LEPONEX 25 MG TABLETS

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
CLOZAPINE 25 MG
Available from:
NOVARTIS PHARMA SERVICES AG
ATC code:
N05AH02
Pharmaceutical form:
TABLETS
Administration route:
PER OS
Manufactured by:
NOVARTIS PHARMACEUTICALS LTD, UK
Therapeutic group:
CLOZAPINE
Therapeutic indications:
Treatment of resistant schizophrenic patients who are non-responsive to, or intolerant of classic neuroleptics. Reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death.
Authorization number:
058752314700
Authorization date:
2012-10-01

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Patient Information leaflet Patient Information leaflet - Hebrew

20-01-2021

רשואוקדבנונכותותואירבהדרשמ י"עעבקנהזןולעטמרופ טסוגואב 2012

םיחקורה תונקת יפלןכרצלןולע

ו"משתה (םירישכת) - 1986

אפורםשרמבתבייחוזהפורת

בתנתינהפורתה 18 םינושארהתועובשה לעקרוךאלופיטל - יתבברטאיכיספאפורםשרמ יפ

ה עובשהמ לחהו,םילוח 19 לעךליאולופיטל - הליהקברטאיכיספאפורםשרמ יפ

םרטבופוסדעןולעהתא ןויעבי/ארק הפורתבי/שמתשת

סקנופל סקנופל

ג"מ 100 ג"מ

תוילבט תוילבט

:בכרה

:הליכמהילבטלכ הילבטלכ :הליכמ

Clozapine25 mg Clozapine100 mg

:םיליעפיתלבםיביכרמ

Lactosemonohydrate;maizestarch;povidone;silica, colloidalanhydrous;magnesium

stearate;talc.

סקנופללשהילבט לכ 25 הליכמ ג"מ 48 טרדיהונומזוטקלג"מ .

סקנופללשהילבט לכ 100 הליכמ ג"מ 192 טרדיהונומ זוטקלג"מ .

זוטקללםישיגרהםילוחלצאתיגרלאהבוגתלםורגללולעוזוטקלליכמרישכתה .

:תיטיופרת הצובק

יטנא .םיפיטאםיטוכיספ

:תיאופרתוליעפ

.תויטוכיספיטנא תופורת תצובקלךיישסקנופל

הבוגת ןיא רשאכהינרפוזיכסבלופיטלהפורת איהסקנופל תקפסמ רשאכוא תורחאתופורתל

.תולבסניתלביאוולתועפותלתומרוגתורחאתופורת

יטנא תועפשהלותיתועמשמוהריהמהעגרהלםרוגרישכתה - .תויתועמשמתויטוכיספ

לםגתדעוימ הפורתה התתחפה לןוכיס תינדבואתוגהנתה ב םילבוסהםילפוטמ מ הינרפוזיכס וא

יטקפאוזיכסהערפהמ יב ת (חורהבצמבהעיגפםעהינרפוזיכסלשבוליש) .

,הבישחבתוערפהבתניפואמהשפנתלחמוזהינרפוזיכס ב רתובוגתותוגהנתה .תוישג

ןטלוקהתמיסחורושיקידילערקיעבלעופסקנופל D4 ןכומכ.חומב(ןימאפודלןטלוקה) ידילע,

םינטלוקהלשםישלחהמיסחורושיק D1 , D2 , D3 ו - D5 ומב םימרותהםיפסונםינטלוק לשוח

תוליעיל ו .

רוטינ ךלהמב לופיטה סקנופלב :

שי ךורעל תוקידב םד תורידס ךלהמב לכ לופיטה ךשמבו 4 תועובש רחאל תקספה לופיטה אפורה.

.תוקידבהתא עצבלשייתמךתוא החני בושח עצבל תא לכ תוקידב םדה יפכ וצלמוהש לע ידי

אפורה .

םא (תרכוס)םדבההובגרכוס תמרמ ת/לבוסךנה , קודביאפורהשןכתי תועיבקב תא תמר רכוסה

םדב םורגליושעסקנופל. יונישל םינמושב םדב . סקנופל יושע םורגל היילעל לקשמב . ןכתי

אפורהש קודבי תא ךלקשמ תומרו םינמושה םדב .

לתונפלשיךרובעהמשרנעודמ ואהפורתהתוליעפלעתולאשל .אפור

.הזןולעבשעדימהמ תונושןהםא םגאפורהתוארוהלכרחאאלמלשי

לופיטהתליחתינפל סקנופלב , הבוח עצבל .הפורתהתא לוטילןתינשאדוולידכםדתקידב

?רישכתבשמתשהלןיאיתמ

םא ת/יגרלא ךנה ואןיפזולקל הפורתהיביכרממדחאל ןולעהתליחתבםיטרופמה

לוכיךניאםא םדתוקידברובעל תורידס

תנחבואםעפיא םא כ שםירקמ דבלמ ,הכומנתונבלםדתוירודכתריפסמ ת/לבוס םהב

לופיטתובקעבאיההעפותה ןטרסב

/לבוסךניהםא ת וא תלבס רבעב לחממ ה םצעהחמב

בלבואתוילכב,דבכבתויעבךלשיםא

מ ת/לבוסךניהםא םיסוכרפ םיטלשנאל

שתויעבךלשיםא םימס וא לוהוכלאלתורכמתהל

בצמ לכואיעמ תמיסח,הרומחתוריצעמ רבעבתלבסוא ת/לבוסךניהםא רחא עיפשמה

יעמהלע

.סקנופלבלופיטהךלהמבקיניהלןיא

לכב "נה םיבצמהמ דחא ל , שי עדייל תא אפורה אלו לוטיל סקנופל .

םא ךנה בשוח ת/ ךנהש יגרלא ת/ סקנופלל ,(ןיפזולק) שי הל י ץעוו אפורב ינפל תליטנ סקנופל .

לופיטה תלחתה ינפלאפורבץעוויהלילבמ הפורתבשמתשהלןיא :

םא לשתיתחפשמ הירוטסהואבלתלחמ ,ץבשךלהיה תייעב הכלוה הגירח בלב

עטקמ תכראה"תארקנה QT "

ת/לבוסךנהםא רבעבתלבס וא בצמ)המוקואלג,םיסוכרפ,תינומרעהתטולבתלדגהמ

ובש תרכוס,(ידימהובגןיעבלזונהץחל , תביוקילמ ,דבכה,םדילכוא/ובלה:דוקפ

כה ,(השירק ןוגכ)םדהתכרעמ ,ןתשהתכרעמ/היל יבצמב היצנמדמ האצותכתוזוכיספ

םילוחב(ןויטיש) םישישק וא יאופרבצמ לכ רומח רחא .

םא דחא םיבצממ הלא יטנבלר ךייבגל , שי עדייל תא אפורה ינפל תליטנ סקנופל .

חקורה ואאפורה תאעדיילשי .ןוירהבךנהשתבשוחוא ןוירהבךנהםאסקנופלבשומישינפל

.ןוירהךלהמבוזהפורתבשומישהלשםיירשפאהםינוכיסהותונורתיהיבגלךתיאןודיאפורה

?ךלשםויםויהייחלעהפורתה עיפשת ךיא

לולעוזהפורתבשומישה דחוימב,םונמנלםורגל ,לופיטהתליחתב ואהגיהנמ ענמיהלךילעןכל

והפורתללגרתתשדעתונוכמבשומיש םלעיםונמנה לעדיפקהלשיהרקמ לכב. הגיהנבתוריהז

כמתלעפהב,בכרב .תונרעתבייחמהתוליעפלכבותונו

הבוגת םע לוהוכלא לוהוכלאתותשלןיא.לוהוכלאלשתועפשהריבגהליושעסקנופל:

ליטנךלהמב .סקנופלת

וא ןושיעתקספהמתועפשומ תויהלתויושעםדבסקנופלהתומר מ רפסמביוניש

שןיאפק םיליכמהתואקשמה /ךרוצךנה .םויבת שי עדייל תא אפורה הזכשיונישלכלע

.ךילגרהב

:תורהזא

תונבלהםדהתוירודכרפסמבהדירילםורגלהלולעהפורתהשןוויכמ , ינפלעצבלשי

לופיטהתליחת םדהתריפס םא קר.תלדבמ םדתריפסותונבלםדתוירודכתריפס

.לופיטבליחתהלןתינ,הניקת תאצמ

מ תונבלםדתוירודכתריפסךורעלשי י ךשמבעובשיד 18 ,לופיטלםינושארהתועובשה

לתחאתוחפלןכמ רחאלו - 4 תועובש דועלכ לפוטמה .סקנופללבקמ

שי הל י ץעוו אפורב דימ לכואןורגבאכ,םוח,תעפש,תוררקתהלןושארהןמיסהתעפוהב

תושיגרלליבוהלוםדבםינבלהםיאתהרפסמ תא תיחפהללוכיסקנופל.רחאםוהיז

טוקניךרוצהתדימבוךלשםדהתריפס תאקודביאפורהשןכתי.םוהיזלרתויההובג

.םיפסונםיעצמאב

מ תוחפםדהתריפסוא/וםוהיזאצמנםא 3500/mm 3 וקמ יתועמשמ ןפואבהתחפוא

לעמ הריפסהםא םג)סיסבה 3500/mm 3 ( , .תידיימ תלדבמ םדתריפסעצבלהבוח

לתחתמ הנבלהריפסתתמאמ וזהקידבםא - 3500/mm 3 הריפס לעהארמ וא/ו

ןיבםיטיצולונרגליפורטיונלשתיטולוסבא 2000/mm 3 ל - 1500/mm 3 דבלשי, קו

םיטיצוקיול .עובשבםיימעפםיטיצולונרגו

מתוחפאיהתונבלהםדהתוירודכתריפס םא – 3000/mm 3

לשתיטולוסבא הריפסו

לתחתמאיהםיטיצולונרגליפורטיונ – 1500/mm 3 , שי סקנופלבלופיטהתא דימקיספהל

ךשמבתונבלםדתוירודכתריפס ךורעלךישמהלו 4 .הפורתהתקספהרחאלתועובש

ירודכתריפס םא מתוחפאיהתונבלהםדהתו – 2000/mm 3 םיטיצולונרגליפורטיונוא/ו

מתוחפ - 1000/mm 3 רשפא םאוםיאתמ לופיט יבגלגולוטמהאפורםעץעייתהלשי, , שי

.תיגולוטמההקלחמלהלוחהתא ריבעהל

לתחתמתונבלםדתוירודכתריפסבהדיריהתיהלופיטהתקספהתביס םא - 3000/mm 3

לוסבא הריפסו מתוחפםיליפורטיונלשתיטו - 1500/mm 3 , ןיא הלוחהתאריזחהל

.סקנופלבלופיטל

הלשי י דימאפורבץעוו ה/שחךנהםא ןכתי,החונמ בצמבךשמנהרידסאלוריהמקפוד

תויושעהלאתועפשה.םיילגרהואםיילגרהתופכתוחפנתהוהמישנרצוקבהוולמש

.םיפסונםיעצמאבטוקנלאפורהלעהיהישןכתיולופיטהתליחתבדחוימבשחרתהל

פיטהתליחתבדחוימב,ןופלעואתרוחרחס שיגרתשןכתי,סקנופלתליטנךלהמב תאזולו

.ךלשםדהץחלבהדיריבקע

,ןופלעוא תרוחרחס תשוחתלךלםרוגסקנופלםא לשבצממהמיקבתוריהזבטוקנלשי

.הבישיואהביכש

יפקתה תוומלליבוהלםילולעשבל וחווד יבגל סקנופל .

סקנופל לולע םורגל תוינונשיל ו תכשוממ תוהשל הטימב ישב בול היילע לקשמב היושעה

ליבוהל ישירקל םד םילפוטמב םימיוסמ .

םא םינימסתמ דחא ךלשי הלא , שי ל עדי תא אפורה דימ .

.הפורתהתליטנינפלאפורלךכלעעידוהלךילע,יהשלכהפורתלואוהשלכןוזמלה/שיגרךניהםא

ןוירה הקנהו

שי חוודל אפורל דימ .סקנופלבלופיטהךלהמבןוירהלתסנכנםא תוקוניתל תוהמאלודלונש

ךלהמבתויטוכיספיטנא תופורת תולטונה שילשה ישילשה ןוירהל ןכתי םייפגחתפלרבגומןוכיס

,דער,תושקונ יא טקש , ק ןויש םירירש , ר ןויפ ,םונמנ,םירירש המישנ הרצק הדודרו תוערפהו

,םירחאםירקמב,םמצעמםירבועהלא םינימסת םימיוסמ םירקמב.הדילהרחאלהלכאהב

לוקקדזיתוקונית פיט ו ל ב זופשאלואץרמנלופיטלהדיחי .

