SIMOVIL 20 MG

ו"משתה(םירישכת)םיחקורהתונקתיפלןכרצלןולע - 1986

אפורםשרמבתבייחוזהפורת

הפורתבי/שמתשתםרטבואולמבןולעהתאןויעבאורקלשי

לערשואוקדבנונכותותואירבהדרשמי"עעבקנהזןולעטמרופ - ודי ב רבמצד 2012

ליבומיס ® 10 ג"מ ליבומיס ® 20 ג"מ ס ליבומי ® 40 "מ ג

תוילבט תוילבט תוילבט

:בכרה

:הליכמהילבטלכ

Simvastatin 10 ג"מ Simvastatin 20 ג"מ Simvastatin 40 ג"מ

:םיליעפיתלבםיביכרמ

Ascorbic acid, citric acid monohydrate, hydroxypropyl cellulose, hydroxypropyl methylcellulose,red

ferric oxide, yellow ferric oxide, lactosehydrous, magnesium stearate, microcrystallinecellulose,

pregelatinizedstarch, talc, and titanium dioxide. Butylated hydroxyanisole is added as a preservative.

:תיטיופרתהצובק םיזנאהבכעמ HMG-CoA reductase .

:תיאופרתוליעפ

ליבומיס דירומ תומר LDL ו,םדבםירחאםיינמושםיביכרמו הלעמ תומר HDL - םעםילוחב לשההובגהמר)הימדיפילרפיה

,הימלורטסלוכרפיהותילילכבלתלחמםעםילוחב.(םדבםינמוש ליבומיס התומתלןוכיסהתאתיחפמ תדרוהי"עתללוכ

בלתולחממהתומתה ; ינלטקוניאשבלףקתהלןוכיסהתאתיחפמ ; תובחרהןוגכ)תוינשלופתולועפעוציבלןוכיסהתאתיחפמ

יחומץבשלןוכיסהתיחפמו,(םיפקעמיחותינואןולב ףלוחימכסיאףקתהלו ) Transient Ischemic Attack – TIA ( .

?רישכתבשמתשהלןיאיתמ

הלןיא :וזהפורתבשמתש

/יגרלאךניהםא .הפורתהיביכרממדחאלכלת

.הליעפדבכתלחמםעת/ןחבואמךניהםא

בשמתשהלןיא.ןוירהבךניהםא ליבומיס תסנכנםא.ןוירהבןניהיכתודשוחשואןוירהלסנכיהלתוסנמה,תורהםישנב

תליטנןמזבןוירהל ליבומיס רהםערשקירצוותואלוטיליקיספה, .דימךלשאפו

תולטונהםישנלעהקנהההרוסא.הקינמךניהםא ליבומיס .

לטונךניהםא / :תואבהתופורתהמתחאלכת

יטנאתופורת - לוזאנוקוטק,לוזאנוקארטיאןוגכ)תומייוסמתויתיירטפ , לוזאנוקאסופ לוזאנוקירוווא (

יבכעמ HIV זאטורפ יווקאסוריבאנטויר,ריבאניפלנ,ריבאנידניאןוגכ) (ריבאנ

םייוסמזאטורפיבכעמ לש סיטיטפהסוריו C (ריברפאלטואריברפסובןוגכ)

(ןיצימורטילתואןיצימורטיראלק,ןיצימורטיראןוגכ)תומייוסמתוקיטויביטנא

ןודוזאפנןואכידהדגונ

(לורטסלוכתדרוהלהפורת,תירביפהצמוח)ליזורביפמ'ג

ןירופסולקיצ

לוזאנד

אךלשאפורהתאי/לאש .הלעמלהעיפומךלשהפורתהםאה/חוטבךניאם

,אפורבץעוויהלילב,וזהפורתבשמתשהלןיא לופיטהתלחתהינפל :

.ןהשלכתויגרלאואןהשלכתויאופרתויעבמרבעבתלבסואת/לבוסךניהםא

.דבכתלחמלשהירוטסיהךלשיואלוהוכלאלשתויתועמשמתויומכת/ךרוצךניהםא

ועךניהםא .יתועמשמיביטקלאחותינרובעלת/דמ

.תוילכבתויעבמת/לבוסךניהםא

.הרומחתואירתלחממת/לבוסךניהםא

.םירבסומיתלבםירירשתשלוחואתושיגר,םירירשיבאכמת/לבוסךניהםא

.תיתשרותםירירשתלחממםילבוסםיבורקהךתחפשמינבמדחאואה/תאםא

םירירשבתויעבמרבעבתלבסםא .םיטארביפואםיניטטסתוארקנהלורטסלוכתדרוהלתופורתתליטנתעב

.(דיאורית)סירתהתטולבדוקפתביוקילמת/לבוסךניהםא

ליגלעמךניהםא 65 .

