AMARYL 2 MG

Israel - English - Ministry of Health

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Active ingredient:
GLIMEPIRIDE
Available from:
SANOFI - AVENTIS ISRAEL LTD
ATC code:
A10BB12
Pharmaceutical form:
TABLETS
Composition:
GLIMEPIRIDE 2 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
SANOFI S.P.A., ITALY
Therapeutic group:
GLIMEPIRIDE
Therapeutic area:
GLIMEPIRIDE
Therapeutic indications:
Non-insulin-dependent diabetes melitus ( adult-onset diabetes, type II diabetes), when diet, regular physical exercise, and weight reduction alone cannot maintain therapeutically suitable blood glucose levels.
Authorization number:
118 83 29932 00
Authorization date:
2020-05-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

20-06-2019

Patient Information leaflet Patient Information leaflet - Hebrew

20-06-2019

םיחקורה תונקת יפל ןכרצל ןולע 1986 - ו"משתה )םירישכת( .דבלב אפור םשרמ יפ לע תקוושמ הפורתה ראוני ךיראתב תואירבה דרשמ י"ע רשואו קדבנ הז ןולע ךיראתב תואירבה דרשמ תוארוהל םאתהב ןכדועו 2014 .2019 ראורבפ ,ג"מ 2 לירמא ,ג"מ 1 לירמא ג"מ 4 לירמא ,ג"מ 3 לירמא תוילבט :ליעפ רמוח - ג"מ 1 דיריפמילג הליכמ ג"מ 1 לירמא לש הילבט לכ

Glimepiride 1 mg

- ג"מ 2 דיריפמילג הליכמ ג"מ 2 לירמא לש הילבט לכ

Glimepiride 2 mg

- ג"מ 3 דיריפמילג הליכמ ג"מ 3 לירמא לש הילבט לכ

Glimepiride 3 mg

- ג"מ 4 דיריפמילג הליכמ ג"מ 4 לירמא לש הילבט לכ

Glimepiride 4 mg

.6 ףיעס האר - םיליעפ יתלב םירמוח שמתשת םרטב ופוס דע ןולעה תא ןויעב ארק .הפורתב .בוש וב אורקל ךרטצתו ןכתיי ,הז ןולע לע רומש תולאש ךל שי םא .הפורתה לע יתיצמת עדימ ליכמ הז ןולע .חקורה לא וא אפורה לא הנפ ,תופסונ איה .םירחאל התוא ריבעת לא .ךרובע המשרנ וז הפורת יאופרה םבצמ יכ ךל הארנ םא וליפא םהל קיזהל הלולע .המוד ליגל תחתמ םירגבתמלו םידליל תדעוימ הניא הפורתה

אלש יאוול תעפות העיפוה םא וא הרימחמ יאוול תעפות םא .חקורל וא אפורל הנפ אנא הז ןולעב תניוצמ ?הפורתה תדעוימ המל .1 .2 גוסמ תרכוסב לופיטל תדעוימ הפורתה תצובקל ךייש ליעפה רמוחה :תיטיופרת הצובק ןילוסניאה תומכ תא םילעמה םירישכת - האירואלינופלוסה

בלבלה ידי לע תררחושמה הפורתב שומיש ינפל .2 םא הפורתב שמתשהל ןיא םיביכרמהמ דחא לכל וא ליעפה רמוחל )יגרלא( שיגר התא .)6 ףיעס האר( הפורתה הליכמ רשא םיפסונה וא האירואלינופלוס לש תורחא תורזגנל שיגר ךנה הפורתל םג היגרלא חתפתתו ןכתיי .םידימאנופלוסל .וז תועפותו תוירוע תובוגת םיללוכ תיגרלא הבוגת ינמיס קוש וא םד ץחלב הדירי ,המישנ רצוק ןוגכ תורומח .יטקליפנא תרכוסב ,1 גוסמ תרכוסב לופיטל תדעוימ הניא וז הפורת לש ךוביסכ סיזודיצא וא סיזוטק ,הביצי יתלב וא הרומח .תיתרכוס תמדרת ,תרכוס הפורתב שומישל תועגונה תודחוימ תורהזא לולע ,האירואלינופלוסה תצובקמ תופורתה לכ ומכ ,לירמא

רבדה .)םדב תוכומנ רכוס תומר( הימקילגופיהל םורגל .םינכוסמ םיבצמל םורגלו זוכירבו תונרעב םוגפל לולע דציכ חקורה וא אפורה םע חחוש - וז הפורת תליטנ ינפל

הז בצמב גוהנלו תוהזל וא םירתסומ תויהל םילוכי הימקילגופיה ינמיס ,ךתעידיל

תויטילוטפמיס תצובקמ תופורת םילטונש םילפוטמב םלעיהל ןידיטנאוג ,ןידינולק ,אטב ימסוח ןוגכ ,)

sympatholythic

.ןיפרזרו הלולע הבוגתה .תורומח תויגרלא תובוגת לש םירקמ וחווד םד ץחלב הדירי ,המישנ רצוק :םיאבה םינמיסה תא לולכל הבוגתמ לבוס ךנהש דשוח ךנה םא .יטקליפנא קוש וא תונפלו הפורתב לופיטה תא דימ קיספהל שי ,תיגרלא .אפורל היילעל ןוכיס םייק האירואלינופלוסה תצובקמ תופורתב .תויבבל תויעבמ התומתה ירקמ תוחיכשב :םא ךאפורל רפס ,לירמאב לופיטה ינפל שומיש הז הרקמב .

G6PD

םיזנאב רסוח ךל שיש ךל עודי

הימנאל םורגל לולע ,האירואלינופלוס םיליכמה םירישכתב

תיטילומה .הנוזת תת וא/ו השלוחמ לבוס ךנה תטולב ,הילכה תרתוי ,תוילכה :דוקפתב תויעבמ לבוס ךנה

דבכה ,)דיאורית( סירתה בקעמו תוקידב ןיבולגומה ,םדב רכוס תומר רחא בוקעל שי לופיטה תפוקתב םד תוקידב ךורעלו ,ןתשב רכוס ,

)Hemoglobin A1C

( ררכוסמ .דבכ ידוקפתו םדה יאת תומר רחא בקעמל :תויתפורת ןיב תובוגת/תויצקארטניא תורחא תופורת ,הנורחאל תחקל םא וא ,חקול התא םא ךכ לע רפס ,הנוזת יפסותו םשרמ אלל תופורת ללוכ חקורה וא אפורה תא עדייל שי דחוימב .חקורל וא אפורל :חקול התא םא םורגלו לירמא לש העפשהה תא ריבגהל תויושעה תופורת .א :ןוגכ ,)םדב רכוסה תומרב הדירי( הימקילגופיהל לופיטל תוימופ תופורת( תרכוסב לופיטל תופורת

.)ןילוסניאו טטצא דיטנילמרפ ,תרכוסב לוכיעה תכרעמב תויצמוחבו םיביכב לופיטל תופורת

2 רוטפצרה לש םיטסינוגטנא( ,ןפיסקופורפ ןוגכ( םיבאכבו תוקלדב לופיטל תופורת ,םידיאורטס םניאש םייתקלד יטנא םירישכת .)םיטאליצילס ,לוזאנוקימ ןוגכ( םיקדייחו תוירטפ ימוהיזב לופיטל תופורת ,םידימאנופלוס ,םינולוניווק ,םינילקיצארטט ,לוזאנוקולפ .)לוקינפמרולכ .)םינירמוק גוסמ( םד תשירק תויעבב לופיטל תופורת םיילובאנא םידיאורטס( רירש תיינבל תודעוימה תופורת .)םינגורדנאו .םירבגב יפולח ילנומרוה לופיטל תופורת

תצובקמו ןיטסקואולפ ןוגכ( ןואכידב לופיטל תופורת

םיזנאה יבכעמ .)םיטרביפ( םדב םינמושה תומר תדרוהל תופורת

תצובקמו ןידיתנאוג ןוגכ( םד ץחל תדרוהל תופורת

ACE inhibitors

.)דימאריפוזיד ןוגכ( בל בצקב תויעבב לופיטל תופורת ,ןוזאריפניפלוס ןוגכ( ןודגישב לופיטל תופורת

.)דיצנבורפ .)דימאפסופולקיצ ןוגכ( ןטרסב לופיטל תופורת .)ןיליפיסקוטנפ( םד תמירז רופישל תופורת .)לודימרינפ ןוגכ( םירירש רורחשל תופורת לירמא לש העפשהה תא תיחפהל תויושעה תופורת

:םדב זוקולגה תומרב היילעל םורגלו לופיטל( םיישנ ןימ ינומרוה תוליכמה תופורת

ילנומרוה לופיט ,ןוירה דגנ תולולג ,לוזנד - סיזוירטמודנאב .)םישנב יפולח םידיזאית תצובקמ םד ץחל רתיב לופיטל תופורת .םירחא םינתשמו סירתה תטולב תוליעפ תתב לופיטל תופורת

.)ןיסקוריתובל( תויגרלאו תוקלדב לופיטל תופורת

.)םידיאורטסוקיטרוק( םיטוכיספיטנא( תוישפנ תולחמב לופיטל תופורת

.)םיניזאיתונפ ,םייפיטא ,המטסאב לופיט ,בל בצק תאלעהל תושמשמה תופורת םוריח יבצמב לופיטל ,תוננטצהו לועיש ,ףאב שדוג .)םיטמימוטפמיס( םייאופר הצמוח( תוהובג לורטסלוכ תומרב לופיטל תופורת .)תיניטוקינ .)םילשלשמ( תוריצעב לופיטל תופורת .)ןיאוטינפ( היספליפאב לופיטל תופורת הניש תויעבו תונבצע ,היספליפאב לופיטל תופורת .)םיטרוטיברב( הכומנ רכוס תמרב וא הובג םד ץחלב לופיטל תופורת .)דיסקוזאיד( דיזאינוזיא( תפחש ןוגכ םינוש םימוהיזב לופיטל תופורת

