JANUET 50/850 MG TABLETS

Israel - English - Ministry of Health

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Active ingredient:
METFORMIN HYDROCHLORIDE 850 MG; SITAGLIPTIN AS MONOHYDRATE PHOSPHATE 50 MG
Available from:
MERCK SHARP & DOHME ISRAEL LTD
ATC code:
A10BA02
Pharmaceutical form:
TABLETS
Administration route:
PER OS
Manufactured by:
MERCK SHARP & DOHME CORP., USA
Therapeutic group:
METFORMIN
Therapeutic indications:
Januet is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus. Important limitations of use:Januet should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.Januet has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Januet.
Authorization number:
139903190211
Authorization date:
2009-01-01

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

15-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

15-01-2021

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۱۹۸٦- )تارضحتسم(ةلدايصلاةمظنأبجومبكلهتسمللةيبطةرشن

بيبطةفصوبمزلمءاودلااذه

ءاودلاي/لمعتستنألبقاهلماكبةرشنلاةءارقبجي

۲۰۱۱راذآيفاهلبقنمصخرواهاوتحمصحفوةرشنلاهذهةغيصةحصلاةرازوترقأ

تيوناج

غلم٥۰۰/غلم٥۰

صارقأ

:بيكرتلا

:ىلعيوتحيصرقلك

Sitagliptin50mg

MetforminHydrochloride500mg

تيوناج

غلم۸٥۰/غلم٥۰

صارقأ

:بيكرتلا

:ىلعيوتحيصرقلك

Sitagliptin50mg

MetforminHydrochloride850mg

تيوناج

غلم۱۰۰۰/غلم٥۰

صارقأ

:بيكرتلا

:ىلعيوتحيصرقلك

Sitagliptin50mg

MetforminHydrochloride1000mg

:ةلاعفريغلاداوملا

Microcrystallinecellulose,polyvinylpyrrolidone(povidone),sodiumlauryl

sulfate,andsodiumstearylfumarate.

:ةيلاتلاةلاعفريغلاتابكرملاىلعصرقلاءلاطيوتحي

Polyvinylalcohol,macrogol/polyethyleneglycol,talc,titaniumdioxide,iron

oxidered,andironoxideblack.

:ةيجلاعلاةليصفلا

.DPP-4ميزناتاطبثم:نﻴﺘﭙﻴلﺠاﺘﻴﺴ

.ديناوغيب:نيمروفتيم

:ةيبطلاةيلاعفلا

نيذللا,نيمروفتيمو(اﻴﭭوناج)تافسوفنﻴﺘﭙﻴلﺠاﺘﻴﺴ,بيبطةفصوبنيمزلمنيئاودىلعيوتحيصرقوهتيوناج

تاطبثم)DPP-4تاطبثمىعدتيتلاةيودلأاةليصفىلإنﻴﺘﭙﻴلﺠاﺘﻴﺴيمتني.مدلايفركسلاةبسننمناضفخي

ىلعةرطيسلايفاعمنلامعيثيح,تاديناوجيبلاةليصفىلإيمتنييذلا,نيمروفتيمو,(ليديتببلايئانث٤-زاديتبب

.جيزملااذهمهبسانينيذلاىضرملاىدل,۲عوننممدلايفيركسلاتايوتسم

.۲عوننميركسلاىضرمىدلمدلايفركسلاضيفختلصصخُم,ةيندبةضايرجمانربواهبىصومةيمحعمتيوناج

؟لامعتسلاازوجيلاىتم

:ءاودلااذهلامعتسازوجيلا

.۱عوننميركسلانمن/يناعتتنكاذإ

.ىلكلايفلكاشميأنمن/يناعتتنكاذإ

نمةعفترمتايوتسم) ّيِرَّكُسٌّيِنوتيكٌضامُحوأيِبلاْقِتْساٌضامُحىعدتتلااحنمن/يناعتتنكاذإ

,مدلايفركسلانمةعفترمتايوتسملمشتيتلاويركسلاضرمتافعاضم:لوبلاوأمدلايفتانوتيكلا

.(تاؤيقتوأنايثغ,نزوللعيرسنادقف

ءاطعإنعفقوتلابجي ,)نجتنر(ةَّيِعاعُشٌةَروصءارجلإنيابت-داوموأغابصةنقحيقلتددصبتنكاذإ

دنبىلإي/رظنأ)ءاطعإديدجتدعوموتيوناجفقودعومناشبكبيبطعمي/ملكت.ةزيجوةرتفلتيوناج

.("تاريذحت"

.تيوناجتابكرمدحا,)اﻴﭭوناج(نﻴﺘﭙﻴلﺠاﺘﻴﺴوأتيوناجل)ةّيساسح(يجرألعفدركيدلتناكاذإ

:جلاعلاءدبلبق,بيبطلاةراشتسانود,ءاودلااذهلامعتسازوجيلا

ةعفترمتايوتسم ,ٌةَّيِلْوُحُك,ةرارملايفةاصح,سايِركنَبلاباهِتْلا:نميضاملايفتيناعوأن/يناعتتنكاذإ

.مدلايفديرسيلغلا ُّيِثَلاُثنم

.ىلكلابلكاشمكيدلتدجواذإ

.دبكلايفلكاشمكيدلتدجواذإ

.ءاودلاتابكرمىدحلإ(ةّيساسح)يجرألعفدريضاملايفكيدلناكاذإ

.يِناقِتْحلاابْلَقلالَشَفكلذيفامب,بلقلايفلكاشمكيدلتدجواذإ

ىلكلافئاظوصحفمتاذإلاإ,تيوناجلوانتاماع۸۰قوفامىضرمللزوجيلا.اماع۸۰كنسزواجتاذإ

.ةميلستدجوو

.(ةريصقةينمزةرتفللاخلوحكلانمةريبكةيمكوأةبراقتمتارتفيف)لوحكلابرشبني/فرستتنكاذإ

عميملكت,لاماحتنكاذإ.كنينجبرضيتيوناجناكاذإافورعمسيل.لمحلاىلإنيططختوألاماحتنكاذإ

.لمحلاءانثأكيدلركسلاةبسنىلعةرطيسللةقيرطلضفألوحكبيبط

عميملكت.كيدلملأابيلحىلإلقتنيتيوناجناكاذإافورعمسيل.عاضرلإانيططختوأةعضرمتنكاذإ

.تيوناجنيلوانتتتنكاذإكعيضرماعطلإةقيرطلضفأنعكبيبط

:تاريذحت

.ءاودلااذهبجلاعلاءدبلبقكلذنعبيبطلاغلابإكيلعف,امءاودلوأامماعطلة/اساسحتنكاذإ

سايِركنَبلاباهِتْلابضرمللربكأةصرفكيدلناكاذإاًفورعمسيل,سايِركنَبلاباهِتْلانميضاملايفتيناعاذإ

("ةيبناجلاضارعلأا"اضيأي/رظنأ).تيوناجني/لوانتتامنيب

تاداشرلإاىلعلوصحللكبيبطىلإي/ثدحت.ةريصقةرتفلتيوناجبجلاعلافقوكيلعبجوتينألمتحملانم

:تنكاذإ

تاؤيقتنمن/يناعتوة/اضيرمتنكاذإفافجلاثدحيدق.(مسجلالئاوسنمريثكلاتدقف)فافجلابة/اباصم

.داتعملانمريثكبلقالئاوسةيمكني/برشتتنكاذإوأ,ةنوخسوألاهسإ,ةديدش

.ةيحارجةيلمعءارجإددصبتنكاذإ

زوجيلاىتم"ةرقفىلإي/رظنأ).ةَّيِعاعُشةَروصءارجلإنيابت-داوموأغابصةنقحيقلت ددصبتنكاذإ

("؟رضحتسملالامعتسا

تاطوغضلانمةفلتخمعاونأتحتادوجومكمسجنوكيامدنع,اهيلإني/جاتحتيتلايركسللةيودلأاةيمكريغتتدق

كيدلتدجواذإاًروفكبيبطىلإي/ثدحت.ةيحارجةيلمعوأثولت,(قرطلاثداوحلثم)ةمدص,ةنوخسلثم

.بيبطلاتاميلعتبسحي/لمعاوتلااحلاهذهىدحإ

.بيبطلاتاميلعتبسح,كيدلمدلابركسلاةبسني/دصرا

.تيوناجلوانتءانثأةيندبلاةيلاعفلاجمانربلوكلىطعملاةيمحلاجمانرببي/كسمت

مَّدلا ِرَّكُسطْرَف,(ايميكلجوبيه)مَّدلا ِرَّكُس ُصْقَنىلعةرطيسلاوصيخشت,يدافتةيفيكنعكبيبطعمي/ملكت

.يركسلاضرمتافعاضمو,(ايميكلجربيه)

مدلايفركسلاىوتسمكلذيفامب,ةينيتورةيومدتاصوحفقيرطنعكيدلركسلاةبسندصربكبيبطموقيس

.A1Cنيبولغوميهلاو

.تيوناجبجلاعلاللاخولبق,كيدلىلكلافئاظوصحفلمدتاصوحفبيبطلاكليرجيفوس

:ةيودلأانيبتلاعافتلا

ةفصونودبعابتيتلاةيودلأاكلذيفامب,رخآءاودبجلاعلاوتللتيهنأاذإوأ,ايفاضإ ًءاودني/لوانتتتنكاذإ

ةعاجنلامدعوأراطخلأايدافتلكلذو,جلاعملابيبطلاغلابإكيلعبجيف,ةيبطلاباشعلأاوتانيماتيفبيبط

.ةيودلأانيبتلاعافتلانعةجتانلا

.تيوناجةعاجنىلعىرخأةيودأرثؤتدقو,ىرخاةيودأةعاجنىلعتيوناجرثؤيدق

.ديدجءاوديأبجلاعلاءدبلبقكبيبطعمي/ملكت

:ةيبناجلاضارعلأا

.ةيبناجضارعأهلامعتساءانثأرهظتدق,ءاودللةبوغرملاةيلاعفلاىلإةفاضلإاب

:كلذيفامب ,تيوناجنولوانتينيذلاسانلأاىدلةميخوةيبناجضارعأثودحنكمي

ميخوهنكلوردانيبناجضرعلببسينأهنكمي,تيوناجبتابكرملاىدحإ,نيمروفتيم .يِكيتْكلاٌضامُح.۱

.توملاىلإيدؤيدقثيح,(مدلايفكيتكلالاُضْمَحمكارت)(lacticacidosis)يِكيتْكَلاضامُحىعدييذلا

םינימסתהמדחאת/חתפמךניהםאדימךלשאפורהםעי/רבדוטאונ'גתחקלי/קספה

:)lacticacidosis(תיטקלתצמחלשםיאבה

.ה/ףייעוה/שלחדאמה/שיגרמךניה

.(םיילמרונאל)םיליגראלםירירשיבאכךלשיםא

.המישניישקךלשיםא

.ליגרהמרתויךוראןמזלה/ןשיךניהוא,רתיתוינונשיה/שחךניהםא

ואתואקהותוליחבבתוולמהתוימואתפםייעמתויעבואםיימואתפןטביבאכךלשיםא

.םילושלש

.םיילגרבותועורזבדחוימב,ךלרקםא

.ת/ררחוסמואתרוחרחסה/שיגרמךניהםא

.ליגראלואיטיאבלבצקךלשיםא

:ה/תאםא)lacticacidosis(תיטקלתצמחחתפלרתויהובגיוכיסךלשי

לוטילןיקתןפואבתולעופןניאםהלשתוילכהשםישנאלעןיא.הילכבתויעבמת/לבוס

.טאונ'ג

.דבכבתויעבמת/לבוס

.יתפורתלופיטתשרודהבלתקיפס-יאמת/לבוס

.רצקןמזךותהלודגלוהוכלאתומכהתושואדאמתובורקםיתיעללוהוכלאהתוש

םעהלוחךניהםאתורקללולערבדה.(ףוגילזונידמרתויתדביא)תושבייתהמת/לבוס

ךלהמבהברהה/עיזמה/תאםאםגתורקלהלוכיתושבייתה.םילושלשואתואקה,םוח

.םילזונקיפסמהתושךניאותינפוגתוליעפואהליגרתוליעפ

.ךפוגךותלםיקרזומהדוגינ-ירמוחואעבצירמוחםעןגטנרתוקידבת/רבוע

.חותינת/רבוע

.ץבשוארומחםוהיז,בלףקתהמלבוס

.הילכידוקפתתוקידבתרבעאלוהלעמו80ת/ןב

.תוומלליבוהלוהרומחתויהלהלוכירשא(בלבלהלשתקלד) סיטיטארקנפ.2

.סיטיטארקנפבתולחלךלשיוכיסהתאתולעמתומייוסמתויאופרתויעב

םינבא,בלבלהתקלדמרבעבתלבסםאךלשאפורלי/רומא,טאונ'גבלופיטהתליחתינפל

.םדבםידירצילגירטלשתוהובגתומרואםזילוהוכלאלשהירוטסיה,הרמהסיכב

ךלשןטבהרוזיאבבאכךלשיםאדימךלשאפורהםערשקי/רוצוטאונ'גלוטילי/קספה

לוכיבאכה.ךלשבגהדעןטבהמרבועבאכהתאי/שיגרתוןכתיי.ףלוחוניאשורומחוניהש

.בלבלבתקלדלשםינימסתתויהלםילוכיהלא.האקהאללואםעעיפוהל

תולוכירשאתופסונתופורתםעטאונ'גת/לטונךניהםא. )הימקילגופיה(םדבךומנרכוס.3

ךומנרכוסמלובסלךלשןוכיסה,ןילוסניאואתואירואלינופלוסןוגכ,םדבךומנרכוסלםורגל

גוסמהפורתהלשרתויתוכומנתונמךלםושריךלשאפורהוןכתיי.רתויהובגאוהםדב

.םדבךומנרכוסמת/לבוסךניהםאךלשאפורלי/רפס.ןילוסניאואהאירואלינופלוס

,תרוחרחס,השלוח,םונמנ,שארבאכ:לולכלםילוכיםדבךומנרכוסלשםינימסתוםינמיס

.חתמתשוחת,העזה,תוריהמבלתוקיפד,בער,תונזגר,לובלב

תופורתהתחא,ןיטפילגטיסואואטאונ'גםעתורקלתולוכי תורומחתויגרלאתובוגת.4

תוחיפנו,דרג,החירפלולכלםילוכיהרומחתיגרלאהעפותלשםינימסת.טאונ'גבתוללכנה

הבוגתמת/לבוסךניהםא.העילבבואהמישנבישוק,ןורגהוןושל,םייתפש,םינפהלש

הפורתךלםושריאפורהוןכתיי.דימךלשאפורהםעי/רבדוטאונ'גלוטילי/קספה,תיגרלא

.ךלשתרכוסלתרחאהפורתו,ךלשתיגרלאההבוגתבלופיטל

:תוללוכטאונ'גתליטנןמזבתוצופניאוולתועפות

.ןורגבםיבאכולזונואםותסףא

.תונוילעההמישנהיכרדבתקלד

.םילושלש

.תואקהותוליחב

.לוכיעבתויעב,ןטבבתוחונ-יא,םיזג

.השלוח

.שארבאכ

לשתוצופנהתוינטבהיאוולהתועפותתתחפהברוזעלהלוכיתוחוראהםעטאונ'גתליטנ

תוינטביאוולתועפותמת/לבוסךניהםא.לופיטהתליחתבללכךרדבתורוקרשא,ןימרופטמ

רחואמבלשבתוליחתמרשאןטבבתויעב.ךלשאפורהםעי/רבד,תויופצ-אלואןפודתואצוי

.רתוייניצרוהשמלןמיסתויהלתולולעלופיטהלשרתוי

:ללוכ,תורחאיאוולתועפותתויהלתולוכיטאונ'גל

תרחאהפורתםעבולישבטאונ'גת/לטונךניהםאתורקלהלוכיםיילגרבוםיידיבתוחיפנ

.הידנבאםשבתרכוסל

.דבכימיזנאבהיילע

.(הזילאידתושרודםיתיעלש)הילכבתויעב

תודירטמשיאוולתועפותוא,הזןולעבונייוצאלשיאוולתועפותה/שיגרמךניהובשהרקמלכב

.דימךלשאפורהםעץעייתהלךילע,תיללכהךתשגרהביונישלחםאואתופלוחןניאשואךתוא

:ןונימוןתמ

.דבלבאפורהתוארוהיפלןונימה

.ןתואלוטילךילעתורידתהזיאבולוטילךילעטאונ'גתוילבטהמכךלרמאיךלשאפורה

.ךלהרוהךלשאפורהשיפכקוידבטאונ'גלוטילשי

תכרעמבתוערפהמלובסלךלשןוכיסהתאתיחפהלתנמלעתוחוראהםעטאונ'גלוטילשי

.לוכיעה

.ךלשםדברכוסהתומרבטולשלתנמלעהנמהתאלידגהלךרטציאפורהוןכתיי

תומרתדרוהלתפסונהפורת)האירואלינופלוסםעבולישבטאונ'גךלםושריךלשאפורהוןכתיי

.םדברכוסלשתוכומנתומרלרבגומןוכיסלעעדימל"יאוולתועפות" קרפי/האר.(םדברכוסה

.תאזתושעלךלרמואךלשאפורהדועלכטאונ'גלוטילי/ךשמה

.אפורהךלהרוהשיפכךלשםדברכוסהתומרתאי/רטנ

.טאונ'גתליטנןמזבתינפוגהתוליעפהתינכתבוךלהמשרנשהטאידבי/ךשמה

םדברכוסלשתוכומנתומרבלפטלותוהזל,עונמלןתינדציכךלשאפורהםעי/רבד

.תרכוסלשםיכוביסבו,(הימקילגרפיה)םדברכוסלשתוהובגתומרב,(הימקילגופיה)