.השיאךניהםא

תורהזא :

.דבכידוקפיתתוקידבךורעלשי,וזהפורתבלופיטהתפוקתב

ךלשאפורה,וזהפורתבת/לפוטמךניהשןמזב עצבי ךירחאקודהבקעמ .תרכוסחתפלןוכיסבךניהואתרכוסךלשיםא

ץחלוףדועלקשמךלשי,ךלשםדבםינמושוםירכוסלשתוהובגתומרךלשיםאתרכוסחתפלןוכיסבךניהשןכתיי - םד

.הובג

ןיבתובוגת - תויתפורת :

,תפסונהפורתת/לטונךניהםא )אפורםשרמאללתולטינהתופורתללוכ OTC ,( ,אפרמיחמצוםינימטיו הזתרמגםאוא

,תרחאהפורתבלופיטההתע יאואםינוכיסעונמלידכ,לפטמהאפורלחוודלךילע - ןיבתובוגתמםיעבונהתוליעי - .תויתפורת

ולךילע ת/לטונךניהיכהשדחהפורתךלםשורשאפורלרמ ליבומיס .

תליטנשןוויכמ ליבומיס תופורתהמתחאלכםע רמוחהוא םי םיאבה י/האר)םירירשתויעבלןוכיסהתאריבגהלהלוכי

ולדחוימבבושח,("יאוולתועפות" :ת/לטונךניהםאךלשאפורלרמ

יטנאתופורת - לוזאנוקאסופ,לוזאנוקוטק,לוזאנוקארטיאןוגכ)תויתירטפ לוזאנוקירוווא, (

יבכעמ HIV זאטורפ קאסו,ריבאנוטיר,ריבאניפלנ,ריבאנידניאןוגכ) (ריבאניוו

סוריובםוהיזבלופיטלתושמשמהתופורת)ריברפאלטואריברפסוב ה סיטיטפה C (

ןיצימורטילתוא,ןיצימורטיראלק,ןיצימורטיראתויקיטויביטנא

ןודוזאפנןואכידהדגונ

ןירופסולקיצ

לוזאנד

גומכ)תירביפהצמוחתורזגנ ' (טארביפאזבוליזורביפמ

ןוראדוימא ןוראדנורדוא ורת) פ תו בלבצקבלופיטל אל - (רידס

לימאפארוו , םזאיטליד ןיזאלונרוא,ןיפידולמא, ץחלרתיבלופיטלתופורת) - וא,הניגנא,םד םירחאםייבבלםיבצמ (

תליטנןמזבותכירצמעמיהלשיש)תוילוכשאץימ ליבומיס (

ומכ - תשירקתודגונתופורתת/לטונךניהוהדימבאפורלרמולבושחןכ - תופורת)םד התוענומה י ומכ,םדישירקתורצוו

,ןיראפרוו ןומוקורפנפ אוא צ וקונ ,(לוראמ ,ןיסקוגיד לשתורחאתורזגנ,טרביפונפוא,ןיצאינ,(טואגבלופיטלהפורת)ןיציכלוק

.ת/יניסךניהוןיצאינליכמהרצומואןיצאינת/לטונךניהםאךלשאפורלי/רפס,ןכומכ.תירביפהצמוח

לןיא לוטי ס ליבומי .תוילוכשאץימםע

."?רישכתבשמתשהלןיאיתמ"קרפםגי/האר

יאוולתועפות :

עיפוהלתולולעוזהפורתבשומישהןמזב,הפורתהלשהיוצרהתוליעפלףסונב תועפות .יאוול ליבומיס ךרדבלבסנ - ללכ

ךרדב.בטיה - תורצקותולקויהיאוולהתועפות,ללכ - .לוכיעהתכרעמבתוערפהןהרתויבתוחיכשהיאוולהתועפות.חווט

עפות ו חיכשיאוולת תו תוחפ יה ןנ השלוח ו באכ - ואתושיגר,םירירשיבאכןהרתוידועהכומנתוחיכשביאוולתועפות.שאר

שלוח ה םירידנםירקמברשא) דואמ ולע תול תקספהרחאלףולחלאל ליבומיס ( צרםיתיעל)דבכבתויעב, ,לדןורכיז,(תויני

,לובלב,ןורכיזןדבוא ,ןואכיד,ןושילהיעב תויעב ,הפקיזב תילאיציטסרטניאהאירתלחמ ) דימתמלועישללוכהמישנתויעב

םוחואהמישנרצוקוא/ו ( םוח,קרפמבבאכללוכ,םינימסתרפסמןהלתויהלםייושערשאתויגרלאתובוגת)רתיתושיגרו,

.(המישנרצוקו

י/רוצ תוריהמבךלשאפורהםערשק תויעב,םירידנםירקמבשןוויכמתאז.השלוחוא,תושיגר,םירירשיבאכהווחךניהםא

