLING

RISPERDAL

CONSTA

(risperidone) is available in dosage strengths of 25 mg, 37.5 mg, or 50 mg risperidone.

It is provided as a dose pack, consisting of a vial containing the risperidone microspheres, a pre filled syringe

containing 2 mL of diluent for RISPERDAL

CONSTA

, a vial adapter, and two Terumo

SurGuard 3 needles

for intramuscular injection (a 21 G UTW 1-inch needle with needle protection device for

deltoid administration

and a 20 G TW 2-inch needle with needle protection device for gluteal administration).

25-mg vial/kit: 78 mg (equivalent to 25 mg of risperidone) of a white to off-white powder provided in a vial with a

pink flip-off cap.

37.5-mg vial/kit: 116 mg (equivalent to 37.5 mg of risperidone) of a white to off-white powder provided in a vial

with a green flip-off cap.

50-mg vial/kit: 152 mg (equivalent to 50 mg of risperidone) of a white to off-white powder provided in a vial with

a blue flip-off cap.

Shelf life

The expiry date of the product is indicated on the packaging materials.

Storage and Handling

The entire dose pack should be stored in the refrigerator (2°- 8°C) and protected from light.

If refrigeration is unavailable, RISPERDAL® CONSTA® can be stored at temperatures not exceeding 25°C for

no more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 25°C.

After reconstitution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C. From a

microbiological point of view, the product should be used immediately. If not used immediately, in-use storage

times and conditions prior to use are the responsibility of the user and should normally not be longer than 6 hours

at 25°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Page

41

41

Keep out of reach of children

16

PATIENT COUNSELING INFORMATION

Physicians are advised to discuss the following issues with patients for whom they prescribe RISPERDAL

CONSTA

Orthostatic Hypotension

Patients should be advised of the risk of orthostatic hypotension and instructed in nonpharmacologic interventions

that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several

minutes before attempting to stand in the morning and slowly rising from a seated position)

[see Warnings and

Precautions (5.7)]

Interference with Cognitive and Motor Performance

Because RISPERDAL

CONSTA

has the potential to impair judgment, thinking, or motor skills, patients should

be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that

treatment with RISPERDAL

CONSTA

does not affect them adversely

[see Warnings and Precautions (5. 10)]

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-

the-counter drugs, since there is a potential for interactions

[see Drug Interactions (7)]

Alcohol

Patients should be advised to avoid alcohol during treatment with RISPERDAL

CONSTA

[see Drug

Interactions (7.1)]

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with

RISPERDAL CONSTA

. Advise patients that RISPERDAL CONSTA

may cause extrapyramidal and/or withdrawal

symptoms in a neonate.

[see Use in Specific Populations (8.1)]

Lactation

Advise breastfeeding women using RISPERDAL CONSTA

to monitor infants for somnolence, failure to thrive, jitteriness, and

extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs

[see

Use in Specific Populations (8.2)]

Infertility

Advise females of reproductive potential that RISPERDAL CONSTA

may impair fertility due to an increase in serum prolactin

levels. The effects on fertility are reversible

[see Use in Specific Populations (8.3)].

Manufacturer

: Cilag AG, Schaffhausen, Hochstrasse 201 ch-8205 Schaffhausen, Switzerland

Registration Holder

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

The content of this leaflet was approved by the Ministry of Health in 06/2016 and updated according to the guidelines of the

Ministry of Health in 11-2018

מ"עב רק 'תלה יס יי'ג

םייפש ץוביק

60990

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09-959-1111

'לט

09-958-3636

סקפ

ראוני

2019

ה/דבכנ ה/אפור

ה/דבכנ ת/חקור

ןודנה

ןוכדע

ולעב ןכרצלו אפורל םינ

לש

רישכתה

consta

isperdal

וננוצרב

איבהל

םכתעידיל

ןוכדע לח יכ

ולע םינ

אפורל

ןכרצלו

ישכתה לש םיר

Risperdal consta

.וינונימ לכ לע

יוותהה תו

מושרה תו

:ץראב

Risperdal consta is indicated for the treatment of schizophrenia and schizoaffective disorders.

Risperdal consta is indicated as monotherapy for the maintenance treatment of bipolar I

disorder to delay occurrence of mood episodes.