םדבךלשרכוסהתומרללוכ,תוליגרםדתוקידבידילעךלשתרכוסהתארטניךלשאפורה

.ךלשA1Cןיבולגומההתומרו

לופיטהינפלךלשהילכהידוקפתתאקודבלתנמלעםדתוקידבלךתואחלשיךלשאפורה

.וכלהמבוטאונ'גב

.דימךלשאפורהםעי/רבד,טאונ'גתוילבטידמרתויתלטנםא

ןמזהעיגהשדעתרכזנאלםא.תרכזנשעגרבלכואםעהתואי/חק,הנמלוטילתחכשםא

לוטילןיא.ליגרההליטנה-ינמזחוללי/רוזחוהחכשנשהנמהלעי/גלד,האבההנמהתאלוטיל

.ןמזותואבטאונ'גלשתונמיתש

.םינש18ליגלתחתמםידליבןתמלתדעוימהניאוזהפורת

שומישהןפוא

.םימטעמםעהילבטהעולבלשי

.לכואהםעהפורתהתאלוטילשי

?לופיטהתחלצהלעייסלי/לכותדציכ

.אפורהי"עץלמוהשיפכלופיטהתאםילשהלךילע

.אפורהםעתוצעייתהאללהפורתבלופיטהתאקיספהלןיא,ךתואירבבצמברופישלחםאםג

!הלערהי/ענמ

וא/וםידלילשםדיגשיהלץוחמרוגסםוקמברומשלשי,תרחאהפורתלכומכ,וזהפורת

.הלערהענמתךכידילעו,תוקונית

םילוחתיבלשןוימרדחלדימי/הנפ,הפורתהןמדליעלבתועטבםאוארתיתנמתלטנםא

.ךתיאהפורתהתזיראי/אבהו

!אפורמתשרופמהארוהאללהאקהלםורגלןיא

וזהפורתי/ןתיתלא.קיזהלהלולעאיה,ת/רחאהלוחב;ךתלחמבלופיטלהמשרנוזהפורת

.ךירכמואךינכש,ךיבורקל

.הפורתת/לטונךניהשםעפלכבהנמהותיוותהקודבלשי!ךשוחבתופורתלוטילןיא

.םהלה/קוקזךניהםאםייפקשמביכרהלשי

:הנסחא

.רדחהתרוטרפמטבטאונ'גןסחאלשי

.דבלבתלבגומהפוקתלתורמשנתופורת,םיצלמומההנסחאה/הזיראהיאנתיפלםג

חקורבץעוויהלךילע,קפסלשהרקמלכב!רישכתהלשהגופתהךיראתלבלםישלאנ

.הפורתהתאךלקפיסש

.הזיראהתואבתונושתופורתןסחאלןיא

:הפורתהםושיר'סמ

139.89.31706.00/11 :ג"מ500/ג"מ50טאונ'ג

139.90.31902.00/11 :ג"מ850/ג"מ50טאונ'ג

139.88.31705.00/11 :ג"מ1000/ג"מ50טאונ'ג

ב"הרא ,יסר’ג-וינ,ןשייטססואהטייו,.פרוקםהודופראשקרמ :ןרצי

1986-ו"משתה)םירישכת(םיחקורהתונקתיפלןכרצלןולע

אפורםשרמבתבייחוזהפורת

הפורתבי/שמתשתםרטבואולמבןולעהתאןויעבאורקלשי

2011ץרמבודי-לערשואוקדבנונכותותואירבהדרשמי"עעבקנהזןולעטמרופ

® טאונ'ג

ג"מ500/ג"מ50

תוילבט

:בכרה

:הליכמהילבטלכ

Sitagliptin 50 mg

Metformin Hydrochloride 500 mg

® טאונ'ג

ג"מ850/ג"מ50

תוילבט

:בכרה

:הליכמהילבטלכ

Sitagliptin 50 mg

Metformin Hydrochloride 850 mg

® טאונ'ג

ג"מ1000/ג"מ50

תוילבט

:בכרה

:הליכמהילבטלכ

Sitagliptin 50 mg

Metformin Hydrochloride 1000 mg

:םיליעפיתלבםיביכרמ

Microcrystallinecellulose,polyvinylpyrrolidone(povidone),sodiumlaurylsulfate

andsodiumstearylfumarate.

:םיאבהםיליעפיתלבהםיביכרמהתאליכמהילבטהיופיצ

Polyvinylalcohol,macrogol/polyethyleneglycol,talc,titaniumdioxide,iron

oxideredandironoxideblack.

:תיטיופרתהצובק

.DPP-4םיזנאהבכעמ:ןיטפילגטיס

.םידינאוגיב:ןימרופטמ

:תיאופרתוליעפ

,ןימרופטמו( ® היבונ'ג)טפסופןיטפילגטיס,םשרמתופורתיתשהליכמההילבטהניהטאונ'ג

DPP-4יבכעמתארקנהתופורתתצובקלךייתשמןיטפילגטיס.םדברכוסהתאתודירומרשא

םילעופ,םידינאוגיבהתצובקלךייתשמה,ןימרופטמו,(dipeptidylpeptidase-4inhibitors)

.הזבולישםיאתמםהלםילוחב,2גוסמתרכוסםעםילוחבםדברכוסהתומרבטולשלידכדחי

םדברכוסהתומרתדרוהלתדעוימ,ינפוגןומיאתינכותותצלמומהטאידםעבולישבטאונ'ג

.2גוסמתרכוסםעםילוחב

?רישכתבשמתשהלןיאיתמ

:וז הפורתב שמתשהל ןיא

.1גוסמ תרכוסמ ת/לבוס ךניה םא

.תוילכב ןהשלכ תויעבמ ת/לבוס ךניה םא

תומר( יתרכוססיזודיצאוטק וא ילובטמ סיזודיצא םיארקנה םיבצממ ת/לבוס ךניהםא

,םדב תוהובג רכוס תומר ללוכה תרכוס לש ךוביס :ןתשב וא םדב םינוטק לש תורבגומ

.)תואקה וא תוליחב ,לקשמ לש ריהמ ןדבוא

קיספהל שי ,ןגטנר םוליצ ךרוצל דוגינ-ירמוחוא עבצ תקירז לבקל ת/דמוע ךניה םא

שודיח דעומלו טאונ'ג תקספה דעומל רשאב ךלש אפורה םע י/רבד .רצק ןמזל טאונ'ג ןתמ

.("תורהזא" קרפ י/האר( ןתמה

םיביכרמהמ דחא,) ® היבונ'ג( ןיטפילגטיסל וא טאונ'גל תיגרלאהבוגת ךל התיה םא

.טאונ'גלש

:לופיטהתלחתהינפל,אפורבץעוויהלילב,וזהפורתבשמתשהלןיא

תומר,םזילוהוכלא,הרמהסיכבםינבא,בלבלהתקלד:מרבעבתלבסואת/לבוסךניהםא

.םדבםידירצילגירטלשתוהובג

.הילכבתויעבךלשיםא

.דבכבתויעבךלשיםא

.הפורתהיביכרממדחאלתיגרלאהבוגתרבעבךלהתיהםא

.בלתקיפס-יאללוכ,בלבתויעבךלשיםא

ידוקפתןכםאאלא,טאונ'גלוטילרוסא80ליגלעמםילוחל.םינש80לעהלועךליגםא

.םיניקתואצמנווקדבנםהלשהילכה

.(רצקןמזךותהלודגלוהוכלאתומכואתובורקםיתיעל)לוהוכלאהברההתושךניהםא

ךניהםא.ךלשרבועבעגפתטאונ'גםאעודיאל.ןוירהלסנכיהלתננכתמואןוירהבךניהםא

ןמזבךלשרכוסהתומרבטולשלרתויבהבוטהךרדלעגונבךלשאפורהםעירבד,ןוירהב

.ןוירהה

םעירבד.ךלשםאהבלחלרובעתטאונ'גםאעודיאל.קינהלתננכתמואהקינמךניהםא

.טאונ'גתלטונךניהםאךלשקוניתהתאליכאהלרתויבהבוטהךרדהלעךלשאפורה

:תורהזא

תלחתהינפלאפורלךכלעעידוהלךילע,יהשלכהפורתלואוהשלכןוזמלה/שיגרךניהםא

.וזהפורתבלופיטה

תולחלרתויהובגיוכיסךלשיםאעודיאל,(בלבלהתקלד)סיטיטארקנפמרבעבתלבסםא

.("יאוולתועפות" קרפי/האר).טאונ'גת/לטונה/תאשכסיטיטארקנפב

םאתויחנהתלבקלךלשאפורהםעי/רבד.רצקןמזלטאונ'גבלופיטקיספהלךילעהיהיוןכתיי

:ה/תא

ת/לבוס הלוחךניהםאתורקלהלוכיתושבייתה.(ףוגילזונידמרתויתדביא)ת/שבוימ

.ליגרהמםילזונתוחפהברההתושךניהםאוא,םוחואםילושלש,תורומחתואקהמ

.חותינרובעלת/דמוע

ןיאיתמ" קרפי/האר).ןגטנרםוליצךרוצלדוגינ-ירמוחואעבצתקירזלבקלת/דמועךניהםא

("?רישכתבשמתשהל

,(םיכרדתנואתןוגכ)המוארט,םוחןוגכץחללשםינושםיגוסתחתאצמנךלשףוגהרשאכ

אפורלי/רומא.תונתשהלהלולעהלה/קוקזךניהשתרכוסלתופורתהתומכ,חותינואםוהיז

.אפורהתוארוהיפללעפווללהםיבצמהמדחאךלשיםאדימךלש

.אפורהתוארוהיפל,ךלשםדברכוסהתאי/רטנ

.טאונ'גתליטנןמזבתינפוגהתוליעפהתינכתלוךלהנתינשהטאידהתינכתלי/דמציה

תומרב,(הימקילגופיה)םדבךומנרכוסבלפטלותוהזל,עונמלדציכךלשאפורהםעי/רבד

.תרכוסלשםיכוביסבו,(הימקילגרפיה)םדברכוסלשתוהובג

םדברכוסהתמרתקידבללוכ,תויתרגשםדתוקידבידילעךלשתרכוסהתארטניךלשאפורה

.A1Cןיבולגומההו

.טאונ'גםעלופיטהךלהמבוינפל,ךלשהילכהידוקפתתקידבלםדתוקידבךלךורעיאפורה

:תויתפורת-ןיבתובוגת

תופורתללוכ,תרחאהפורתבלופיטהתעהזתמייסםאוא,תפסונהפורתת/לטונךניהםא

עונמלידכ,לפטמהאפורלחוודלךילע,אפרמיחמצוםינימטיואפורםשרמאללתולטינה

.תויתפורת-ןיבתובוגתמםיעבונהתוליעי-יאואםינוכיס

לעעיפשהלתולולעתורחאתופורתו,תורחאתופורתלשןתוליעילעעיפשהלהלולעטאונ'ג

.טאונ'גלשהתוליעי

.השדחהפורתלכבלופיטתלחתהינפלךלשאפורהםעי/רבד

יאוולתועפות

.יאוולתועפותעיפוהלתולולעהבשומישהןמזב,הפורתהלשהיוצרהתוליעפלףסונב

:ללוכ,טאונ'גםילטונהםישנאבתורקלתולוכיתורומחיאוולתועפות

ךאהרידניאוולתעפותלםורגללוכי,טאונ'גבםיביכרמהדחא,ןימרופטמ .תיטקלתצמח.1

רשא,(םדבתיטקלהצמוחלשתורבטצה)(lacticacidosis)תיטקלתצמחתארקנההרומח

70018463/00-4 6747, 6748, 6749

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PATIENTPACKAGEINSERTINACCORDANCEWITHTHEPHARMACISTS'

REGULATIONS(PREPARATIONS) –1986

Thedispensingofthismedicinerequiresadoctor'sprescription

Readthepackageinsertcarefullyinitsentiretybeforeusingthismedicine

TheformatofthisleafletwasdeterminedbytheMinistryofHealthandits

contentwascheckedandapprovedinMarch2011

JANUET®

50mg/500mg

Tablets

COMPOSITION:

Eachtabletcontains:

Sitagliptin50mg

MetforminHydrochloride500mg

JANUET®

50mg/850mg

Tablets

COMPOSITION:

Eachtabletcontains:

Sitagliptin50mg

MetforminHydrochloride850mg

JANUET®

50mg/1000mg

Tablets

COMPOSITION:

Eachtabletcontains:

Sitagliptin50mg

MetforminHydrochloride1000mg

Inactiveingredients:

Microcrystallinecellulose,polyvinylpyrrolidone(povidone),sodiumlaurylsulfate

andsodiumstearylfumarate.

Thetabletfilmcoatingcontainsthefollowinginactiveingredients:

Polyvinylalcohol,macrogol/polyethyleneglycol,talc,titaniumdioxide,ironoxide

redandironoxideblack.

THERAPEUTICGROUP:

Sitagliptin:DPP-4enzymeinhibitors.

Metformin:biguanide.

THERAPEUTICACTIVITY:

JANUETisatabletthatcontainstwoprescriptionmedicines,sitagliptinphosphate

(JANUVIA®)andmetformin,whichlowerbloodsugar.Sitagliptin,amemberof

aclassofmedicinescalledDPP-4inhibitors(dipeptidylpeptidase-4inhibitors),

andmetformin,amemberofthebiguanideclassofmedicines,worktogetherto

controlbloodsugarlevelsinpatientswithtype2diabetesmellitus,inwhomthis

combinationisappropriate.

JANUET,alongwitharecommendeddietandexerciseprogramisintendedtolower

bloodsugarinpatientswithtype2diabetes.

WHENSHOULDTHEPREPARATIONNOTBEUSED?

Do not use this medicine:

If you have type 1 diabetes mellitus.

If you have certain kidney problems

If you have conditions called metabolic acidosis or diabetic ketoacidosis

(increased ketone levels in the blood or urine: diabetes complication which

includes high blood sugar, rapid weight loss, nausea or vomiting).

If you are going to receive an injection of dye or contrast agents for an x-ray

procedure,JANUET will need to be stopped for a short time.Talk to your doctor

about when to stop JANUET and when to start again (see also“Warnings”)

If you have had an allergic reaction to JANUET or to sitagliptin (JANUVIA),

one of the components of JANUET.

DONOTTAKETHISMEDICINEWITHOUTCONSULTINGADOCTORBEfORE

STARTINGTREATMENT:

Ifyousufferorhavesufferedinthepastfrom:pancreatitis,gallstones,alcoholism,

highbloodtriglyceridelevels.

Ifyouhavekidneyproblems.

Ifyouhaveliverproblems.

Ifyoupreviouslyhadanallergicreactiontooneoftheingredientsofthismedicine.

Ifyouhaveheartproblems,includingcongestiveheartfailure.

Ifyouareolderthan80years.Patientsover80yearsshouldnottakeJANUET

unlesstheirkidneyfunctionischeckedanditisnormal.

Ifyoudrinkalcoholalot(veryoftenorshort-term“binge”drinking).

Ifyouarepregnantorplantobecomepregnant.ItisnotknownifJANUETwill

harmyourunbornbaby.Ifyouarepregnant,talkwithyourdoctoraboutthebest

waytocontrolyourbloodsugarwhileyouarepregnant.

Ifyouarebreast-feedingorplantobreast-feed.ItisnotknownifJANUETwillpass

intoyourbreastmilk.Talkwithyourdoctoraboutthebestwaytofeedyourbaby

ifyouaretakingJANUET.

WARNINGS:

Ifyouaresensitivetoanytypeoffoodormedicine,informyourdoctorbefore

commencingtreatmentwiththismedicine.

Ifyouhavehadpancreatitis(inflammationofthepancreas)inthepast,itisnot

knownifyouhaveahigherchanceofgettingpancreatitiswhileyoutakeJANUET.

(seealso“SIDEEFFECTS”).

YoumayneedtostoptakingJANUETforashorttime.Callyourdoctorforinstructions

ifyou:

Aredehydrated(havelosttoomuchbodyfluid).Dehydrationcanoccurifyouaresick

withseverevomiting,diarrheaorfever,orifyoudrinkalotlessfluidsthannormal.

Plantohavesurgery.

Aregoingtoreceiveaninjectionofdyeorcontrastagentforanx-rayprocedure

(seealso“WHENSHOULDTHEPREPARATIONNOTBEUSED?”).