ללוכ,תורומחתויהלתויושעםירירש .תוומלליבוהללולערשאהילכלקזנאיהותאצותשםירירשקוריפ

םילטונרשאםילוחברתוילודגםירירשקוריפלןוכיסה יתוהובגתונמ לשרתו ליבומיס לשהנמדחוימב, 80 ןוכיסה.ג"מ

)םירגובמםילוחבםגרתוילודגםירירשקוריפל 65 שנתולפוטמ,(הלעמוםינש אלהילכידוקפתםעתו/םילפוטמ,םי -

.(דיאורית)סירתהתטולבבתויעבםעתו/םילוחו,םיילמרונ

אפורהתאי/האר מרתאקודבלידכעובקןפואבךלש לורטסלוכהת ךירצךלשאפורה.יאוולתועפותקודבלידכוךלש

לוטילה/ליחתמה/תאשינפלךלשדבכהתאקודבלידכםדתוקידבךלתושעל ליבומיס לשםינימסתךלשיםאקודבלידכו

תליטנןמזבדבכבתויעב ליבומיס דימךלשאפורהםערשקי/רוצ. :דבכבתויעבלשםיאבהםינימסתהתאךלשיםא

תשגרה השלוחואתופייע

ןובאיתןדבוא

הנוילעןטבבבאכ

ההכןתש

ךלשםייניעבןבלהלשוארועהלשהבהצה

.םיניטטסםעוחוודםדברכוסהתומרבתוילעואתרכוס םדבםינמושוםירכוסלשתוהובגתומרךלשיםארתויריבסרבדה

לקשמךלשי,ךלש ףדוע ץחלו - ךלשאפורה.הובגםד ךירחאבוקעי ב .וזהפורתתליטנןמז

תויושעיאוולהתועפותמקלח,תרחאםשרמתפורתלכםעומכו,תורידנםיתיעלשחרתהלתויושעתורחאיאוולתועפות

.ףסונעדימלעךלשאפורהתאי/לאש.תויניצרתויהל

הךתשגרהביונישלחםאוא,הזןולעבונייוצאלשיאוולתועפותה/שיגרמךניהובשהרקמלכב םעץעייתהלךילע,תיללכ

.דימאפורה

ןונימוןתמ :

.דבלבאפורהתוארוהיפלןונימה

.ץלמומהןונימהלערובעלןיא

אוהץלמומהיתלחתההןונימה 10 וא 20 .ברעב,םויבםעפג"מ

לשןונימ,םירירשתויעבלרבגומהןוכיסהללגב 80 לשןונימםילטונרשאםילוחרובעקרוניהג"מ 80 ג"מ )ינורכןפואב 12

(הלעמוםישדוח אלל םעדחיתורחאתומייוסמתופורתתחקלםיכירצאלרשאורירשלקזנ ליבומיס ריבגהלתולולערשא,

התא יוכיס .רירשבקזנחתפלךלש

ת/לטונךניהםאדחוימב,רתויםיכומנםינונימךלםושריךלשאפורהוןכתיי ישואהלעמלתועיפומהתומייוסמתופורת ךלש

לוטילי/ךשמה.הילכבםימייוסמםיבצמ ליבומיס לוטילי/קיספתםא.קיספהלךלרמאךלשאפורהםאאלא ליבומיס ,

עליושעךלשלורטסלוכה ל .בושתו

ליגלתחתמםירגבתמוםידלילןתמלתדעוימהניאוזהפורת 20 .םינש

לפטמהאפורהי"עעבקנשיפכםיבוצקםינמזבוזהפורתבשמתשהלשי .

.ליגרההליטנהחוללרוזחלשי,תפסונהנמלוטילןיא,עבקנשןמזבוזהפורתלוטילתחכשםא

תלדהטאידלעדיפקהלשי,וזהפורתבלופיטהתפוקתב ןמוש .

שומישהןפוא :

עולבלשי הפורתה םימטעמםע .

לוטילןיא ליבומיס םע .תוילוכשאץימ

.ברעבהפורתהתאלוטילץלמומ

ציכ ?לופיטהתחלצהלעייסלי/לכותד

.אפורהי"עץלמוהשיפכלופיטהתאםילשהלךילע

.אפורהםעתוצעייתהאללהפורתבלופיטהתאקיספהלןיא,ךתואירבבצמברופישלחםאםג

הלערהי/ענמ :

,תוקוניתוא/וםידלילשםדיגשיהלץוחמרוגסםוקמברומשלשי,תרחאהפורתלכומכ,וזהפורת ענמתךכידילעו

.הלערה

הפורתהתזיראאיבהלוםילוחתיבלשןוימרדחלדימתונפלשי,הפורתהןמדליעלבתועטבםאוארתיתנמתלטנםא

.ךתיא

האקהלםורגלןיא !אפורמתשרופמהארוהאלל

רחאהלוחב;ךתלחמבלופיטלהמשרנוזהפורת ת/ .קיזהלהלולעאיה, ורקלוזהפורתי/ןתיתלא ,ךיב ש .ךירכמואךינכ

ךשוחבתופורתלוטילןיא הנמהותיוותהקודבלשי! םעפלכב .הפורתת/לטונךניהש

.םהלה/קוקזךניהםאםייפקשמביכרהלשי

א הנסח :

לתחתמוזהפורתןסחאלשי - 30˚C .