.)זאטורפ יאכדמ תצובקמ(

-ו ,)ןיפמפירו דחוימב תוכומנ זוקולג תומרב לופיטל תונתינש תופורת .)ןוגקולג( .)ןיפורטאמוס ןוגכ( הלידג ינומרוה יעמב הרמ יחלמ תרשוקה לורטסלוכ תדרוהל הפורת לירמא לוטיל שי וז היצקארטניא תעינמל .)םלבסלוק( ףיעס האר( םלבסלוק תחיקל ינפל תועש 4 תוחפל

לש העפשהה תא תיחפהל וא ריבגהל תויושעה תופורת .ג :לירמא תקיפס יא וא םד ץחלב לופיטל תויטילוטפמיס תופורת .)ןיפרזר ,ןידינולק ,אטב ימסוח תצובק ןוגכ( בל ,הימקילגופיה ינמיס ךסמל תולולע תויטילוטפמיס תופורת לטונ ךנה םא ,אפורה לצא בקעמב דימתהל שי ןכל .הלא תופורת ןוזמו הפורתב שומיש תירקיעה החוראה םע וא רקוב תחורא םע לירמא לוטיל ש

.םויב הנושארה

AMAR-TAB-1/2/3/4-17.0

לוהוכלא תכירצו הפורתב שומיש םע לופיטה תפוקתב םיפירח תואקשמ וא תוניי תותשל ןיא תעפשה תא שילחהל וא ריבגהל לולע לוהוכלא .הפורתה .םדב רכוס תומר תדרוה לע הפורתה תוירופו הקנה ,ןוירה קינהל תננכתמ וא הקינמ ,ןוירה תננכתמ ,ןוירהב ךנה םא .תופורתב שומישה ינפל אפורב ץעוויהל שי הימקילגופיה לש םינמיס רחא בוקעל שי ,הקינמ ךנה םא םוח ,המישנ תקספה ,ןולחיכ ,תונבצע ,אמגודל( קוניתה לצא .)םיסוכרפ ,לוכאל ןוצר יא ,תרבגומ הניש ,ךומנ תונוכמב שומישו הגיהנ הפורתב שומישה ןמזב תונכוסמ תונוכמ ליעפהל וא גוהנל ןיא .תונרעב םוגפל לולע וז הפורתב שומישהש ללגב הפורתה לש םיביכרמהמ קלח לע בושח עדימ התאש אפורה ידי לע ךל רמאנ םא - זוטקל ליכמ רישכתה ינפל אפורב ץעוויהל שי - םימיוסמ םירכוסל תושיגרמ לבוס .וז הפורת תליטנ ?הפורתב שמתשת דציכ .3 .אפורה תוארוה יפל דימת הפורתב שמתשהל שי .חוטב ךניא םא חקורה וא אפורה םע קודבל ךילע .דבלב אפורה ידי לע ועבקי לופיטה ןפואו ןונימה םעפ ג"מ 2 וא ג"מ 1 אוה לבוקמה יתלחתהה ןונימה .םויב תוילכה דוקפתב תויעב םע םילפוטמו םישישק םילפוטמ רובע .םויב ג"מ 1 אוה ץלמומה יתלחתהה ןונימה .לפטמה אפורה תייחנהב קר עצבתת הפורתה ןונימב היילע .םויב םעפ ג"מ 8 וניה ילמיסקמה ןונימה הרישק ידי לע לורטסלוכ תדרוהל( םלבסלוק לטונ ךנה םא תועש 4 תוחפל לירמא לוטיל שי ,)יעמב הרמ יחלמ לש .םלבסלוק תחיקל ינפל .תצלמומה הנמה לע רובעל ןיא .םימ םע הפורתה תא עולבל שי .הילבטה תא סועלל ןיא ,הייצחה וק ךרואל םיווש םיאצח ינשל הילבטה תא תוצחל ןתינ דחי םיאצחה ינש תא לוטיל שי .העילבה לע הלקה ךרוצל .הילבטה תייצחל ךומסב החוראה םע וא רקובה תחורא םע הילבטה תא לוטיל שי .םויב הנושארה תירקיעה לובסל לולע ךנה ,רתוי הובג ןונימ תועטב תלטנ םא .הימקילגופיהמ באכ ,רוויח רוע ,הרק העיז :תוללוכ הימקילגופיהה תועפות הלולע הרומח הימקילגופיה .דער ,רבגומ בער ,ךשמתמ שאר .תויגולוריונ תוערפהו תויוצווכתה ,המוקל םורגל ,הפורתה ןמ דלי עלב תועטב םא וא רתי תנמ תלטנ םא תזירא אבהו םילוח תיב לש ןוימ רדחל וא אפורל דימ הנפ

ךתיא הפורתה הפורתה תא לוטיל תחכש םא הנמ לוטיל ןיא ,שורדה ןמזב וז הפורת לוטיל תחכש םא .אפורב ץעוויהו ליגרה ןמזב האבה הנמה תא חק .הלופכ .אפורה ידי לע ץלמוהש יפכ לופיטב דימתהל שי לופיטה קיספהל ןיא ,ךתואירב בצמב רופיש לח םא םג .חקורה וא אפורה םע תוצעייתה אלל הפורתב הפורתה תליטנ תא קיספמ התא םא הלולע ךתלחמו ,םדב תונזואמ ןניא רכוסה תומרו ןכתיי ךאפורש דע ,הפורתה תליטנ תא ךישמהל שי .רימחהל .לופיטה תא קיספהל ךתוא החני לכב הנמהו תיוותה קודב !ךשוחב תופורת לוטיל ןיא ךנה םא םייפקשמ בכרה .הפורת לטונ ךנהש םעפ .םהל קוקז ץעוויה ,הפורתב שומישל עגונב תופסונ תולאש ךל שי םא .חקורב וא אפורב יאוול תועפות .4 תועפותל םורגל לולע לירמאב שומישה ,הפורת לכב ומכ תמישר ארקמל להבית לא .םישמתשמהמ קלחב יאוול .ןהמ תחא ףאמ לובסת אלו ןכתיי .יאוולה תועפות ןוימ רדחל וא אפורל דימ תונפלו שומישה תא קיספהל שי :תואבה תועפותהמ לבוס ךנה םא םילוח תיב לש הימקילגופיה הבוגתב הרמחהו תוירוע תויגרלא תובוגת לש הרמחה םד ץחלב הדירי ,המישנ רצוקב אטבתהל הלוכיש תיגרלא .יטקליפנא קוש וא םיזנאב רסוח אלל וא םע םילוחב תיטילומה הימנא

G6PD

לבוס ךנה םא ירשפאה םדקהב אפורל תונפל שי :תואבה תועפותהמ הרמ יחלמ תמרב היילעב הוולמה( דבכה דוקפתב העיגפ תקיפס יאל חתפתהל הלולעש דבכ תקלדו )תבהצבו .דבכ יוריג ,תיגרלא סיטילוקסו ,שמשה רואל תושיגר לש תובוגת

רועב החירפ וא תויסט תמרב הדירי ,םדב םינבל םד יאת רפסמב הדירי

וא

10,000/µl

-ל תחתמ תויסט יכרע ןוגכ ןוציק יבצמ ללוכ(

)תירוע תחרפת .)הימרתנופיה( םדב תוכומנ ןרתנ תומר יבאכ ,השלוח וא תופייע ,תרוחרחס :תופסונ יאוול תועפות דוביא ,םעטה שוחב יוניש ,לקשמב היילע ,תוליחב ,שאר .רעיש יאוולה תועפותמ תחא םא ,יאוול תעפות העיפוה םא אלש יאוול תעפותמ לבוס התא רשאכ וא ,הרימחמ .אפורה םע ץעייתהל ךילע ,ןולעב הרכזוה תועצמאב תואירבה דרשמל יאוול תועפות לע חוודל ןתינ לופיט בקע יאוול תועפות לע חוויד“ רושיקה לע הציחל תואירבה דרשמ רתא לש תיבה ףדב אצמנש "יתפורת תועפות לע חווידל ןווקמה ספוטל הנפמה )

www.health.gov.il

:רושיקל הסינכ י"ע וא ,יאוול

https://forms.gov.il/globaldata/getsequence/getsequence.aspx

?formType=AdversEffectMedic@moh.gov.il

?הפורתה תא ןסחאל ךיא .5 רומשל שי תרחא הפורת לכו וז הפורת !הלערה ענמ תוקונית וא/ו םידלי לש םדי גשיהל ץוחמ רוגס םוקמב הארוה אלל האקהל םורגת לא .הלערה ענמת ךכ ידי לעו .אפורהמ תשרופמ

)exp. date(

הגופתה ךיראת ירחא הפורתב שמתשהל ןיא ןורחאה םויל סחייתמ הגופתה ךיראת .הזיראה יבג לע עיפומה

שדוח ותוא לש

30°C

לע הלועה הרוטרפמטב ןסחאל ןיא :ןוסחא יאנת ףסונ עדימ .6 :םג הליכמ הפורתה ליעפה רמוחה לע ףסונ

Lactose monohydrate, microcrystalline cellulose, sodium starch

glycolate, polividone 25000, magnesium stearate.