Whenyourbodyisundersometypesofstress,suchasfever,trauma(suchasacar

accident),infectionorsurgery,theamountofdiabetesmedicinethatyouneedmay

change.Tellyourdoctorrightawayifyouhaveanyoftheseconditionsandfollow

yourdoctor'sinstructions.

Monitoryourbloodsugarasyourdoctortellsyouto.

StayonyourprescribeddietandexerciseprogramwhiletakingJANUET.

Talktoyourdoctorabouthowtoprevent,recognizeandmanagelowbloodsugar

(hypoglycemia),highbloodsugar(hyperglycemia),andcomplicationsofdiabetes.

Yourdoctorwillmonitoryourdiabeteswithregularbloodtests,includingyourblood

sugarlevelsandyourhemoglobinA1C.

Yourdoctorwilldobloodteststocheckyourkidneyfunctionbeforeandduring

treatmentwithJANUET.

DRUGINTERACTIONS:

Ifyouaretakinganotherdrugconcomitantlyorifyouhavejustfinishedtreatment

withanothermedicine,includingthoseobtainedwithoutaprescription,vitamins

andherbalsupplements,informtheattendingdoctor,inordertopreventhazardsor

inefficacyarisingfromdruginteractions.

JANUETmayaffecthowwellotherdrugsworkandsomedrugscanaffecthowwell

JANUETworks.

Talktoyourdoctorbeforeyoustartanynewmedicine.

SIDEEffECTS:

Inadditiontothedesiredeffectofthemedicine,adversereactionsmayoccurduring

thecourseoftakingthismedicine.

SerioussideeffectscanhappeninpeopletakingJANUET,including:

1.LacticAcidosis.Metformin,oneofthemedicinesinJANUET,cancauseararebut

seriousconditioncalledlacticacidosis(abuild-upoflacticacidintheblood)thatcan

StoptakingJANUETandcallyourdoctorrightawayifyougetanyofthefollowing

symptoms,whichcouldbesignsoflacticacidosis:

Youfeelveryweakortired.

Youhaveunusual(notnormal)musclepain.

Youhavetroublebreathing.

Youhaveunusualsleepinessorsleeplongerthanusual.

Youhavesuddenstomachorintestinalproblemswithnauseaandvomitingor

diarrhea.

Youfeelcold,especiallyinyourarmsandlegs.

Youfeeldizzyorlightheaded.

Youhaveasloworirregularheartbeat.

Youhaveahigherchanceofgettinglacticacidosisifyou:

Havekidneyproblems.Peoplewhosekidneysarenotworkingproperlyshould

nottakeJANUET.

Haveliverproblems.

Havecongestiveheartfailurethatrequirestreatmentwithmedicines.

Drinkalcoholveryoften,ordrinkalotofalcoholinshort-term“binge”drinking.

Getdehydrated(losealargeamountofbodyfluids).Thiscanhappenifyouare

sickwithafever,vomiting,ordiarrhea.Dehydrationcanalsohappenwhenyou

sweatalotwithactivityorexerciseanddonotdrinkenoughfluids.

Havecertainx-raytestswithdyesorcontrastagentsthatareinjectedintoyourbody.

Havesurgery.

Haveaheartattack,severeinfection,orstroke.

Are80yearsofageorolderandhavenothadyourkidneystested.

2.Pancreatitis(inflammationofthepancreas)whichmaybesevereandleadtodeath.

Certainmedicalproblemsmakeyoumorelikelytogetpancreatitis.

BeforeyoustarttakingJANUET,tellyourdoctorifyouhaveeverhadpancreatitis,

stonesinyourgallbladder(gallstones),ahistoryofalcoholism,orhighblood

triglyceridelevels.

StoptakingJANUETandcallyourdoctorrightawayifyouhavepaininyourstomach

area(abdomen)thatissevereandwillnotgoaway.Thepainmaybefeltgoingfrom

yourabdomenthroughtoyourback.Thepainmayhappenwithorwithoutvomiting.

Thesemaybesymptomsofpancreatitis.

3.Lowbloodsugar(hypoglycemia).IfyoutakeJANUETwithanothermedicinethat

cancauselowbloodsugar,suchassulfonylureasorinsulin,yourriskofgettinglow

bloodsugarishigher.Yourdoctormayprescribelowerdosesofthesulfonylureaor

insulin.Tellyourdoctorifyouarehavingproblemswithlowbloodsugar.

Signsandsymptomsoflowbloodsugarmayinclude:headache,drowsiness,weakness,

dizziness,confusion,irritability,hunger,fastheartbeat,sweating,feelingjittery.

4.SeriousallergicreactionscanhappenwithJANUETorsitagliptin,oneofthe

medicinesinJANUET.Symptomsofaseriousallergicreactionmayincluderash,hives,

andswellingoftheface,lips,tongue,andthroat,difficultyinbreathingorswallowing.

Ifyouhaveanallergicreaction,stoptakingJANUETandcallyourdoctorrightaway.

Yourdoctormayprescribeamedicationtotreatyourallergicreactionandadifferent

medicationforyourdiabetes.

CommonsideeffectswhentakingJANUETinclude:

Stuffyorrunnynoseandsorethroat.

Upperrespiratoryinfection.

Diarrhea.

Nauseaandvomiting.

Gas,stomachdiscomfort,indigestion.

Weakness.

Headache.

TakingJANUETwithmealscanhelpreducethecommonstomachsideeffectsof

metforminthatusuallyoccuratthebeginningoftreatment.Ifyouhaveunusualor

unexpectedstomachproblems,talkwithyourdoctor.Stomachproblemsthatstart

uplaterduringtreatmentmaybeasignofsomethingmoreserious.

JANUETmayhaveothersideeffects,including:

SwellingofthehandsandlegscanhappenifyoutakeJANUETincombination

withAvandia®,anothertypeofdiabetesmedicine.

Elevatedliverenzymes.

Kidneyproblems(sometimesrequiringdialysis).

Intheeventthatyouexperiencesideeffectsnotmentionedinthisleaflet,orside

effectsthatbotheryouorthatdonotgoaway,orifthereisachangeinyourgeneral

health,consultyourdoctorimmediately.

ADMINISTRATIONANDDOSAGE:

Dosageisaccordingtodoctor'sinstructionsonly.

YourdoctorwilltellyouhowmanyJANUETtabletstotakeandhowoftenyoushould

takethem.

TakeJANUETexactlyasyourdoctortellsyou.

TakeJANUETwithmealstoloweryourchanceofanupsetstomach.

Yourdoctormayneedtoincreaseyourdosetocontrolyourbloodsugar.

YourdoctormayprescribeJANUETalongwithasulfonylurea(anothermedicineto

lowerbloodsugar).See“SIDEEFFECTS”forinformationaboutincreasedriskoflow

bloodsugar.

ContinuetotakeJANUETaslongasyourdoctortellsyou.

Monitoryourbloodsugarasyourdoctortellsyouto.

StayonyourprescribeddietandexerciseprogramwhiletakingJANUET.

Talktoyourdoctorabouthowtoprevent,recognizeandmanagelowbloodsugar

(hypoglycemia),highbloodsugar(hyperglycemia),andcomplicationsofdiabetes.

Yourdoctorwillmonitoryourdiabeteswithregularbloodtests,includingyourblood

sugarlevelsandyourhemoglobinA1C.

Yourdoctorwilldobloodteststocheckyourkidneyfunctionbeforeandduring

treatmentwithJANUET.

IfyoutaketoomuchJANUET,callyourdoctorrightaway.

Ifyoumissadose,takeitwithfoodassoonasyouremember.Ifyoudonotremember

untilitistimeforyournextdose,skipthemisseddoseandgobacktoyourregular

schedule.DonottaketwodosesofJANUETatthesametime.

Thismedicineisnotintendedforadministrationtochildrenunder18yearsofage.

DIRECTIONSfORUSE:

Swallowthemedicinewithasmallamountofwater.

Thismedicineshouldbetakenwithfood.

HOWCANYOUCONTRIBUTETOTHESUCCESSOfTHETREATMENT?

Completethefullcourseoftreatmentasinstructedbythedoctor.

Evenifthereisanimprovementinyourhealth,donotdiscontinueuseofthismedicine,

withoutconsultingyourdoctor.

AVOIDPOISONING!

Thismedicine,asallothermedicine,mustbestoredinasafeplaceoutofthereach

ofchildrenand/orinfants,inordertoavoidpoisoning.

Ifyouhavetakenanoverdose,orifachildhasaccidentallyswallowedthemedicine,

proceedimmediatelytoahospitalemergencyroomandbringthepackageofthe

medicinewithyou.

Donotinducevomitingunless explicitly instructed to do so by a doctor!

This medicine has been prescribed for the treatment of your ailment; in another

patient it may cause harm.Do not give this medicine to your relatives, neighbors

or acquaintances.

Donottakemedicinesinthedark!Check the label and the doseeachtimeyou take

your medicine.Wear glasses if you need them.

STORAGE:

Store JANUET at room temperature.

Even if kept in their original container and stored as recommended, medicines may

be kept for a limited period only. Please note the expiry date of the medicine! In case

of doubt, consult the pharmacist who dispensed the medicine to you.

Do not store different medications in the same package.

Drug Registration Number:

JANUET 50 mg/500 mg: 139.89.31706.00/11

JANUET 50 mg/850 mg: 139.90.31902.00/11

JANUET 50 mg/1000 mg:139.88.31705.00/11

Manufacturer:Merck Sharp & Dohme Corp.,Whitehouse Station, New-Jersey, USA

License Holder:Merck Sharp & Dohme (Israel-1996)Company Ltd., P.O. Box 7121,

ضامُحللةيلاتلاضارعلأاىدحإتروطدقتنكاذإاًروفكبيبطىلإي/ثدحتوتيوناجذخانعي/فقوت

:)lacticacidosis(يِكيتْكلالا

.ة/قهرمواًدجة/فيعضكنابني/رعشت

.(ةيعيبطريغ)تلاضعلايفةيدايتعاريغملاآكيدلتدجواذإ

.سفنتلايفتابوعصكيدلتدجواذإ

.داتعملانمرثكأةليوطةرتفلني/مانتتنكاذإوأ,طرفمساعنبني/رعشتتنكاذإ

.لاهسإوأتاؤيقتونايثغبةبوحصملاةئجافمةيوعملكاشموأنطبلايفةئجافمملاآكيدلتدجواذإ

.لجرلأاو(نيعارذلا)يديلأابةصاخ,دربلابني/رعشتتنكاذإ

.ة/خئادوأراودلابني/رعشتتنكاذإ

.يدايتعاريغوأئيطببلقمظنكيدلدجواذإ

:تنكاذإ)lacticacidosis(ّيِكيتْكلالاضامُحلاريوطتلربكالامتحاكيدلنوكي

.تيوناجلوانتميلسلكشبمهيدلىلكلالمعتلانيذلاىضرملاىلعزوجيلا.ىلكلابلكاشمنمن/يناعت

.دبكلايفلكاشمنمن/يناعت

.ءاودلاباًجلاعبلطتييذلايِناقِتْحلاابْلَقلالَشَفن/يناعت

.ةريصقةينمزةرتفللاخلوحكلانمةريبكةيمكني/برشتوأاًدجةبراقتمنايحأيفلوحكلاني/برشت

تاؤيقت,ةنوخسعمة/اضيرمتنكاذإكلذلصحيدق.(مسجلالئاوسنمريثكلاتدقف)فافجلانمن/يناعت

ني/برشتملوةيندبةيلاعفوأةيدايتعاةيلاعفللاخني/قرعتتتنكاذإاًضيأفافجلالوصحنكمي.لاهسإوأ

.ةيفاكلئاوس

.كمسجلخادبنقحتيتلانيابتداوموأغابصةدامعمةعشأتاصوحفن/يرجت

.ةيحارجةيلمعءارجإددصب

.ةتكسوأديدشثولت,ةيبلقةتكسنمن/يناعت

.ىلكلاةفيظولصوحفيرجتملوقوفاموةنس۸۰رمعب

.توملاىلإيدؤيواًميخونوكيدقيذلا سايِركنَبلاُباهِتْلا

.سايِركنَبلاباهِتْلابةباصلإلهضرعرثكأكلعجتةنيعمةيبطلكاشم

ةرارملايفةاصح,سايِركنَبلاباهِتْلانميضاملايفتيناعاذإكبيبطي/غلبأ,تيوناجبجلاعلاءدبلبق

.مدلايفديرسيلغلايِثَلاُثنمةيلاعتايوتسموألوحكلاىلعنامدلإانمةيضرم ُقِباَوَس,(ةَّيِوارْفَصةاصَح)

.نطبلاةقطنميفيضقنيلاوديدشملأكيدلناكاذإروفلاىلعكبيبطبي/لصتاوتيوناجلوانتنعي/فقوت

ضارعأهذهنوكتدق.ؤيقتنودوأعممللأارهظيدق.رهظلاىتحنطبلانملقتنيمللأابني/رعشتنألمتحُي

.سايِركنَبلاباهِتْلا

ركسصقنيفببستلااهنكمييتلاىرخأةيودأعمتيوناجني/لوانتتتنكاذإ. )ايميكلجوبيه(مَّدلاِرَّكُسُصْقَن

نأنكمملانم.ىلعأنوكتمدلاركسصقنىلإكضرعتةروطخف,نيلوسنيلااوأايروألينوفلوسلالثم,مدلا

كيدلتناكاذإكبيبطي/غلبأ.نيلوسنلااوأايروألينوفلوسعوننمكئاودنملقأتاعرجكبيبطكللجسي

.مدلاركسصقننملكاشم

بلقتاضبن,عوج,ةيبصع,كابترا,راود,نهو,ساعن,عادُص:مدلاركسصقنضارعأوتاراشإلمشتدق

.رتوتلابروعش,قرعت,ةعيرس

.تيوناجبةدوجوملاةيودلأاىدحإ,نﻴﺘﭙﻴلﺠاﺘﻴﺴوأتيوناجعمثودحلااهنكمي ةميخوةّيِجَرَأتلاعافت

,قلحلاوناسللا,نيتفشلا,هجولايفمروتو,ةكح,يدلجحفطلمشتنأنكميةميخوةيجرأةرهاظلضارعأ

ىلإي/ثدحتوتيوناجلوانتنعي/فقوت ,ّيِجَرَألعفدرنمن/يناعتتنكاذإ.علبلاوأسفنتلايفةبوعص

.كيدليركسلاضرملرخآءاودو,كيدلةّيساسحلاجلاعلءاودبيبطلاكلفصينألمتحي.اًروفكبيبط

:لمشت تيوناج لوانت ءانثأ ةرشتنم ةيبناجضارعأ

قلحلاملاآوفنلأانلايسوأدادسنا

يولعلايسفنتلازاهجلايفباهتلا

لاهسإ

تاؤيقتونايثغ

مضهلايفلكاشم,ةدعملايفكعوت,تازاغ

نهو

عادُص

ثدحتيتلا,نيمروفتيملةرشتنملانطبلايفةيبناجلاضارعلأاليلقتبةدعاسملاهنكميماعطلاعمتيوناجلوانت

عمي/ملكت,نطبلايفةعقوتمريغوأةيدايتعاريغةيبناجضارعأنمن/يناعتتنكاذإ.جلاعلاةيادبيفةداع

.ةيدجرثكأءيشىلإةراشإنوكتدقجلاعلانمةرخأتمةلحرميفأدبتيتلانطبلايفلكاشملا.كبيبط

:لمشت,ىرخأةيبناجضارعأتيوناجلنوكتدق

يركسللرخآءاودعم(ةيوس)ةفيلوتبتيوناجني/لوانتتتنكاذإثودحلااهنكميلجرلأاويديلأايفمروت

.ايدناﭭأمساب

.دبكلاتاميزنإبعافترا

.(ازيلايدلابلطتتانايحا)ىلكلابلكاشم

وأةقياضملاكلببستيتلاةيبناجضارعأوأ,ةرشنلاهذهيفركذتملةيبناجضارعأبني/رعشتتنكولاحيف

.اًروفبيبطلاةراشتساكيلع,ماعلاكروعشىلعرييغتأرطاذإوأ,يضقنتلااهنأ

:ةعرجلاوءاودلاءاطعإ

.طقفبيبطلاتاميلعتبسحةعرجلا

.هلوانتكيلعرتاوتيأبوي/لوانتتنأكيلعتيوناجنماصرقمككبيبطكللوقيفوس

.هلوانتببيبطلاكيلإراشأامكاًمامتتيوناجلوانتبجي

.يمضهلازاهجلايفتابارطضانمةاناعملانمكيدللامتحلاانمليلقتلاةيغبماعطلاعمتيوناجلوانتبجي

.كيدلمدلايفركسلاتايوتسمىلعةرطيسللكلذوةعرجلاةدايزىلإبيبطلاجاتحيدق

ةرقفي/رظنأ.(مدلايفركسلاضفخلرخآءاود)ايروألينوفلوسعمةفيلوتبتيوناجكبيبطكلفصيدق

.مدلايفركسلاتايوتسمضافخنلادئازرطخ لامتحا لوحتامولعمىلعلوصحلل"ةيبناجلاضارعلأا"