ה/הזיראהיאנתיפלםג א .דבלבתלבגומהפוקתלתורמשנתופורת,םיצלמומההנסח

םישלאנ .הפורתהתאךלקפיסשחקורבץעוויהלךילע,קפסלשהרקמלכב!רישכתהלשהגופתהךיראתלבל

.הזיראהתואבתונושתופורתןסחאלןיא

םיעצמאבהטיקנ.ךרוצדועןהבןיאשתופורתדימשהלדציכחקורבי/ץעוויה.תיתיבההפשאלואהלסאלתופורתךילשהלןיא

סהתוכיאלעהרימשבעייסתולא .הביב

:הפורתהםושיר'סמ

ליבומיס 10 ג"מ :תוילבט 127 532669400

ליבומיס 20 ג"מ :תוילבט 127 5226695 00

ליבומיס 40 ג"מ :תוילבט 127 5126696 00

םהודופראשקרמ:ןרצי B.V. דנלוה,םלראאה,

:םושירהלעב שקרמתרבח א לארשי)םהודופר - 1996 ב( .ד.ת,מ"ע 7121 חתפ - הוקת 49170 .

HIGHLIGHTS OF PRESCRIBING INFORMATION

Thesehighlightsdonot include all the information needed to use

SIMOVILsafelyandeffectively.See full prescribing information

for SIMOVIL.

SIMOVIL ® (simvastatin) Tablets

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

Dosage and Administration

Recommended Dosing (2.1)

Restricted Dosing for 80 mg (2.2)

Coadministration with Other Drugs (2.3)

Patients with Homozygous Familial

Hypercholesterolemia (2.4)

Chinese Patients Taking Lipid-Modifying Doses

1 g/dayNiacin) of Niacin-Containing Products (2.7)

Contraindications (4)

Warnings and Precautions

Myopathy/Rhabdomyolysis (5.1)

Liver Dysfunction (5.2)

Endocrine Function (5.3)

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

SIMOVIL ® is an HMG-CoA reductase inhibitor (statin) indicated as an

adjunctive therapyto diet:

Toreducetherisk of total mortalitybyreducing coronarydeath and

reducetherisk of non-fatal myocardial infarction, stroke, and

transient ischemic attacks;reduce the risk for undergoing

revascularization procedures. (1.1)

To reduce elevated total-C, LDL-C, ApoB,TGandincreaseHDL-C

inpatients with primaryhyperlipidemia (heterozygous familial and

nonfamilial) and mixed dyslipidemia. (1.2)

For the treatment of patients with hypertriglyceridemia (1.3)

Forthe treatment of patients with primarydysbetalipoproteinemia.

(1.4)

Toreducetotal-C,andApo B in patients with homozygous familial

hypercholesterolemia. (1.5)

-----------------------DOSAGEANDADMINISTRATION------------------------

Dose range is 5 to 40 mg/day. (2.1)

Recommended usual starting dose is 10 or 20mg once a dayin

the evening. (2.1)

Due to the increased risk ofmyopathy,includingrhabdomyolysis,

useofthe80-mgdoseof SIMOVIL should be restricted to patients

whohavebeentakingsimvastatin 80 mg chronically(e.g., for

12 months or more) withoutevidence of muscle toxicity . (2.2)

Patientswho are currentlytolerating the 80-mg dose of SIMOVIL

who need to be initiated on aninteractingdrugthatis

contraindicated or is associatedwith a dose cap forsimvastatin

should be switched to an alternative statin withlesspotentialforthe

drug-drug interaction. (2.2)

Due to the increased risk ofmyopathy,includingrhabdomyolysis,

associatedwiththe 80-mg dose of SIMOVIL, patients unable to

achieve their LDL-C goal utilizing the 40-mg dose of SIMOVIL

should not be titratedtothe80-mg dose, but should be placed on

alternative LDL-C-lowering treatment(s) that provides greater LDL-C

lowering. (2.2)

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

Tablets: 10 mg; 20 mg; 40 mg (3)

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

Concomitant administration of strong CYP3A4 inhibitors. (4, 5.1)

Concomitant administration ofgemfibrozil, cyclosporine,or

danazol. (4, 5.1)