.Red Ferric Oxide

E172

( םג ליכמ ג"מ 1 לירמא .זוטקל ג"מ 68.975 הליכמ הילבט לכ :םג ליכמ ג"מ 2 לירמא

.Yellow Ferric Oxide )E172(, Indigo Carmine Aluminium Lake )E132(

.זוטקל ג"מ 137.200 הליכמ הילבט לכ

Yellow Ferric Oxide )E172(

םג ליכמ ג"מ 3 לירמא .זוטקל ג"מ 136.950 הליכמ הילבט לכ

Indigo Carmine Aluminium Lake )E132(

םג ליכמ ג"מ 4 לירמא .זוטקל ג"מ 135.850 הליכמ הילבט לכ לירמא תוילבט :הזיראה ןכות המו הפורתה תיארנ דציכ .תוילבט 30 לש תוזיראב תוקוושמ .דורו עבצב תוילבט :ג"מ 1 לירמא .קורי עבצב תוילבט :ג"מ 2 לירמא .ריהב בוהצ עבצב תוילבט :ג"מ 3 לירמא .תלכת עבצב תוילבט :ג"מ 4 לירמא ,10 ןואג ינב ,מ"עב לארשי סיטנווא יפונאס :םושירה לעב

.הינתנ ,4250499 ,8090 .ד.ת .הילטיא ,.א.פ.ס יפונאס :ןרציה םש הלאש ךל שי םא .רישכתה לע עדימה לכ תא ללוכ אל הז ןולע .אפורל הנפ אנא ,המ רבדב חוטב ךניא םא וא יהשלכ דרשמב יתכלממה תופורתה סקנפב הפורתה םושיר רפסמ :תואירבה 118822993400 :ג"מ 1 לירמא 118832993200 :ג"מ 2 לירמא 118842993300 :ג"מ 3 לירמא 141683191700 :ג"מ 4 לירמא .רכז ןושלב חסונ הז ןולע ,האירקה תלקהלו תוטשפה םשל .םינימה ינש ינבל תדעוימ הפורתה ,תאז ףא לע

89034377 1/6

89034377 6/6

89034377 5/6

PATIENT PACKAGE INSERT

IN ACCORDANCE WITH THE PHARMACISTS’

REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with

a doctor’s prescription only.

This leaflet was checked and approved by the Ministry of

Health in January 2014, and was updated in February 2019,

in accordance with the Ministry of Health guidelines.

Amaryl 1 mg, Amaryl 2 mg,

Amaryl 3 mg, Amaryl 4 mg

Tablets

Active ingredient:

Each tablet of Amaryl 1 mg contains Glimepiride 1 mg.

Each tablet of Amaryl 2 mg contains Glimepiride 2 mg.

Each tablet of Amaryl 3 mg contains Glimepiride 3 mg.

Each tablet of Amaryl 4 mg contains Glimepiride 4 mg.

Inactive ingredients - see section 6.

Read this leaflet carefully in its entirety before using

the medicine. Save this leaflet, it is possible that you will

need to read it again.

This leaflet contains concise information about the

medicine. If you have further questions, refer to the doctor

or pharmacist.

This medicine has been prescribed for you. Do not pass it

on to others. It may harm them, even if it seems to you

that their medical condition is similar.

The medicine is not intended for children and adolescents

under the age of 18.

If a side effect worsens or if you experience a side effect

not mentioned in this leaflet, please refer to a doctor or

pharmacist.

1. WHAT IS THE MEDICINE INTENDED fOR?

The medicine is intended for the treatment of type 2

diabetes.

Therapeutic group: The active ingredient belongs to the

sulfonylurea group - preparations that increase the amount

of insulin released by the pancreas.

2. BEfORE USING THE MEDICINE

Do not use the medicine if

You are sensitive )allergic( to the active ingredient or

any of the additional ingredients contained in the

medicine )see section 6(.

You are sensitive to other derivatives of sulfonylurea or

sulfonamides. It is possible you will develop an allergy

to this medicine too.

Signs of an allergic reaction including skin reactions and

severe reactions such as shortness of breath, decreased

blood pressure or anaphylactic shock.

This medicine is not intended for treatment of type 1

diabetes, severe or unstable diabetes, ketosis or acidosis

as a complication of diabetes, diabetic coma.

Special warnings regarding use of this medicine

Amaryl, as with all medicines from the sulfonylurea

group, may cause hypoglycemia )low blood sugar levels(.

This may affect alertness and ability to concentrate and

cause risky conditions. Before taking this medicine -

talk to the doctor or pharmacist in order to identify this

condition and act accordingly.

For your information, signs of hypoglycemia can be

concealed or may disappear in patients who are taking

medicines from the sympatholythic group, such as beta-

blockers, clonidine, guanethidine and reserpine.

Cases of severe allergic reactions have been reported. The

reaction may include the following symptoms: shortness

of breath, decreased blood pressure or anaphylactic

shock. If you suspect that you are suffering from an

allergic reaction, stop treatment with the medicine

immediately and refer to a doctor.

With medicines from the sulfonylurea group, there is a

risk of increased incidence of cardiovascular mortality.

Before beginning treatment with Amaryl, tell your

doctor if:

You have a known deficiency of enzyme G6PD. In such a

case, use of sulfonylurea-based preparations may cause

hemolytic anemia.

You suffer from weakness and/or malnutrition.

You suffer from impaired function of the: kidneys,

adrenal gland, thyroid, liver.

Tests and follow-up

During the treatment period, the following should be

monitored: blood glucose levels, glycosylated hemoglobin

)hemoglobin A1C(, glucose in urine and tests should be

carried out to follow up on blood cell levels and liver

functions.

Drug interactions

If you are taking, or have recently taken, other

medicines, including non-prescription medicines and

nutritional supplements, tell the doctor or pharmacist.

It is especially important to inform the doctor or pharmacist

if you are taking:

a. Medicines that may increase the effect of Amaryl and

cause hypoglycema )decrease in blood sugar levels(,

such as:

Medicines to treat diabetes )oral anti-diabetics,

pramlintide acetate and insulin(.

Medicines to treat ulcers and gastric acidity )H2

receptor antagonists(.

Medicines to treat pain and inflammation )e.g.,

propoxyphene, non-steroidal anti-inflammatories,

salicylates(.

Medicines to treat fungal and bacterial infections )e.g.,

miconazole, fluconazole, tetracyclines, quinolones,

sulfonamides, chloramphenicol(.

Medicines to treat abnormal blood clotting )e.g.,

coumarins(.

Muscle-building medicines )anabolic steroids and

androgens(.

Hormone replacement therapy for men.

Anti-depressants )e.g., fluoxetine, medicines from the

monoamine oxidase inhibitor group )MAOI(.

Medicines lowering blood lipid levels )fibrates(.

Medicines for lowering blood pressure )e.g.,

guanethidine and ACE inhibitors group(.

Medicines to treat abnormal heart beat )e.g.,

disopyramide(.

Medicines to treat gout )e.g., sulfinpyrazone,

probenecid(.

Medicines to treat cancer )e.g., cyclophosphamide(.

Medicines

used

improve

blood

flow

)pentoxifylline(.

Muscle relaxants )e.g., phenyramidol(.

b. Medicines that may reduce the effect of Amaryl and

cause an increase in blood glucose levels:

Medicines that contain female sex hormones )to treat

endometriosis - danazol, oral contraceptives, hormone

replacement treatment for women(.

Medicines to treat hypertension from the thiazide

group and other diuretics.

Medicines to treat reduced thyroid function

)levothyroxine(.

Medicines to treat inflammations and allergies

)corticosteroids(.

Medicines

treat

mental

illness

)atypical

antipsychotics, phenothiazines(.

Medicines that increase heart rate, asthma treatment,

nasal congestion, cough and cold preparations,

medicines for treating emergency medical conditions

)sympathomimetics(.

Medicines to treat high cholesterol levels )nicotinic

acid(.

Medicines to treat constipation )laxatives(.

Medicines to treat epilepsy )phenytoin(.

Medicines to treat epilepsy, nervousness and sleeping

problems )barbiturates(.

Medicines to treat high blood pressure or low blood

sugar levels )diazoxide(.

Medicines to treat different infections such as

tuberculosis )isoniazid and rifampin(, and HIV )from

the protease inhibitor group(.

Medicines given for treatment of especially low serum

glucose levels )glucagon(.

Growth hormones )e.g., somatropin(.

Medicine used to reduce cholesterol associated with

bile acids in the intestine )colesevelam(. To prevent

this interaction, take Amaryl at least 4 hours before

taking colesevelam )see section 3(.

c. Medicines that may increase or reduce the effect of

Amaryl:

Sympatholytic medicines to treat blood pressure

or heart failure )e.g., beta-blockers, clonidine and

reserpine(.

Sympatholytic medicines may mask signs of

hypoglycemia. Therefore, have regular check-ups at

the doctor if you are taking these medicines.

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Use of the medicine and food

Take Amaryl with breakfast or with your first main meal

of the day.

Use of the medicine and alcohol consumption

Do not drink wines or alcoholic beverages during treatment

with the medicine. Alcohol may increase or weaken the

effect of the medicine on reducing blood glucose levels.

Pregnancy, breastfeeding and fertility

If you are pregnant, planning to become pregnant,

breastfeeding or planning to breastfeed, consult with the

doctor before using medicines.