.اذهلعفبيبطلاكللوقياملاطتيوناجلوانتي/لصاو

.بيبطلاكيلإراشأامككيدلمدلايفركسلاتايوتسمي/دصرأ

.تيوناجلوانتءانثأةيندبلاةيلاعفلاجمانربوكلةفوصوملاةيمحلاي/لصاو

,(ايميكلغوبيه)مدلايفركسلانمةضفخنمتايوتسمجلاعوصيخشت,يدافتةيفيكلوحكبيبطعمي/ثدحت

.يركسلا تافعاضمو ,)ايميكلجربيه)مدلايفركسلانمةعفترمتايوتسم

مدلايفركسلاىوتسمكلذيفامب,ةينيتورةيومدتاصوحفقيرطنعكيدلركسلاةبسندصربكبيبطموقيس

.A1Cنيبولغوميهلاو

.هللاخوتيوناجبجلاعلالبقكيدلىلكلاةفيظوصحفلكلذومدتاصوحفكبيبطكليرجيفوس

ةبجولالوانتتقونيحىتحي/ركذتتملاذإ.كركذتروفماعطلاعمةعرجلاي/لوانت,ةعرجلوانتتيسناذإ

نيتعرجلوانتزوجيلا.يداعلاةعرجلالوانتنمزلودجىلإي/دعوتيسُنيتلاةعرجلاي/ىطخت,ةيلاتلا

!تقولاتاذبتيوناجنم

.اماع۱۸نوداملافطلألىطعُيلصصخمريغءاودلااذه

:لامعتسلااةيفيك

.ءاملانمليلقلاعمءاودلاعلببجي

.ماعطلاعمءاودلالوانتبجي

؟جلاعلاحاجنيفةمهاسملاكنكميفيك

.بيبطلاهبىصوأامكجلاعلالامكإكيلع

.ةيحصلاكتلاحىلعنسحتأرطولوىتحبيبطلاةراشتسانودبءاودلااذهبجلاعلانعفقوتلازوجيلا

!ممستلاي/بنجت

.ممستلاني/عنمتكلذبو,عضرلاوأ/ولافطلأايديأنعاًديعبقلغمناكميفرخآءاودلكوءاودلااذهظفحبجي

ئراوطلاةفرغىلإهجوتلاكيلع,ءاودلااذهنمأطخلابلفطلاعلباذإوأةيئاودلاةعرجلالوانتيفتطرفأاذإ

.كعمءاودلاةوبعة/ابحطصملااحىفشتسملايف

!بيبطلانمةحيرصتاميلعتنودؤيقتلايفببستلازوجيلا

كناريج,كبراقأىلإءاودلااذهي/طعتلا.رخآضيرملررضلاببسيدقو؛كضرمجلاعلفصوءاودلااذه

.كفراعموأ

/لوانتتةرملكيفةيئاودلاةعرجلاوءاودلاىلعدوجوملاقصلملانمي/ققحت!ملاظلايفةيودلأالوانتزوجيلا

.ءاودلااهيفني

.كلذرملأامزلاذإةيبطلاتاراظنلاعضوبجي

:نيزختلا

.ةفرغلاةرارحةجردبتيوناجنيزختبجي

.اهبىصوملانيزختلا/بيلعتلافورظيفىتح,طقفةدودحمتارتفلةحلاصةيودلأاىقبت

اذهكلفرصيذلايلديصلاةراشتساكيلع,كشةلاح ِّيأيف!رضحتسملاةّيحلاصءاهتنإخيراتلهابتنلااىجري

.ءاودلا

.ةوبعلاسفنيفةفلتخمةيودأنيزختزوجيلا

:ءاودلاليجستمقر

۱۳۹.۸۹.۳۱٧۰٦.۰۰/۱۱ :غلم٥۰۰/غلم٥۰تيوناج

۱۳۹.۹۰.۳۱۹۰۲.۰۰/۱۱ :غلم۸٥۰/غلم٥۰تيوناج

۱۳۹.۸۸.۳۱٧۰٥.۰۰/۱۱ :غلم۱۰۰۰/غلم٥۰تيوناج

ةدحتملاتايلاولا,يسريجوين,نشيتسسواهتياو,پروكمودوپراشكريم :جتنملا

70018463/00-4 6747, 6748, 6749

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

JANUET safelyand effectively.See full prescribing information for JANUET.

JANUET™ (sitagliptin/metformin HCl) tablets

WARNING: LACTIC ACIDOSIS

See full prescribing information for complete boxed warning.

Lactic acidosis can occur due to metformin accumulation. The risk increases with conditionssuchassepsis,

dehydration, excess alcohol intake, hepatic insufficiency,renal impairment, and acute congestive heart failure.

(5.1)

Symptoms include malaise, myalgias, respiratorydistress, increasing somnolence, and nonspecific abdominal

distress. Laboratoryabnormalities include lowpH, increased anion gap and elevated blood lactate. (5.1)

If acidosis is suspected, discontinue JANUET and hospitalize the patient immediately.(5.1)

---------------------------RECENT MAJOR CHANGES---------------------------

Indications and Usage (1) 04/2010

Dosage and Administration

Recommended Dosing (2.1) 04/2010

Warnings and Precautions

Pancreatitis (5.2) 04/2010

Use with Medications Known toCause Hypoglycemia (5.9)04/2010

----------------------------INDICATIONS AND USAGE----------------------------

JANUET is a dipeptidylpeptidase-4 (DPP-4) inhibitor and biguanide combination productindicatedas an adjunct to diet

and exercise to improve glycemic controlinadultpatientswithtype 2 diabetes mellitus when treatment with both sitagliptin

and metformin is appropriate. (1)

Important Limitations of Use:

JANUET should not be used in patients with type 1 diabetesor for the treatment of diabetic ketoacidosis. (1)

JANUET has not been studied in patients witha historyof pancreatitis. (1), 5.2).

-----------------------DOSAGE AND ADMINISTRATION------------------------

Individualize the starting dose of JANUET based on the patient’s current regimen. (2.1)

Mayadjust the dosing based on effectiveness andtolerabilitywhile not exceeding the maximum recommended daily

dose of 100 mg sitagliptin and 2000 mg metformin. (2.1)

JANUET should be given twice dailywithmeals,withgradualdose escalation, to reduce the gastrointestinal (GI) side

effects due to metformin. (2.1)

---------------------DOSAGE FORMS AND STRENGTHS---------------------

Tablets: 50 mg sitagliptin/500 mg metformin HCl and, 50 mg sitagliptin/850 mg metformin HCl and 50 mg

sitagliptin/1000 mg metformin HCl (3)

-------------------------------CONTRAINDICATIONS-------------------------------

Renal dysfunction, e.g., serum creatinine≥1.5 mg/dL [males],≥1.4 mg/dL [females] or abnormal creatinine clearance.

(4, 5.1, 5.4)

Acute or chronic metabolic acidosis, including diabetic ketoacidosis,with or without coma. (4, 5.1)

Historyof a serious hypersensitivityreaction to JANUET or sitagliptin (oneofthecomponents of JANUET), such as

anaphylaxis or angioedema. (5.14, 6.2)

Temporarilydiscontinue JANUET in patients undergoing radiologic studies involving intravascularadministrationof

iodinated contrast materials. (4, 5.1, 5.11)

------------------------WARNINGS AND PRECAUTIONS------------------------

Do not use JANUET in patients with hepatic disease. (5.1, 5.3)

Before initiating JANUET and at least annuallythereafter, assess renal function and verifyas normal. (4, 5.1, 5.4, 5.10)

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing

pancreatitis. If pancreatitis is suspected, promptlydiscontinue JANUET. (5.2)

Measure hematologic parameters annually. (5.5, 6.1)

Warn patients against excessive alcohol intake. (5.1, 5.6)

Mayneed to discontinue JANUET and temporarilyuse insulinduring periods of stress and decreased intake of fluids

and food as mayoccur with fever, trauma, infection or surgery.(5.7, 5.8, 5.12, 5.13)

Promptlyevaluate patients previouslycontrolled on JANUET who develop laboratoryabnormalities or clinical illness for

evidence of ketoacidosis or lacticacidosis. (5.1, 5.8, 5.12, 5.13)

When used with an insulin secretagogue (e.g., sulfonylurea) orwithinsulin, a lower dose of the insulin secretagogue or

insulin maybe required to reduce the risk of hypoglycemia. (2.1, 5.9)

There have been postmarketing reports of serious allergicand hypersensitivityreactions in patients treatedwith

sitagliptin (one of the components of JANUET), suchas anaphylaxis, angioedema,andexfoliative skin conditions

including Stevens-Johnson syndrome. In such cases, promptlystop JANUET, assess for other potential causes,

institute appropriate monitoring and treatment, and initiatealternative treatment for diabetes. (5.14, 6.2)

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

anyother anti-diabetic drug. (5.15)

------------------------------ADVERSE REACTIONS-------------------------------

The most common adverse reactions reportedin≥5% of patients simultaneouslystarted on sitagliptin and metformin

and more commonlythan in patients treatedwithplacebowere diarrhea, upper respiratorytract infection, and

headache. (6.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING – LACTIC ACIDOSIS

1INDICATIONS AND USAGE

2DOSAGE AND ADMINISTRATION

2.1Recommended Dosing

3DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

5.2 Pancreatitis

5.3 Impaired Hepatic Function

5.4 Assessment of Renal Function

5.5 Vitamin B

Levels

5.6 Alcohol Intake

5.7 Surgical Procedures

5.8Changein Clinical Status of Patients with Previously

Controlled Type 2 Diabetes

5.9 Use with Medications Known to Cause Hypoglycemia

5.10 ConcomitantMedicationsAffecting Renal Functionor

Metformin Disposition

5.11RadiologicStudieswith Intravascular Iodinated Contrast

Materials

5.12 Hypoxic States

5.13Loss of Control of Blood Glucose

5.14 Hypersensitivity Reactions

5.15 Macrovascular Outcomes

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

7.1 Cationic Drugs

7.2 Digoxin

7.3 Glyburide

7.4 Furosemide

7.5 Nifedipine

7.6 The Use of Metformin with Other Drugs

8USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICALPHARMACOLOGY

12.1Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICALTOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICALSTUDIES

16HOW SUPPLIED/STORAGE AND HANDLING

17PATIENT COUNSELING INFORMATION

17.1 Instructions

17.2 Laboratory Tests

*Sections or subsectionsomitted from the full prescribing information

are not listed.

FULL PRESCRIBING INFORMATION

WARNING: LACTIC ACIDOSIS

Lactic acidosis is a rare, but serious complication that can occur due tometformin

accumulation. The risk increases with conditionssuch as sepsis, dehydration, excess alcohol

intake, hepatic insufficiency, renal impairment, and acute congestive heart failure.

The onset is often subtle, accompanied onlybynonspecific symptoms suchasmalaise,

myalgias, respiratorydistress, increasing somnolence, and nonspecific abdominal distress.

Laboratoryabnormalities include lowpH, increased anion gap and elevated blood lactate.

If acidosis is suspected, JANUET 1 should be discontinued andthepatienthospitalized

immediately.[See Warnings and Precautions (5.1).]

1 INDICATIONS AND USAGE

JANUET is indicated as an adjunct to diet and exerciseto improve glycemic control in adult patients with

type 2 diabetes mellitus when treatment withboth sitagliptin and metformin is appropriate.[See Clinical

Studies (14).]

Important limitations of use:

JANUET should not be used in patientswith type 1 diabetes or for the treatment of diabetic ketoacidosis,

as it would not be effective in these settings.

JANUEThasnotbeenstudiedinpatients with a history of pancreatitis. It is unknown whether patients with

a history of pancreatitis are at increased risk for the development of pancreatitiswhileusingJANUET. [See

Warnings and Precautions (5.2).]

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

Thedosage of JANUET should be individualized on thebasis of the patient’s current regimen,

effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100mg

sitagliptin and 2000mg metformin. Initial combination therapy or maintenanceof combination therapy

should be individualized and left to the discretion of the health care provider.

JANUET should generally be given twice dailywithmeals, with gradual dose escalation, to reduce the

gastrointestinal (GI) side effects due to metformin.

The starting dose of JANUET should be based on thepatient’s current regimen. JANUET should be

given twice daily with meals. The following doses are available:

50 mg sitagliptin/500 mg metformin hydrochloride

50 mg sitagliptin/850 mg metformin hydrochloride

50 mg sitagliptin/1000 mg metformin hydrochloride.

The recommended starting dose in patients not currently treated with metformin is 50mg

sitagliptin/500mg metformin hydrochloride twicedaily,withgradual dose escalation recommended to

reduce gastrointestinal side effects associated with metformin.

The starting dose in patients alreadytreatedwithmetformin should provide sitagliptin dosed as 50mg

twice daily (100 mg total daily dose) and the dose of metformin already being taken.

Patients treated with an insulin secretagogue or insulin

Co-administration of JANUET with an insulin secretagogue (e.g., sulfonylurea) or insulinmayrequire

lowerdoses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia[see Warnings and

Precautions (5.9)].

No studies have been performed specifically examining the safety and efficacyof JANUET inpatients

previously treated with other oral antihyperglycemic agents and switched to JANUET. Any change in

therapy of type 2 diabetes should be undertaken withcare and appropriate monitoring as changes in

glycemic control can occur.

3 DOSAGE FORMS AND STRENGTHS

50mg/500mg tablets are light pink, capsule-shaped, film-coated tablets with “575”debossed

on one side.

50mg/850mg tablets are pink, capsule-shaped, film-coated tablets with “515” debossedon

one side.

50mg/1000mgtablets are red, capsule-shaped,film-coated tablets with “577” debossed on

one side.

4 CONTRAINDICATIONS

JANUET (sitagliptin/metformin HCl) iscontraindicated in patients with:

Renal disease or renal dysfunction, e.g., as suggested by serum creatininelevels≥1.5 mg/dL

[males],≥1.4mg/dL[females]or abnormal creatinine clearance which may also result from

conditions such as cardiovascular collapse (shock), acute myocardial infarction,andsepticemia

[see Warnings and Precautions (5.1)] .

Acute or chronic metabolic acidosis, includingdiabetic ketoacidosis, with or without coma.

History of a serious hypersensitivity reaction toJANUET or sitagliptin(one of thecomponentsof

JANUET), such as anaphylaxis or angioedema.[See Warnings and Precautions (5.14); Adverse

Reactions (6.2).]

JANUET should be temporarily discontinued in patients undergoing radiologic studiesinvolving

intravascular administration of iodinated contrastmaterials, because use of such products may result in

acute alteration of renal function[see Warnings and Precautions (5.11)].

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

Metformin hydrochloride

Lactic acidosis is a rare, but serious, metaboliccomplication that can occur due to metformin

accumulation during treatment with JANUET; when it occurs,itis fatal in approximately 50% of cases.

Lactic acidosis may also occur in associationwith a number ofpathophysiologicconditions,including

diabetes mellitus, and whenever there is significanttissue hypoperfusion and hypoxemia.Lacticacidosis

is characterized by elevated blood lactate levels (>5mmol/L), decreased blood pH,electrolyte

disturbances with an increased anion gap, and an increasedlactate/pyruvateratio. When metformin is

implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is verylow

(approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years).

In more than 20,000 patient-years exposure to metformin inclinical trials, therewere no reports of lactic

acidosis. Reported cases have occurred primarily in diabetic patients with significant renalinsufficiency,

including both intrinsic renal disease and renal hypoperfusion, often in the setting ofmultipleconcomitant

medical/surgical problems and multiple concomitantmedications. Patients with congestive heart failure

requiring pharmacologic management, in particular thosewithunstable or acute congestive heart failure

who are at risk ofhypoperfusionandhypoxemia, are at increased risk of lactic acidosis. The risk of lactic

acidosisincreases with the degree of renal dysfunction and the patient's age. Therisk of lactic acidosis

may, therefore, besignificantlydecreased by regular monitoring ofrenal function in patients taking

metformin and by use of theminimumeffectivedoseofmetformin. In particular, treatment of the elderly

should be accompanied by careful monitoring of renal function. Metformin treatment shouldnotbe

initiated in patients≥80 years of age unless measurement of creatinine clearance demonstrates that renal

function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition,

metformin should be promptly withheld in the presenceof any condition associated with hypoxemia,

dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear

lactate, metformin should generally be avoided in patients with clinical or laboratory evidence ofhepatic

disease. Patients should becautionedagainstexcessivealcohol intake, either acute or chronic, when

taking metformin, since alcohol potentiates theeffectsof metformin hydrochloride on lactate metabolism.

In addition, metformin should be temporarily discontinuedprior to any intravascular radiocontrast study

and for any surgical procedure[see Warnings and Precautions (5.4, 5.6, 5.7, 5.11)].

The onset of lactic acidosis often is subtle, and accompanied only bynonspecific symptoms suchas

malaise, myalgias, respiratorydistress,increasing somnolence, and nonspecific abdominal distress.

There may be associated hypothermia,hypotension, and resistant bradyarrhythmias with more marked

acidosis. The patient and the patient's physician must be aware ofthe possible importance of such

symptomsandthepatient should be instructed tonotify the physician immediately if they occur[see

Warningsand Precautions (5.12)] . Metformin should be withdrawn until the situation is clarified. Serum

electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin

levels may be useful. Once a patientisstabilized on any dose level of metformin, gastrointestinal

symptoms, which are common during initiation oftherapy,areunlikelyto be drug related. Later

occurrence of gastrointestinal symptoms could be dueto lactic acidosis orother serious disease.