שי חוודל אפורל וא חקורל .הקינימ ךנהםא ןיפזולק , רמוחה ליעפה סקנופלב , יושע רובעל בלחל

םאה עיפשהלו לע קוניתה ןיא. .סקנופלבלופיטהךלהמבקיניהל

םישנ ליגב ןוירפה העינמיעצמא,

תויטוכיספיטנא תופורתבתולפוטמהםישנהמקלחל תומיוסמ רוזחמןיא תסו .רידסוניאשוא

רוזחמהתעפוה ןכתת תובקעב יוניש מ בלופיט לתרחא תיטוכיספיטנאהפורת בלופיט סקנופל .

ולא תוביסנב העינמ יעצמאבשמתשהלשי, .ןימא

:תויתפורת ןיבתובוגת

,תרחאהפורתבלופיטהתעהזתרמגםא וא ,תפסונהפורת ת/לטונךניהםא אללתופורתללוכ

,םשרמ יא ואםינוכיסעונמלידכלפטמהאפורלחוודלךילע - ןיבתובוגתמםיעבונהתוליעי

תויתפורת , :תואבהתוצובקהמ תופורת יבגלדחוימב תופורת ,הנישלתופורת ,העגרה תופורת דגנ

,הקיטויביטנא,היגרלא ,ןואכידבלופיטלתופורת ב םיסוכרפ וא ב ןטבהלשםיביכ ו תופורת

יתירטפםימוהיזל םי וא םייפיגנ .

.לופיטלעירפהלתולולעהלאתופורת

מגודל,םצעהחמתוליעפתאאכדלתולולעהתופורתלליבקמבשומישלרוסא סקנופל ה

.ןיפזמברק

העפשהןכתת :תואבהתופורתהוסקנופלןיב נתופורת ו דג תו ןואכיד ) מ ,םויתיל יבכע MAO ,(

ידוזנב א ,םיניפז ,הקיטוקרנ בלופיטלתופורת היספליפא (ןיאוטינפןוגכ) , ,םדץחלתדרוהלתופורת

תופורת תעינמל תויגרנילוכיטנאתופורת,םינימטסיהיטנא,םדתשירק , לופיטלתופורת

,ןוסניקרפ ןיסקוגיד , ס ןילנרדא,ןידיטמי תכרעמ לעתאכדמ תוליעפתלעבתופורת ,ויתורזגנו

המישנה .

יאוולתועפות :

שי ןכדעל םדקהב ירשפאה וא אפורהתא תא תאםא חקורה / שיגרמ ה ה/ ב םינימסת יופצאל םי

בשוחךניא םא םג,סקנופלבשומישהךלהמב ת/ שיש הל ם .הפורתלרשק

דואמ תוחיכשיאוולתועפות

הלתויושע מרתוילעעיפש - 10 מ לכ 100 םילפוטמ

םונמנ

תרוחרחס

תוריצע , שי עדיל תא אפורה םא תוריצעה הרימחמ

רוציי רבגומ לש קור

תוחיכשיאוולתועפות

הלתויושע לעעיפש ןיב 1 ל - 10 מ לכ 100 םילפוטמ

היילע לקשמב

רוביד אל רורב

תועונת ,תוגירח רסוח ,העונתליחתהלתלוכי רסוח ,העונתאללראשהלתלוכי השוחת

תימינפ לש רסוח החונמ , םייפג תושקונ , םיידי תודעור

תודיער

ןויש םירירש

באכ שאר

הייאר תשטשוטמ , םיישק האירקב

םייוניש .ג.ק.א רישכמב בל

תרוחרחס תעב הדימע בקע הדירי ץחלב םדה

היילע ץחלב םדה

הליחב , האקה , שבוי הפב

היילע תמרב ימיזנא דבכ

תויעב הנתשהב וא תריצאב ןתש

םוח

תופייע

תוחיכשאליאוולתועפות

הלתויושע לעעיפש ןיב 1 ל - 10 מ לכ 1,000 םילפוטמ

םוגמג רובידב

תורידניאוולתועפות

הלתויושע לעעיפש ןיב 1 ל - 10 מ לכ 10,000 םילפוטמ

ןואמ זרפומ הפבשבוי, ו תלטה תויומכ ןתש תובר םילולע םינמיסתויהל לש מר ו רכוסת

תוהובג נהםא .(תרכוס)םדב ך שח ה/ ,םהמ דחאב שי עדייל תא אפורה םדקהב ירשפאה

רימחהלואתרכוסלםורגללולעסקנופלשןוויכ ה .

לובלב

קפוד אל רידס

םיישק העילבב

היילע ימיזנאב רירשה

תועפות יאוול תורידנ דואמ

תויושע עיפשהל לע תוחפ לפוטממ 1 לכמ 10,000 םילפוטמ

לורטסלוכ הובג

תוצמוח ןמוש תוהובג םדב

תועונת אל תוינוצר תורסח תילכת יוועהןוגכ ה , ץומצמ םייתפש , ץומצמ םייניע ריהמ

תובשחמ תויתייפכ תוגהנתהו תרזוח תיתייפכ

תוחיפנ לש תוטולבה םייחלב

תובוגת תוירוע

תועפות יאוול תויושעשתורחא שחרתהל העודיאלןתוחיכשךא

םייוניש תנוכמב ילג חומ /םרגולפצנאורטקלא) EEG (

לושלש

יא תוחונ ןטבב ,תברצ, יא תוחונ ןטבב רחאל החורא

תשלוח םירירש

תותיווע םירירש

באכ םירירש

שדוג ףאב

שי עדייל תא אפורה םא תחא תועפותמ הלא העיפשמ ךילע ןפואב רומח .

תועפות יאוול :תדחוימ תוסחייתה תובייחמה

תועפות יאוול תומיוסמ תויושע תושרודותורומחתויהל החגשה תיאופר

יאוולתועפות תוחיכש :דואמ תויושע מרתוילעעיפשהל - 10 מ לכ 100 םילפוטמ

קפוד ריהמ אלו רידס שמנש ך בצמב החונמ תוחיפנוהמישנרצוקביווילבןכתי, לש תופכ

םיילגרה םיילגרהוא

ןיבלעעיפשהלתויושע:תוחיכשיאוולתועפות 1 ל - 10 לכמ 100 םילפוטמ

םינמיס םוהיזל תורומרמצ,םוחןוגכ תורומח ,ןורגבאכ, םייתפשהלעםינבלםימתכ וא

ללוכיסקנופל.הפהללחבםיביכ תיחפה םדבתונבלהםדהתוירודכרפסמ תא ליבוהלו

תושיגרל רתויההובג םימוהיזל

םיסוכרפ

המר ההובג לש תוירודכ םד תונבל גוסמ םיוסמ , תריפס תוירודכ םד תונבל תלדגומ

דוביא הרכה , ןופליע

ןיבלעעיפשהלתויושע:תוחיכשאליאוולתועפות 1 ל - 10 לכמ 1,000 םילפוטמ

םוח , םיצוויכ ב םירירש , תודונת ץחלב םדה , רסוח תואצמתה , לובלב

:תורידניאוולתועפות ןיבלעעיפשהלתויושע 1 ל - 10 לכמ 10,000 םילפוטמ

הליפנ תיתועמשמ םדהץחלב

באכ הזחב בקע תקלד לש רירש בלה

באכ הזחב בקע תקלד לש םורק בלה

שירק םד

המר הכומנ לש יאת םד םימודא

תסינכ לכוא האירל

םינמיס םוהיזל יכרדב המישנה וא תקלד תואיר םיפוצפצ,המישניישק,לועיש,םוחןוגכ

המישנהןמזב

באכ ןטב בקע תקלד לש בלבלה

רוע םייניעו םיבוהצ הליחב, ,ןובאיתדוביאוא/ו ןתש ההכ , םינמיס לש ,דבכבהערפה תקלד

דבכ

לפוטממתוחפלעעיפשהלתויושע:דואמ תורידניאוולתועפות 1 לכמ 10,000 םילפוטמ

םומיד וא תולבח םיינטנופס , םינמיס םיירשפא תמרל תויסט הכומנ םדב (הינפוטיצובמורת)

תומר תוהובג לש תויסט םדב

תואצמתה ,הבורמהנתשה,האקה/הליחב,לובלב/היוקל באכ ןטב םע תמר רכוס ההובג

םדב

באכ הזחב , קפוד אל רידס יאו תקיפס בל

רצוק המישנ

תשגרה הליחב , האקה םע תוריצע הרומח תכשוממ/

רוע בוהצ בקע תקלד דבכ הרומח , באכ ןטב

תקלד כה היל

הפק תכשוממ

תוומ ימואתפ יתלב רבסומ

תועפות יאוול ב העודיאלןתוחיכשךאשחרתהלתויושע:העודיאלתוחיכש

העזה םינימסת)לושלשוהאקה,הליחב,שארבאכ,הבר לש תנומסת תיגרנילוכ (

ףקתה בל לולעה םורגל תוומל

באכ ץחומ הזחב םינמיס) תמירזל םד ןצמחו יתלב תקפסמ רירשל בלה (

יא הקיפס יתיליכ ת

תוערפה כ י דב תוי ,דבכיאתתומ ,ינמושדבכתלחמללוכ תוליער וא העיגפ דבכב

תוערפה תוידביכ תוללוכה ה ת פלח ו ת דבכתמקר הניקת ב מקר ת תקלצ , רבד דוביאלליבומה

דבכהדוקפית , ללוכ םתוא םירקמ םייחינכסמ )דבכהלשכןוגכ לולעה העיגפ,(תוומלםורגל

,דבכיאתבהעיגפ)דבכב ב רוניצ הרמ דבכב וא םהינשב ( .דבכתלתשהו

בה/שיגרמ ה/תא םא מתחא לא תועפות ה , תונפלשי אפורל דימ .

כב ךתשגרהביונישלחםא וא ,הזןולעבוניוצאלשיאוולתועפות ה/שיגרמ ךניהובשהרקמ ל

,תיללכה תאעדיילשי אפורה חקורהוא .דימ

ןונימ

ארוהיפלןונימ ו .דבלבאפורהת

.תצלמומההנמהלערובעלןיא

םישישק ) ליג 60 הלעמו (

םא לופיטהתא ךלםיאתיאפורהשןכתי ךנה ןב 60 הלעמו .

לשי אפורהתא ןכדע חקורהוא מ לבוסךניהםא היצנמד ) ןויטיש ( .

םידלי םירגבתמו

םידליבלופיטה ליגדע 16 ץלמומ וניא .םינותנברוסחמבקע,

ה ןפוא שומיש

.הפורתהתאלוטילשייתמ רוכזלעייסת םוילכבןמזותואבסקנופלתליטנ

.הפהךרדסקנופלןתמ

ןתינהייצחוקםעתוילבט .םיוושםיאצחלקלחל

!סועללןיא .םימטעמםעהפורתהתאעולבלשי

?לופיטה תחלצהלעייסלי/לכות דציכ

שי לופיטהתא םילשהל יפכ .אפורהידילעץלמוהש

קיספהלןיא ךתואירבבצמברופישלחםא םג תא .אפורםעתוצעייתהאללהפורתבלופיטה

לוטילתחכשםא הנמ ןמזב ה בוצק , ךא ,תרכזנשכדימ הנמ לוטילשי תא לוטילןמזהעיגהםא

ואהאבההנמה מתוחפורתונ - 4 לתועש הינפ האבההנמ לוטילוהחכשנשהנמהלעגלדלשי, תא

ןמזבהאבההנמה ןוכנה דחיבתונמיתשלוטילןיא ןפוא םושב. החכשנשהנמהלעתוצפלידכ !

אלםא סקנופלתלטנ יא,םיימוימרתויךשמל הפורתהתליטנבשדחמליחתהלן תונפלשיו אפורל

םדקהב .

תקספה ה לופיט

ןוכיס תועפותל הלימג

קיספהלןיא תא שומישה סקנופלב תוימואתפב .

תיחפיאפורה,יהשלכהביסמלופיטהתא קיספהלשיםא ךשמביתגרדהןפואבןונימהתא הפוקת

לש םייעובשדעעובש יאוולתועפותמ ענמהלידכ . וא סקנופלבלופיטהלשתימואתפהקספה

התחפה יאוולתועפותלםורגלםילולעןונימהלשהריהמ , ואותחפשמולפוטמהשבושח,ךכיפל

.סקנופלמ הלימגהינמיס תאתוהזלולכויובםילפטמה

הלימגינימסתוםייטוכיספםינימסתונכתי,סקנופלבלופיטהלשתימואתפהקספההצוחנםא

רהעזהןוגכ .לושלשוהאקה,הליחב,שארבאכ,הב

שי דימאפורלחוודל םא םינמיסמ דחאךלשי הלא הלאםינמיסתובקעב. ונכתיי יאוולתועפות

רתויתורומח אלל לופיט ידיימ .