If you are breastfeeding, monitor the baby for signs of

hypoglycemia )e.g., jitters, cyanosis, apnea, hypothermia,

excessive sleeping, unwillingness to feed, seizures(.

Driving and operating machinery

Do not drive or operate dangerous machinery while taking

the medicine because use of this medicine may impair

alertness.

Important information about some of the ingredients

in the medicine.

The product contains lactose – if you have been told by

the doctor that you suffer from sensitivity to some sugars

– consult the doctor before taking this medicine.

3. HOW SHOULD yOU USE THE MEDICINE?

Always use the medicine according to the doctor’s

instructions.

Check with the doctor or pharmacist if you are not sure.

The dosage and treatment regimen will be determined

by the doctor only.

The usual starting dose is 1 mg or 2 mg once a day.

For elderly patients and patients with kidney failure, the

recommended starting dosage is 1 mg per day.

Increasing the dosage of the medicine will only be done

following instructions from the attending doctor. The

maximum dose is 8 mg per day.

If you are taking colesevelam )for reducing cholesterol

by binding the bile acids in the intestine(, take Amaryl at

least 4 hours before taking colesevelam.

Do not exceed the recommended dosage.

Do not chew the tablet. Swallow the medicine with

water.

To ease swallowing, the tablet can be divided into two

equal halves along the score line. Take the two halves

together, soon after halving the tablet.

Take the tablet with breakfast or the first main meal of

the day.

If you accidentally took a higher dosage, you may suffer

from hypoglycemia.

Signs of hypoglycemia include: cold sweat, pale skin,

persistent headache, increased appetite, tremor. Severe

hypoglycemia may cause coma, seizures and neurological

disturbances.

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

swallowed the medicine, refer immediately to a doctor

or proceed to a hospital emergency room, and bring the

package of the medicine with you.

If you forgot to take the medicine

If you forgot to take the medicine at the required time,

do not take a double dose. Take the next dose at the

scheduled time and consult the doctor.

Be sure to adhere to the treatment as recommended by

the doctor.

Even if there is an improvement in your health, do not

stop treatment with the medicine without consulting the

doctor or pharmacist.

If you stop taking the medicine

It is possible that the serum glucose levels are unbalanced

and your illness may worsen. Continue taking the medicine

until your doctor instructs you to stop treatment.

Do not take medicines in the dark! Check the label and

the dose each time you take medicine. Wear glasses

if you need them.

If you have further questions regarding use of the

medicine, consult a doctor or pharmacist.

4. SIDE EffECTS

As with any medicine, use of Amaryl may cause side effects

in some users. Do not be alarmed by the list of side effects.

You may not suffer from any of them.

Stop treatment and refer immediately to a doctor or

proceed to a hospital emergency room if you suffer

from the following effects:

Hypoglycemia

Worsening of allergic skin reactions and worsening of

allergic reaction that can be manifested by shortness

of breath, a drop in blood pressure or anaphylactic

shock.

Hemolytic anemia in patients with or without a G6PD

enzyme deficiency.

Refer to the doctor as soon as possible if you suffer

from the following effects:

Impaired liver function )accompanied by an increase in

bile acids and jaundice( and hepatitis that may turn into

liver failure.

Photosensitivity reactions, allergic vasculitis, itching or

skin rash.

Decreased white blood cells, thrombocytopenia:

)including severe cases with platelet count less than

10,000/µl and thrombocytopenic purpura(.

Low serum sodium levels )hyponatremia(.

Additional side effects: dizziness, fatigue or weakness,

headache, nausea, weight gain, change in the sense of

taste, hair loss.

If a side effect occurs, if one of the side effects worsens,

or if you suffer from a side effect not mentioned in

the leaflet, consult with the doctor.

Side effects can be reported to the Ministry of Health

by clicking on the link “Report Side Effects of Drug

Treatment” found on the Ministry of Health homepage

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

reporting side effects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.

aspx?formType=AdversEffectMedic@moh.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine, and any other medicine,

should be kept in a safe place out of the reach of children

and/or infants in order to avoid poisoning. Do not induce

vomiting unless explicitly instructed to do so by the

doctor.

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

appearing on the package. The expiry date refers to the

last day of that month.

Storage conditions: Do not store at a temperature above

6. fURTHER INfORMATION

In addition to the active ingredient, the medicine also

contains:

Lactose monohydrate, microcrystalline cellulose,

sodium starch glycolate, polyvidone 25000, magnesium

stearate.

Amaryl 1 mg also contains: red ferric oxide )E172(.

Each tablet contains 68.975 mg of lactose.

Amaryl 2 mg also contains: indigo carmine aluminium

lake )E132(, yellow ferric oxide )E172(.

Each tablet contains 137.200 mg of lactose.

Amaryl 3 mg also contains: yellow ferric oxide )E172(.

Each tablet contains 136.950 mg of lactose.

Amaryl 4 mg also contains: indigo carmine aluminium

lake )E132(. Each tablet contains 135.850 mg of lactose.

What does the medicine look like and what are the

contents of the package: Amaryl tablets are marketed in

packages of 30 tablets.

Amaryl 1 mg: Tablets are pink.

Amaryl 2 mg: Tablets are green.

Amaryl 3 mg: Tablets are light yellow.

Amaryl 4 mg: Tablets are light blue.

License holder: sanofi-aventis Israel ltd., 10 Beni Gaon St.,

P.O. Box 8090, Netanya 4250499.

Manufacturer: Sanofi S.p.A., Italy.

This leaflet does not contain all the information about

your medicine. If you have any questions or you are not

sure about anything, please ask your doctor.

Registration number of the medicine in the National Drug

Registry of the Ministry of Health:

Amaryl 1 mg: 118822993400

Amaryl 2 mg: 118832993200

Amaryl 3 mg: 118842993300

Amaryl 4 mg: 141683191700

89034377 4/6

89034377 3/6

89034377 2/6

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The format of this leaflet was determined by the Ministry of Health and its content was checked and

approved by the Ministry of Health on September 2017.

The leaflet was updated according to the instructions of the Ministry of Health on February 2019.

1. Name of the medicinal product

AMARYL 1mg, 2mg, 3mg, 4mg

Glimepiride tablets

2. Therapeutic indications

Amaryl is indicated for non-insulin-dependent diabetes melitus (adult-onset diabetes, type II

diabetes), when diet, regular physical exercise and weight reduction alone cannot maintain

therapeutically suitable blood glucose levels.

Limitations of Use

AMARYL should not be used for the treatment of type 1 diabetes mellitus or diabetic

ketoacidosis, as it would not be effective in these settings.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dosing

AMARYL should be administered with breakfast or the first main meal of the day.

The recommended starting dose of AMARYL is 1 mg or 2 mg once daily. Patients at increased

risk for hypoglycemia (e.g., the elderly or patients with renal impairment) should be started on 1

mg once daily [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5, 8.6)].

After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or

2 mg based upon the patient’s glycemic response. Uptitration should not occur more frequently

than every 1 to 2 weeks. A conservative titration scheme is recommended for patients at

increased risk for hypoglycemia [see Warnings and Precautions (5.1) and Use in Specific

Populations (8.5, 8.6)].

The maximum recommended dose is 8 mg once daily.

Patients being transferred to AMARYL from longer half-life sulfonylureas (e.g., chlorpropamide)

may have overlapping drug effect for 1 to 2 weeks and should be appropriately monitored for

hypoglycemia.

When colesevelam is coadministered with glimepiride, maximum plasma concentration and total

exposure to glimepiride is reduced. Therefore, Amaryl should be administered at least 4 hours

prior to colesevelam.

4. DOSAGE FORMS AND STRENGTHS

AMARYL is formulated as tablets of:

1 mg (pink, oblong tablets, biplanar with score-line on both sides, imprinted on both sides).

2 mg (green, tablets, biplanar with score-line on both sides, imprinted on both sides).

3mg (yellow, tablets, biplanar with score-line on both sides, imprinted on both sides).

4 mg (blue, tablets, biplanar with score-line on both sides, imprinted on both sides).

Tablets for oral administration.

The tablets can be divided into two equal doses along the score line.

5. CONTRAINDICATIONS

AMARYL is contraindicated in patients with a history of a hypersensitivity reaction to:

Glimepiride or any of the product’s ingredients [see Warnings and Precautions (5.2].

Sulfonamide derivatives: Patients who have developed an allergic reaction to sulfonamide

derivatives may develop an allergic reaction to AMARYL. Do not use AMARYL in

patients who have a history of an allergic reaction to sulfonamide derivatives.

6. WARNINGS AND PRECAUTIONS

6.1 Hypoglycemia

All sulfonylureas, including AMARYL, can cause severe hypoglycemia [see Adverse Reactions

(6.1)]. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia.

These impairments may present a risk in situations where these abilities are especially important,

such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness

or convulsions and may result in temporary or permanent impairment of brain function or death.

Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating

and increasing AMARYL doses in patients who may be predisposed to hypoglycemia (e.g., the

elderly, patients with renal impairment, patients on other anti-diabetic medications). Debilitated

or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly

susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also

more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when

alcohol is ingested.

Early warning symptoms of hypoglycemia may be different or less pronounced in patients with

autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking

medications or other sympatholytic agents. These situations may result in severe hypoglycemia

before the patient is aware of the hypoglycemia.