Levels of fasting venous plasmalactate above the upperlimitofnormal but less than 5mmol/L in

patients taking metformin do not necessarily indicateimpendinglactic acidosis and may be explainable

byothermechanisms,such as poorly controlled diabetes or obesity, vigorous physical activity, or

technical problems in sample handling[see Warnings and Precautions (5.8, 5.13)].

Lactic acidosis should be suspected in any diabetic patientwithmetabolic acidosis lacking evidence of

ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that mustbe treated in a hospital setting. In apatientwith

lactic acidosis who is taking metformin,the drug should be discontinued immediately and general

supportivemeasures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance

of up to 170mL/min under good hemodynamicconditions), prompt hemodialysis is recommended to

correct the acidosis and remove the accumulated metformin. Such management oftenresultsinprompt

reversal of symptoms and recovery[see Contraindications (4); Warnings and Precautions (5.6,5.7,5.10,

5.11, 5.12)] .

5.2 Pancreatitis

There have been postmarketing reports of acutepancreatitis, including fatal and non-fatal hemorrhagic or

necrotizingpancreatitis,inpatients taking JANUET. After initiation of JANUET, patients should be observed

carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUET shouldpromptlybe

discontinued and appropriate management should be initiated. It is unknown whether patientswithahistoryof

pancreatitis are at increased risk for the development of pancreatitis while using JANUET.

5.3 Impaired Hepatic Function

Since impaired hepatic function has been associated withsome cases of lactic acidosis, JANUET

should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

5.4 Assessment of Renal Function

Metformin and sitagliptin are known to be substantially excreted by thekidney. The risk of metformin

accumulationand lactic acidosis increases with thedegree of impairment of renalfunction. Thus, patients

with serum creatinine levels above the upper limit ofnormal for their age should not receive JANUET. In

the elderly, JANUET should becarefullytitratedtoestablish the minimum dose for adequate glycemic

effect, because aging can be associated with reduced renalfunction.[SeeWarnings and Precautions

(5.1) and Use in Specific Populations (8.5).]

Beforeinitiation of therapy with JANUET and atleast annually thereafter, renal function should be

assessedandverified as normal. In patients in whomdevelopment of renal dysfunction is anticipated,

particularly in elderly patients, renal functionshouldbeassessed more frequently and JANUET

discontinued if evidence of renal impairment is present.

5.5 Vitamin B

12 Levels

In controlled clinical trials of metformin of 29weeks duration, a decrease tosubnormallevelsof

previously normal serumVitaminB

levels, without clinical manifestations, was observed in

approximately 7% of patients. Such decrease, possibly due to interference with B

absorption from the

-intrinsic factor complex, is, however, very rarely associated with anemia and appears toberapidly

reversible with discontinuation of metformin or VitaminB

supplementation. Measurement of hematologic

parameters on an annual basis is advised in patientsonJANUETand any apparent abnormalities should

be appropriately investigated and managed.[SeeAdverse Reactions (6.1).]

Certain individuals (those with inadequate VitaminB

12 or calcium intake or absorption) appear to be

predisposed to developing subnormal Vitamin B

levels. In these patients,routineserumVitaminB

measurements at two- to three-year intervals may be useful.

5.6 Alcohol Intake

Alcohol is known to potentiate the effectofmetformin on lactate metabolism.Patients, therefore,

should be warned against excessive alcohol intake,acute or chronic, while receiving JANUET.

5.7 Surgical Procedures

Use of JANUET should be temporarily suspendedforany surgical procedure (except minor

procedures not associated with restricted intake offoodandfluids)and should not be restarted until the

patient's oral intake has resumed and renal function has been evaluated as normal.

5.8 Change in Clinical Status of Patientswith PreviouslyControlled Type 2 Diabetes

A patient with type 2diabetespreviouslywell controlled on JANUET who develops laboratory

abnormalitiesor clinical illness (especially vague andpoorly defined illness) should be evaluated promptly

for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones,

blood glucose and, if indicated, bloodpH, lactate, pyruvate, and metforminlevels. If acidosis of either

form occurs, JANUET must be stopped immediately and other appropriate corrective measures initiated.

5.9 Use with Medications Known to Cause Hypoglycemia

Sitagliptin

When sitagliptin was used in combination with a sulfonylurea or with insulin,medicationsknownto

cause hypoglycemia, the incidenceofhypoglycemiawas increased over that of placebo used in

combinationwith a sulfonylurea or with insulin[see Adverse Reactions (6)].Therefore, patients also

receiving an insulin secretagogue (e.g., sulfonylurea) orinsulin may require a lower dose of the insulin

secretagogue or insulin to reduce the risk of hypoglycemia[see Dosage and Administration (2.1)].

Metformin hydrochloride

Hypoglycemia does not occur in patients receiving metforminaloneunderusual circumstances of use,

but could occur when caloric intake is deficient, whenstrenuous exercise is notcompensated by caloric

supplementation, or during concomitant use with other glucose-lowering agents (suchassulfonylureas

and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal orpituitary

insufficiencyor alcohol intoxication are particularlysusceptible to hypoglycemic effects. Hypoglycemia

may be difficult to recognize in the elderly, and in people who are takingβ-adrenergic blocking drugs.

5.10Concomitant Medications Affecting Renal Function or Metformin Disposition

Concomitant medication(s) that may affectrenalfunction or result in significant hemodynamic change

or may interfere with the disposition of metformin,suchascationicdrugs that are eliminated by renal

tubular secretion[see Drug Interactions (7.1)], should be used with caution.

5.11Radiologic Studies with Intravascular Iodinated Contrast Materials

Intravascular contrast studies with iodinated materials (for example, intravenous urogram, intravenous

cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast

materials) can lead to acute alteration of renal functionandhavebeen associated with lactic acidosis in

patients receiving metformin[seeContraindications (4)].Therefore, in patientsinwhom any such study is

planned,JANUET should be temporarilydiscontinued at the time of or prior to the procedure, and

withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-

evaluated and found to be normal.

5.12 Hypoxic States

Cardiovascular collapse (shock) from whatevercause,acute congestive heart failure, acute

myocardial infarction and other conditions characterized by hypoxemia have beenassociated with lactic

acidosis and may also cause prerenalazotemia. When such events occur in patients on JANUET

therapy, the drug should bepromptly discontinued.

5.13Loss of Control of Blood Glucose

When a patient stabilized on any diabetic regimen isexposed to stress such as fever, trauma,

infection, or surgery, a temporarylossofglycemiccontrol mayoccur.Atsuch times,itmaybe necessary

to withhold JANUET and temporarily administer insulin. JANUET may be reinstituted after the acute

episode is resolved.

5.14HypersensitivityReactions

There have been postmarketing reports of serious hypersensitivityreactionsin patients treated with

sitagliptin, one of the components of JANUET. These reactionsinclude anaphylaxis, angioedema,and

exfoliative skin conditionsincludingStevens-Johnsonsyndrome. Because these reactions are reported

voluntarily from a population of uncertain size, itis generally not possible to reliably estimate their

frequency or establish a causal relationship to drug exposure. Onset of thesereactionsoccurredwithin

the first 3 months after initiation oftreatmentwithsitagliptin, with some reports occurring after the first

dose. If a hypersensitivity reactionis suspected, discontinue JANUET, assess forotherpotentialcauses

for the event, and institute alternative treatment for diabetes.[See Adverse Reactions (6.2).]

5.15 Macrovascular Outcomes

Therehavebeen no clinical studies establishing conclusive evidence of macrovascular risk reduction

with JANUET or any other anti-diabetic drug.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widelyvaryingconditions,adverse reaction rates observed

in the clinical trials of a drug cannotbedirectlycompared to rates in the clinical trials of another drug and

may not reflect the rates observed in practice.

Sitagliptin and Metformin Co-administration inPatients with Type 2 Diabetes Inadequately Controlled on

Diet and Exercise

Table 1 summarizes the most common ( ≥5% of patients) adverse reactionsreported (regardless of

investigator assessment of causality)ina24-weekplacebo-controlled factorial study in which sitagliptin

and metformin were co-administeredtopatientswith type 2 diabetes inadequately controlled on diet and

exercise.

Table1:Sitagliptin and Metformin Co-administeredtoPatients withType2 Diabetes

InadequatelyControlled on Dietand Exercise:

Adverse ReactionsReported(Regardless ofInvestigatorAssessment ofCausality)in5%of

Patients ReceivingCombinationTherapy(andGreater thaninPatients ReceivingPlacebo)

Number of Patients (%)

Placebo

Sitagliptin

100 mg QD

Metformin 500 mg/

Metformin 1000 mg bid ††

Sitagliptin

50 mg bid +

Metformin 500 mg/

Metformin 1000 mg bid ††

N = 176 N = 179 N = 364 ††

N = 372 ††

Diarrhea 7 (4.0) 5 (2.8) 28 (7.7) 28 (7.5)

Upper Respiratory

Tract Infection 9 (5.1) 8 (4.5) 19 (5.2) 23 (6.2)

Headache 5 (2.8) 2 (1.1) 14 (3.8) 22 (5.9)

† Intent-to-treat population.

†† Data pooled for the patients given thelower and higher doses of metformin.

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone

Ina24-week placebo-controlled trial of sitagliptin 100mg administered once daily added to a twice

daily metformin regimen, there were no adversereactions reported regardless ofinvestigator assessment

of causality in≥5% of patients and more commonly than inpatients given placebo.Discontinuation of

therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptinand

metformin, 1.9%; placebo and metformin, 2.5%).

Gastrointestinal Adverse Reactions

The incidences of pre-selected gastrointestinal adverseexperiences in patients treated with sitagliptin

and metformin were similar to those reported for patients treated with metformin alone. See Table 2.

Table 2: Pre-selectedGastrointestinalAdverse Reactions(Regardless ofInvestigatorAssessment ofCausality)

ReportedinPatients withType2 Diabetes ReceivingSitagliptinandMetformin

Number of Patients (%)

Studyof Sitagliptin and Metformin in Patients InadequatelyControlled

on Diet and Exercise Studyof Sitagliptin Add-on in

Patients InadequatelyControlled

on Metformin Alone

Placebo

Sitagliptin

100 mg

QD

Metformin 500 mg/

Metformin 1000 mg

bid

Sitagliptin 50 mg bid +

Metformin 500 mg/

Metformin 1000 mg bid

Placebo and

Metformin

1500 mg

daily Sitagliptin 100 mg

QD and Metformin

1500 mg daily

N = 176 N = 179 N = 364 N = 372 N = 237 N = 464

Diarrhea 7 (4.0) 5 (2.8) 28 (7.7) 28 (7.5) 6 (2.5) 11 (2.4)

Nausea 2 (1.1) 2 (1.1) 20 (5.5) 18 (4.8) 2 (0.8) 6 (1.3)

Vomiting 1 (0.6) 0 (0.0) 2 (0.5) 8 (2.2) 2 (0.8) 5 (1.1)

Abdominal

Pain †† 4 (2.3) 6 (3.4) 14 (3.8) 11 (3.0) 9 (3.8) 10 (2.2)

† Data pooled for the patients given thelower and higher doses of metformin.

†† Abdominal discomfort was included in the analysis ofabdominal pain in the studyof initial therapy.

Sitagliptin in Combination with Metformin and Glimepiride

Ina 24-week placebo-controlled study of sitagliptin 100

mg as add-on therapy in patients with type 2

diabetes inadequately controlled on metforminandglimepiride (sitagliptin, N=116; placebo, N=113), the

adverse reactions reported regardless of investigator assessment of causality in ≥5%of patients treated

with sitagliptin and more commonly than in patientstreated with placebo were: hypoglycemia (Table 3)

and headache (6.9%, 2.7%).

Sitagliptin in Combination with Metformin and Rosiglitazone

Inaplacebo-controlled study of sitagliptin 100

mg as add-on therapy in patients with type 2 diabetes

inadequately controlled on metforminandrosiglitazone(sitagliptin, N=181; placebo, N=97), the adverse

reactionsreported regardless of investigatorassessment of causality through Week 18 in ≥5% of patients

treated with sitagliptin and more commonly than inpatients treated with placebo were:upperrespiratory

tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the

adverse reactions reported regardless of investigator assessment of causality in ≥5%of patients treated

with sitagliptin and more commonly than in patients treated with placebo were:upperrespiratorytract

infection (sitagliptin, 15.5%;placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%,

5.2%), and headache (5.5%, 4.1%).

Sitagliptin in Combination with Metformin and Insulin

In a 24-week placebo-controlled study of sitagliptin100mg as add-on therapy in patients with type 2

diabetes inadequately controlled on metformin and insulin(sitagliptin, N=229; placebo, N=233), the only

adverse reaction reported regardless ofinvestigator assessment of causality in ≥5% of patients treated

with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).

Hypoglycemia

Inall (N=5) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic

hypoglycemia;a concurrent glucose measurementwas not required although most (77%) reports of

hypoglycemia were accompanied bya blood glucose measurement≤70mg/dL.When the combination of

sitagliptin and metformin was co-administered witha sulfonylurea or with insulin, the percentageof

patients reporting at least one adversereactionofhypoglycemia was higher than that observed with

placebo and metformin co-administered with asulfonylurea or with insulin (Table 3).

Table3

Incidenceand Rateof Hypoglycemia (Regardless ofInvestigatorAssessment ofCausality)in

Placebo-Controlled ClinicalStudiesof Sitagliptinin Combination with Metformin Co-administered

with Glimepiride or Insulin

Add-On to Glimepiride +

Metformin (24 weeks) Sitagliptin 100 mg

+ Metformin

+ Glimepiride Placebo

+ Metformin

+ Glimepiride

N = 116 N = 113

Overall (%) 19 (16.4) 1 (0.9)

Rate (episodes/patient-year) ‡ 0.82 0.02

Severe (%) § 0 (0.0) 0 (0.0)

Add-On to Insulin

+ Metformin (24 weeks) Sitagliptin 100 mg

+ Metformin

+ Insulin Placebo

+ Metformin

+ Insulin

N = 229 N = 233

Overall (%) 35 (15.3) 19 (8.2)

Rate (episodes/patient-year) ‡ 0.98 0.61

Severe (%) § 1 (0.4) 1 (0.4)

Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose

measurement was not required: Intent to Treat Population.

Based on total number of events (i.e., a single patient mayhave had multiple events).

Severe events of hypoglycemia were defined as those eventsrequiring medical assistance orexhibiting depressed level/loss

of consciousness or seizure.

The overall incidence of reported adverse reactionsof hypoglycemia in patients with type 2diabetes

inadequately controlled on diet and exercise was 0.6% in patients givenplacebo, 0.6% inpatientsgiven

sitagliptinalone, 0.8% in patients given metformin alone, and 1.6% inpatients given sitagliptin in

combination with metformin. In patients with type2diabetesinadequately controlled on metformin alone,

theoverallincidenceof adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin

and 2.1% in patients given add-on placebo.

In the study of sitagliptin and add-on combination therapy with metformin and rosiglitazone,theoverall

incidence of hypoglycemia was 2.2%inpatients given add-on sitagliptin and 0.0% in patients given add-

on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in

patients given add-on sitagliptin and 1.0% in patients given add-on placebo.

With the combination of sitagliptin and metformin, noclinically meaningful changes in vitalsignsorin

ECG (including in QTc interval) were observed.

The most common adverse experience in sitagliptin monotherapy reportedregardless of investigator

assessment of causalityin≥5% of patients and more commonlythan in patients given placebo was

nasopharyngitis.

The most common (>5%) established adverse reactions due to initiation of metformin therapy are

diarrhea, nausea/vomiting, flatulence, abdominaldiscomfort, indigestion, asthenia, and headache.

Laboratory Tests

Sitagliptin

The incidence of laboratoryadversereactionswassimilar in patients treated with sitagliptin and

metformin (7.6%) compared to patients treated withplacebo and metformin (8.7%). In most but notall

studies, a small increase in white blood cell count (approximately200cells/microLdifference in WBC vs

placebo;meanbaseline WBC approximately 6600cells/microL) was observed due to a small increase in

neutrophils. This change in laboratory parameters isnot considered to be clinically relevant.

Metformin hydrochloride

In controlled clinical trials of metformin of 29weeks duration, a decrease tosubnormallevelsof

previously normal serumVitaminB

levels, without clinical manifestations, was observed in

approximately 7% of patients. Such decrease, possibly due to interference with B

absorption from the

-intrinsic factor complex, is, however, very rarely associated with anemia and appears toberapidly

reversiblewithdiscontinuation of metformin or Vitamin B

supplementation.[See Warnings and

Precautions (5.5).]

6.2 Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of JANUET orsitagliptin,

one of the components of JANUET. Thesereactionshavebeen reported when JANUET or sitagliptin

have been used alone and/or in combinationwith other antihyperglycemicagents. Because these

reactions are reported voluntarily fromapopulationofuncertain size, it is generally not possible to reliably

estimate their frequency or establish acausal relationship to drug exposure.