Risperdal consta is indicated for adjunctive maintenance treatment to delay occurrence of

mood

episodes in patients with frequently relapsing bipolar disorder

אפורל ןולעב :םיפיעסב ןוקית לח

5

WARNINGS AND PRECAUTIONS

5.1

Falls

Somnolence, postural hypotension, motor and sensory instability have been reported

, which may lead to

®

with the use of antipsychotics, including RISPERDAL CONSTA

related injuries. For patients,

-

res or other fall

falls and, consequently, fractu

particularly the elderly, with diseases, conditions, or medications that could exacerbate

these effects, assess the risk of falls when initiating antipsychotic treatment and

term antipsychotic therapy.

-

recurrently for patients on long

6

ADVERSE REACTIONS

Falls [see Warnings and Precautions (5.8)]

8

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for

extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations).

Overall, available data from published epidemiologic studies of pregnant women exposed to

risperidone have not established a drug-associated risk of major birth defects, miscarriage, or

adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with

untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including

RISPERDAL CONSTA

®

, during pregnancy (see Clinical Considerations). Risperidone has been

detected in plasma in adult subjects up to 8 weeks after a single-dose administration of

RISPERDAL CONSTA

®

[see Clinical Pharmacology (12.3)]. The clinical significance of

RISPERDAL CONSTA

®

administered before pregnancy or anytime during pregnancy is not

known.

Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the

maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times the

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MRHD based on mg/m

2

body surface area. Risperidone was not teratogenic in rats or rabbits at

doses up to 6-times the MRHD based on mg/m

2

body surface area. Increased stillbirths and

decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-

times the MRHD based on mg/m

2

body surface area. Learning was impaired in offspring of rats

when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1

to 3 times the MRHD based on mg/m

2

body surface area.

The estimated background risk of major birth defects and miscarriage for the indicated

population is unknown. All pregnancies have a background risk of birth defect, loss, or other

adverse outcomes. In the U.S. general population, the estimated background risk of major birth

defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including

increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are

associated with increased adverse perinatal outcomes, including preterm birth. It is not known if

this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor,

somnolence, respiratory distress, and feeding disorder have been reported in neonates who were

exposed to antipsychotic drugs, including RISPERDAL CONSTA

®

, during the third trimester of

pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or

withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within

hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical

antipsychotics during pregnancy do not report a clear association with antipsychotics and major

birth defects. A prospective observational study including 6 women treated with risperidone

demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid

database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall

increased risk for major birth defects. There was a small increase in the risk major of birth defects

(RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in a

subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however,

there is no mechanism of action to explain the difference in malformation rates.

Animal Data

Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at

10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m

2

body surface area;

maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when

administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up

to 6 times the MRHD of 16 mg/day risperidone based on mg/m

2

body surface area. Learning was

impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times

the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during

pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m

2

body

surface area; postnatal development and growth of the offspring were also delayed.

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were

dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16

mg/day based on mg/m

2

body surface area. It is not known whether these deaths were due to a

direct effect on the fetuses or pups or to effects on the dams:

The teratogenic potential of oral risperidone was studied in three embryofetal development

studies in Sprague-

Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the oral maximum

recommended human dose [MRHD]

on a mg/m

2

basis) and in one embryofetal development

study in New Zealand rabbits (0.31-5 mg/kg or 0.4 to 6

times the oral MRHD on a mg/m

2

basis). The incidence of malformations was not increased compared to control

in offspring of

rats or rabbits given 0.4 to 6 times the oral MRHD on a mg/m

2

basis. In three reproductive

studies

in rats (two peri/post-natal development studies and a multigenerational study),

there was an increase in pup

deaths during the first 4 days of lactation at doses of 0.16 5

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mg/kg or 0.1 to 3 times the oral MRHD on a mg/m

2

basis. It is not known whether these

deaths were due to a direct effect on the fetuses or pups or to effects on the

dams.

There wasaA no no-effect dose for increased could not be determined. The rate of

stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m

2

body

surface area.