Active liver disease,which mayinclude unexplained persistent

elevations in hepatic transaminase levels. (4, 5.2)

Women who are pregnant or maybecome pregnant. (4, 8.1)

Nursing mothers. (4, 8.3)

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

Patientsshould be advised of the increased risk of myopathy

including rhabdomyolysis with the 80-mg dose. (5.1)

Skeletal muscle effects (e.g., myopathyand rhabdomyolysis): Risks

increase with higher doses andconcomitant use of certain

medicines. Predisposing factors include advanced age (≥65), female

gender,uncontrolledhypothyroidism, and renal impairment. (4, 5.1,

8.5, 8.6)

Patients should be advised toreport promptlyanyunexplained

and/or persistent muscle pain,tenderness or weakness. SIMOVIL

therapyshould bediscontinuedimmediatelyif myopathyis

diagnosed or suspected. See Drug Interaction table. (5.1)

Liver enzyme abnormalities: Persistent elevations in hepatic

transaminases can occur.Checkliver enzyme tests before initiating

therapyand as clinicallyindicated thereafter. (5.2)

------------------------------ADVERSEREACTIONS-------------------------------

Most common adversereactions (incidence≥5.0%) are: upper

respiratoryinfection, headache,abdominal pain, constipation, and

nausea. (6.1)

-------------------------------DRUGINTERACTIONS-------------------------------

Drug Interactions Associated with Increased Risk of

Myopathy/Rhabdomyolysis(2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)

Interacting Agents Prescribing Recommendations

Strong CYP3A4 Inhibitors

(e.g., itraconazole,

ketoconazole, posaconazole,

voriconazole, erythromycin,

clarithromycin, telithromycin,

HIV protease inhibitors,

boceprevir, telaprevir,

nefazodone), gemfibrozil,

cyclosporine, danazol Contraindicated with simvastatin

Verapamil, diltiazem,

dronedarone Do not exceed 10 mg simvastatin

daily

Amiodarone, amlodipine,

ranolazine Do not exceed 20 mg simvastatin

daily

Grapefruit juice Avoid grapefruit juice

Other Lipid-lowering Medications: Usewithother fibrate products or

lipid-modifying doses (≥1g/day) of niacin increases the risk of

adverse skeletal muscle effects. Caution should be usedwhen

prescribing with simvastatin. (5.1, 7.2, 7.4)

Coumarin anticoagulants: Concomitant usewithSIMOVILprolongs

INR.AchievestableINRprior to starting SIMOVIL. Monitor INR

frequentlyuntilstable upon initiation or alteration of SIMOVIL

therapy. (7.6)

-----------------------USEINSPECIFIC POPULATIONS -----------------------

Severe renal impairment: patients should be started at 5mg/dayand

be closelymonitored. (2.6, 8.6)

See 17 for PATIENT COUNSELINGINFORMATION.

FULL PRESCRIBING INFORMATION: CONTENTS*

1INDICATIONS AND USAGE

1.1 Reductions in Risk of CHD Mortalityand Cardiovascular

Events

1.2 Hyperlipidemia

1.3 Adolescent Patients with Heterozygous Familial

Hypercholesterolemia (HeFH)

1.4 Limitations of Use

2DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

2.2 Restricted Dosing for 80 mg

2.3 Coadministration with Other Drugs

2.4 Patients with Homozygous Familial Hypercholesterolemia

2.6 Patients with Renal Impairment

2.7 Chinese Patients Taking Lipid-Modifying Doses ( 1 g/day

Niacin) of Niacin-Containing Products

3DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis

5.2 Liver Dysfunction

5.3 Endocrine Function

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

7.1 Strong CYP3A4 Inhibitors, cyclosporine, or danazol

7.2 Lipid-Lowering Drugs That Can Cause MyopathyWhen

Given Alone

7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel

Blockers

7.5 Digoxin

7.6 Coumarin Anticoagulants

7.7 Colchicine

8USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

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

13.2Animal Toxicologyand/or Pharmacology

14 CLINICALSTUDIES

14.1Clinical Studies in Adults

16HOW SUPPLIED/STORAGE AND HANDLING

17PATIENT COUNSELING INFORMATION

17.1 Muscle Pain

17.2 Liver Enzymes

17.3 Pregnancy

17.4 Breastfeeding

*Sections or subsectionsomitted from the full prescribing information

are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 CoronaryHeart Disease

In patients with coronary heart disease and hypercholesterolemia, Simovil is indicated to:

Reduce the risk of total mortality by reducing coronary death;

Reduce the risk of non-fatal myocardial infarction;

Reduce the risk for undergoing myocardial revascularization procedures.

Reduce the risk of stroke and transient ischemic attacks (TIA).