!הלערהי/ענמ

לעותוקוניתוא/וםידלילשםדיגשיהלץוחמ רוגס םוקמברומשלשיתרחא הפורת לכווזהפורת

ידי - ךכ .הלערהי/ענמת

תיבלשןוימ רדחלדימי/הנפ,הפורתהןמ דליעלבתועטבםא וא רתיתנמתלטנםא - ,םילוח

אהפורתהתזירא י/אבהו י ךת תיאופרהחגשהבךרוצהיהישןכתי, .

םורגלןיא האקהל !אפורמ תשרופמ הארוהאלל

ךתלחמבלופיטלהמשרנוזהפורת ; .קיזהלהלולעאיהת/רחאהלוחב

.ךירכמ וא ךינכש,ךיבורקלוזהפורת ןתת לא

!ךשוחבתופורתלוטילןיא קודבלשי הנמהותיוותה םעפלכב .הפורתלטונךניהש

ביכרהלשי .םהלה/קוקזךניהםא םייפקשמ

:הנסחא

םדיגשיהמ הפורתהתא קיחרהלשי םוחתמו םתייאר .םידלילש

לתחתמ הפורתהתא ןסחאלשי - 30°C תירוקמההזיראבו .

בלםישלאנ.דבלבתלבגומהפוקתלתורמשנתופורת ,םיצלמומההנסחאה/הזיראהיאנתיפלםג

בץעוויהלךילע,קפס לשהרקמ לכב!רישכתהלשהגופתהךיראתל חקור .הפורתהתאךלקפיסש

הפורתבשמתשהלןיא םא ה המוגפהזירא נמיסםעוא הלבחי .

.הזירא התואבתונושתופורתןסחאלןיא

:הפורתה םושיר'סמ

סקנופל 25 :תוילבט ג"מ 058 75 23147

סקנופל 100 :תוילבטג"מ 047 98 23148

:ןרציה נ הילגנא,מ"עבסלקיטיוצמראפסיטרבו , ץיווש,לזב,י'גייא המראפסיטרבונרובע .

:םושירהלעב נ ו ייא ססיורס המראפסיטרב י'ג חר, ' םחש 36 חתפ, - וקת ו ה .

Document Outline

ודילערשואוקדבנונכותותואירבהדרשמ י"עעבקנהזןולעטמרופ טסוגואב 2012

LEPONEX

(clozapine)

Leponex cancauseagranulocytosis.Itsuseshould belimited topatients:

withschizophreniawhoare non-responsiveto orintolerantofclassicalantipsychotic

agents,or withschizophreniaor schizoaffective disorder whoare atriskofrecurrent

suicidalbehaviour (see section3 Indications),

who haveinitially normalleukocytefindings(whiteblood cellcount(WBC)

3500/mm 3

( ≥3.5 x 10 9

/L),and absoluteneutrophilcounts(ANC) ≥2000/mm 3

( ≥2.0 x

10 9

/L)),

and inwhomregularwhiteblood cellcountsand absoluteneutrophilcountscanbe

performedasfollows:weeklyduringthe first18weeksoftherapy,andatleastevery

4weeksthereafterthroughouttreatment.Monitoringmustcontinuethroughout

treatmentandfor 4weeksafter complete discontinuationofLeponex(see section6

Warningsand precautions).

Prescribingphysiciansshould complyfullywith therequired safetymeasures.Ateach

consultation,apatientreceivingLeponexshould bereminded tocontactthetreating

physician immediatelyifanykind ofinfection beginstodevelop. Particularattention

should bepaidtoflu-like complaintssuchasfever or sore throatandtoother evidence

ofinfection, whichmay beindicativeofneutropenia(seesection6 Warningsand

precautions).

Leponexmustbedispensed understrictmedicalsupervisioninaccordance withofficial

recommendations(see section6Warningsandprecautions).

Myocarditis

Clozapine isassociatedwithanincreasedriskofmyocarditiswhichhas,inrare cases,

beenfatal.The increasedriskofmyocarditisisgreatestinthe first2monthsof

treatment.Fatalcasesofcardiomyopathy havealso beenreportedrarely.

Myocarditisorcardiomyopathyshould besuspected in patientswhoexperience

persistenttachycardiaatrest,especiallyinthe first2monthsoftreatment,and/or

palpitations, arrhythmias,chestpain and othersignsand symptomsofheartfailure(e.g.

unexplained fatigue,dyspnoea,tachypnoea)orsymptomsthatmimicmyocardial

infarction.

Ifmyocarditisorcardiomyopathy aresuspected, Leponex treatmentshouldbepromptly

stoppedandthe patientimmediatelyreferredtoacardiologist.

Patientswho developclozapine-induced myocarditisorcardiomyopathyshouldnotbe

re-exposedtoclozapine.

Increasemortalityinelderlypatientswithdementiarelatedpsychosis

Elderlypatientswithdementia-relatedpsychosistreatedwithatypicalantipsychotic

drugsareatanincreasedriskofdeathcomparedto placebo. Analysesofseventeen

placebocontrolledtrials(modaldurationof10weeks)inthese patientsrevealedariskof

death in thedrug-treatedpatientsofbetween1.6 to 1.7 timesthatseeninplacebo-

treatedpatients.Over the course ofatypical10weekcontrolledtrial,the rate ofdeath

indrug treatedpatientswasabout4.5%, comparedto a rateofabout2.6%inthe

placebogroup.Although thecausesofdeath werevaried,mostofthedeathsappeared to

be either cardiovascular(e.g. heartfailure, suddendeath)orinfectious(e.g. pneumonia)

innature.Leponex(clozapine)isnotapprovedfor the treatmentofpatientswith

dementia-relatedpsychosis.

1 Tradename

LEPONEX25 mgand 100 mgtablets

2 Description and composition

25 mgTablet:Each tabletcontains25 mgclozapine.

100 mgTablet:Each tabletcontains100 mgclozapine.

Pharmaceuticalform

Tablets.Thescored tabletscan bedivided into equalhalves.

Active substance

Clozapine

Active moiety

Clozapine

Excipients

Leponextablets:Lactosemonohydrate;maizestarch;povidone;silica,colloidalanhydrous;

magnesiumstearate;talc.

3 Indications

Treatmentofresistantschizophrenicpatientswho arenon-responsiveto, orintolerantof

classic neuroleptics.

Reducingtherisk ofrecurrentsuicidalbehaviorinpatientswith schizophreniaor

schizoaffectivedisorderwho arejudged to beatchronicrisk forre-experiencingsuicidal

behavior,based on historyandrecentclinicalstate. Suicidalbehaviorrefersto actionsbya

patientthatputhim/herselfat riskfordeath.

4 Dosageand administration

Thedosagemustbeadjusted individually.Foreach patientthelowesteffectivedoseshould

beused.Cautioustitration and adivided dosageschedulearenecessarytominimizetherisks

ofhypotension, seizure, and sedation.

InitiationofLeponextreatment must berestrictedtothosepatientswithaWBCcount

≥3500/mm³ (3.5 x10 9

/L)anda ANC ≥2000/mm³ (2.0 x10 9

/L), and within standardised

normal limits.

Doseadjustmentisindicated in patientswho arealso receivingmedicinalproductsthathave

pharmacokineticinteractionswith clozapine, such asbenzodiazepinesorselectiveserotonin

re-uptakeinhibitors(see section8Interactions).

MethodofAdministration

Leponexisadministeredorally.

Switching froma previousantipsychotictherapy to Leponex

Itisgenerallyrecommended thatLeponexshould notbeused incombination with other

antipsychotics. WhenLeponextherapyisto beinitiated in apatientundergoingoral

antipsychotictherapy, itisrecommendedthatthedosageofotherantipsychoticsbereducedor

discontinued bygraduallytapering itdownwards. Based ontheclinicalcircumstances, the

prescribingphysician should judgewhetherornotto discontinuetheotherantipsychotic

therapybeforeinitiatingtreatment withLeponex.

Treatment-resistantschizophrenia

Startingtherapy

Leponexshould bestarted with12.5 mg(halfa25-mgtablet)onceortwiceonthefirst day,

followed byoneortwo 25 mgtabletson thesecond day.Ifwelltolerated, thedailydosemay

then beincreased slowlyin incrementsof25 mgto 50 mgin orderto achieveadoselevelof

up to 300 mg/daywithin 2 to 3 weeks. Thereafter,ifrequired, thedailydosemaybefurther

increased in incrementsof50 mgto 100 mgathalf-weeklyor,preferably,weeklyintervals.

Therapeuticdoserange

In mostpatients, antipsychoticefficacycan beexpected with300to 450 mg/daygiven in

divided doses.Somepatientsmaybetreated withlowerdoses, and somepatientsmayrequire

dosesup to 600mg/day.Thetotaldailydosemaybedivided unevenly, with thelargerportion

beingtakenatbedtime.

Maximumdose

To obtain fulltherapeuticbenefit, afewpatientsmayrequirelargerdoses, in which case

judiciousincrements(notexceeding100 mg)arepermissibleup to 900 mg/day.However,the

possibilityofincreased adversereactions(in particularseizures)occurringatdosesover450

mg/daymustbebornein mind.

Maintenance dose

Afterachievingmaximum therapeuticbenefit,manypatientscanbemaintainedeffectivelyon

lowerdoses. Carefuldownward titration isthereforerecommended. Treatmentshould be

maintained foratleast6 months.Ifthedailydosedoesnotexceed 200 mg,oncedaily

administration in theeveningmaybeappropriate.

Endingtherapy

In theeventofplanned termination ofLeponextherapy, agradualreductionin doseovera1-

to 2-week period isrecommended.Ifabruptdiscontinuation isnecessary(e.g.because of

leucopenia), thepatientshould becarefullyobserved fortherecurrence ofpsychotic

symptomsandsymptomsrelated to cholinergicrebound(seesection 6 Warningsand

precautions).

Re-startingtherapy

In patientsin whomtheintervalsincethelastdoseofLeponexexceeds2 days, treatment

should bere-initiated with 12.5 mg(halfa25 mgtablet)given onceortwiceon thefirstday.

Ifthisdoseiswell tolerated,it maybefeasibletotitratethedosetothetherapeuticlevel more

quicklythan isrecommended forinitialtreatment.However, in anypatientwho has

previouslyexperiencedrespiratoryorcardiacarrestwithinitial dosing(seesection6

Warningsand precautions), butwasthen ableto besuccessfullytitrated toatherapeuticdose,

re-titration should bedonewith extremecaution.

Reducingtherisk ofsuicidalbehaviour inschizophreniaandschizoaffective disorder

Thedosageand administration recommendationsdescribed in theprecedingsection(4

Dosageandadministration)regardingtheuseofLeponexin patientswith treatment-resistant

schizophreniashould also befollowed when treatingpatientswith schizophreniaor

schizoaffectivedisorderatrisk forrecurrentsuicidalbehaviour.

Acourseoftreatment withLeponexofat least twoyearsisrecommendedinordertomaintain

thereduction ofrisk forsuicidalbehaviour.Itisrecommended thatthepatient’srisk of

suicidalbehaviourbereassessedaftertwoyearsoftreatmentandthatthereafterthe decision

to continuetreatmentwithLeponexbere-visited atregularintervals, basedon thorough

assessmentsofpatient’srisk forsuicidalbehaviourduringtreatment.

Specialpopulations

Cardiovascular disorders

In patientssufferingfromcardiovasculardisorders(note:severecardiovasculardisordersare

contraindications)theinitialdoseshould be12.5mggiven onceonthefirstday,and dosage

increaseshould beslowand in smallincrements.

Renal impairment

Inpatientswithmildtomoderaterenal impairment theinitial doseshouldbe12.5mggiven

onceon thefirstday,anddosageincreaseshould beslowand in smallincrements.

Hepaticimpairment

Patientswithhepaticimpairment shouldreceiveLeponexwithcautionalongwithregular

monitoringofliverfunction tests(seesection 6 Warningsand precautions).

Pediatrics

No pediatricstudieshavebeen performed. ThesafetyandefficacyofLeponexin children

and adolescentsundertheageof16havenotbeenestablished.

Patients60 yearsofageandolder

It isrecommendedthat treatment inpatients60yearsandolderisinitiatedat aparticularly

lowdose(12.5 mggivenonceon thefirstday)with subsequentdoseincrementsrestricted to

25 mg/day.

5 Contraindications

Known hypersensitivitytoclozapineorto anyofthe excipientsofLeponex.

Patientsunableto undergo regularblood tests.

Historyoftoxicoridiosyncraticgranulocytopenia/agranulocytosis(with theexception of

granulocytopenia/agranulocytosisfrompreviouschemotherapy).

HistoryofLeponex-induced agranulocytosis

Impaired bonemarrowfunction.

Uncontrolled epilepsy.

Alcoholicand othertoxicpsychoses, drugintoxication, comatoseconditions.

Circulatorycollapseand/orCNSdepression ofanycause.

Severe renalorcardiac disorders(e.g.myocarditis).