6.2 Hypersensitivity Reactions

There have been postmarketing reports of hypersensitivity reactions in patients treated with

AMARYL, including serious reactions such as anaphylaxis, angioedema, and Stevens -Johnson

Syndrome [see Adverse Reactions (6.2)]. If a hypersensitivity reaction is suspected, promptly

discontinue AMARYL, assess for other potential causes for the reaction, and institute alternative

treatment for diabetes.

6.3 Hemolytic Anemia

Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase

(G6PD) deficiency. Because AMARYL is a sulfonylurea, use caution in patients with G6PD

deficiency and consider the use of a non-sulfonylurea alternative. There are also postmarketing

reports of hemolytic anemia in patients receiving AMARYL who did not have known G6PD

deficiency [see Adverse Reactions (6.2)].

6.4 Increased Risk of Cardiovascular Mortality with Sulfonylureas

The administration of oral hypoglycemic drugs has been reported to be associated with increased

cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This

warning is based on the study conducted by the University Group Diabetes Program (UGDP), a

long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering

drugs in preventing or delaying vascular complications in patients with non-insulin-dependent

diabetes. The study involved 823 patients who were randomly assigned to one of four treatment

groups.

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide

(1.5 grams per day) had a rate of cardiovascular mortality approximately 2 and a half times that of

patients treated with diet alone. A significant increase in total mortality was not observed, but the

use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus

limiting the opportunity for the study to show an increase in overall mortality. Despite

controversy regarding the interpretation of these results, the findings of the UGDP study provide

an adequate basis for this warning. The patient should be informed of the potential risks and

advantages of AMARYL and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is

prudent from a safety standpoint to consider that this warning may also apply to other oral

hypoglycemic drugs in this class, in view of their close similarities in mode of action and

chemical structure.

6.5 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk

reduction with AMARYL or any other anti-diabetic drug.

7. ADVERSE REACTIONS

The following serious adverse reactions are discussed in more detail below and elsewhere in the

labeling:

Hypoglycemia [see Warnings and Precautions (5.1)]

Hemolytic anemia [see Warnings and Precautions (5.3)]

7.1 Clinical Trials Experience

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

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

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

Approximately 2,800 patients with type 2 diabetes have been treated with AMARYL in the

controlled clinical trials. In these trials, approximately 1,700 patients were treated with

AMARYL for at least 1 year. In clinical trials, the most common adverse reactions with

AMARYL were hypoglycemia, dizziness, asthenia, headache, and nausea.

Table 1 summarizes adverse events, other than hypoglycemia, that were reported in 11 pooled

placebo-controlled trials, whether or not considered to be possibly or probably related to study

medication. Treatment duration ranged from 13 weeks to 12 months. Terms that are reported

represent those that occurred at an incidence of ≥5% among AMARYL-treated patients and more

commonly than in patients who received placebo.

Table 1. Eleven Pooled Placebo-Controlled Trials ranging from 13 weeks to 12 months:

Adverse Events (Excluding Hypoglycemia) Occurring in ≥5% of AMARYL-treated

Patients and at a Greater Incidence than with Placebo*

AMARYL

N=745

Placebo

N=294

Headache

Accidental Injury

Flu Syndrome

Nausea

Dizziness

*AMARYL doses ranged from 1-16 mg administered daily

†Insufficient information to determine whether any of the accidental injury events were associated with hypoglycemia

Hypoglycemia:

In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration,

patients already on sulfonylurea therapy underwent a 3-week washout period then were

randomized to AMARYL 1 mg, 4 mg, 8 mg or placebo. Patients randomized to AMARYL 4 mg

or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated

[see Clinical Studies (14.1)]. The overall incidence of possible hypoglycemia (defined by the

presence of at least one symptom that the investigator believed might be related to hypoglycemia;

a concurrent glucose measurement was not required) was 4% for AMARYL 1 mg, 17% for

AMARYL 4 mg, 16% for AMARYL 8 mg and 0% for placebo. All of these events were self-

treated.

In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration,

patients received a starting dose of either 1 mg AMARYL or placebo daily. The dose of

AMARYL was titrated to a target fasting plasma glucose of 90-150 mg/dL. Final daily doses of

AMARYL were 1, 2, 3, 4, 6 or 8 mg [see Clinical Studies (14.1)]. The overall incidence of

possible hypoglycemia (as defined above for the 14-week trial) for AMARYL vs. placebo was

19.7% vs. 3.2%. All of these events were self-treated.

Weight gain:

AMARYL, like all sulfonylureas, can cause weight gain [see Clinical Studies (14.1)].

Allergic Reactions:

In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or

maculopapular eruptions, occurred in less than 1% of AMARYL-treated patients. These may

resolve despite continued treatment with AMARYL. There are postmarketing reports of more

serious allergic reactions (e.g., dyspnea, hypotension, shock) [see Warnings and Precautions

(5.2)].

Laboratory Tests:

Elevated Serum Alanine Aminotransferase (ALT):

In 11 pooled placebo-controlled trials of AMARYL, 1.9% of AMARYL-treated patients and

0.8% of placebo-treated patients developed serum ALT greater than 2 times the upper limit of the

reference range.

7.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of AMARYL.

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

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

exposure.

Serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-

Johnson Syndrome [see Warnings and Precautions (5.2)]

Hemolytic anemia in patients with and without G6PD deficiency [see Warnings and

Precautions (5.3)]

Impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis,

which may progress to liver failure.

Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis.

Leukopenia, agranulocytosis, aplastic anemia, and pancytopenia.

Thrombocytopenia: (including severe cases with platelet count less than 10,000/µl) and

thrombocytopenic purpura.

Hepatic porphyria reactions and disulfiram-like reactions

Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH),

most often in patients who are on other medications or who have medical conditions

known to cause hyponatremia or increase release of antidiuretic hormone

Dysgeusia

Alopecia

8. DRUG INTERACTIONS

8.1 Drugs Affecting Glucose Metabolism

A number of medications affect glucose metabolism and may require AMARYL dose adjustment

and particularly close monitoring for hypoglycemia or worsening glycemic control.

The following are examples of medications that may increase the glucose-lowering effect of

sulfonylureas including AMARYL, increasing the susceptibility to and/or intensity of

hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting

enzyme (ACE) inhibitors, H

receptor antagonists, fibrates, propoxyphene, pentoxifylline,

somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol,

guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide,

quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-

inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and

monoamine oxidase inhibitors. When these medications are administered to a patient receiving

AMARYL, monitor the patient closely for hypoglycemia. When these medications are

withdrawn from a patient receiving AMARYL, monitor the patient closely for worsening

glycemic control.

The following are examples of medications that may reduce the glucose-lowering effect of

sulfonylureas including AMARYL, leading to worsening glycemic control: danazol, glucagon,

somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and

clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics,

corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin,

nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When

these medications are administered to a patient receiving AMARYL, monitor the patient closely

for worsening glycemic control. When these medications are withdrawn from a patient receiving

AMARYL, monitor the patient closely for hypoglycemia.

Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of

AMARYL’s glucose-lowering effect.

Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of

AMARYL in an unpredictable fashion.

The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such

as beta-blockers, clonidine, guanethidine, and reserpine.

8.2 Miconazole

A potential interaction between oral miconazole and sulfonylureas leading to severe

hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms of

miconazole is not known.

8.3 Cytochrome P450 2C9 Interactions

There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers

(e.g., rifampin) of cytochrome P450 2C9. Fluconazole may inhibit the metabolism of

glimepiride, causing increased plasma concentrations of glimepiride which may lead to

hypoglycemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma

concentrations of glimepiride which may lead to worsening glycemic control.

8.4 Concomitant Administration of Colesevelam

Colesevelam can reduce the maximum plasma concentration and total exposure of glimepiride

when the two are coadministered. However, absorbtion is not reduced when glimepiride is

administered 4 hours prior to cloesevelam. Therefore, Amaryl should be administered at least 4

hours prior to colesevelam.

9. USE IN SPECIFIC POPULATIONS

9.1 Pregnancy

Risk Summary

Available data from a small number of published studies and postmarketing experience with

AMARYL use in pregnancy over decades have not identified any drug associated risks for major

birth defects, miscarriage, or adverse maternal outcomes. However, sulfonylureas (including

glimepiride) cross the placenta and have been associated with neonatal adverse reactions such as

hypoglycemia. Therefore, AMARYL should be discontinued at least two weeks before expected

delivery (see Clinical Considerations). Poorly controlled diabetes in pregnancy is also associated

with risks to the mother and fetus (see Clinical Considerations). In animal studies (see Data),

there were no effects on embryo-fetal development following administration of glimepiride to

pregnant rats and rabbits at oral doses approximately 4000 times and 60 times the maximum

human dose based on body surface area, respectively. However, fetotoxicity was observed in rats

and rabbits at doses 50 times and 0.1 times the maximum human dose, respectively.

The estimated background risk of major birth defects is 6% to 10% in women with pre-

gestational diabetes with a HbA1c >7% and has been reported to be as high as 20% to 25% in

women with a HbA1c >10%. The estimated background risk of miscarriage for the indicated

population is unknown. In the U.S. general population, the estimated background risk of major

birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%,

respectively.

Clinical Considerations

Disease-associated maternal and/or embryo-fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis,

preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly

controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia-

related morbidity.

Fetal/neonatal adverse reactions

Neonates of women with gestational diabetes who are treated with sulfonylureas during

pregnancy may be at increased risk for neonatal intensive care admission and may develop

respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe

hypoglycemia, lasting 4–10 days, has been reported in neonates born to mothers receiving a

sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged

half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage

accordingly.