1.2 Hyperlipidemia

Simovilis indicated as an adjunct to diet to reduce elevated TOTAL-C, LDL-C, Apo B and TG, and to

increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and

mixeddyslipidemia(FredericksonTypes IIa and IIb) Simovil therefore, lowersthe LDL-C/HDL-C and the

total-C/HDL-C ratios.

1.3 Hypertriglyceridemia (Fredrickson type IV hyperlipidemia)

Simovilisindicatedfor the treatment of patients with hypertriglyceridemia (Fredrickson type lV

hyperlipidemia).

1.4 Dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia)

Simovil is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson typelll

hyperlipidemia).

1.5 Homozygous Familial Hypercholesterolemia

Simovil is also indicated as an adjunct to diet andothernon-dietary measures in reducing elevated total

cholesterol, LDL-cholesterol and apolipoprotein B in patients with homozygous familial

hypercholesterolemia when responseto these measures is inadequate.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The usual dosage range is 5 to 40mg/day. Inpatients with CHD, SIMOVIL can be started

simultaneously with diet. The recommended usual starting dose is 10 or 20mg once a day in the

evening. Lipid determinations should be performed after4 weeks of therapy and periodically thereafter.

2.2Restricted Dosing for 80 mg

Dueto the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of

treatment, use of the 80-mg dose of SIMOVIL shouldberestricted to patients who have been taking

simvastatin 80mg chronically (e.g., for 12monthsor more) without evidence of muscle toxicity[see

Warnings and Precautions (5.1)].

Patients who are currently tolerating the 80-mgdose of SIMOVIL who need to beinitiatedonan

interacting drug that is contraindicated or isassociatedwitha dose cap for simvastatin should be

switched to an alternative statin with less potential for the drug-drug interaction.

Duetotheincreasedrisk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of

SIMOVIL, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of SIMOVIL should notbe

titratedtothe 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides

greater LDL-C lowering.

2.3Coadministration with Other Drugs

Patients taking Verapamil, Diltiazemor Dronedarone

The dose of SIMOVIL should notexceed10mg/day[see Warnings and Precautions (5.1), Drug

Interactions (7.3), and Clinical Pharmacology (12.3)].

Patients taking Amiodarone, Amlodipine or Ranolazine

The dose of SIMOVIL should notexceed20mg/day[see Warnings and Precautions (5.1), Drug

Interactions (7.3), and Clinical Pharmacology (12.3)].

2.4Patients with Homozygous Familial Hypercholesterolemia

The recommended dosage is 40mg/day in the evening[see Dosage and Administration,Restricted

Dosing for 80mg(2.2)]. SIMOVIL should be used as an adjunct toother lipid-lowering treatments (e.g.,

LDL apheresis) in these patients or ifsuch treatments are unavailable.

2.6Patients with Renal Impairment

Because SIMOVIL does not undergo significant renalexcretion, modification of dosage should not be

necessaryinpatients with mild to moderate renalimpairment. However, caution should be exercised

when SIMOVIL is administered to patients with severerenal impairment; such patients should be started

at 5mg/day and be closely monitored[seeWarningsandPrecautions (5.1) and Clinical Pharmacology

(12.3)].

2.7ChinesePatientsTaking Lipid-Modifying Doses ( 1g/dayNiacin) of Niacin-Containing

Products

Because of an increased risk for myopathy inChinesepatients taking simvastatin 40mg

coadministered with lipid-modifying doses( 1g/day niacin) of niacin-containing products, caution should

be used when treating Chinese patientswithsimvastatin doses exceeding 20mg/day coadministered

with lipid-modifying doses of niacin-containingproducts. Because the risk for myopathy is dose-related,

Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of

niacin-containing products. The cause of the increasedrisk of myopathy is not known. Itisalsounknown

iftherisk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing

products observed in Chinese patients applies to other Asian patients.[See WarningsandPrecautions

(5.1).]

3 DOSAGE FORMS AND STRENGTHS

Tablets SIMOVIL 10mg are peach, oval, film-coatedtablets, coded MSD735 on one side and plain

on the other.

Tablets SIMOVIL 20mg aretan,oval,film-coated tablets, coded MSD740 on one side and plain on

the other.

Tablets SIMOVIL 40mg are brick red, oval, film-coated tablets, coded MSD749ononesideand

plain on the other.

4 CONTRAINDICATIONS

SIMOVIL is contraindicated in the following conditions:

Concomitantadministration of strong CYP3A4inhibitors (e.g., itraconazole, ketoconazole,

posaconazole, voriconazole, HIV protease inhibitors, boceprevir,telaprevir, erythromycin,

clarithromycin, telithromycin and nefazodone)[see Warnings and Precautions (5.1)].

Concomitant administration of gemfibrozil, cyclosporine, or danazol[see Warnings and Precautions

(5.1)].