Active liverdisease associatedwithnausea,anorexia orjaundice;progressiveliver

disease,hepatic failure.

Paralytic ileus.

Leponextreatment must not bestartedconcurrentlywithsubstancesknownto havea

substantialpotentialforcausingagranulocytosis;concomitantuseofdepotantypsychotics

isto bediscouraged.

6 Warningsand precautions

Specialprecautionarymeasure

Agranulocytosis

Leponexcancause agranulocytosis.The incidenceofagranulocytosisandthe fatalityrate in

thosedevelopingagranulocytosishavedecreasedmarkedlysincetheinstitution ofWBC

countsand ANCmonitoring.

Becauseoftheassociation ofLeponexwithagranulocytosis,thefollowingprecautionary

measuresare mandatory:

Drugsknownto haveasubstantialpotentialto depressbonemarrowfunction should

notbeusedconcurrentlywithLeponex.Inaddition, theconcomitantuseoflong-

acting depotantipsychoticsshould beavoided becauseoftheimpossibilityof

removingthesemedications, which maybepotentiallymyelosuppressive, fromthe

bodyrapidlyin situationswherethismayberequired, e.g.granulocytopenia.

Patientswith ahistoryofprimarybonemarrowdisordersmaybetreatedonlyifthe

benefitoutweighstherisk. Theyshould becarefullyreviewed byahaematologistprior

to startingLeponex.

Patientswho havelowwhiteblood cell(WBC)countsbecauseofbenign ethnic

neutropeniashould begiven specialconsideration and maybestarted onLeponex

afteragreement ofahaematologist.

Leponexmustbedispensed understrictmedicalsupervision in accordancewith official

recommendations.

BeforeinitiatingLeponextherapypatientsshould haveablood test(see“agranulocytosis”)

and ahistoryand physicalexamination. Patientswith historyofcardiacillnessorabnormal

cardiac findingson physicalexamination should bereferred to aspecialistforother

examinationsthatmightincludean ECG, and thepatienttreated onlyiftheexpected benefits

clearlyoutweighthe risks(see Section5 Contraindications). Thetreatingphysicianshould

considerperformingapre-treatment ECG.

Priortotreatment initiation,physiciansmust ensure,tothebest oftheirknowledge,that the

patienthasnotpreviouslyexperiencedanadversehaematologicalreactiontoclozapine that

necessitated itsdiscontinuation. Prescriptionsshould notbeissued forperiodslongerthan the

intervalbetween two blood counts.

Immediatediscontinuation ofLeponexismandatoryifeithertheWBCcountislessthan

3000/mm 3

(3.0x10 9

/L)ortheANCislessthan1500/mm 3

(1.5x10 9

/L)at anytimeduring

Leponextreatment. Patientsin whomLeponexhasbeen discontinued asaresultofeither

WBCorANCdeficienciesmustnotbe re-exposed toLeponex.

Ateachconsultation, apatientreceivingLeponexmustbereminded to contactthetreating

physician immediatelyifanykind ofinfection beginsto develop. Particularattention should

bepaid to flu-likecomplaintssuch asfeverorsorethroatand to otherevidenceofinfection,

which maybeindicativeofneutropenia. Patientsand theircaregiversmustbeinformed that,

in theeventofanyofthesesymptoms, theymusthaveablood cellcountperformed

immediately.

Prescribersareencouragedtokeeparecordofallpatients'bloodresultsand to takeanysteps

necessarytopreventthese patientsfromaccidentallybeingrechallengedinthe future.

WhiteBloodCell (WBC)countsandAbsoluteNeutrophilCount(ANC)monitoring

Whitebloodcellcount(WBC)and differentialblood countsmustbeperformed within

10dayspriortostartingLeponextreatmenttoensurethatonlypatientswith normalleukocyte

(WBC ≥3500/mm 3

( ≥3.5 x10 9

/L))andabsoluteneutrophilcounts(ANC ≥2000/mm 3

( ≥2.0 x

/L))willreceiveLeponex.Afterthe startofLeponextreatment,regularWBCcountand

ANCmustbeperformed andmonitored weeklyforthefirst18weeks,andthereafteratleast

everyfourweeksthroughouttreatment, and for4 weeksaftercompletediscontinuation of

Leponex.

Prescribingphysiciansshould complyfullywith therequired safetymeasures.Ateach

consultation, thepatientmustberemindedtocontact thetreatingphysicianimmediatelyif

anykind ofinfectionbeginsto develop.Particularattention should bepaid to flu-like

complaintssuch asfeverorsorethroatand to otherevidenceofinfection, which maybe

indicativeofneutropenia.Adifferentialblood countmustbeperformed immediatelyifany

symptomsorsignsofaninfection occur.

LowWBCcountand/orANC

Ifduringthefirst18 weeksofLeponextherapy, theWBCcountfallsto between

3500/mm 3

(3.5 x10 9

/L)and 3000/mm 3

(3.0 x10 9

/L)and/orthe ANCfallstobetween

2000/mm 3

(2.0 x10 9

/L)and 1500/mm 3

(1.5 x10 9

/L),haematologicalevaluationsmustbe

performedatleasttwiceweeklyuntil thepatient’sWBCcount andANCstabilisewithinthe

range3000-3500/mm 3 (3.0-3.5 x10 9 /L)and 1500-2000 mm 3 (1.5-2.0 x10 9 /L), respectively,

orhigher.

After18 weeksofLeponextherapy,haematologicalevaluationsshould beperformedatleast

twiceweekly iftheWBCcountfallstobebetween3000/mm 3

and 2500/mm 3

and/ortheANC

fallstobetween1500/mm 3

and 1000/mm 3

In addition,if,duringLeponextherapy, theWBCcountisfound to havedropped bya

substantialamountfrombaseline, arepeatWBCcountandadifferentialblood countshould

be performed.Asubstantialdrop isdefined asasingledropof3000mm 3

ormorein theWBC

countoracumulativedrop of3000mm 3

or more withinthree weeks.

Immediatediscontinuation ofLeponexismandatoryiftheWBCcountislessthan 3000/mm 3

ortheANCislessthan 1500/mm 3

atanytime duringLeponextreatment. WBCcountsand

differentialblood countsshould then beperformed dailyand patientsshould becarefully

monitored forflu-likesymptomsorothersymptomssuggestiveofinfection.

Followingdiscontinuation ofLeponex, haematologicalevaluationisrequired until

haematologicalrecoveryhasoccurred.

IfLeponexhasbeenwithdrawnand WBCcountfallsfurtherto below2000/mm 3

(2.0 x10 9

/L)

and/ortheANCfallsbelow1000/mm 3 (1.0 x10 9 /L), themanagementofthiscondition must

beguided byanexperienced haematologist.Ifpossible, thepatientshould bereferred to a

specialisedhaematologicalunit, whereprotectiveisolation and theadministration ofGM-CSF

(granulocyte-macrophagecolonystimulating factor)orG-CSF(granulocytecolony

stimulatingfactor)maybeindicated.It isrecommendedthat thecolonystimulatingfactor

therapybediscontinuedwhen theneutrophilcounthasreturned to alevelabove1000/mm 3 .

Discontinuationoftherapy forhaematologicalreasons

Patientsin whomLeponexhasbeen discontinued asaresultofwhitebloodcelldeficiencies

(seeabove)mustnotbere-exposed toLeponex.

It isrecommendedthat thehaematological valuesbeconfirmedbyperformingtwoblood

countson two consecutivedays;however,Leponexshould bediscontinuedafterthefirst

blood count.

Table6-1: Blood monitoring

Bloodcellcount Actionrequired

WBC/mm³(/L) ANC/mm³ (/L)

≥3500 (≥3.5 x10 9

) ≥2000 (≥2.0 x10 9

) Continue Leponextreatment.

Between ≥3000and <3500

≥3.0 x10 9 and <3.5 x10 9 ) Between ≥1500and

<2000( ≥1.5x10 9 and2.0 x

) ContinueLeponextreatment,sample blood

twice weeklyuntilcountsstabiliseorincrease.

<3000(<3.0 x10 9

) <1500(<1.5 x10 9

) Immediatelystop Leponextreatment,sample

blooddailyuntilhaematologicalabnormalityis

resolved,monitorforinfection.Do notre-

expose the patient.

In theeventofinterruption oftherapyfornon-haematologicalreasons

Patientswho havebeen onLeponexformorethan18 weeksand havehadtheirtreatment

interrupted formorethan3 daysbutlessthan 4weeksshould havetheirWBCcountand

ANCmonitored weeklyforan additional6 weeks.Ifno haematologicalabnormalityoccurs,

monitoringatintervalsnotexceeding4 weeksmayberesumed.IfLeponextreatmenthas

been interrupted for4weeksorlonger, weeklymonitoringisrequired forthenext18 weeks

oftreatment.(Seesection4 DosageandAdministration).

Otherprecautions

Patientswithrare hereditaryproblemsofgalactose intolerance,theLapplactose deficiencyor

glucose-galactosemalabsorption should nottakethismedicine.

Eosinophilia

In theeventofeosinophilia,discontinuation ofLeponexisrecommendediftheeosinophil

countrisesabove3000/mm 3

(3.0 x10 9

/L). Therapyshouldbere-startedonlyafterthe

eosinophilcounthasfallen below1000/mm 3 (1.0 x10 9 /L).

Thrombocytopenia

In theeventofthrombocytopenia,discontinuation ofLeponextherapyisrecommendedif

theplatelet count fallsbelow50000/mm 3

(50 x10 9

/L).

Cardiovasculardisorders

In patientssufferingfromcardiovasculardisorders(note:severecardiovasculardisordersare

contraindications)theinitialdoseshould be12.5 mggiven onceon thefirstday,and dosage

increaseshould beslowand in smallincrements(seesection 4 DosageandAdministration).

Orthostatichypotension, with orwithoutsyncope, can occurduringLeponextreatment.

Rarely(aboutonecaseper3000Leponex-treatedpatients),collapsecan beprofound and may

be accompaniedbycardiac and/or respiratoryarrest.Sucheventsare morelikelytooccur

with concurrentuseofbenzodiazepineoranyotherpsychotropicagent(seesection8

Interactions)andduringinitial titrationinassociationwithrapiddoseescalation; onveryrare

occasionstheyoccurredeven afterthefirstdose.Therefore,patientscommencingLeponex

treatmentrequire close medicalsupervision.Tachycardia thatpersistsatrest,accompaniedby

arrhythmias, shortnessofbreath orsignsand symptomsofheartfailure, mayrarelyoccur

duringthefirstmonth oftreatmentand veryrarelythereafter. Theoccurrenceofthesesigns

and symptomsnecessitatesan urgentdiagnosticevaluation formyocarditis, especiallyduring

thetitration period.Ifthediagnosisofmyocarditisisconfirmed,Leponexshould be

discontinued.Laterin treatment, thesamesignsand symptomsmayveryrarelyoccurand

maybelinked to cardiomyopathy.Furtherinvestigation should beperformed and ifthe

diagnosisisconfirmed, thetreatmentshould bestopped unlessthe benefitclearlyoutweighs

therisktothepatient.

Analysisofsafetydatabasessuggeststhatthe useofLeponexisassociatedwithanincreased

riskofmyocarditisespeciallyduring,but not limitedto,thefirst twomonthsoftreatment.

Some casesofmyocarditishave beenfatal.Pericarditis/pericardialeffusionand

cardiomyopathyhavealso been reported in association withLeponexuse;thesereportsalso

includefatalities. Myocarditisorcardiomyopathyshould besuspected in patientswho

experiencepersistent tachycardiaat rest,especiallyinthefirst twomonthsoftreatment,

and/orpalpitations, arrhythmias, chestpain and othersignsand symptomsofheartfailure

(e.g. unexplained fatigue,dyspnoea,tachypnoea),orsymptomsthat mimicmyocardial

infarction. Othersymptomswhich maybepresentin addition to theaboveincludeflu-like

symptoms.Ifmyocarditisorcardiomyopathyissuspected,Leponextreatmentshould be

promptlystopped and thepatientimmediatelyreferred to acardiologist.

Patientswithclozapine-induced myocarditisorcardiomyopathyshould notbere-exposed to

Leponex.

Myocardialinfarction

Inaddition, therehavebeen postmarketingreportsofmyocardialinfarction which maybe

fatal.Causalityassessmentwasdifficultinthe majorityofthese casesbecause ofseriouspre-

existingcardiac diseaseandplausible alternative causes.

QT intervalprolongation

Aswith otherantipsychotics, cautionisadvised inpatientswith known cardiovasculardisease

orfamilyhistoryofQTprolongation.

Aswith otherantipsychotics, caution should beexercised whenLeponexisprescribedwith

medicinesknowntoincrease the QTc interval.

Cerebrovascularadverse events

An increased risk ofcerebrovascularadverseeventshasbeen seen in thedementiapopulation

with someatypicalantipsychotics. Themechanismforthisincreased risk isnotknown. An

increased risk cannotbeexcluded forotherantipsychoticsorotherpatientpopulations.