Hypersensitivity reactions including anaphylaxis,angioedema, rash, urticaria, cutaneous vasculitis,

and exfoliative skin conditions including Stevens-Johnson syndrome[see Warnings and Precautions

(5.14)]; upper respiratory tract infection; hepatic enzymeelevations; acute pancreatitis, including fatal and

non-fatal hemorrhagic and necrotizing pancreatitis[see Limitations of Use (1); Warnings and Precautions

(5.2)] ; worsening renal function, including acute renal failure (sometimes requiring dialysis); constipation;

vomiting; headache.

7 DRUG INTERACTIONS

7.1 Cationic Drugs

Cationic drugs (e.g., amiloride, digoxin, morphine,procainamide, quinidine, quinine, ranitidine,

triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have

the potential for interaction with metformin by competing for common renal tubular transport systems.

Such interaction between metformin and oral cimetidinehasbeen observed in normal healthy volunteers

inbothsingle- and multiple-dose metformin-cimetidine drug interaction studies, with a 60% increase in

peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood

metformin AUC. There was no change in eliminationhalf-life in the single-dose study. Metforminhadno

effect on cimetidine pharmacokinetics.Althoughsuchinteractions remain theoretical (except for

cimetidine), careful patient monitoring and dose adjustmentofJANUETand/or the interfering drug is

recommendedin patients who are taking cationic medications that are excretedvia the proximal renal

tubular secretory system.

7.2 Digoxin

There was a slight increase in the areaunder the curve (AUC, 11%) and mean peak drug

concentration (C

, 18%) of digoxin withtheco-administration of 100mg sitagliptin for 10 days. These

increases are not considered likelyto be clinically meaningful. Digoxin, as acationicdrug,hasthe

potential to compete with metformin for common renaltubular transport systems,thus affecting the serum

concentrations of either digoxin,metforminorboth. Patients receiving digoxin should be monitored

appropriately. No dosage adjustment of digoxin or JANUET is recommended.

7.3 Glyburide

Inasingle-dose interaction study in type 2 diabetes patients, co-administration of metformin and

glyburide did not result in anychangesineither metformin pharmacokinetics or pharmacodynamics.

Decreases in glyburide AUC and C

were observed, but were highlyvariable. The single-dose natureof

this study and the lack of correlationbetweenglyburide blood levels and pharmacodynamic effects make

the clinical significance ofthisinteraction uncertain.

7.4 Furosemide

A single-dose, metformin-furosemide drug interactionstudy in healthy subjects demonstrated that

pharmacokineticparameters of both compounds wereaffected by co-administration. Furosemide

increased the metformin plasma and bloodC

by 22% and blood AUC by 15%, without any significant

change in metformin renal clearance. When administered with metformin, the C

and AUCof

furosemide were 31% and 12% smaller, respectively, than when administered alone, andtheterminal

half-life was decreased by 32%, without any significant change infurosemide renal clearance.No

information is available about the interactionofmetforminand furosemide when co-administered

chronically.

7.5 Nifedipine

A single-dose, metformin-nifedipine drug interaction study in normalhealthyvolunteersdemonstrated

that co-administration of nifedipine increasedplasmametforminC

and AUC by 20% and 9%,

respectively, and increased the amount excreted in theurine.T

and half-life were unaffected.

Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

7.6 The Use of Metformin with Other Drugs

Certaindrugstendto produce hyperglycemia and maylead to loss of glycemic control. These drugs

include the thiazides andotherdiuretics,corticosteroids, phenothiazines, thyroid products, estrogens,

oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and

isoniazid. When such drugs are administered to a patient receiving JANUET thepatient should beclosely

observed to maintain adequate glycemic control.

Inhealthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and

ibuprofen were not affected when co-administered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly

protein-bounddrugssuch as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared

to the sulfonylureas, which are extensively bound to serum proteins.

8 USE IN SPECIFICPOPULATIONS

8.1 Pregnancy

Pregnancy Category B:

JANUET

There are no adequate and well-controlled studiesinpregnant women with JANUET or its individual

components; therefore, the safetyof JANUET in pregnant womenisnot known. JANUET should be used

during pregnancy only if clearly needed.

No animal studies have beenconductedwiththecombined products in JANUET to evaluate effects on

reproduction. The following data are based on findings instudiesperformedwith sitagliptin or metformin

individually.

Sitagliptin

Reproductionstudieshave been performed in rats andrabbits. Doses of sitagliptin up to 125mg/kg

(approximately 12 times the human exposure at the maximum recommended human dose) did not impair

fertility or harm the fetus. There are, however,noadequate and well-controlled studies with sitagliptin in

pregnant women.

Sitagliptin administered to pregnant femaleratsand rabbits from gestation day 6 to 20

(organogenesis) was not teratogenic at oral dosesupto250mg/kg(rats) and 125mg/kg (rabbits), or

approximately 30 and 20 times human exposure atthe maximum recommended human dose (MRHD) of

100mg/day based on AUC comparisons. Higher doses increased the incidence ofribmalformationsin

offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.

Sitagliptin administered to female rats fromgestation day 6 to lactation day 21 decreased body

weightinmale and female offspring at 1000mg/kg.No functional or behavioral toxicity was observed in

offspring of rats.

Placental transfer of sitagliptin administered topregnant rats was approximately 45% at 2 hours and

80% at 24 hours postdose. Placentaltransfer of sitagliptin administered to pregnant rabbits was

approximately 66% at 2 hours and 30% at 24 hours.

Metformin hydrochloride

Metformin was not teratogenic in rats and rabbitsatdosesupto 600mg/kg/day. This represents an

exposure of about 2 and 6 times the maximumrecommended human daily dose of2,000mgbasedon

bodysurfacearea comparisons for rats and rabbits, respectively. Determination of fetal concentrations

demonstrated a partial placental barrier to metformin.

8.3 Nursing Mothers

Nostudiesinlactating animals have been conducted with the combined components of JANUET. In

studies performed with the individualcomponents, both sitagliptin and metformin are secreted in themilk

of lactating rats. It is not known whethersitagliptin is excreted in human milk.Because many drugs are

excreted in human milk, caution should be exercisedwhen JANUET is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of JANUET in pediatricpatients under 18 years have not been established.

8.5 Geriatric Use

JANUET

Because sitagliptin and metformin aresubstantially excreted by the kidney, and because aging can be

associated with reduced renal function, JANUETshould be used with caution as age increases. Care

should be taken in dose selection andshouldbebasedoncarefulandregularmonitoringofrenal

function.[See Warnings and Precautions (5.1, 5.4); Clinical Pharmacology (12.3).]

Sitagliptin

Of the total number of subjects (N=3884)inPhaseII and III clinical studies of sitagliptin, 725 patients

were 65 years and over, while 61 patients were 75 years and over. No overalldifferencesinsafetyor

effectiveness were observed betweensubjects65years and over and younger subjects. While this and

other reported clinical experiencehave not identified differences inresponses between the elderly and

younger patients, greater sensitivity of some older individuals cannot be ruled out.

Metformin hydrochloride

Controlled clinical studies of metformin did notinclude sufficient numbers of elderly patients to

determine whether they responddifferentlyfromyounger patients, although other reported clinical

experience has not identified differencesinresponses between the elderly andyoung patients. Metformin

should only be used in patients with normal renalfunction.The initial and maintenance dosing of

metformin should be conservative in patients withadvanced age, due to the potential for decreasedrenal

function in this population. Any dose adjustmentshould be based on a careful assessment of renal

function.[SeeContraindications (4);Warnings and Precautions (5.4); andClinical Pharmacology (12.3).]

10 OVERDOSAGE

Sitagliptin

Duringcontrolled clinical trials in healthy subjects, single doses of up to 800mg sitagliptin were

administered.Maximal mean increases in QTc of 8.0msec were observed in one study at a dose of

800mg sitagliptin, a mean effect thatisnot considered clinically important[see Clinical Pharmacology

(12.2)] . There is no experience with doses above 800mgin humans. In Phase I multiple-dose studies,

there were no dose-related clinical adverse reactionsobserved with sitagliptin with doses of upto400mg

per day for periods of up to 28 days.

In the event of anoverdose,itis reasonable to employ the usualsupportive measures, e.g., remove

unabsorbed material from thegastrointestinal tract, employ clinical monitoring (including obtaining an

electrocardiogram), and institute supportive therapyas indicated by the patient's clinical status.

Sitagliptin is modestly dialyzable.Inclinicalstudies, approximately 13.5%of the dose was removed

overa3-to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically

appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin hydrochloride

Overdose of metformin hydrochloride has occurred, includingingestionof amounts greater than

50grams.Hypoglycemiawas reported in approximately10% of cases, but no causal association with

metforminhydrochloridehas been established. Lactic acidosis has been reported in approximately 32%

of metformin overdose cases[seeWarningsand Precautions (5.1)]. Metformin is dialyzable with a

clearance of up to 170mL/min under good hemodynamicconditions.Therefore, hemodialysis may be

useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

11 DESCRIPTION

JANUET (sitagliptin/metformin HCl)tablets contain twooralantihyperglycemic drugs used in the

management of type 2 diabetes: sitagliptin and metformin hydrochloride.

Sitagliptin

Sitagliptin is an orally-active inhibitor of the dipeptidylpeptidase-4 (DPP-4) enzyme. Sitagliptin is

present in JANUET tablets in the form of sitagliptin phosphatemonohydrate. Sitagliptin phosphate

monohydrate is described chemicallyas7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-

tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate withanempirical

formula of C

OH

H

O and a molecular weight of 523.32. The structural formula is:

Sitagliptin phosphate monohydrate is a white to off-white,crystalline, non-hygroscopic powder. It is

soluble in water and N,N-dimethyl formamide; slightlysoluble in methanol; very slightly solubleinethanol,

acetone, and acetonitrile; and insolublein isopropanol and isopropyl acetate.

Metformin hydrochloride

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is notchemicallyor

pharmacologically related to any otherclassesoforal antihyperglycemic agents. Metformin hydrochloride

isawhitetooff-white crystalline compound with a molecular formula of C

HCl and a molecular

weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insolubleinacetone,

ether,and chloroform. The pK

of metformin is 12.4. The pH of a 1% aqueous solution of metformin

hydrochloride is 6.68. The structural formula is as shown:

JANUET

JANUET is available for oral administration astablets containing 64.25mg sitagliptin phosphate

monohydrate and metformin hydrochloride equivalentto: 50mg sitagliptin as free baseand500mg

metformin hydrochloride (JANUET 50mg/500mg)or 1000mg metforminhydrochloride(JANUET

50mg/1000mg). Each film-coated tablet of JANUET contains thefollowing inactive ingredients:

microcrystalline cellulose, polyvinylpyrrolidone (Povidone), sodium lauryl sulfate, and sodiumstearyl

fumarate. In addition, the film coatingcontainsthe following inactive ingredients: polyvinyl alcohol,

macrogol/polyethylene glycol, talc, titanium dioxide, iron oxide red, and iron oxide black.

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action

JANUET

JANUET combines two antihyperglycemicagentswith complementary mechanisms of action to

improveglycemiccontrol in patients with type 2 diabetes: sitagliptin, a dipeptidyl peptidase-4 (DPP-4)

inhibitor, and metformin hydrochloride,a member of the biguanide class.

Sitagliptin

Sitagliptin is a DPP-4 inhibitor, which isbelievedtoexert its actions in patients with type 2 diabetes by

slowingthe inactivation of incretin hormones. Concentrations of the active intact hormones are increased

by sitagliptin, thereby increasing and prolongingtheactionof these hormones. Incretin hormones,

including glucagon-like peptide-1 (GLP-1) andglucose-dependent insulinotropic polypeptide (GIP), are

released by the intestine throughout the day, and levels are increased in response to a meal. These

hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part ofanendogenoussystem

involved in the physiologic regulation of glucose homeostasis.Whenblood glucose concentrations are

normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by

intracellular signaling pathways involving cyclicAMP. GLP-1 also lowers glucagon secretion from

pancreatic alpha cells, leading to reduced hepaticglucose production. By increasing andprolonging

active incretin levels, sitagliptin increases insulinrelease and decreases glucagon levels in the circulation

in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit

DPP-8 or DPP-9 activityin vitroat concentrations approximating those from therapeutic doses.

Metformin hydrochloride

Metformin is an antihyperglycemicagentwhichimproves glucose tolerance in patients with type 2

diabetes, lowering both basal and postprandial plasmaglucose. Its pharmacologic mechanismsofaction

aredifferentfromother classes of oral antihyperglycemic agents. Metformindecreases hepatic glucose

production, decreases intestinal absorptionofglucose, and improves insulin sensitivity by increasing

peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin doesnotproduce

hypoglycemia in either patients withtype 2 diabetes or normal subjects(except in special circumstances

[see Warnings and Precautions (5.9)] )and does not cause hyperinsulinemia. With metformin therapy,

insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response

may actually decrease.

12.2 Pharmacodynamics

Sitagliptin

General

In patients with type 2 diabetes, administration ofsitagliptin led to inhibition of DPP-4 enzyme activity

for a 24-hour period. After an oral glucose load orameal, this DPP-4 inhibition resulted in a 2- to 3-fold

increase in circulating levels of activeGLP-1 and GIP, decreased glucagon concentrations, and

increased responsiveness of insulin release to glucose, resulting in higher C-peptideandinsulin

concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting

glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

Sitagliptin and Metformin hydrochloride Co-administration

In a two-day study inhealthysubjects,sitagliptin alone increased active GLP-1 concentrations,

whereasmetformin alone increased active and totalGLP-1 concentrations to similar extents. Co-

administration of sitagliptin and metformin hadanadditive effect on active GLP-1 concentrations.

Sitagliptin, but not metformin, increased active GIPconcentrations. It is unclearwhat these findings mean

for changes in glycemic controlin patients with type 2 diabetes.

In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.

Cardiac Electrophysiology

In a randomized, placebo-controlled crossover study, 79 healthy subjects were administeredasingle

oral dose of sitagliptin 100mg, sitagliptin 800mg(8 times the recommended dose), and placebo.Atthe

recommended dose of 100mg, there was no effect onthe QTc interval obtained at the peakplasma

concentration, or at any other time during the study. Following the 800-mg dose, themaximumincrease

in the placebo-corrected mean change in QTc from baselineat3 hours postdose was 8.0msec. This

increase is not considered to be clinically significant.At the 800-mg dose, peak sitagliptin plasma

concentrations were approximately 11 times higherthan the peak concentrations following a 100-mg

dose.

In patients with type 2 diabetes administered sitagliptin100mg (N=81) or sitagliptin 200mg (N=63)

daily, there were no meaningful changes in QTc intervalbasedonECG data obtained at the time of

expected peak plasma concentration.

12.3 Pharmacokinetics

JANUET

The results of a bioequivalence study in healthysubjectsdemonstrated that the JANUET

(sitagliptin/metformin HCl) 50mg/500mg and 50mg/1000mg combination tablets are bioequivalent to

co-administration of correspondingdoses of sitagliptin (JANUVIA ®2 ) and metformin hydrochloride as

individual tablets.

Absorption

Sitagliptin

The absolute bioavailability of sitagliptin is approximately87%.Co-administration of a high-fat meal

with sitagliptin had no effect on the pharmacokinetics of sitagliptin.

Metformin hydrochloride

The absolute bioavailability of a metformin hydrochloride 500-mg tablet given under fastingconditions

is approximately 50-60%. Studies using single oraldoses of metformin hydrochloride tablets 500mg to

1500mg, and 850mg to 2550mg, indicate that thereisalack of dose proportionality with increasing

doses,whichis due to decreased absorption rather than an alteration inelimination. Food decreases the

extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean

peak plasma concentration (C

),a 25% lower area under the plasma concentration versus time curve

(AUC), and a 35-minute prolongation of time to peak plasma concentration (T

) following administration

of a single 850-mg tabletofmetforminwithfood,compared to the same tablet strength administered

fasting. The clinical relevanceof these decreases is unknown.

Distribution

Sitagliptin

Themeanvolumeof distribution at steady state following a single 100-mg intravenous dose of

sitagliptin to healthy subjects is approximately198liters. The fraction of sitagliptin reversibly bound to

plasma proteins is low (38%).

Metformin hydrochloride

The apparent volume of distribution (V/F) of metformin following single oral dosesofmetformin

hydrochloride tablets 850mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in

contrast to sulfonylureas, which are more than 90%protein bound. Metformin partitions into erythrocytes,

most likely as a function of time.At usual clinical doses anddosingschedules of metformin hydrochloride

tablets, steady-state plasmaconcentrations of metformin are reached within 24-48 hours and are

generally <1 mcg/mL. During controlled clinical trialsof metformin, maximum metformin plasma levels did

not exceed 5 mcg/mL, even at maximum doses.

Metabolism

Sitagliptin

Approximately79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor

pathway of elimination.