Hypersensitivity to any component of this medication[see Adverse Reactions (6.2)].

Activeliver disease, which may include unexplained persistent elevationsin hepatic transaminase

levels[see Warnings and Precautions (5.2)].

Womenwhoare pregnant or may become pregnant.

Serum cholesterol and triglycerides increase

during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal

development. Because HMG-CoA reductase inhibitors(statins) decrease cholesterol synthesis and

possibly the synthesis of other biologically active substancesderived from cholesterol, SIMOVIL may

causefetalharmwhen administered to a pregnant woman. Atherosclerosis is a chronic process and

the discontinuation of lipid-lowering drugs duringpregnancyshouldhave little impact on the outcome

of long-term therapy of primary hypercholesterolemia. There are no adequate andwell-controlled

studiesofuse with SIMOVIL during pregnancy; however, in rare reports congenital anomalies were

observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies,

simvastatin revealed no evidence of teratogenicity.SIMOVIL should be administered to women of

childbearing age onlywhen such patients are highlyunlikelyto conceive.If the patient

becomespregnantwhile taking this drug, SIMOVIL should be discontinued immediately and the

patient should be apprised of the potential hazard to the fetus[see Use in Specific Populations (8.1)].

Nursing mothers. It is not known whether simvastatin is excreted into human milk; however,asmall

amount of another drug in this class does pass intobreast milk. Because statins have the potential for

serious adverse reactions in nursing infants, women who require treatment withSIMOVILshouldnot

breastfeed their infants[see Use in Specific Populations (8.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis

Simvastatinoccasionally causes myopathy manifested as muscle pain, tenderness or weakness with

creatinekinase(CK)above tentimes the upper limitof normal (ULN). Myopathy sometimes takes the

form of rhabdomyolysis with or without acute renalfailure secondary to myoglobinuria, and rarefatalities

haveoccurred.The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing

factors for myopathy include advanced age (≥65 years), female gender, uncontrolledhypothyroidism,and

renal impairment.

The risk of myopathy,including rhabdomyolysis, is dose related.In a clinical trial database in

which 41,413 patients were treated withSIMOVIL,24,747 (approximately 60%) of whom were enrolled in

studies with a median follow-up of at least 4 years, the incidence of myopathywas approximately 0.03%

and 0.08% at 20 and 40mg/day, respectively. Theincidence of myopathy with 80mg (0.61%) was

disproportionately higher than that observedatthe lower doses. In these trials, patients were carefully

monitored and some interacting medicinal products were excluded.

In a clinical trial in which 12,064 patients with ahistory of myocardial infarction were treated with

SIMOVIL(meanfollow-up 6.7years), the incidence of myopathy (defined as unexplained muscle

weakness or pain with a serum creatine kinase [CK]>10times upper limit of normal [ULN]) in patientson

80mg/day was approximately 0.9% compared with0.02%for patients on 20mg/day. The incidence of

rhabdomyolysis (defined as myopathywith a CK>40timesULN) in patients on 80mg/day was

approximately 0.4% compared with0% for patients on 20mg/day. The incidence of myopathy, including

rhabdomyolysis, was highest during thefirstyear and then notably decreased during the subsequent

years of treatment. In this trial, patients were carefullymonitored and some interacting medicinal products

were excluded.

Theriskofmyopathy,including rhabdomyolysis, is greater in patients on simvastatin 80mg

comparedwithotherstatintherapies with similar or greater LDL-C-lowering efficacyand

compared with lower doses of simvastatin. Therefore, the80-mgdoseofSIMOVILshouldbeused

onlyin patients who havebeen taking simvastatin 80mg chronically(e.g., for 12monthsormore)

without evidence of muscle toxicity[see Dosage and Administration, Restricted Dosing for 80mg

(2.2)].If,however, a patient who is currentlytolerating the 80-mg dose of SIMOVIL needs to be

initiated on an interacting drug that is contraindicated orisassociatedwithadosecapfor

simvastatin,thatpatientshould be switched to analternative statin with less potential for the

drug-drug interaction. Patients should be advised of the increased risk of myopathy,including

rhabdomyolysis, and to report promptlyanyunexplainedmusclepain,tendernessorweakness.If

symptoms occur, treatment should be discontinuedimmediately.[See Warnings and Precautions

(5.2).]

There have been rare reports of immune-mediatednecrotizing myopathy (IMNM), an autoimmune

myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness andelevated

serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsyshowing

necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

All patients starting therapywith SIMOVIL, or whose doseofSIMOVILisbeingincreased,

shouldbe advised of the risk of myopathy,including rhabdomyolysis, and told to report promptly

anyunexplainedmuscle pain, tenderness or weakness particularlyif accompanied bymalaise or

fever or if muscle signs and symptoms persist after discontinuing SIMOVIL. SIMOVILtherapy

should be discontinued immediatelyif myopathyis diagnosedorsuspected.Inmostcases,muscle

symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK

determinationsmay be considered in patients starting therapy with SIMOVIL or whose dose is being

increased, but there is no assurance thatsuch monitoring will prevent myopathy.