Dose adjustments during pregnancy and the postpartum period

Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a

sulfonylurea at the time of delivery, AMARYL should be discontinued at least two weeks before

expected delivery (see Fetal/Neonatal Adverse Reactions).

Data

Animal data

In animal studies, there was no increase in congenital anomalies, but an increase in fetal deaths

occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times (rabbits) the

maximum recommended human dose (based on body surface area). This fetotoxicity was

observed only at doses inducing maternal hypoglycemia and is believed to be directly related to

the pharmacologic (hypoglycemic) action of glimepiride, as has been similarly noted with other

sulfonylureas.

9.2 Lactation

Risk Summary

Breastfed infants of lactating women using AMARYL should be monitored for symptoms of

hypoglycemia (see Clinical Considerations). It is not known whether glimepiride is excreted in

human milk and there are no data on the effects of glimepiride on milk production. Glimepiride

is present in rat milk [see Data]. The developmental and health benefits of breastfeeding should

be considered along with the mother's clinical need for AMARYL and any potential adverse

effects on the breastfed child from AMARYL or from the underlying maternal condition.

Clinical Considerations

Monitoring for adverse reactions

Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia,

excessive sleepiness, poor feeding, seizures).

Data

During prenatal and postnatal studies in rats, significant concentrations of glimepiride were

present in breast milk and the serum of the pups. Offspring of rats exposed to high levels of

glimepiride during pregnancy and lactation developed skeletal deformities consisting of

shortening, thickening, and bending of the humerus during the postnatal period. These skeletal

deformations were determined to be the result of nursing from mothers exposed to glimepiride.

9.3 Pediatric Use

The pharmacokinetics, efficacy and safety of AMARYL have been evaluated in pediatric patients

with type 2 diabetes as described below. AMARYL is not recommended in pediatric patients

because of its adverse effects on body weight and hypoglycemia.

The pharmacokinetics of a 1 mg single dose of AMARYL was evaluated in 30 patients with type

2 diabetes (male = 7; female = 23) between ages 10 and 17 years. The mean (± SD) AUC

(0-last)

(339±203 nghr/mL), C

(102±48 ng/mL) and t

(3.1±1.7 hours) for glimepiride were

comparable to historical data from adults (AUC

(0-last)

315±96 nghr/mL, C

103±34 ng/mL and

5.3±4.1 hours).

The safety and efficacy of AMARYL in pediatric patients was evaluated in a single-blind, 24-

week trial that randomized 272 patients (8-17 years of age) with type 2 diabetes to AMARYL

(n=135) or metformin (n=137). Both treatment-naive patients (those treated with only diet and

exercise for at least 2 weeks prior to randomization) and previously treated patients (those

previously treated or currently treated with other oral antidiabetic medications for at least 3

months) were eligible to participate. Patients who were receiving oral antidiabetic agents at the

time of study entry discontinued these medications before randomization without a washout

period. AMARYL was initiated at 1 mg, and then titrated up to 2, 4 or 8 mg (mean last dose 4

mg) through Week 12, targeting a self-monitored fasting finger-stick blood glucose < 126 mg/dL.

Metformin was initiated at 500 mg twice daily and titrated at Week 12 up to 1000 mg twice daily

(mean last dose 1365 mg).

After 24 weeks, the overall mean treatment difference in HbA1c between AMARYL and

metformin was 0.2%, favoring metformin (95% confidence interval -0.3% to +0.6%). Based on

these results, the trial did not meet its primary objective of showing a similar reduction in HbA1c

with AMARYL compared to metformin.

Table 2: Change from Baseline in HbA1c and Body Weight in Pediatric Patients Taking

Amaryl or Metformin

Metformin

AMARYL

Treatment- Naive Patients*

N=69

N=72

HbA1c (%)

Baseline (mean)

Change from baseline (adjusted LS

mean) +

-1.2

-1.0

Adjusted Treatment Difference**

(95%CI)

0.2 (-0.3; 0.6)

Previously Treated Patients*

N=57

N=55

HbA1c (%)

Baseline (mean)

Change from baseline (adjusted LS

mean) +

-0.2

Adjusted Treatment Difference

(95%CI)

0.4 (-0.4; 1.2)

Body Weight (kg)*

N=126

N=129

Baseline (mean)

67.3

66.5

Change from baseline (adjusted LS

mean)+

Adjusted Treatment Difference

(95% CI)

1.3 (0.3; 2.3)

* Intent-to-treat population using last-observation-carried-forward for missing data (AMARYL, n=127; metformin,

n=126)

+ adjusted for baseline HbA1c and Tanner Stage

Difference is AMARYL – metformin with positive differences favoring metformin

The profile of adverse reactions in pediatric patients treated with AMARYL was similar to that

observed in adults [see Adverse Reactions (6)].

Hypoglycemic events documented by blood glucose values <36 mg/dL were observed in 4% of

pediatric patients treated with AMARYL and in 1% of pediatric patients treated with metformin.

One patient in each treatment group experienced a severe hypoglycemic episode (severity was

determined by the investigator based on observed signs and symptoms).

9.4 Geriatric Use

In clinical trials of AMARYL, 1053 of 3491 patients (30%) were >65 years of age. No overall

differences in safety or effectiveness were observed between these patients and younger patients,

but greater sensitivity of some older individuals cannot be ruled out.

There were no significant differences in glimepiride pharmacokinetics between patients with type

2 diabetes 65 years (n=49) and those >65 years (n=42) [see Clinical Pharmacology (12.3)].

Glimepiride is substantially excreted by the kidney. Elderly patients are more likely to have renal

impairment. In addition, hypoglycemia may be difficult to recognize in the elderly [see Dosage

and Administration (2.1) and Warnings and Precautions (5.1)]. Use caution when initiating

AMARYL and increasing the dose of AMARYL in this patient population.

9.5 Renal Impairment

To minimize the risk of hypoglycemia, the recommended starting dose of AMARYL is 1 mg

daily for all patients with type 2 diabetes and renal impairment [see Dosage and Administration

(2.1) and Warnings and Precautions (5.1)].

A multiple-dose titration study was conducted in 16 patients with type 2 diabetes and renal

impairment using doses ranging from 1 mg to 8 mg daily for 3 months. Baseline creatinine

clearance ranged from 10-60 mL/min. The pharmacokinetics of AMARYL was evaluated in the

multiple-dose titration study and the results were consistent with those observed in patients

enrolled in a single-dose study. In both studies, the relative total clearance of AMARYL

increased when kidney function was impaired. Both studies also demonstrated that the

elimination of the two major metabolites was reduced in patients with renal impairment [see

Clinical Pharmacology (12.3)].

10. OVERDOSAGE

An overdosage of AMARYL, as with other sulfonylureas, can produce severe hypoglycemia.

Mild episodes of hypoglycemia can be treated with oral glucose. Severe hypoglycemic reactions

constitute medical emergencies requiring immediate treatment. Severe hypoglycemia with coma,

seizure, or neurological impairment can be treated with glucagon or intravenous glucose.

Continued observation and additional carbohydrate intake may be necessary because

hypoglycemia may recur after apparent clinical recovery [see Warnings and Precautions (5.1)].

11. DESCRIPTION

AMARYL is an oral sulfonylurea that contains the active ingredient glimepiride. Chemically,

glimepiride is identified as 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)

ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea (C

S) with a molecular weight

of 490.62. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless

powder and is practically insoluble in water.

The structural formula is:

AMARYL tablets contain the active ingredient glimepiride and the following inactive

ingredients:

Lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, plividone 25000,

magnesium stearate.

In addition, AMARYL 1 mg tablets contain Red Ferric Oxide (E172), AMARYL 2 mg tablets

contain Yellow Ferric Oxide and Indigo Carmine Aluminum Lake (E312), AMARYL 3mg

tablets contain Yellow Ferric Oxide (E172) and AMARYL 4 mg tablets contain Indigo Carmine

Aluminum Lake (E312).

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic

beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma

membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the

release of insulin.

12.2 Pharmacodynamics

In healthy subjects, the time to reach maximal effect (minimum blood glucose concentrations)

was approximately 2-3 hours after single oral doses of AMARYL. The effects of AMARYL on

HbA1c, fasting plasma glucose, and post-prandial glucose have been assessed in clinical trials

[see Clinical Studies (14)].

12.3 Pharmacokinetics

Absorption:

Studies with single oral doses of glimepiride in healthy subjects and with multiple oral doses in

patients with type 2 diabetes showed peak drug concentrations (C

) 2 to 3 hours post-dose.

When glimepiride was given with meals, the mean C

and AUC (area under the curve) were

decreased by 8% and 9%, respectively.

Glimepiride does not accumulate in serum following multiple dosing. The pharmacokinetics of

glimepiride does not differ between healthy subjects and patients with type 2 diabetes. Clearance

of glimepiride after oral administration does not change over the 1 mg to 8 mg dose range,

indicating linear pharmacokinetics.

In healthy subjects, the intra- and inter-individual variabilities of glimepiride pharmacokinetic

parameters were 15-23% and 24-29%, respectively.

Distribution:

After intravenous dosing in healthy subjects, the volume of distribution (Vd) was 8.8 L (113

mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than

99.5%.

Metabolism:

Glimepiride is completely metabolized by oxidative biotransformation after either an intravenous

or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the

carboxyl derivative (M2). Cytochrome P450 2C9 is involved in the biotransformation of

glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M2 is

inactive. In animals, M1 possesses about one-third of the pharmacological activity of

glimepiride, but it is unclear whether M1 results in clinically meaningful effects on blood glucose

in humans.