In arat pup mortality. In one peri/post-natal development study, there was

an increase in

stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the oral MRHD on a mg/m

2

basis. In a rat

cross-

fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a

decrease in the number of live

pups and an increase inoffspring was decreased, the number of

dead pups at birth (Day 0), stillbirths increased and a decrease inthe birth weight was

decreased in pups offspring of drug-

treated dams were observedpregnant rats. In addition,

there was an increase inin the number of deaths increased by Day 1 among pups offspring of

drug-treated

damspregnant rats, regardless of whether or not the pups offspring were cross-

fostered. Risperidone also appeared to impair maternal

behavior in that pup offspring body

weight gain and survival (from Days 1 to 4 of lactation) were reduced in pups offspring born to

control but reared by drug-treated dams. All of tThese effects were all notedoccurred at the

one dose of risperidone tested, i.e., 5

mg/kg or which is 3 times the oral MRHD based on a mg/m

2

basisand the only dose tested in the study.

No studies were conducted with RISPERDAL

®

CONSTA

®

.

Placental transfer of risperidone occurs in rat pups. There are no adequate and well controlled

studies in pregnant

women. However, there was one report of a case of agenesis of the

corpus callosum in an infant exposed to

risperidone in utero. The causal relationship to oral

RISPERDAL

®

therapy is unknown.

Non_Teratogenic Effects

Neonates exposed to antipsychotic drugs (including RISPERDAL

®

) during the third trimester

of pregnancy are at

risk for extrapyramidal and/or withdrawal symptoms following delivery.

There have been reports of agitation,

hypertonia, hypotonia, tremor, somnolence, respiratory

distress, and feeding disorder in these neonates. These

complications have varied in severity;

while in some cases symptoms have been self-limited, in other cases

neonates have required

intensive care unit support and prolonged hospitalization.

RISPERDAL

®

CONSTA

®

should be used during pregnancy only if the potential benefit

justifies the potential risk

to the fetus.

Labor and Delivery

The effect of RISPERDAL

®

CONSTA

®

on labor and delivery in humans is unknown.

Nursing Mothers

Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore,

women should not

breast-feed during treatment with RISPERDAL

®

CONSTA

®

and for at

least 12 weeks after the last injection.

b.

Lactation

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Risk Summary

Limited data from published literature reports the presence of risperidone and its metabolite, 9-

hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3% and 4.7% of the

maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and

extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to

risperidone

(see Clinical Considerations).

Risperidone has been detected in plasma in adult subjects up

to 8 weeks after a single-dose administration of RISPERDAL CONSTA

[see Clinical Pharmacology

(12.3)]

, and the clinical significance on the breastfed infant is not known.

There is no information on the

effects of risperidone on milk production. The developmental and health benefits of breastfeeding should

be considered along with the mother’s clinical need for RISPERDAL CONSTA

and any potential

adverse effects on the breastfed child from RISPERDAL CONSTA

or from the mother’s underlying

condition.

Clinical Considerations

Infants exposed to RISPERDAL CONSTA

through breastmilk should be monitored for excess sedation,

failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

c.

Females and Males of Reproductive Potential

Infertility

Females

Based on the pharmacologic action of risperidone (D2 receptor antagonism), treatment with

RISPERDAL CONSTA

may result in an increase in serum prolactin levels, which may lead to a

reversible reduction in fertility in females of reproductive potential

[see Warnings and Precautions

(5.6)].

:םיאבה םיפיעסב ןוקית לח ןכרצל ןולעב

.תוזוכיספל הרושקה היצנמדמ םילבוסה םישישק םילוחב התומתב היילע :הרהזא

יטנא תופורתב םילפוטמה תוזוכיספל הרושקה היצנמדב םילוחה םישישק םילוח

רבגומ ןוכיס ילעב םה תויטוכיספ ה היצנמד םע םילוחל תרשואמ הניא הטסנוק לדרפסיר .תוומל .תוזוכיספל הרושק

ולעב םינמוסמ םייונישה

רוצמה

שגדומה טסקטה רשאכ

קוחמה טסקטה וליאו ןולעל ףסוה

שגדומ .הצוח וק םע

אפורל ןולעה

םוסרפל חלשנ אולמב

ש תופורתה רגאמ .תואירבה דרשמ רתאב

,ןכ ומכ לבקל ןתינ

ןופלטל ונילא הינפב ספדומ

09-9591111

,הכרבב

ןהכ רירפצ

נוממ חקור

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