Following a [ 14 C]sitagliptin oral dose, approximately 16%of the radioactivity was excreted as

metabolites of sitagliptin. Six metabolites were detected at trace levels and arenot expected tocontribute

to the plasma DPP-4 inhibitory activity of sitagliptin.In vitrostudies indicated that the primaryenzyme

responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

Metformin hydrochloride

Intravenoussingle-dose studies in normal subjectsdemonstrate that metformin is excreted unchanged

in the urine and does not undergohepaticmetabolism(no metabolites have been identified in humans)

nor biliary excretion.

Excretion

Sitagliptin

Following administration of an oral [ 14 C]sitagliptin dose tohealthysubjects, approximately 100% of the

administered radioactivity was eliminated in feces (13%) or urine (87%) within one weekofdosing.The

apparent terminal t

1/2 following a 100-mg oral doseofsitagliptin was approximately 12.4 hours and renal

clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renalexcretion and involves active tubular secretion.

Sitagliptin is a substrate for human organic aniontransporter-3 (hOAT-3), which may be involved in the

renaleliminationof sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been

established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involvedinmediatingthe

renal elimination of sitagliptin. However, cyclosporine, a p-glycoproteininhibitor, did not reduce the renal

clearance of sitagliptin.

Metformin hydrochloride

Renal clearance is approximately 3.5 times greaterthan creatinine clearance, which indicates that

tubular secretion is the major route of metformin elimination. Following oral administration,approximately

90% of the absorbed drug is eliminated via the renalroute within the first 24 hours, withaplasma

elimination half-life of approximately 6.2 hours. Inblood, the elimination half-life is approximately 17.6

hours, suggesting that the erythrocyte massmay be a compartment of distribution.

Special Populations

Renal Insufficiency

JANUET

JANUET should not be used in patients with renal insufficiency[seeContraindications (4);Warnings

and Precautions (5.4)].

Sitagliptin

Anapproximately2-foldincrease in the plasma AUC of sitagliptin was observed in patients with

moderate renal insufficiency, and an approximately 4-foldincreasewasobserved in patients with severe

renalinsufficiency including patients with ESRD on hemodialysis, as compared to normal healthy control

subjects.

Metformin hydrochloride

Inpatients with decreased renal function (basedon measured creatinine clearance), the plasma and

blood half-life of metformin is prolonged andtherenal clearance is decreased in proportion to the

decrease in creatinine clearance.

Hepatic Insufficiency

Sitagliptin

In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), meanAUCandC

of

sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls

following administration of a single 100-mg dose of sitagliptin.These differences are not considered to be

clinically meaningful.

There is no clinical experience in patients withsevere hepatic insufficiency (Child-Pugh score >9).

Metformin hydrochloride

No pharmacokinetic studies of metformin have beenconducted in patients with hepatic insufficiency.

Gender

Sitagliptin

Gender had no clinically meaningful effect onthepharmacokineticsof sitagliptin based on a

composite analysis of Phase I pharmacokineticdata and on a population pharmacokinetic analysis of

Phase I and Phase II data.

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjectsand

patientswithtype 2 diabetes when analyzed according togender. Similarly, in controlled clinical studies

in patients with type 2 diabetes, theantihyperglycemic effect of metformin was comparable in males and

females.

Geriatric

Sitagliptin

Whentheeffectsofage on renal function are takeninto account, age alone did not have a clinically

meaningful impact on the pharmacokinetics of sitagliptin based on apopulation pharmacokinetic analysis.

Elderly subjects (65 to 80 years) had approximately19% higher plasma concentrations ofsitagliptin

compared to younger subjects.

Metformin hydrochloride

Limiteddata from controlled pharmacokinetic studies of metformin inhealthy elderly subjects suggest

that total plasma clearance of metforminis decreased, the half life is prolonged, and C

max is increased,

compared to healthy young subjects. Fromthesedata, it appears that the change in metformin

pharmacokinetics with aging is primarily accounted for by a changeinrenalfunction(see

GLUCOPHAGE 3 prescribing information:CLINICAL PHARMACOLOGY, Special Populations,

Geriatrics).

JANUET treatment should notbe initiated in patients≥80 years of age unless measurement of

creatinine clearance demonstrates that renal function is not reduced[seeWarnings and Precautions (5.1,

5.4)] .

Pediatric

No studies with JANUET have beenperformed in pediatric patients.

Race

Sitagliptin

Race had no clinically meaningful effect on thepharmacokinetics of sitagliptin based on a composite

analysis of available pharmacokineticdata, including subjects of white,Hispanic, black, Asian, and other

racial groups.

Metformin hydrochloride

No studies of metforminpharmacokineticparameters according to race have been performed. In

controlled clinical studies of metformin inpatientswith type 2 diabetes, the antihyperglycemic effect was

comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Body Mass Index (BMI)

Sitagliptin

Body mass index had no clinically meaningful effecton the pharmacokinetics of sitagliptin based ona

composite analysis of Phase I pharmacokineticdata and on a population pharmacokinetic analysis of

Phase I and Phase II data.

Drug Interactions

Sitagliptin and Metformin hydrochloride

Co-administration of multiple doses ofsitagliptin (50mg) and metformin (1000mg) given twice daily

did not meaningfully alter the pharmacokinetics of either sitagliptin ormetformin in patients with type 2

diabetes.

Pharmacokineticdrug interaction studies withJANUET have not been performed; however, such

studies have been conducted with the individualcomponents of JANUET (sitagliptinandmetformin

hydrochloride).

Sitagliptin

In Vitro Assessment of Drug Interactions

Sitagliptin is not an inhibitorofCYPisozymesCYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not

an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but doesnotinhibitp-glycoprotein

mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause

interactions with other drugsthat utilize these pathways.

Sitagliptinisnotextensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be

involved in clinically meaningful drug-drug interactionsmediatedby plasma protein binding displacement

is very low.

In Vivo Assessment of Drug Interactions

Effect of Sitagliptin on Other Drugs

In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of

metformin, glyburide, simvastatin, rosiglitazone,warfarin, or oral contraceptives, providingin vivo

evidence of a low propensity for causing drug interactions with substratesof CYP3A4,CYP2C8,

CYP2C9, and organic cationic transporter (OCT).

Digoxin: Sitagliptinhad a minimal effect on the pharmacokinetics of digoxin. Following administration

of 0.25mg digoxin concomitantly with 100mg of sitagliptin dailyfor10 days, the plasma AUC of digoxin

was increased by 11%, and the plasma C

by 18%.

Sulfonylureas: Single-dose pharmacokinetics of glyburide,a CYP2C9 substrate, was notmeaningfully

altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be

expectedwithother sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are

primarily eliminated by CYP2C9[see Warnings and Precautions(5.9)].

Simvastatin: Single-dose pharmacokinetics ofsimvastatin,a CYP3A4 substrate, was not meaningfully

altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of

CYP3A4-mediated metabolism.

Thiazolidinediones: Single-dosepharmacokinetics of rosiglitazone was not meaningfully altered in

subjects receiving multiple daily doses of sitagliptin, indicating that sitagliptin is not aninhibitorof

CYP2C8-mediated metabolism.

Warfarin: Multiple daily doses of sitagliptin did notmeaningfully alter the pharmacokinetics, as

assessed by measurement of S(-)or R(+) warfarin enantiomers, orpharmacodynamics (as assessed by

measurement of prothrombin INR)of a single dose of warfarin. Because S(-) warfarinisprimarily

metabolized by CYP2C9, these data alsosupport the conclusion that sitagliptin is not a CYP2C9 inhibitor.

Oral Contraceptives: Co-administration with sitagliptin did not meaningfully alter the steady-state

pharmacokinetics of norethindrone or ethinyl estradiol.

Effect of Other Drugs on Sitagliptin

Clinical data described below suggest thatsitagliptin is not susceptible to clinically meaningful

interactions by co-administered medications.

Cyclosporine: A study was conducted to assess the effectof cyclosporine, apotent inhibitor of

p-glycoprotein, on the pharmacokineticsof sitagliptin. Co-administrationofasingle 100-mg oral dose of

sitagliptin and a single 600-mgoraldoseof cyclosporine increased the AUC and C

of sitagliptin by

approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokineticswere

not considered to be clinically meaningful. Therenalclearance of sitagliptin was also not meaningfully

altered. Therefore, meaningful interactions wouldnot be expected with other p-glycoprotein inhibitors.

Metformin hydrochloride

[See Drug Interactions (7.1, 7.3, 7.4, 7.5, 7.6).]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility

JANUET

No animal studies have been conducted with the combined products in JANUET to evaluate

carcinogenesis, mutagenesis or impairment of fertility. The following data are based onthefindingsin

studies with sitagliptin and metformin individually.

Sitagliptin

Atwo-yearcarcinogenicity study was conducted in maleand female rats given oral doses of sitagliptin

of 50, 150, and 500mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma

in males and females and of livercarcinomainfemales at 500mg/kg. This dose results in exposures

approximately60times the human exposure atthe maximum recommended daily adult human dose

(MRHD) of 100mg/day based on AUC comparisons. Liver tumors were not observedat150mg/kg,

approximately 20 times the human exposure at theMRHD. A two-yearcarcinogenicity study was

conducted in male and female mice given oral dosesofsitagliptin of 50, 125, 250, and 500mg/kg/day.

There was no increase in the incidence oftumorsin any organ up to 500mg/kg, approximately 70 times

humanexposureat the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic

activation in the Ames bacterialmutagenicityassay, a Chinese hamster ovary (CHO) chromosome

aberration assay, anin vitrocytogenetics assay in CHO, anin vitrorat hepatocyte DNA alkaline elution

assay, and anin vivomicronucleus assay.

Inratfertilitystudies with oral gavage doses of125, 250, and 1000mg/kg, males were treated for 4

weeks prior to mating, during mating, up to scheduled termination (approximately 8weekstotal),and

femalesweretreated 2 weeks prior to mating throughgestation day 7. No adverse effect on fertility was

observed at 125mg/kg (approximately 12timeshuman exposure at the MRHD of 100mg/day based on

AUC comparisons). At higher doses,nondose-relatedincreased resorptions in females were observed

(approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).

Metformin hydrochloride

Long-term carcinogenicity studies have been performedin rats (dosing duration of 104 weeks) and

mice (dosing duration of 91 weeks) at dosesup to and including 900mg/kg/day and 1500mg/kg/day,

respectively. These doses are both approximately four times the maximumrecommendedhumandaily

doseof 2000mg based on body surface area comparisons. No evidence of carcinogenicity with

metforminwasfoundin either male or femalemice. Similarly, there was no tumorigenic potential

observed with metformin in male rats. There was,however,an increased incidence of benign stromal

uterine polyps in female rats treated with 900 mg/kg/day.

Therewas no evidence of a mutagenic potential of metformin in the followingin vitrotests:Ames test

(S. typhimurium), gene mutation test (mouse lymphoma cells),orchromosomal aberrations test (human

lymphocytes). Results in thein vivomouse micronucleus test were also negative. Fertility of male or

femalerats was unaffected by metformin when administered at doses as high as 600mg/kg/day, which is

approximately three times the maximum recommendedhumandaily dose based on body surface area

comparisons.

14 CLINICAL STUDIES

The co-administration of sitagliptin and metforminhas been studied in patients with type 2 diabetes

inadequately controlled on diet and exercise and in combination with other antihyperglycemic agents.

There have been no clinical efficacy studies conductedwith JANUET; however, bioequivalence of

JANUET with co-administered sitagliptin and metformin hydrochloride tablets was demonstrated.

Sitagliptin and Metformin Co-administration in Patients with Type 2 Diabetes Inadequately

Controlled on Diet and Exercise

Atotalof 1091 patients with type 2 diabetes andinadequate glycemic control on diet and exercise

participated in a 24-week, randomized, double-blind,placebo-controlled factorial studydesignedto

assess the efficacy of sitagliptin and metformin co-administration. Patients onan antihyperglycemicagent

(N=541) underwent a diet, exercise, and drug washoutperiod of up to 12 weeks duration. After the

washout period, patients with inadequate glycemic control (A1C 7.5%to 11%) were randomized after

completing a 2-week single-blind placebo run-inperiod. Patients not on antihyperglycemic agents at

study entry (N=550) with inadequateglycemic control (A1C 7.5%to 11%) immediately entered the

2-week single-blind placebo run-in period and thenwere randomized. Approximately equal numbers of

patients were randomized to receive placebo, 100mgof sitagliptin once daily, 500mg or 1000mg of

metformintwicedaily,or 50mg of sitagliptin twice daily in combination with 500mg or 1000mg of

metformin twice daily. Patients who failed to meet specific glycemic goals during thestudyweretreated

with glyburide (glibenclamide) rescue.

Sitagliptin and metformin co-administration provided significant improvements in A1C, FPG, and 2-

hourPPGcomparedto placebo, to metformin alone, and to sitagliptin alone (Table4, Figure 1). Mean

reductions from baseline in A1C were generally greaterforpatientswith higher baseline A1C values. For

patients not on an antihyperglycemicagent at study entry, mean reductions from baseline in A1C were:

sitagliptin 100 mg once daily, -1.1%; metformin 500mg bid, -1.1%;metformin1000mgbid,-1.2%;

sitagliptin50mg bid with metformin 500mg bid, -1.6%; sitagliptin 50mg bid with metformin 1000mg bid,

-1.9%;andfor patients receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in

body weight in the groups given sitagliptin in combinationwithmetforminwas similar to that in the groups

given metformin alone or placebo.

Table4:

Glycemic Parameters at Final Visit (24-Week Study)

for Sitagliptin and Metformin, Aloneand in Combination in Patientswith Type2DiabetesInadequatelyControlled

onDiet andExercise

Placebo

Sitagliptin

100 mg QD

Metformin

500 mg bid

Metformin

1000 mg

bid Sitagliptin

50 mg bid +

Metformin

500 mg bid Sitagliptin

50 mg bid +

Metformin

1000 mg bid

A1C(%) N = 165 N = 175 N = 178 N = 177 N = 183 N = 178

Baseline (mean) 8.7 8.9 8.9 8.7 8.8 8.8

Change from baseline (adjusted mean ‡ ) 0.2-0.7-0.8-1.1-1.4 -1.9

Difference from placebo (adjusted mean ‡ )

(95% CI) -0.8 §

(-1.1, -0.6) -1.0 §

(-1.2, -0.8) -1.3 §

(-1.5, -1.1) -1.6 §

(-1.8, -1.3) -2.1 §

(-2.3, -1.8)

Patients (%) achieving A1C <7% 15 (9%) 35(20%) 41 (23%) 68 (38%) 79 (43%) 118 (66%)

% Patients receiving rescue medication 32 21 17 12 8 2

FPG (mg/dL) N = 169 N = 178 N = 179 N = 179 N = 183 N = 180

Baseline (mean) 196 201 205 197 204 197

Change from baseline (adjusted mean ‡ ) 6-17-27-29-47-64

Difference from placebo (adjusted mean ‡ )

(95% CI) -23 §

(-33, -14) -33 §

(-43, -24) -35 §

(-45, -26) -53 §

(-62, -43) -70 §

(-79, -60)

2-hour PPG (mg/dL) N = 129 N = 136 N = 141 N = 138 N = 147 N = 152

Baseline (mean) 277 285 293 283 292 287

Change from baseline (adjusted mean ‡ ) 0-52-53-78-93-117

Difference from placebo (adjusted mean ‡ )

(95% CI) -52 §

(-67, -37) -54 §

(-69, -39) -78 §

(-93, -63) -93 §

(-107, -78) -117 §

(-131, -102)

Intent to Treat Population using last observation onstudyprior to glyburide (glibenclamide) rescue therapy.

Least squares means adjusted for prior antihyperglycemic therapystatus and baseline value.

p<0.001 compared to placebo.

Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin,

Alone and in Combination in Patients with Type2 Diabetes InadequatelyControlled with Diet and

Exercise

Week

-2.0 -1.5 -1.0 -0.5 0.0

L S M ean Chan ge f rom Baseline

Placebo Metformin1000 mgb.i.d.

Sitagliptin100 mgq.d. Sitagliptin50 mgb.i.d. + Metformin500 mgb.i.d.

Metformin500 mgb.i.d. Sitagliptin50 mgb.i.d. + Metformin1000mgb.i.d.

Intention to Treat Population; Least squares means adjusted for prior antihyperglycemic therapyand baseline value.

In addition, this study included patients (N=117) with more severe hyperglycemia (A1C >11% or

blood glucose >280mg/dL) who were treated with twicedailyopen-label sitagliptin 50mg and metformin

1000mg. In this group of patients, the mean baseline A1C value was 11.2%, mean FPG was314mg/dL,

andmean2-hour PPG was 441mg/dL. After 24 weeks, mean decreases from baseline of -2.9% for A1C,

-127 mg/dL for FPG, and -208 mg/dL for 2-hour PPG were observed.

Initial combination therapy ormaintenanceofcombination therapy should be individualized and are

left to the discretion of the health care provider.

Sitagliptin Add-on Therapyin Patients with Type2 Diabetes InadequatelyControlled on Metformin

Alone

Atotalof701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind,

placebo-controlled study designed to assess the efficacyof sitagliptin incombinationwithmetformin.