Leponexshould beused with caution in patientswith risk factorsforstroke.

Riskofthromboembolism

Since Leponexmaybe associatedwiththromboembolism,immobilisationofpatientsshould

beavoided.

MetabolicChanges

Atypicalantipsychoticdrugs, includingLeponex, havebeen associated with metabolic

changesthatmayincrease cardiovascular/cerebrovascularrisk.These metabolic changesmay

includehyperglycemia,dyslipidemia, and bodyweightgain. Whileatypicalantipsychotic

drugsmayproducesomemetabolicchanges,each drugin theclasshasitsown specificrisk

profile.

Hyperglycemia

Impairedglucose tolerance and/ordevelopmentorexacerbationofdiabetesmellitushasbeen

reported rarelyduringtreatmentwith clozapine. Amechanismforthispossibleassociation

hasnotyetbeendetermined.Casesofseverehyperglycaemiawithketoacidosisor

hyperosmolarcomahavebeenreportedveryrarelyin patientswith no priorhistoryof

hyperglycaemia, someofwhich havebeenfatal.When follow-updata were available,

discontinuation ofclozapineresulted mostlyin resolution oftheimpaired glucose tolerance,

and reinstitutionofclozapineresulted in itsreoccurrence.

Patientswithanestablisheddiagnosisofdiabetesmellituswhoarestartedonatypical

antipsychoticsshould bemonitored regularlyforworseningofglucosecontrol. Patientswith

risk factorsfordiabetesmellitus(e.g., obesity, familyhistoryofdiabetes)whoare starting

treatmentwith atypicalantipsychoticsshould undergo fastingbloodglucosetestingatthe

beginningoftreatmentand periodicallyduringtreatment.Exacerbationshould beconsidered

in patientsreceivingLeponexwho develop symptomsofhyperglycemia, such aspolydipsia,

polyuria, polyphagiaorweakness.

Patientswho develop symptomsofhyperglycemiaduringtreatmentwith atypical

antipsychoticsshould undergo fastingbloodglucosetesting.In somecases, hyperglycemia

hasresolved when theatypicalantipsychoticwasdiscontinued;however, somepatients

requiredcontinuation ofantidiabetictreatmentdespitediscontinuation ofthesuspectdrug.

Thediscontinuationofclozapineshould beconsidered in patientswhereactivemedical

managementoftheirhyperglycaemia hasfailed.

Thereisariskofalteringthemetabolicbalanceresultinginslight impairment ofglucose

homeostasisand apossibilityofunmaskingapre-diabeticcondition oraggravatingpre-

existingdiabetes.

Dyslipidemia

Undesirablealterationsinlipidshave beenobservedinpatientstreatedwithatypical

antipsychotics, includingLeponex. Clinicalmonitoring, including baselineand periodic

follow-up lipid evaluationsin patientsusingclozapine, isrecommended.

WeightGain

Weightgain hasbeen observed with atypicalantipsychoticuse, includingLeponex. Clinical

monitoringofweightisrecommended.

Seizures

Leponexmaylowerseizurethreshold.Inpatientswithahistoryofseizurestheinitial dose

should be12.5 mggiven onceon thefirstday,and dosageincreaseshould beslowand in

small increments(Seesection 4 Dosageandadministration).

Patientswith ahistoryofepilepsyshould becloselyobserved duringLeponextherapysince

dose-related convulsionshavebeen reported.In such cases, thedoseshouldbereduced (see

section4 Dosageand administration)and, ifnecessary, an anti-convulsanttreatmentshould be

initiated.

Anticholinergic effects

Clozapineexertsanticholinergicactivity, which mayproduceundesirableeffectsthroughout

thebody. Carefulsupervision isindicated in thepresenceofprostatic enlargementand

narrow-angleglaucoma. Probablyonaccountofitsanticholinergicproperties,Leponexhas

beenassociatedwithvaryingdegreesofimpairmentofintestinal peristalsis, rangingfrom

constipationtointestinalobstruction,faecalimpactionandparalyticileus(see section7

Adverse drugreactions).On rareoccasionsthese caseshaveprovedfatal.

Particularcareisnecessaryin patientswhoarereceivingconcomitantmedicationsknown to

causeconstipation (especiallythosewith anticholinergicpropertiessuch assome

antipsychotics,antidepressantsand antiparkinsonian treatments), haveahistoryofcolonic

disease ora historyoflowerabdominalsurgeryasthese mayexacerbate the situation.Itis

vital that constipationisrecognisedandactivelytreated.

Fever

DuringLeponextherapy,patientsmayexperience transienttemperatureelevationsabove

38°C, with thepeak incidencewithin thefirst3weeksoftreatment. Thisfeverisgenerally

benign.Occasionally,itmaybe associatedwithanincrease ordecrease inthe WBCcount.

Patientswith fevershould becarefullyevaluatedto ruleoutthepossibilityofanunderlying

infection orthedevelopmentofagranulocytosis. In thepresenceofhigh fever, thepossibility

ofneurolepticmalignantsyndrome(NMS)mustbeconsidered.Ifthediagnosis ofNMSis

confirmed,Leponexshould bediscontinued immediatelyand appropriatemedicalmeasures

should beadministered.

Specialpopulations

Hepaticimpairment

Patientswithstablepre-existingliverdisordersmayreceiveLeponex, butmustundergo

regularliverfunction tests. Such testsshouldbeperformedimmediatelyinpatientswho

develop symptomsofpossibleliverdysfunctionsuch asnausea, vomitingand/oranorexia

duringLeponextreatment.Ifthe elevationofthe valuesisclinicallyrelevant(morethan 3

timestheUNL)orifsymptomsofjaundiceoccur, treatmentwithLeponexmustbe

discontinued.Itmayberesumed (seesection4 Dosageand administration-Re-starting

therapy)onlywhentheresultsofliverfunction testsarenormal.Insuchcases, liverfunction

should becloselymonitoredafterre-introduction ofLeponex.

Renal impairment

Inpatientssufferingfrom mildtomoderaterenal impairment,aninitial doseof12.5mg/day

(halfa25 mgtablet)isrecommended (seesection4 Dosageandadministration).

Patientsaged60 yearsandolder

It isrecommendedthat treatment beinitiatedat aparticularlylowdose(12.5 mggiven once

on thefirstday)and subsequentdoseincrementsberestricted to 25 mg/day.

Clinicalstudieswith Leponexdid notincludesufficientnumbersofsubjectsaged60years

and overto determinewhetherornottheyresponddifferentlyfromyoungersubjects.

Orthostatichypotensioncan occurwithLeponextreatmentandtherehavebeen rarereportsof

tachycardia,which maybesustained,in patientstakingLeponex.Patientsaged60yearsand

older, particularlythosewith compromised cardiovascularfunction, maybemoresusceptible

tothese effects.

Patientsaged 60yearsand oldermayalsobeparticularlysusceptibletotheanticholinergic

effectsofclozapine, suchasurinaryretention andconstipation.

Patientsaged 60 yearsand olderwithDementia-relatedPsychosis

Inpatientsaged 60yearsand olderwithdementia-related psychosis, theefficacyandsafetyof

clozapinehasnotbeen studied. Observationalstudiessuggestthatpatientsaged 60yearsand

olderwithdementia-relatedpsychosistreatedwithantipsychotic drugsare atanincreasedrisk

ofdeath.In thepublishedliterature, risk factorsthatmaypredisposethispatientpopulation to

increased risk ofdeath when treatedwith antipsychoticsincludesedation, thepresenceof

cardiacconditions(e.g. cardiacarrhythmias)orpulmonaryconditions(e.g.pneumonia, with

orwithout aspiration).Leponexshould beused with caution in patientsaged60yearsand

olderwithdementia.

Rebound,withdrawaleffects

Acutewithdrawalreactionshavebeenreportedfollowingabruptcessation ofclozapine

thereforegradualwithdrawalisrecommended.

IfabruptdiscontinuationofLeponexisnecessary(e.g.because ofleucopenia),the patient

should becarefullyobserved fortherecurrenceofpsychoticsymptomsand symptomsrelated

to cholinergicrebound such asprofusesweating, headache, nausea, vomitingand diarrhoea.

Driving and using machines

Owingto theabilityofLeponexto causesedationand lowertheseizurethreshold, activities

such asdrivingoroperatingmachineryshould beavoided, especiallyduringtheinitialweeks

oftreatment.

7 Adversedrug reactions

Summaryof thesafetyprofile

The adverse effectsofclozapine are mostoftenpredictable basedonitspharmacological

propertieswith theexception ofagranulocytosis(see section6 Warningsand precautions).

Themostseriousadversereactionsexperiencedwith clozapineareagranulocytosis, seizure,

cardiovasculareffectsand fever(seesection 6 Warningsand precautions). Themostcommon

sideeffectsaredrowsiness/sedation, dizziness,tachycardia,constipation andhypersalivation.

Data fromthe clinicaltrialsexperience showedthata varyingproportionofclozapine-treated

patients(from7.1 to 15.6%)werediscontinueddueto anadverseevent, includingonlythose

thatcould bereasonablyattributed to clozapine. Themorecommon eventsconsidered to be

causesofdiscontinuation wereleukopenia;somnolence;dizziness(excludingvertigo);and

psychoticdisorder.

Because oftherisk foragranulocytosis,useofLeponexisrestrictedtotreatment-resistant

schizophreniain caseswherestandard treatmenthasfailed. Whileblood monitoringisan

essentialpartofthecareofpatientsreceivingclozapine, thephysicianshould beawareof

otherrarebutseriousadverseevents, which maybediagnosed in theearlystagesonlyby

carefulobservation and questioningofthepatientin orderto preventmorbidityand mortality.

Bloodandlymphaticsystem

Developmentofgranulocytopeniaand agranulocytosisisarisk inherentto Leponex

treatment. Althoughgenerallyreversibleonwithdrawal oftreatment,agranulocytosismay

resultinsepsisandcanprove fatal.Because immediate withdrawalofthe drugisrequiredto

preventthedevelopmentoflife-threateningagranulocytosis, monitoringoftheWBCcountis

mandatory(see section6Warningsand precautions).Table7-1belowsummarisesthe

estimated incidenceofagranulocytosisforeachLeponextreatmentperiod.

Table7-1:Estimatedincidenceofagranulocytosis 1

Treatmentperiod Incidence ofagranulocytosisper

100,000 person-weeks 2

ofobservation

Weeks0-18 32.0

Weeks19-52 2.3

Weeks53 and higher 1.8

FromtheUKClozarilPatient MonitoringServicelifetimeregistryexperiencebetween1989

and 2001.

Person-timeisthesumofindividual unitsoftimethat thepatientsintheregistryhavebeen

exposed toLeponexbeforeexperiencingagranulocytosis. Forexample, 100,000 person-

weekscould beobservedin 1,000 patientswho werein theregistryfor100weeks

(100*1000=100,000), orin 200 patientswho werein theregistryfor500 weeks

(200*500=100,000)beforeexperiencingagranulocytosis.

Thecumulativeincidenceofagranulocytosisin theUKClozarilPatient MonitoringService

lifetimeregistryexperience(0-11.6yearsbetween 1989 and 2001)is0.78%. Themajorityof

cases(approximately70%)occurwithinthe first18weeksoftreatment.

Metabolic andNutritionalDisorders

Impairedglucose tolerance and/ordevelopmentorexacerbationofdiabetesmellitushasbeen

reported rarelyduringtreatmentwith clozapine. On veryrareoccasions, severe

hyperglycaemia, sometimesleadingto ketoacidosis/hyperosmolarcoma,hasbeen reported in

patientsonLeponextreatmentwith no priorhistoryofhyperglycaemia.Glucose levels

normalised in mostpatientsafterdiscontinuationofLeponexand in afewcases

hyperglycaemiarecurredwhen treatmentwasreinitiated. Although mostpatientshad risk

factorsfor non-insulin-dependentdiabetesmellitus, hyperglycaemiahasalsobeen

documented in patientswith no known risk factors(seesection6Warningsand precautions).

NervousSystemDisorders

Theverycommon adverseeventsobserved includedrowsiness/sedation, and dizziness.

Leponexcancause EEGchanges,includingthe occurrence ofspike andwave complexes.It

lowerstheseizurethreshold in adose-dependentmannerand mayinducemyoclonicjerksor

generalised seizures. Thesesymptomsaremorelikelyto occurwith rapid doseincreasesand

inpatientswithpre-existingepilepsy.In such casesthedoseshould bereduced and, if

necessary, anticonvulsanttreatmentinitiated. Carbamazepineshould beavoided becauseofits

potentialto depressbonemarrowfunction, and with otheranticonvulsantdrugsthepossibility

ofapharmacokineticinteraction should beconsidered.In rarecases, patientstreated with

Leponexmayexperiencedelirium.