Excretion:

When

C-glimepiride was given orally to 3 healthy male subjects, approximately 60% of the

total radioactivity was recovered in the urine in 7 days. M1 and M2 accounted for 80-90% of the

radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was approximately 3:2 in

two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered

in feces. M1 and M2 accounted for about 70% (ratio of M1 to M2 was 1:3) of the radioactivity

recovered in feces. No parent drug was recovered from urine or feces. After intravenous dosing

in patients, no significant biliary excretion of glimepiride or its M1 metabolite was observed.

Specific Populations

Geriatric Patients:

A comparison of glimepiride pharmacokinetics in patients with type 2 diabetes ≤65 years and

those >65 years was evaluated in a multiple-dose study using AMARYL 6 mg daily. There were

no significant differences in glimepiride pharmacokinetics between the two age groups. The

mean AUC at steady state for the older patients was approximately 13% lower than that for the

younger patients; the mean weight-adjusted clearance for the older patients was approximately

11% higher than that for the younger patients.

Gender:

There were no differences between males and females in the pharmacokinetics of glimepiride

when adjustment was made for differences in body weight.

Race:

No studies have been conducted to assess the effects of race on glimepiride pharmacokinetics but

in placebo-controlled trials of AMARYL in patients with type 2 diabetes, the reduction in HbA1c

was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics (n = 63).

Renal Impairment:

In a single-dose, open-label study AMARYL 3 mg was administered to patients with mild,

moderate and severe renal impairment as estimated by creatinine clearance (CLcr): Group I

consisted of 5 patients with mild renal impairment (CLcr > 50 mL/min), Group II consisted of 3

patients with moderate renal impairment (CLcr = 20-50 mL/min) and Group III consisted of 7

patients with severe renal impairment (CLcr < 20 mL/min). Although, glimepiride serum

concentrations decreased with decreasing renal function, Group III had a 2.3-fold higher mean

AUC for M1 and an 8.6-fold higher mean AUC for M2 compared to corresponding mean AUCs

in Group I. The apparent terminal half-life (T

) for glimepiride did not change, while the half-

lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus

M2 as a percentage of dose decreased from 44.4% for Group I to 21.9% for Group II and 9.3%

for Group III.

Hepatic Impairment:

It is unknown whether there is an effect of hepatic impairment on AMARYL pharmacokinetics

because the pharmacokinetics of AMARYL has not been adequately evaluated in patients with

hepatic impairment.

Obese Patients:

The pharmacokinetics of glimepiride and its metabolites were measured in a single-dose study

involving 28 patients with type 2 diabetes who either had normal body weight or were morbidly

obese. While the t

, clearance, and volume of distribution of glimepiride in the morbidly obese

patients were similar to those in the normal weight group, the morbidly obese had lower C

AUC than those of normal body weight. The mean C

, AUC

0-24

, AUC

0-∞

values of glimepiride

in normal vs. morbidly obese patients were 547 ± 218 ng/mL vs. 410 ± 124 ng/mL, 3210 ± 1030

hours·ng/mL vs. 2820 ± 1110 hours·ng/mL and 4000 ± 1320 hours·ng/mL vs. 3280 ± 1360

hours·ng/mL, respectively.

Drug Interactions:

Aspirin:

In a randomized, double-blind, two-period, crossover study, healthy subjects were given either

placebo or aspirin 1 gram three times daily for a total treatment period of 5 days. On Day 4 of

each study period, a single 1 mg dose of AMARYL was administered. The AMARYL doses

were separated by a 14-day washout period. Co-administration of aspirin and AMARYL resulted

in a 34% decrease in the mean glimepiride AUC and a 4% decrease in the mean glimepiride C

Colesevelam:

Concomitant administration of colesevelam and glimepiride resulted in reductions in glimepiride

0-∞

and C

of 18% and 8%, respectively. When glimepiride was administered 4 hours prior

to colesevelam, there was no significant change in glimepiride AUC

0-∞

or C

, -6% and 3%,

respectively [see Dosage and Administration (2.1) and Drug Interactions (7.4)].

Cimetidine and Ranitidine:

In a randomized, open-label, 3-way crossover study, healthy subjects received either a single 4

mg dose of AMARYL alone, AMARYL with ranitidine (150 mg twice daily for 4 days;

AMARYL was administered on Day 3), or AMARYL with cimetidine (800 mg daily for 4 days;

AMARYL was administered on Day 3). Coadministration of cimetidine or ranitidine with a

single 4 mg oral dose of AMARYL did not significantly alter the absorption and disposition of

glimepiride.

Propranolol:

In a randomized, double-blind, two-period, crossover study, healthy subjects were given either

placebo or propranolol 40 mg three times daily for a total treatment period of 5 days. On Day 4

or each study period, a single 2 mg dose of AMARYL was administered. The AMARYL doses

were separated by a 14-day washout period. Concomitant administration of propranolol and

AMARYL significantly increased glimepiride C

, AUC, and T

by 23%, 22%, and 15%,

respectively, and decreased glimepiride CL/f by 18%. The recovery of M1 and M2 from urine

was not changed.

Warfarin:

In an open-label, two-way, crossover study, healthy subjects received 4 mg of AMARYL daily

for 10 days. Single 25 mg doses of warfarin were administered 6 days before starting AMARYL

and on Day 4 of AMARYL administration. The concomitant administration of AMARYL did

not alter the pharmacokinetics of R- and S-warfarin enantiomers. No changes were observed in

warfarin plasma protein binding. AMARYL resulted in a statistically significant decrease in the

pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time

(PT) curve and maximum PT values during AMARYL treatment were 3.3% and 9.9%,

respectively, and are unlikely to be clinically relevant.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Studies in rats at doses of up to 5000 parts per million (ppm) in complete feed (approximately

340 times the maximum recommended human dose, based on surface area) for 30 months

showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months

resulted in an increase in benign pancreatic adenoma formation that was dose-related and was

thought to be the result of chronic pancreatic stimulation. No adenoma formation in mice was

observed at a dose of 320 ppm in complete feed, or 46-54 mg/kg body weight/day. This is about

35 at least 28 times the maximum human recommended dose of 8 mg once daily based on surface

area.

Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames

test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, and mouse

micronucleus test).

There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg

body weight (>1, 500 times the maximum recommended human dose based on surface area).

Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg

body weight (approximately 4,000 times the maximum recommended human dose based on

surface area).

14. CLINICAL STUDIES

14.1 Monotherapy

A total of 304 patients with type 2 diabetes already treated with sulfonylurea therapy participated

in a 14-week, multicenter, randomized, double-blind, placebo-controlled trial evaluating the

safety and efficacy of AMARYL monotherapy. Patients discontinued their sulfonylurea therapy

then entered a 3-week placebo washout period followed by randomization into 1 of 4 treatment

groups: placebo (n=74), AMARYL 1 mg (n=78), AMARYL 4 mg (n=76) and AMARYL 8 mg

(n=76). All patients randomized to AMARYL started 1 mg daily. Patients randomized to

AMARYL 4 mg or 8 mg had blinded, forced titration of the AMARYL dose at weekly intervals,

first to 4 mg and then to 8 mg, as long as the dose was tolerated, until the randomized dose was

reached. Patients randomized to the 4 mg dose reached the assigned dose at Week 2. Patients

randomized to the 8 mg dose reached the assigned dose at Week 3. Once the randomized dose

level was reached, patients were to be maintained at that dose until Week 14. Approximately

66% of the placebo-treated patients completed the trial compared to 81% of patients treated with

glimepiride 1 mg and 92% of patients treated with glimepiride 4 mg or 8 mg. Compared to

placebo, treatment with AMARYL 1 mg, 4 mg and 8 mg daily provided statistically significant

improvements in HbA1C compared to placebo (Table 3).

Table 3. 14-week Monotherapy Trial Comparing AMARYL to Placebo in Patients

Previously Treated With Sulfonylurea Therapy

*p<0.001

A total of 249 patients who were treatment- naive or who had received limited treatment with

antidiabetic therapy in the past were randomized to receive 22 weeks of treatment with either

AMARYL (n=123) or placebo (n=126) in a multicenter, randomized, double-blind, placebo-

controlled, dose-titration trial. The starting dose of AMARYL was 1 mg daily and was titrated

upward or downward at 2-week intervals to a goal FPG of 90-150 mg/dL. Blood glucose levels

for both FPG and PPG were analyzed in the laboratory. Following 10 weeks of dose adjustment,

patients were maintained at their optimal dose (1, 2, 3, 4, 6 or 8 mg) for the remaining 12 weeks

of the trial. Treatment with AMARYL provided statistically significant improvements in HbA1c

and FPG compared to placebo (Table 4).