Patientsalready on metformin (N=431) at a dose ofat least 1500mg per day were randomized after

completing a 2-week, single-blindplaceborun-in period. Patients on metformin and another

antihyperglycemic agent (N=229) andpatients not on any antihyperglycemic agents (off therapy for at

least 8 weeks, N=41) were randomizedafterarun-inperiod of approximately 10 weeks on metformin (at

a dose of at least 1500mg perday)inmonotherapy.Patients were randomized to the addition of either

100mg of sitagliptin or placebo, administered once daily.Patientswho failed to meet specific glycemic

goals during the studies were treated with pioglitazone rescue.

In combination with metformin, sitagliptin provided significant improvementsin A1C, FPG, and 2-hour

PPG compared to placebo withmetformin(Table5).Rescue glycemic therapy wasused in 5% of patients

treated with sitagliptin 100mg and 14% of patientstreated with placebo. A similar decrease inbody

weight was observed for both treatment groups.

Table 5: Glycemic Parameters at Final Visit (24-Week Study) of Sitagliptin as Add-on Combination

Therapywith Metformin

Sitagliptin 100 mg QD +

Metformin Placebo +

Metformin

A1C(%) N = 453 N = 224

Baseline (mean) 8.0 8.0

Change from baseline (adjusted mean ‡ ) -0.7 -0.0

Difference from placebo +metformin (adjusted mean ‡ )

(95% CI) -0.7 §

(-0.8, -0.5)

Patients (%) achieving A1C <7% 213 (47%) 41 (18%)

FPG (mg/dL) N = 454 N = 226

Baseline (mean) 170 174

Change from baseline (adjusted mean ‡ ) -17 9

Difference from placebo +metformin (adjusted mean ‡ )

(95% CI) -25 §

(-31, -20)

2-hour PPG (mg/dL) N = 387 N = 182

Baseline (mean) 275 272

Change from baseline (adjusted mean ‡ ) -62 -11

Difference from placebo +metformin (adjusted mean ‡ )

(95% CI) -51 §

(-61, -41)

Intent to Treat Population using last observation on studyprior to pioglitazone rescue therapy.

Least squares means adjusted for prior antihyperglycemic therapyand baseline value.

p<0.001 compared to placebo + metformin.

Sitagliptin Add-on Therapyin Patients withType 2 Diabetes InadequatelyControlled on the

Combination of Metformin and Glimepiride

A total of 441 patients with type 2 diabetes participated in a 24-week, randomized,double-blind,

placebo-controlled study designed toassess the efficacy of sitagliptinin combination with glimepiride,

with or without metformin. Patientsentereda run-in treatment period on glimepiride (≥4mg per day)

alone or glimepiride in combinationwithmetformin(≥1500mg per day). After a dose-titration and dose-

stable run-in period of up to 16weeksanda2-week placebo run-in period, patients with inadequate

glycemic control (A1C 7.5% to 10.5%) were randomized to the addition ofeither 100mg of sitagliptin or

placebo, administered once daily. Patients who failed tomeet specific glycemic goals during the studies

were treated with pioglitazone rescue.

Patientsreceiving sitagliptin with metformin andglimepiride had significant improvements in A1C and

FPGcomparedto patients receiving placebo withmetformin and glimepiride (Table6), with mean

reductions from baseline relative to placebo in A1Cof -0.9% and in FPG of -21 mg/dL. Rescue therapy

was used in 8% of patients treated with add-on sitagliptin100mgand29% of patients treated with add-

onplacebo.Thepatients treated with add-on sitagliptinhad a mean increase in body weight of 1.1kg vs.

add-on placebo (+0.4kg vs. -0.7 kg). In addition,add-on sitagliptin resulted in an increased rate of

hypoglycemia compared toadd-onplacebo.[See Warnings and Precautions (5.9); Adverse Reactions

(6.1).]

Table 6: Glycemic Parameters at Final Visit (24-Week Study)

for Sitagliptin in Combination with Metformin and Glimepiride

Sitagliptin 100 mg

+ Metformin

and Glimepiride Placebo

+ Metformin

and Glimepiride

A1C (%) N = 115 N = 105

Baseline (mean) 8.3 8.3

Change from baseline (adjusted

mean ‡ ) -0.6 0.3

Difference from placebo (adjusted

mean ‡ ) (95% CI) -0.9 §

(-1.1, -0.7)

Patients (%) achieving A1C <7% 26 (23%) 1 (1%)

FPG (mg/dL) N = 115 N = 109

Baseline (mean) 179 179

Change from baseline (adjusted

mean ‡ ) -8 13

Difference from placebo (adjusted

mean ‡ ) (95% CI) -21 §

(-32, -10)

Intent to Treat Population using last observation on studyprior to pioglitazone rescue therapy.

Least squares means adjusted for prior antihyperglycemic therapystatus and baseline value.

p<0.001 compared to placebo.

Sitagliptin Add-on Therapyin Patients withType 2 Diabetes InadequatelyControlled on the

Combination of Metformin and Rosiglitazone

A total of 278 patients with type 2 diabetes participated in a 54-week, randomized,double-blind,

placebo-controlled study designed to assess the efficacy of sitagliptinincombination with metformin and

rosiglitazone. Patients on dual therapy withmetformin≥1500 mg/day and rosiglitazone≥4 mg/day or with

metformin≥1500mg/day and pioglitazone≥30mg/day (switched to rosiglitazone≥4mg/day) entered a

dose-stable run-in period of 6 weeks. Patients onother dual therapy were switched to metformin

≥1500 mg/dayandrosiglitazone≥4mg/day in a dose titration/stabilization run-in period of up to 20

weeksin duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%)

were randomized 2:1 to the addition ofeither100mgof sitagliptin or placebo, administered once daily.

Patients who failed to meet specific glycemic goals during the studies were treated with glipizide (or other

sulfonylurea) rescue. The primary time point forevaluation of glycemic parameters was Week 18.

In combination with metformin and rosiglitazone, sitagliptin provided significant improvements inA1C,

FPG,and2-hourPPG compared to placebo with metformin and rosiglitazone (Table7) at Week18. At

Week54, mean reduction in A1C was -1.0% for patients treated with sitagliptin and -0.3% for patients

treatedwithplaceboin an analysis based on the intentto treat population. Rescue therapy was used in

18% of patients treated with sitagliptin100mgand40% of patients treated with placebo. There was no

significant difference between sitagliptin and placebo in body weight change.

Table7

Glycemic Parameters at Week 18

for Sitagliptin in Add-on Combination Therapywith Metformin and Rosiglitazone

Week 18

Sitagliptin

100 mg +

Metformin +

Rosiglitazone Placebo +

Metformin +

Rosiglitazone

A1C(%) N =176 N = 93

Baseline(mean)8.8 8.7

Change from baseline (adjusted

mean ‡ ) -1.0 -0.4

Difference from placebo +

rosiglitazone + metformin (adjusted

mean ‡ ) (95% CI) -0.7 §

(-0.9,-0.4)

Patients(%)achievingA1C <7% 39(22%) 9(10%)

FPG (mg/dL) N = 179 N =94

Baseline(mean) 181 182

Change from baseline (adjusted

mean ‡ ) -30 -11

Difference from placebo +

rosiglitazone + metformin (adjusted

mean ‡ ) (95% CI) -18 §

(-26, -10)

2-hour PPG (mg/dL) N = 152 N = 80

Baseline (mean) 256 248

Change from baseline (adjusted

mean ‡ ) -59 -21

Difference from placebo +

rosiglitazone + metformin (adjusted

mean ‡ ) (95% CI) -39 §

(-51, -26)

Intent to Treat Population using last observation on studyprior to glipizide (or other sulfonylurea) rescue

therapy.

Least squares means adjusted for prior antihyperglycemic therapystatus and baseline value.

p<0.001 compared to placebo + metformin + rosiglitazone.

Sitagliptin Add-on Therapyin Patients withType 2 Diabetes InadequatelyControlled on the

Combination of Metformin and Insulin

A total of 641patients with type2diabetesparticipated in a 24-week, randomized, double-blind,

placebo-controlled study designed toassesstheefficacy of sitagliptin as add-on to insulin therapy.

Approximately 75% of patients were also taking metformin.Patients entered a 2-week, single-blind run-in

treatment period on pre-mixed, long-acting, orintermediate-acting insulin, with or without metformin

(≥1500mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin

was administered as part of a pre-mixed insulin. After the run-in period, patientswith inadequate glycemic

control(A1C7.5%to 11%) were randomized to the addition of either 100mg of sitagliptin (N=229) or

placebo (N=233), administered once daily. Patients wereon a stable dose of insulin priortoenrollment

with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific

glycemic goals during the double-blind treatment periodwere to have uptitration ofthebackgroundinsulin

dose as rescue therapy.

Among patients also receiving metformin,themediandaily insulin (pre-mixed, intermediate or long

acting) dose at baseline was 40 units inthesitagliptin-treated patients and 42 units in the placebo-treated

patients.Themedian change from baseline in daily doseof insulin was zero for both groups at the end of

the study. Patients receiving sitagliptin with metformin and insulin had significant improvementsinA1C,

FPG and 2-hour PPG compared to patients receiving placebo with metformin and insulin(Table8).The

adjusted mean change from baselineinbodyweightwas-0.3 kg in patients receiving sitagliptin with

metformin and insulin and -0.2 kg in patients receiving placebo with metformin and insulin. There was an

increased rate of hypoglycemia inpatients treated with sitagliptin.[See Warnings and Precautions (5.9);

Adverse Reactions (6.1).]

Table 8: Glycemic Parameters at Final Visit (24-Week Study)

for Sitagliptin asAdd-on Combination Therapywith Metformin and Insulin

Sitagliptin 100 mg

+ Metformin

+ Insulin Placebo

+ Metformin

+ Insulin

A1C(%) N = 223 N = 229

Baseline (mean) 8.7 8.6

Change from baseline (adjusted mean ‡, § ) -0.7 -0.1

Difference from placebo (adjusted mean ‡ ) (95% CI) -0.5  ( -0.7, -0.4)

Patients (%) achieving A1C (%) <7% 32 (14%) 12 (5%)

FPG (mg/dL) N = 225 N = 229

Baseline (mean) 173 176

Change from baseline (adjusted mean ‡ ) -22 -4

Difference from placebo (adjusted mean ‡ ) (95% CI) -18  ( -28, -8.4)

2-hour PPG (mg/dL) N = 182 N = 189

Baseline (mean) 281 281

Change from baseline (adjusted mean ‡ ) -39 1

Difference from placebo (adjusted mean ‡ ) (95% CI) -40  (-53, -28)

Intent to Treat Population using lastobservation on studyprior to rescue therapy.

Least squares mean adjusted for insulinuse at the screening visit, type of insulinused at the screening visit (pre-mixed vs.

non pre-mixed [intermediate- orlong-acting]), and baseline value.

Treatment byinsulin stratum interaction was not significant (p >0.10).

p<0.001 compared to placebo.

Sitagliptin Add-on Therapyvs. Glipizide Add-onTherapyin Patients with Type 2 Diabetes

InadequatelyControlled on Metformin

The efficacy of sitagliptin was evaluated ina52-week, double-blind, glipizide-controlled noninferiority

trial in patients with type 2 diabetes. Patients noton treatment or onotherantihyperglycemicagents

entered a run-in treatment period of up to 12 weeksdurationwith metformin monotherapy (dose of

≥1500mg per day) which included washout of medicationsother than metformin, if applicable. After the

run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) wererandomized1:1tothe

addition of sitagliptin 100mg once daily or glipizide for 52 weeks. Patients receiving glipizide weregiven

aninitialdosage of 5mg/day and then electively titrated over the next 18 weeks to a maximum dosage of

20mg/day as needed to optimizeglycemiccontrol.Thereafter, the glipizide dose was to be kept constant,

except for down-titration to prevent hypoglycemia.The mean dose of glipizide after the titration period

was 10 mg.

After 52 weeks, sitagliptin and glipizide had similar mean reductions from baselineinA1Cinthe

intent-to-treat analysis (Table9).Theseresults were consistent withthe per protocol analysis (Figure 2).

A conclusion in favor of the non-inferiority of sitagliptintoglipizide may be limited to patients with baseline

A1C comparable to those included in thestudy(over 70% of patients had baseline A1C <8% and over

90% had A1C <9%).

Table9:

Glycemic Parameters ina 52-Week StudyComparing

Sitagliptin to Glipizide as Add-On Therapyin Patients Inadequately

Controlled on Metformin

(Intent-to-Treat Population)

Sitagliptin 100 mg

+ Metformin Glipizide

+ Metformin

A1C (%) N = 576 N = 559

Baseline (mean) 7.7 7.6

Change from baseline (adjusted mean ‡ ) -0.5 -0.6

FPG (mg/dL) N = 583 N = 568

Baseline (mean) 166 164

Change from baseline (adjusted mean ‡ ) -8 -8

The Intent to Treat Analysis used the patients' last observation in the studyprior to discontinuation.

‡ Least squares means adjusted for prior antihyperglycemic therapystatus and baseline A1C value.

Figure 2: MeanChangefromBaseline for A1C (%) Over 52 Weeks ina Study

Comparing Sitagliptin to Glipizide as Add-On Therapyin

PatientsInadequatelyControlled on Metformin

(PerProtocol Population)

The per protocol population (mean baseline A1C of 7.5%) included patients without major protocol violations who had

observations at baseline and at Week 52.

The incidence of hypoglycemia in the sitagliptingroup (4.9%) was significantly (p<0.001) lower than

that in the glipizide group (32.0%).Patients treated with sitagliptin exhibited a significant mean decrease

from baseline in body weight compared to a significantweightgain in patients administered glipizide

(-1.5 kgvs. +1.1 kg).

16 HOW SUPPLIED/STORAGE AND HANDLING

No. 6747— Tablets JANUET, 50mg/500mg, are lightpink, capsule-shaped, film-coated tablets with

“575” debossed on one side.

No. 6748 —TabletsJANUET,50 mg/850 mg,arepink,capsule-shaped, film-coated tablets with “515”

debossed on one side.

No. 6749 —TabletsJANUET,50 mg/1000 mg,are red,capsule-shaped, film-coated tablets with “577”

debossed on one side.

Store at room temperature.

17 PATIENT COUNSELING INFORMATION

See Approved Patient Labeling.

17.1 Instructions

Patients should be informed of the potential risks andbenefits of JANUET and ofalternative modesof

therapy.Theyshould also be informed about the importance of adherence to dietary instructions, regular

physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of

hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periodsofstress

suchasfever, trauma, infection, or surgery,medication requirements may change and patients should be

advised to seek medical advice promptly.

The risks of lactic acidosis due to themetformin component, its symptoms, and conditions that

predispose to its development, as noted in Warningsand Precautions (5.1), should be explained to

patients. Patients should be advisedto discontinue JANUET immediately and to promptly notify their

health practitioner ifunexplainedhyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow

orirregularheartbeat, sensation of feeling cold (especially in the extremities) or other nonspecific

symptoms occur. Gastrointestinal symptoms arecommon during initiation of metformin treatment and

may occur during initiation ofJANUETtherapy;however, patients should consulttheir physician if they

develop unexplained symptoms. Although gastrointestinalsymptomsthat occur after stabilization are

unlikely to be drug related, suchanoccurrenceofsymptoms should be evaluated to determine if it may

be due to lactic acidosis orother serious disease.

Patients should be counseled against excessive alcohol intake, either acute orchronic,whilereceiving

JANUET.

Patients should be informed about the importanceof regular testing of renal functionand

hematological parameters when receiving treatment with JANUET.

Patients should be informed that acute pancreatitis has been reported during postmarketing use of

JANUET. Patients should be informed that persistent severe abdominal pain, sometimes radiating tothe

back, which may or may not be accompanied by vomiting,is the hallmark symptom of acute pancreatitis.

Patients should be instructed to promptly discontinue JANUET and contact their physician ifpersistent

severe abdominal pain occurs[see Warnings and Precautions (5.2)].

Patients should be informed that the incidence ofhypoglycemia is increased when JANUETisadded

to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy and that a lowerdoseoftheinsulin

secretagogue or insulin may be required to reduce the risk of hypoglycemia.

Patientsshouldbe informed that allergic reactions have been reported during postmarketing use of

sitagliptin, one of the components ofJANUET. If symptoms of allergicreactions (including rash,hives,

and swelling of the face, lips, tongue, and throat thatmay cause difficulty in breathingorswallowing)

occur, patients must stop taking JANUET and seek medical advice promptly.

Physicians should instruct their patients to read the Patient Package Insert before starting JANUET

therapy and to reread each time theprescriptionisrenewed. Patients should be instructed to inform their

doctor if they develop any bothersome or unusual symptom, or if any symptom persists or worsens.

17.2 Laboratory Tests

Responsetoall diabetic therapies should be monitored by periodic measurements of blood glucose

and A1C levels, with a goal of decreasing these levelstowardsthenormal range. A1C is especially useful

for evaluating long-term glycemic control.

Initialandperiodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood

cell indices) and renal function(serumcreatinine) should be performed, at least on an annual basis.

While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamin

deficiency should be excluded.

Manufacturer: Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey, USA

License Holder: Merck, Sharp & Dohme (Israel-1996)Company Ltd., P.O. Box 7121, Petah-Tikva, 49170.

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

approved in March 2011.

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