Veryrarely, tardivedyskinesiahasbeenreported in patientsonLeponexwho had been

treatedwith otherantipsychoticagents. Patientsin whomtardivedyskinesiadeveloped with

otherantipsychoticshaveimproved onLeponex.

Cardiac Disorders

Tachycardiaand posturalhypotension with orwithoutsyncopemayoccur,especiallyin the

initial weeksoftreatment. Theprevalenceand severityofhypotension isinfluenced bythe

rateand magnitudeofdosetitration. Circulatorycollapseasaresultofprofound hypotension,

in particularrelated to aggressivetitration ofthedrug,with thepossibleseriousconsequences

ofcardiacorpulmonaryarrest, hasbeen reportedwithLeponex.

AminorityofLeponex-treatedpatientsexperienceECGchangessimilartothose seenwith

otherantipsychoticdrugs, includingS-Tsegmentdepression and flattening orinversion of T

waves,whichnormaliseafterdiscontinuationofLeponex.The clinicalsignificance ofthese

changesisunclear. However, such abnormalitieshavebeen observed in patientswith

myocarditis, which should thereforebeconsidered.

Isolatedcasesofcardiacarrhythmias, pericarditis/pericardialeffusion andmyocarditishave

been reported, someofwhich havebeen fatal. Themajorityofthecasesofmyocarditis

occurred within thefirst2 monthsofinitiation oftherapywithLeponex. Cardiomyopathy

generallyoccurredlaterinthe treatment.

Eosinophiliahasbeen co-reportedwith somecasesofmyocarditis(approximately14%)and

pericarditis/pericardialeffusion;itisnotknown, however,whethereosinophiliaisareliable

predictorofcarditis.

Signsand symptomsofmyocarditisorcardiomyopathyincludepersistenttachycardiaatrest,

palpitations, arrhythmias,chestpain and othersignsand symptomsofheartfailure(e.g.

unexplained fatigue, dyspnoea, tachypnoea), orsymptomsthatmimicmyocardialinfarction.

Othersymptomswhichmaybepresentin addition to theaboveincludeflu-likesymptoms.

Sudden, unexplained deathsareknown to occuramongpsychiatricpatientswho receive

conventionalantipsychoticmedication butalso amonguntreated psychiatricpatients. Such

deathshave beenreportedveryrarelyinpatientsreceivingLeponex.

Vascular Disorders

Rarecasesofthromboembolismhavebeen reported.

Respiratory System

Respiratorydepression orarresthasoccurred veryrarely, with orwithoutcirculatorycollapse

(see sections6 Warningsand precautionsand 8Interactions).

GastrointestinalSystem

Constipation and hypersalivation havebeen observed veryfrequently, andnauseaand

vomitingfrequently.Veryrarelyileusmayoccur(see section6 Warningsand precautions).

RarelyLeponextreatmentmaybeassociatedwith dysphagia. Aspiration ofingestedfood may

occurin patientspresentingwith dysphagiaorasaconsequenceofacuteoverdosage.

HepatobiliaryDisorders

Transient,asymptomaticelevationsofliverenzymesandrarely,hepatitisandcholestatic

jaundicemayoccur. Veryrarely, fulminanthepaticnecrosishasbeenreported.Ifjaundice

develops,Leponexshould bediscontinued (seesection6 Warningsand precautions).Inrare

cases,acute pancreatitishasbeen reported.

RenalDisorders

Isolatedcasesofacute interstitialnephritishave beenreportedinassociationwithLeponex

therapy.

Reproductive andBreastDisorders

Veryrarereportsofpriapismhave beenreceived.

GeneralDisorders

Casesofneurolepticmalignantsyndrome(NMS)havebeen reported in patientsreceiving

Leponexeitheraloneorin combination with lithiumorotherCNS-active agents.

Acute withdrawalreactionshave beenreported(see section6 Warningsandprecautions).

The table belowsummarisesthe adverse reactionsaccumulatedfromreportsmade

spontaneouslyand duringclinicalstudies.

Adversedrugreactions(ADRs)are listedbyMedDRAsystemorganclass(see Table 7-2).

Withineachsystemorganclass,the adversereactionsare rankedbyfrequency, usingthe

followingconvention:Verycommon(1/10), common (1/100, <1/10),uncommon (

1/1,000, <1/100), rare(1/10,000, <1/1,000), veryrare(<1/10,000), includingisolated

reports.Within each frequencygrouping,adversedrugreactionsarepresented in orderof

decreasingseriousness.

Table7-2 Treatment-EmergentAdverse Experience Frequencyestimatefrom

Spontaneous and ClinicalTrialReports

Bloodandlymphaticsystemdisorders

Common Leukopenia/decreasedWBC/neutropenia,

eosinophilia, leukocytosis

Uncommon Agranulocytosis

Rare Anaemia

Veryrare Thrombocytopenia, thrombocythemia

Metabolismand nutrition disorders

Common Weight gain

Rare Diabetesaggravated,impairedglucose

tolerance,newonsetdiabetes

Veryrare Hyperosmolarcoma,Ketoacidosis,severe

hyperglycaemia,hypercholesterolaemia,

hypertriglyceridaemia,

Psychiatric disorders

Common Dysarthria

Uncommon Dysphemia

Rare Agitation,restlessness

Nervoussystemdisorders

Verycommon Drowsiness/sedation, dizziness

Common Seizures/convulsions/myoclonicjerks,

extrapyramidal symptoms,akathisia,tremor,

rigidity,headache

Uncommon Neurolepticmalignantsyndrome

Rare Confusion, delirium

Veryrare Tardivedyskinesia,obsessivecompulsive

symptoms

Eye disorders

Common Blurred vision

Cardiac disorders

Verycommon Tachycardia

Common ECGchanges

Rare Circulatorycollapse,arrhythmias,

myocarditis,pericarditis

Veryrare Cardiomyopathy

Vascularsystemdisorders

Common Syncope, posturalhypotension,hypertension

Rare Thromboembolism

Respiratorydisorders

Rare Aspiration ofingested food, pneumoniaand

lowerrespiratorytract infectionwhichmay

be fatal

Veryrare Respiratorydepression/arrest

Gastrointestinaldisorders

Verycommon Constipation, hypersalivation

Common Nausea, vomiting,anorexia, drymouth

Rare Dysphagia

Veryrare Intestinal obstruction/paralyticileus/faecal

impaction, parotid glandenlargement

Hepatobiliarydisorders

Common Elevatedliverenzymes

Rare Pancreatitis,hepatitis,cholestaticjaundice

Veryrare Fulminanthepaticnecrosis

Skin and subcutaneoustissuedisorders

Veryrare Skin reactions

Renalandurinarydisorders

Common Urinaryretention,urinaryincontinence

Veryrare Interstitial nephritis

Reproductive systemdisorders

Veryrare Priapism

Generaldisorders

Common Fever,benign hyperthermia, disturbancesin

sweating/temperatureregulation, fatigue

Veryrare Suddenunexplained death

Investigations

Rare IncreasedCPK

Adverse drug reactions fromspontaneousreports andliterature(frequencynot

known)

Thefollowingadversedrugreactions(ADRs)werederived frompost-marketingexperience

withLeponexvia spontaneouscasereportsandliteraturecasesandhave beencategorized

accordingtoMedDRAsystemorganclass(see Table 7-3).Because thesereactionshave been

reported voluntarilyfromapopulation ofuncertain sizeand aresubjectto confounding

factors,these post-marketingADRshavebeencategorizedwith afrequencyof“notknown”

sinceit isnot possibletoreliablyestimatetheirfrequency.Adverse drugreactionsarelisted

accordingtosystemorganclassesinMedDRA.Withineachsystemorganclass,ADRsare

presentedinorderofdecreasingseriousness.

Table7-3 Adverse drug reactions fromspontaneousreports andliterature

(frequencynotknown)

Nervous system disorders

Cholinergicsyndrome,EEGchanges

Cardiac disorders

Myocardialinfarction which maybe fatal,chestpain/anginapectoris

Respiratorydisorders

Nasalcongestion

Gastrointestinaldisorders

Diarrhea,Abdominaldiscomfort/heartburn/dyspepsia

Hepatobiliarydisorders

Hepaticsteatosis,hepaticnecrosis,hepatotoxicity,hepaticfibrosis,hepaticcirrhosis,liverdisordersincluding

those hepaticeventsleadingto life-threateningconsequencessuch asliverinjury(hepatic,cholestaticand

mixed),liverfailure whichmaybe fatalandlivertransplant

Musculoskeletalandconnective tissue disorders

Muscle weakness,muscle spasms,musclepain

Renalandurinarydisorders

Renalfailure

Veryrareeventsofventriculartachycardia, cardiacarrestandQTprolongation which maybe

associated with TorsadesDePointeshavebeen observed although thereisno conclusive

causalrelationship to theuseofthismedicine.

8 Interactions

Pharmacodynamic-relatedinteractions

Anticipated pharmacodynamicinteractionsresultingin concomitantusenotbeing

recommended

Medicinalproductsknown to haveasubstantialpotentialtodepressbonemarrowfunction

should notbeused concurrentlywithLeponex(see section6 Warningsandprecautions)

Aswith otherantipsychotics, cautionshould beexercised whenLeponexisprescribedwith

medicinesknowntoincrease the QTc interval,orcausingelectrolyte imbalance.

Observed pharmacodynamicinteractionstobe considered

Particularcaution isrecommended whenLeponextherapyisinitiated in patientswho are

receiving(orhave recentlyreceived)a benzodiazepine oranyotherpsychotropic agent,as

these patientsmayhaveanincreasedriskofcirculatorycollapse, which, onrareoccasions,

can beprofound and maylead to cardiacand/orrespiratoryarrest.

ConcomitantuseoflithiumorotherCNS-active agentsmayincrease the riskofdevelopment

ofneurolepticmalignantsyndrome(NMS).

Rare butseriousreportsofseizures, includingonsetofseizuresin non-epileptic patients,and

isolatedcasesofdeliriumwhereLeponexwasco-administeredwithvalproic acidhave been

reported.Theseeffectsarepossiblydueto apharmacodynamicinteraction, themechanismof

which hasnotbeen determined.

Anticipatedpharmacodynamic interactionstobe considered

Clozapinemayenhancethecentraleffectsofalcohol, MAOinhibitorsand CNSdepressants

such asnarcotics, antihistamines, and benzodiazepines.

Because ofthepossibilityofadditiveeffects, caution isessentialwhen substancespossessing

anticholinergic, hypotensive, orrespiratorydepressanteffectsaregiven concomitantly.

Owingtoitsanti-alpha-adrenergicproperties,clozapinemayreducetheblood pressure-

increasingeffectofnorepinephrineorotherpredominantlyalpha-adrenergicagentsand

reverse the pressoreffectofepinephrine.

Pharmacokinetic-relatedInteractions

ClozapineisasubstrateformanyCYP450 isoenzymes, in particular1A2and 3A4. Therisk

ofmetabolicinteractionscausedbyaneffectonan individualisoformisthereforeminimised.

Nevertheless,cautioniscalledforinpatientsreceivingconcomitant treatment withother

substancesthatareeitherinhibitorsorinducersoftheseenzymes.

No clinicallyrelevantinteractionshavebeen observed thusfarwith tricyclicantidepressants,

phenothiazinesortype1

anti-arrhythmics,which areknown to bind to cytochrome

P4502D6.

Observedpharmacokinetic interactionstobe considered

Concomitantadministration ofsubstancesknown toinducecytochromeP450 enzymesmay

decrease the plasma levelsofclozapine.

Substancesknown to inducetheactivityof3A4 and with reported interactionswith

clozapineinclude, forinstance, carbamazepine, phenytoin andrifampicin.

Concomitantadministration ofsubstancesknowntoinhibittheactivityofcytochromeP450

isozymesmayincrease the plasma levelsofclozapine.

Substancesknown to inhibittheactivityofthemajorisozymesinvolved in the

metabolismofclozapineand with reported interactionsinclude, forinstance, cimetidine,

erythromycin (3A4), fluvoxamine(1A2)and ciprofloxacin (1A2).

The plasma concentrationofclozapine isincreasedbycaffeine (1A2)intake and

decreasedbynearly50%followinga 5-daycaffeine-freeperiod.

Elevatedclozapine plasma concentrationsalsohave beenreportedinpatientsreceiving

thesubstancesin combinationwithselectiveserotoninre-uptakeinhibitors(SSRIs)such

asparoxetine(1A2), sertraline, fluoxetineorcitalopram.

Anticipatedpharmacokinetic interactionstobeconsidered

Concomitantadministration ofsubstancesknown toinducecytochromeP450 enzymesmay

decrease the plasma levelsofclozapine.

Known inducersof1A2include, forinstance, omeprazoleand tobacco smoke.In casesof

sudden cessation oftobaccosmoking,theplasmaclozapineconcentration maybe

increased,thusleadingtoanincreaseinadverseeffects.