Placebo

(N=74)

AMARYL

1 mg (N=78)

4 mg (N=76)

8 mg (N=76)

HbA1c (%)

n=59

n=65

n=65

n=68

Baseline (mean)

Change from Baseline

(adjusted mean

-0.3

-0.4

Difference from Placebo

(adjusted mean

95% confidence interval

-1.2*

(-1.5, -0.8)

-1.8*

(-2.1, -1.4)

-1.8*

(-2.2, -1.5)

Mean Baseline Weight

(kg)

n=67

n=76

n=75

n=73

Baseline (mean)

85.7

84.3

86.1

85.5

Change from Baseline

(adjusted mean

-2.3

-0.2

Difference from Placebo

(adjusted mean

95% confidence interval

2.0*

(1.4, 2.7)

2.8*

(2.1, 3.5)

3.2*

(2.5, 4.0)

Intent-to-treat population using last observation on study

Least squares mean adjusted for baseline value

Table 4: 22-Week Monotherapy Trial Comparing AMARYL to Placebo in Patients Who

Were Treatment-Naïve or Who Had No Recent Treatment with Antidiabetic Therapy

Placebo (N=126)

AMARYL (N=123)

HbA1c (%)

n=97

n=106

Baseline (mean)

Change from Baseline (adjusted mean

-1.1*

-2.2*

Difference from Placebo (adjusted

mean

95% confidence interval

-1.1*

(-1.5, -0.8)

Body Weight (kg)

n=122

n=119

Baseline (mean)

86.5

87.1

Change from Baseline (adjusted mean

-0.9

Difference from Placebo (adjusted

mean

95% confidence interval

(1.9, 3.6)

Intent to treat population using last observation on study

Least squares mean adjusted for baseline value

*p<0.0001

15. HOW SUPPLIED/STORAGE AND HANDLING

AMARYL tablets are available in the following strengths and package sizes:

1mg, 2mg, 3mg, 4mg.

Presentation

Each pack contains 30 tablets.

Storage

Do not store above 30C.

MANUFACTURER

Sanofi S.p.A., Italy.

LICENSE HOLDER

Sanofi Aventis Israel ltd., P.O.B 8090, Netanya 4250499.

וא יפונאס

ןואג ינב 'חר ,לארשי סיטנ

ופ קראפ , .ד.ת ,גל

8090

םורד הינתנ ,

42504

לט

09-8633700

סקפ

09-8851444

ץרמ

2019

:רישכתה םש

tablets

Amaryl 1mg

tablets

Amaryl 2mg

tablets

Amaryl 3mg

tablets

Amaryl 4mg

:ליעפ רמוח :המאתהב הליכמ הילבט לכ

Glimepiride 1mg, 2mg, 3mg, 4mg

תרשואמה היוותהה

הניה

Amaryl is indicated for non-insulin-dependent diabetes melitus (adult-onset diabetes, type II

diabetes), when diet, regular physical exercise and weight reduction alone cannot maintain

therapeutically suitable blood glucose levels.

יפונאס תרבח

רשי סיטנווא תשקבמ מ"עב לא

ולעה ןוכדע לע עידוהל

ןולעהו אפורל ןכרצל

ראורבפ

2019

.םינולעב םיירקיעה םינוכדעה ושענ םהב םיפיעסה יתת קר ןלהל םיטרופמ

:אפורל ןולעב

CONTRAINDICATIONS

AMARYL is contraindicated in patients with a history of a hypersensitivity reaction to:

Glimepiride or any of the product’s ingredients [see Warnings and Precautions

(5.2].

Sulfonamide derivatives: Patients who have developed an allergic reaction to

sulfonamide derivatives may develop an allergic reaction to AMARYL. Do not

use AMARYL in patients who have a history of an allergic reaction to

sulfonamide derivatives.

Reported hypersensitivity reactions include cutaneous eruptions with or without pruritus as well as more

serious reactions (e.g. anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea) [see Warnings and

Precautions (5.2) and Adverse Reactions (6.2)].

וא יפונאס

ןואג ינב 'חר ,לארשי סיטנ

ופ קראפ , .ד.ת ,גל

8090

םורד הינתנ ,

42504

לט

09-8633700

סקפ

09-8851444

9.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of AMARYL in pregnant women. In animal studies there was no increase in

congenital anomalies, but an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times

(rabbits) the maximum recommended human dose (based on body surface area). This fetotoxicity, observed only at doses inducing

maternal hypoglycemia, is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride and has been

similarly noted with other sulfonylureas. AMARYL should be used during pregnancy only if the potential benefit justifies the

potential risk to the fetus. Because data suggest that abnormal blood glucose during pregnancy is associated with a higher incidence of

congenital abnormalities, diabetes treatment during pregnancy should maintain blood glucose as close to normal as possible.

Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers receiving a

sulfonylurea at the time of delivery.

Risk Summary

Available data from a small number of published studies and postmarketing experience

with AMARYL use in pregnancy over decades have not identified any drug associated

risks for major birth defects, miscarriage, or adverse maternal outcomes. However,

sulfonylureas (including glimepiride) cross the placenta and have been associated with

neonatal adverse reactions such as hypoglycemia. Therefore, AMARYL should be

discontinued at least two weeks before expected delivery (see Clinical Considerations).

Poorly controlled diabetes in pregnancy is also associated with risks to the mother and

fetus (see Clinical Considerations). In animal studies (see Data), there were no effects on

embryo-fetal development following administration of glimepiride to pregnant rats and

rabbits at oral doses approximately 4000 times and 60 times the maximum human dose

based on body surface area, respectively. However, fetotoxicity was observed in rats and

rabbits at doses 50 times and 0.1 times the maximum human dose, respectively.

The estimated background risk of major birth defects is 6% to 10% in women with pre-

gestational diabetes with a HbA1c >7% and has been reported to be as high as 20% to

25% in women with a HbA1c >10%. The estimated background risk of miscarriage for

the indicated population is unknown. In the U.S. general population, the estimated

background risk of major birth defects and miscarriage in clinically recognized

pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo-fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic

ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery

complications. Poorly controlled diabetes increases the fetal risk for major birth defects,

still birth, and macrosomia-related morbidity.

וא יפונאס

ןואג ינב 'חר ,לארשי סיטנ

ופ קראפ , .ד.ת ,גל

8090

םורד הינתנ ,

42504

לט

09-8633700

סקפ

09-8851444

Fetal/neonatal adverse reactions

Neonates of women with gestational diabetes who are treated with sulfonylureas during

pregnancy may be at increased risk for neonatal intensive care admission and may

develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age.

Prolonged severe hypoglycemia, lasting 4–10 days, has been reported in neonates born to

mothers receiving a sulfonylurea at the time of delivery and has been reported with the

use of agents with a prolonged half-life. Observe newborns for symptoms of

hypoglycemia and respiratory distress and manage accordingly.

Dose adjustments during pregnancy and the postpartum period

Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a

sulfonylurea at the time of delivery, AMARYL should be discontinued at least two weeks

before expected delivery (see Fetal/Neonatal Adverse Reactions).

Data

Animal data

In animal studies, there was no increase in congenital anomalies, but an increase in fetal

deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times

(rabbits) the maximum recommended human dose (based on body surface area). This

fetotoxicity was observed only at doses inducing maternal hypoglycemia and is believed

to be directly related to the pharmacologic (hypoglycemic) action of glimepiride, as has

been similarly noted with other sulfonylureas.

9.2 LactationNursing Mothers

It is not known whether AMARYL is excreted in human milk. During pre- and post-natal studies in rats, significant concentrations of

glimepiride were present in breast milk and the serum of the pups. Offspring of rats exposed to high levels of glimepiride during

pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the

postnatal period. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride. Based

on these animal data and the potential for hypoglycemia in a nursing infant, a decision should be made whether to discontinue nursing

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

Risk Summary

Breastfed infants of lactating women using AMARYL should be monitored for

symptoms of hypoglycemia (see Clinical Considerations). It is not known whether

glimepiride is excreted in human milk and there are no data on the effects of glimepiride

on milk production. Glimepiride is present in rat milk [see Data]. The developmental and

health benefits of breastfeeding should be considered along with the mother's clinical

need for AMARYL and any potential adverse effects on the breastfed child from

AMARYL or from the underlying maternal condition.

וא יפונאס

ןואג ינב 'חר ,לארשי סיטנ

ופ קראפ , .ד.ת ,גל

8090

םורד הינתנ ,

42504

לט

09-8633700

סקפ

09-8851444

Clinical Considerations

Monitoring for adverse reactions

Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea,

hypothermia, excessive sleepiness, poor feeding, seizures).

Data

During prenatal and postnatal studies in rats, significant concentrations of glimepiride

were present in breast milk and the serum of the pups. Offspring of rats exposed to high

levels of glimepiride during pregnancy and lactation developed skeletal deformities

consisting of shortening, thickening, and bending of the humerus during the postnatal

period. These skeletal deformations were determined to be the result of nursing from

mothers exposed to glimepiride.

ןכרצל ןולעב ע , כדו :אבה ףיעסה ן

רופו הקנה ,ןוירה :תוי

.תופורתב שומישה ינפל אפורב ץעוויהל שי קינהל תננכתמ וא הקינמ ,ןוירה תננכתמ ,ןוירהב ךנה םא

תקספה ,ןולחיכ ,תונבצע ,אמגודל) קוניתה לצא הימקילגופיה לש םינמיס רחא בוקעל שי ,הקינמ ךנה םא

,תרבגומ הניש ,ךומנ םוח ,המישנ

.(םיסוכרפ ,לוכאל ןוצר יא

ולעה םינ

כדועמה םינ

חלש

לבקל ןתינו תואירבה דרשמ רתאבש תופורתה רגאמב םוסרפל

ספדומ םי

םושירה לעבל היינפ ידי לע

יפונאס

ןואג ינב 'חר ,מ"עב לארשי סיטנווא

וא הינתנ :ןופלטב

09-8633700

ןלהל

תואירבה דרשמ רתאל רושיקה

https://data.health.gov.il/drugs/index.html#/byDrug

,הכרבב

דטשכוה הילג

הנוממ תחקור

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