Concomitantadministration ofsubstancesknowntoinhibittheactivityofcytochromeP450

isozymesmayincrease the plasma levelsofclozapine.

PotentinhibitorsofCYP3A, such asazoleantimycoticsand proteaseinhibitors, could

potentiallyalsoincrease clozapine plasma concentrations;nointeractionshavebeen

reported to date, however.

Others

An outlineofdruginteractionsbelieved to bemostimportantwithLeponexisgiven in Table

8-1below(thisisnotan exhaustivelist).

Table8-1:Referenceto themostcommon druginteractionswithLeponex

Drug Interactions Comments

Bonemarrowsuppressants

(e.g.carbamazapine,

chloramphenicol,

sulphonamides(e.g. co-

trimoxazole), pyrazolone

analgesics(e.g.

phenylbutazone),

penicillamine,cytotoxic Interacttoincrease the risk

and/orseverityofbone

marrowsuppression Leponexmustnotbeused

concomitantlywith other

agentshavingawellknown

potentialto suppressbone

marrowfunction (seeSection

4.3 Contraindications)

agentsand long-actingdepot

injectionsofantipsychotics

Benzodiazepines Concomitantusemay

increase riskofcirculatory

collapse, which mayleadto

cardiac and/orrespiratory

arrest Whilstthe occurrence israre,

caution isadvised when

usingthesedrugstogether.

Reportssuggestthat

respiratorydepression and

collapse are more likelyto

occuratthe startofthis

combination orwhen

Leponexisadded to an

established benzodiazepine

regimen.

Anticholinergics Leponexpotentiatesthe

action ofthesedrugsthrough

additiveanticholinergic

activity Observe patientsfor

anticholinergicside–effects,

e.g.constipation, especially

when usingto help control

hypersalivation

Antihypertensives Leponexcanpotentiate the

hypotensiveeffectsofthese

drugsduetoits

sympathomimetic

antagonistic effects Caution isadvised if

Leponexisused

concomitantlywith

antihypertensiveagents.

Patientsshould beadvised of

therisk ofhypotension,

especiallyduringthe period

ofinitial dosetitration

Alcohol, MAOIs, CNS

depressants, including

narcoticsand

benzodiazepines Enhancedcentraleffects.

AdditiveCNSdepression and

cognitiveand motor

performanceinterference

when used in combination

withthesesubstances Caution isadvised if

Leponexisused

concomitantlywithother

CNSactive agents.Advise

patientsofthepossible

additive sedative effectsand

caution themnotto driveor

operate machinery

Highlyprotein bound drugs

(e.g. warfarin and digoxin) Leponexmaycausean

increase inplasma

concentration ofthesedrugs

dueto displacementfrom

plasmaproteins Patientsshould bemonitored

fortheoccurrenceofside

effectsassociatedwiththese

substances,and dosesofthe

protein boundsubstance

adjusted,ifnecessary

Phenytoin Addition ofphenytoin to

Leponexdrugregimenmay

cause a decrease inthe

clozapine plasma

concentrations Ifphenytoin mustbeused,

thepatientshould be

monitored closelyfora

worseningorrecurrenceof

psychoticsymptoms

Lithium Concomitantuse canincrease

therisk ofdevelopmentof

neurolepticmalignant

syndrome(NMS) Observeforsignsand

symptomsofNMS

9 Women ofchild-bearing potential,pregnancy,breast-feeding,

and fertility

Women ofchildbearing potentialandcontraceptive measures

SomefemalepatientstreatedwithantipsychoticsotherthanLeponexmaybecome

amenorrheic.Areturn to normalmenstruation mayoccurasaresultofswitchingfromother

antipsychoticstoLeponex. Adequatecontraceptivemeasuresmustthereforebeensured in

women ofchildbearingpotential.

Pregnancy

Reproduction studiesinanimalshaverevealednoevidenceofimpairedfertilityorharmtothe

fetusdueto clozapine.However, thesafeuseofLeponexin pregnantwomen hasnotbeen

established. Therefore,Leponexshould beusedin pregnancyonlyiftheexpected benefit

clearlyoutweighsanypotentialrisk.

Non-teratogenic effects

Neonatesexposed to antipsychoticdrugs, duringthethird trimesterofpregnancyareatrisk

forextrapyramidal and/orwithdrawal symptomsfollowingdelivery. Therehavebeenreports

ofagitation, hypertonia,hypotonia, tremor, somnolence, respiratorydistressand feeding

disorderinthese neonates.Thesecomplicationshave variedinseverity;while insomecases

symptomshavebeen self-limited, in othercasesneonateshaverequired intensivecareunit

supportand prolonged hospitalization.

Antipsychoticdrugs, includingLeponex, should beused duringpregnancyonlyifthe

potential benefit justifiesthepotential risktothefetus.

Breastfeeding

Animal studiessuggestthat clozapineisexcretedinbreast milkandhasaneffect inthe

sucklingoffspring;therefore,mothersreceivingLeponexshould notbreast-feed.

10 Overdosage

Incasesofacute intentionaloraccidentalLeponexoverdosage,forwhich information on the

outcomeisavailable,todatethemortalityisabout 12%.Most ofthefatalitieswereassociated

with cardiacfailureorpneumoniacaused byaspiration and occurredatdosesabove2000 mg.

There have beenreportsofpatientsrecoveringfromanoverdose inexcessof10000 mg.

However, in afewadultindividuals, primarilythosenotpreviouslyexposed toLeponex, the

ingestion ofdosesaslowas400 mgled to life-threateningcomatoseconditionsand, in one

case,todeath.Inyoungchildren, theintakeof50mgto 200 mgresulted instrongsedation or

comawithoutbeinglethal.

Signsand symptoms

Drowsiness, lethargy,areflexia, coma, confusion,hallucinations, agitation,delirium,

extrapyramidal symptoms,hyper-reflexia, convulsions;hypersalivation, mydriasis, blurred

vision, thermolability;hypotension, collapse, tachycardia,cardiacarrhythmias;aspiration

pneumonia, dyspnoea, respiratorydepression orfailure.

Treatment

Thereare nospecific antidotesforLeponex.

Gastriclavageand/ortheadministrationofactivatedcharcoal withinthefirst 6hoursafter

Leponexingestion.(Peritonealdialysisandhaemodialysisare unlikelytobe effective).

Symptomatictreatmentundercontinuouscardiacmonitoring, surveillanceofrespiration,

monitoringofelectrolytesand acid-basebalance.Theuseofepinephrineshould beavoided in

thetreatmentofhypotension becauseofthepossibilityofa‘reverseepinephrine’effect.

Close medicalsupervisionisnecessaryforatleast5daysbecauseofthepossibilityofdelayed

reactions.

11 Clinicalpharmacology

Pharmacotherapeuticgroup,ATC

Antipsychoticagent,ATCcode N05A H02 .

Mechanismofaction(MOA)

Leponexhasbeen shownto bean antipsychoticagentthatisdifferentfromclassic

antipsychotics.

In pharmacologicalexperiments, thecompound doesnotinducecatalepsyorinhibit

apomorphine-oramphetamine-induced stereotyped behaviour.Ithasonlyweak dopamine

receptor-blockingactivityat D

and D

receptors, butshowshigh potencyfortheD

4

receptor, in addition to potentanti-alpha-adrenergic, anticholinergic, antihistaminic, and

arousalreaction-inhibitingeffects.Ithasalso beenshown to possessantiserotoninergic

properties.

Pharmacodynamics(PD)

ClinicallyLeponexproducesrapidand marked sedation, and exertsantipsychoticeffectsin

patientswith schizophreniaresistant tootherantipsychoticagents. Insuch cases, Leponexhas

proven effectiveinrelievingboth positiveand negativeschizophrenicsymptomsin short-and

long-term trials.

Leponexisuniquein thatitproducesvirtuallynomajorextrapyramidalreactionssuchas

acute dystoniaandtardive dyskinesia.Furthermore,parkinsonian-like sideeffectsand

akathisiaare rare.Incontrastto classicalantipsychotics,clozapineproduceslittleorno

prolactin elevation, thusavoidingadverseeffectssuch asgynaecomastia,amenorrhoea,

galactorrhoea,and impotence.

Potentiallyseriousadverse reactionscausedbyLeponextherapyaregranulocytopenia and

agranulocytosisoccurringatanestimated incidenceof3%and 0.7%respectively.(See section

6 Warningsand precautions).

Pharmacokinetics (PK)

Absorption

Theabsorption oforallyadministered clozapineis90%to 95%;neithertheratenortheextent

ofabsorption isinfluenced byfood.

Clozapineissubjectto moderatefirst-passmetabolism,resultinginanabsolutebioavailability

of50%to 60%.

Distribution

Insteady-stateconditions, whengiven twicedaily,peak blood levelsoccuron an averageat

2.1 hours(range:0.4 to 4.2 hours), and thevolumeofdistribution is1.6 L/kg. Clozapineis

approximately95%bound to plasmaproteins.

Biotransformation/metabolism

Clozapineisalmost completelymetabolisedbeforeexcretion.Ofthemainmetabolitesonly

thedesmethyl metabolitewasfoundtobeactive.Itspharmacologicalactionsresemblethose

ofclozapine, butareconsiderablyweakerand ofshortduration.

Elimination

Itseliminationisbiphasic,withameanterminal half-lifeof12 hours(range:6 to 26 hours).

Aftersingledosesof75mgthemeanterminal half-lifewas7.9 hours;itincreased to 14.2

hourswhen steady-stateconditionswere reachedbyadministeringdailydosesof75 mgforat

least7days.

Onlytraceamountsofunchanged drugaredetected in theurineand faeces,approximately

50%oftheadministereddosebeingexcretedasmetabolitesin theurineand 30%in the

faeces.

Linearity/non-linearity

Dosageincreasesfrom37.5 mgto 75 mgand 150mggiven twicedailywerefound to result

duringsteadystatein linearlydose-proportionalincreasesinthe area underthe plasma

concentration/time curve(AUC), and in thepeak and minimumplasmaconcentrations.

12 Clinicalstudies

Clinicalstudiesintreatment-resistantschizophrenia

Clozapinestudy 16

TheefficacyofLeponexwasevaluated in arandomized, double-blind, multicenter, parallel

groupcomparativetrialofclozapineversuschlorpromazineinhospitalizedpatientswith

treatment resistant schizophrenia.Studyparticipantswere maleorfemale patients,between

theagesof18 to 65years, diagnosed with schizophreniausingDiseaseStatisticalManual

(DSM)-IIcriteria.Aftera baselineperiod of14 days,151 patientswererandomlyassigned to

oneofthetwo treatmentarms(75 in clozapinegroup and 76 in chlorpromazinegroup).

Afterabaselineplaceboperiod ofup to 14 days,patientsreceived individualized dailydosage

ofeitherclozapine(150-900 mg)orchlorpromazine(300–1800 mg). Treatmentduration was

for28 dayswith an optionalextension up to 28 days.

Amongthe studyparticipants,92were male and59werefemale withamedianage of30

yearsand median duration ofpresentillnessofapproximatelytwo months. Efficacywas

assessedbymeasuringmeanchangefrombaseline intheBriefPsychiatric RatingScale

(BPRS),ClinicalGlobalImpression(CGI)scoresandthe NursesObservationScale for

InpatientEvaluation (NOSIE-30).

BPRSitems:Throughoutthestudy,and atendpoint, clozapinepatientshadamorerapid onset

ofaction and showed significantimprovementin BPRSitemscompared to chlorpromazine

patients. Atweek 1, clozapinewasstatisticallysuperiorto chlorpromazineintwo items

assessed:Motorretardation (with ameanchangeof0.67forclozapinevs. 0.12 for

chlorpromazine, p<0.05)and bluntedaffect(with amean changeof0.93 forclozapinevs.

0.34 forchlorpromazine, p<0.01). Atweek 2, statisticallysignificantimprovementsin

emotionalwithdrawal(with ameanchangeof1.48 forclozapinevs. 0.98forchlorpromazine,

p<0.01)and unusualthoughtcontent(with amean changeof2.06 forclozapinevs. 1.45 for

chlorpromazine, p<0.05)wereobserved in patientsreceivingclozapine. Atweek 3, clozapine

wasstatisticallysuperiorin 7outofthe18BPRSitemsassessed. Atendpoint, clozapine

showedstatisticallysignificant improvementsineveryitem assessedwithdifferences

observed in12 outofallitemsassessedduring thestudy. Throughoutthestudy, therewere

only4 items,(somaticconcern,grandiosity,hallucinatorybehaviorand disorientation), where

clozapinewasnot statisticallysuperiorat least once.

BRSfactorsandCGI:Byweek2,statisticallysignificant differencesfavoringclozapine were

observed in theBPRSTotalScoreand maintained throughouttheduration ofstudy. Testsof

comparativeefficacyatendpointshowedclozapineto besignificantlybetterforallfive

Factorsassessed(anxiety/depression (0.85 vs.0.54;p<0.05), anergia(1.15vs. 0.72;p<0.001),

thoughtdisturbance(1.80 vs. 1.28;p <0.01), activation (1.34 vs. 0.89;p<0.01), and

hostile/suspiciousness(1.26 vs. 0.74;p<0.01)). Atendpoint, clozapineshowed statistically

significant improvementsinmean changein TotalScore(22.53 forclozapinevs. 14.64 for

chlorpromazine, p<0.001)and CGI(1.95forclozapinevs. 1.33 forchlorpromazine, p<0.01).

NOSIEfactors:Exceptforsocialcompetence,clozapine patientsgenerallydidbetter

accordingtoassessmentbythewardnurses.Statisticallysignificantdifferencesfavored

clozapinein theimprovementofirritabilityatweeks3 (meanchangeof6.28 forclozapinevs.

0.67 forchlorpromazine,p<0.01)and week 4 (mean changeof6.84 forclozapinevs. 1.36 for

chlorpromazine, p<0.05). Formostofthefactors(and particularlyTotalPatientAssets), there

wasclearevidence ofanearlyonsetoftherapeutic benefitwith clozapine,thuscorroborating

BPRSdata, although no statisticaldifferencewasobserved. Resultsoftheend-pointanalyses

showthatclozapinewassuperiorto chlorpromazineforthefollowingNOSIEfactors:Social

Interest(meanchange of4.14forclozapinevs. 3.24 forchlorpromazine), PersonalNeatness

(meanchangeof3.19forclozapinevs. 2.26forchlorpromazine),Irritability(meanchangeof

3.04 forclozapinevs. 0.60 forchlorpromazine)and ManifestPsychosis(mean changeof

6.32forclozapinevs. 4.24 forchlorpromazine)aswellasTotalAssets(mean changeof20.54

forclozapinevs. 16.66 forchlorpromazine).

To summarize,clozapinehad amorerapid onsetofactionand itssuperioritywasmaintained

orimproved overtheduration ofstudy.

Clozapinestudy 30

TheefficacyofLeponexwasevaluated in arandomized, double-blind, multicenter, parallel

group, 6-week, comparativestudyofclozapineversuschlorpromazineplusbenztropine. The

studypopulation included 319 treatment-resistantschizophrenicpatients, between theagesof

18-60years, who metDSM-IIIcriteria forschizophrenia,witha well-documented historyof

beingrefractorytotreatment.

Eligiblepatientswererandomlyassignedto receiveclozapinealone(upto 900 mg/day)or

chlorpromazineplusbenztropine(up to 1800mg/dayofchlorpromazine, plus6 mg/dayof

benztropine).

EfficacywasassessedusingtheBPRSscore,ClinicalGlobalImpression(CGI)scale,and

Nurses’Observation ScaleforInpatientEvaluation (NOSIE-30)Scale.

Attheend of6 weeks, clozapinewassignificantlysuperiorto chlorpromazinein all

“Positive”, “Negative”and generalsymptomsofBPRS(p<0.001)except‘Grandiosity’and

‘BPRStotalscore’. Clozapineshowed asignificantlysuperiorchangeinCGIscalecompared

to chlorpromazinestartingatweek 1 (p<0.001). Clozapinewassuperiorto chlorpromazineon

all sixNOSIE-30 factorsand totalassetsstartingateitherweek 1 or2 (p-value rangingfrom

p<0.05 to 0.001). ClozapinewasstatisticallysignificantinthefollowingNOSIEfactors,

socialcompetence,socialinterestandpersonalneatness,andtotalassets(p<0.001),aswellas

irritabilityand motorretardation (p<0.01 and p<0.05, respectively).

Insummary, superiorityofclozapinewasnotconfined toaparticularaspectordimension of

psychopathology;clozapinedemonstrated broad-spectrumtherapeutic effectonallmajor

psychoticsignsand symptoms.

Clinicalstudyinriskofrecurrentsuicidalbehavior

InterSeptTrial

The effectivenessofclozapine inreducingthe riskofrecurrentsuicidalbehaviorwasassessed

in theInternationalSuicidePrevention Trial(InterSePT),whichwasaprospective,

randomized, open label,international, parallel-group comparison ofclozapinevs. olanzapine

in patientswith schizophreniaorschizoaffectivedisorder(DSM-IV)judged to beatrisk for

re-experiencingsuicidalbehavior, lastingfor24months.

Patientsmet oneofthefollowingcriteria:

Theyhad attempted suicidewithin the3yearspriorto theirbaselineevaluation.

Theyhad been hospitalized to preventasuicideattemptwithin the3yearspriorto their

baseline evaluation.

Theydemonstratedsuicidalideation with adepressivesymptomwithin1 week priorto

theirbaseline evaluation.

Theydemonstrated moderate-to-severe suicidalideationaccompaniedbycommand

hallucinationsto do self-harmwithin 1 week priorto theirbaselineevaluation.

Enrolled patientswererandomized to treatmentwith eitherclozapineorolanzapinein an

approximate1:1 ratio.Dosingwasflexible, with startingdoseofclozapinebeing12.5 mg

twicedaily, titrated upwardsto adoserangeof200-900mg/day.Patientsreceiving

olanzapinewerestartedatadoseof5 mg daily, titrated upwardstoadoserangeof5-20

mg/day.

The primaryefficacymeasurewastime to(1)a significantsuicideattempt,includinga

completed suicide, (2)hospitalizationdueto imminentsuiciderisk (includingincreased level

ofsurveillanceforsuicidalityforpatientsalreadyhospitalized), or(3)worseningof

suicidalityseverityasdemonstrated by“muchworsening”or“verymuch worsening”from

baselineintheClinicalGlobalImpressionofSeverityofSuicidalityasassessedbythe

BlindedPsychiatrist (CGI-SS-BP)scale.

Secondaryefficacyobjectives:

Evaluation ofthenumberofprimaryefficacymeasureinLeponex-treatedpatients

compared to olanzapine-treatedpatients.

Comparison oftherisk forsuicideamongschizophrenicpatientstreated withLeponex

ascomparedtothatforpatientstreatedwitholanzapine,asmeasuredbypercentage of

patientswho completed suicide, had significantsuicideattempts, and had hospitalizationsdue

toimminent suiciderisk.

Evaluation ofthenumberofrescueinterventionsrequired to preventsuicidesin

Leponextreatedpatientscomparedtorescue interventionsrequiredbyolanzapine-treated

patients.

Comparison oftheintensityofsuicidalideation betweenLeponex-treatedpatientsand

olanzapine-treatedpatientsasmeasuredbychangesfrombaselineontheInterSePTScale for

SuicidalThinking(ISST-BP)and on theCGI-SS-BP(7-pointand 5-pointscales)asratedby

theblinded psychiatrist.

Atotalof980patientswererandomized to thestudyand 956receivedstudymedication. The

meanage ofpatientsentering thestudywas37years(range18-69).Mostpatientswere

Caucasian(71%),15%wereBlack,1%were Oriental,and13%were classifiedasbeingof

“other” races.

Clozapineshowedastatisticallysignificant overall treatment effect comparedtoolanzapine

fortheprimaryefficacymeasure(p=0.0309). Examination ofcomponentsindicated thatthe

treatment effectforType1eventswasstatisticallysignificant infavorofclozapine

(p=0.0316), with ahazard ratio [risk ratio]of0.76 (95%ConfidenceInterval(C.I.):0.58,

0.98).Similarly,thetreatment effect forType2eventswasstatisticallysignificant infavorof

clozapine(p=0.0388), with ahazard ratio of0.78(95%C.I.:0.61, 0.99), [Table12-1].

Table12-1 Primaryanalysis:Multipleeventanalysisoftimetofirstoccurrenceof

Type 1 and Type 2 events (ITTpopulation)

Event Type 1 Coefficient of

Treatment Effect

(Beta 2,3 ) (SE) p-value 2 Hazard

Ratio 2,3

95%C.I.forHazard

Ratio 2

Type 1 -0.280 (0.130) 0.0316 0.76 0.58,0.98

Type 2 -0.250 (0.121) 0.0388 0.78 0.61,0.99

Combined -0.265 (0.123) 0.0309 -- --

Type 1 event=asignificantsuicide attemptorhospitalizationdue to imminentsuiciderisk(including increased levelof

surveillance),confirmed bySMB.

Type 2 event=worsening ofsuicidalityseverityasdemonstrated by7-pointCGI-SS-BPchangescalescore of6or7,orby

implicitworsening ofsuicidalityseverityasdemonstrated byoccurrenceofaType 1 event.

Referto detailedstatisticalanalysisplaninAppendix5.1,1.1.5.3,forinformation oncalculationofthese parameters.

Hazard ratio <1 and beta <0 indicatethatLeponexisbetterthan olanzapine.

Probability(Standard Error, SE)ofexperiencing aType1 eventwashigherforolanzapine

patientscompared to clozapinepatientsatallvisits. Atweek 104, theclozapinetreatment

group demonstratedasignificantlylowerprobabilityofaneventcompared to theolanzapine

treatmentgroup (24%forclozapinevs. 32%forolanzapine;95%C.I. ofthedifference:2%,

14%), [seeFigure12-1].

Similarly, theprobability(SE)ofexperiencingaType2 eventwashigherforolanzapine

patientsthan forclozapinepatientsatallvisits.Atweek 104, theclozapinetreatmentgroup

demonstrated asignificantlylowerprobabilityofan eventcomparedto theolanzapine

treatmentgroup (28%forclozapinevs. 37%forolanzapine;95%C.I. ofthedifference:2%,

15%), [seeFigure12-1].

Figure12-1 Kaplan-Meierestimates ofcumulative probabilityofa Type 1 orType

2event

Incomparison to olanzapine, clozapinereduced therisk forsuicidality(asmeasuredby

suicideattemptsand hospitalizationsto preventsuicide)by24%overa2-yearperiod. This

beneficialeffectwassupported byareduction inboth theoverallnumberofeventsand the

numberofrecorded interventionsnecessaryto preventsuicide, includingtheuseof

antidepressantsandanxiolyticsasconcomitantmedications.

13 Non-clinicalsafetydata

Preclinicaldatarevealno specialhazard forhumansbased on conventionalstudiesofsafety

pharmacology, repeateddosetoxicity,genotoxicityandcarcinogenic potential(for

reproductivetoxicity, seesection9 Women ofchild-bearingpotential, pregnancy,

breastfeeding,andfertility).

Mutagenicity

Clozapineand/oritsmetabolitesweredevoid ofgenotoxicpotentialwhen investigated for

induction ofgenemutations, chromosomeaberrationsand primaryDNA-damage ina

spectrumofinvitromutagenicitytests.Likewise,no genotoxicactivitywasobservedinvivo

(bone marrowmicronucleustestinmice).

Carcinogenicity

InSprague-Dawley(CD)ratstreatedinthe dietfor2years,maximum tolerateddosesof35

mg/kgperdayrevealedno carcinogenicpotentialofclozapine.Likewise, no evidenceof

tumorigeniceffectswasobtained in two1.5-yearfeedingstudiesinCharlesRiver(CD)mice.

Inthefirststudy, oraldoselevelsofup to 64 mg/kgperdaywere administeredtomales,and

ofup to 75 mg/kgperdayto femalesrespectively.In thesecond study, thehighestdosefor

both sexeswas61 mg/kg perday.

Reproductive toxicity

No embryotoxicorteratogenicpotentialofclozapinewasobservedin ratsorrabbitsatdaily

oraldosesofup to 40mg/kg.Inmale ratsreceivingthe same dosagesfor70 dayspriorto

mating,fertilitywasunaffected.

Infemalerats,fertilityaswell aspre-andpostnataldevelopmentoftheoffspringwasnot

adverselyaffectedbyoralclozapine treatmentpriortomating(up to 40 mg/kgperday).

Whenratsweretreatedatthe same dosagesduringthelaterpartofpregnancyand during

lactation, survivalratesoftheyoungfromlactatingdamswere loweredandtheyoungwere

hyperactive.However, therewasno lastingeffecton pup developmentafterweaning.

14 Pharmaceuticalinformation

Incompatibilities

Notapplicable.

Specialprecautionsforstorage

Storebelow30°C

Leponexmustbekeptoutofthereach and sightofchildren.

Natureand contentofcontainer

Leponextabletsare available inPVC/PVDCblisterpacks.

Specialprecautionsfordisposal

Anyunused productorwastematerialshould bedisposed ofin accordancewithlocal

requirements.

Manufacturer:

NovartisPharmaceuticalsLtd., UK.

For:NovartisPharmaAG, Basel, Switzerland.

License Holder:

NovartisPharmaServicesAG,

36 Shachamst.,Petach-Tikva.

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