Many of the patients who have developed rhabdomyolysis on therapywith simvastatin have had

complicated medical histories, including renal insufficiency usually as a consequence of long-standing

diabetes mellitus. Such patients meritclosermonitoring. SIMOVIL therapyshould be discontinued if

markedly elevated CPK levels occurormyopathyisdiagnosed or suspected. SIMOVIL therapy should

also be temporarily withheld in anypatient experiencing an acute or seriouscondition predisposing to the

development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery;

trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

Drug Interactions

The risk of myopathy and rhabdomyolysis is increased by high levels ofstatinactivityinplasma.

Simvastatin is metabolized by the cytochrome P450isoform 3A4. Certain drugs which inhibit this

metabolic pathway can raise the plasma levels ofsimvastatinandmay increase the risk of myopathy.

These include itraconazole, ketoconazole, posaconazole,voriconazole, the macrolide antibiotics

erythromycin and clarithromycin, and the ketolideantibiotic telithromycin, HIV protease inhibitors,

boceprevir, telaprevir, the antidepressantnefazodone, or grapefruit juice.[see Clinical Pharmacology

(12.3)]Combination of these drugs with simvastatin is contraindicated. If short-term treatment with strong

CYP3A4inhibitors is unavoidable, therapy withsimvastatin must be suspended during the course of

treatment.[See Contraindications (4) and Drug Interactions (7.1).]

The combined use of simvastatin with gemfibrozil,cyclosporine, or danazol is contraindicated[see

Contraindications (4) and Drug Interactions (7.1 and 7.2)].

Caution should be used when prescribing other fibrates with simvastatin, as these agents cancause

myopathy when given alone and the risk is increased when theyareco-administered[see Drug

Interactions(7.2)].

Cases of myopathy, including rhabdomyolysis, have been reportedwithsimvastatincoadministered

with colchicine, and cautionshouldbeexercisedwhen prescribing simvastatin with colchicine[see Drug

Interactions(7.7)].

The benefits of the combined use of simvastatin with the following drugs should be carefully weighed

against the potential risks of combinations: otherlipid-lowering drugs (other fibrates or 1 g/day of niacin),

amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine[see Drug Interactions(7.3)

and Table 3 in Clinical Pharmacology (12.3)].

Cases of myopathy,includingrhabdomyolysis, have been observed withsimvastatin coadministered

with lipid-modifying doses ( 1g/dayniacin) of niacin-containing products. In an ongoing, double-blind,

randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the

incidenceof myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40

mgcoadministeredwith lipid-modifying doses ofa niacin-containing product. Caution should be used

when treating Chinese patients with simvastatin indoses exceeding 20mg/day coadministeredwithlipid-

modifying doses of niacin-containingproducts. Because the risk for myopathy is dose-related, Chinese

patients should not receive simvastatin 80mgcoadministered with lipid-modifying doses of niacin-

containing products.It is unknown if the risk for myopathy withcoadministrationof simvastatin with

lipid-modifying doses of niacin-containing products observed in Chinese patients appliestootherAsian

patients[see Drug Interactions (7.4)].

Prescribing recommendations for interacting agents are summarized inTable1[see also Dosage and

Administration (2.3), Drug Interactions(7), Clinical Pharmacology (12.3)].

TABLE 1

Drug Interactions Associated with Increased

Risk of Myopathy/Rhabdomyolysis

Interacting Agents Prescribing Recommendations

Strong CYP3A4 Inhibitors, e.g.:

Itraconazole

Ketoconazole

Posaconazole

Voriconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Boceprevir

Telaprevir

Nefazodone

Gemfibrozil

Cyclosporine

Contraindicated with simvastatin

Verapamil

Diltiazem

Dronedarone Do not exceed 10 mg simvastatin daily

Amiodarone

Amlodipine

Ranolazine Do not exceed 20 mg simvastatin daily

Grapefruit juice Avoid grapefruit juice

5.2 Liver Dysfunction

Persistent increases (to more than 3X the ULN) in serum transaminases haveoccurredin

approximately1%of patients who receivedsimvastatininclinicalstudies. When drug treatment

was interrupted or discontinued inthese patients, the transaminaselevels usually fell slowlyto

pretreatment levels. The increases were not associatedwithjaundiceor other clinical signs or symptoms.

There was no evidence ofhypersensitivity.

In the Scandinavian Simvastatin Survival Study(4S)[see Clinical Studies (14.1)], the number of

patients with more than one transaminase elevation to>3X ULN, over the courseof the study, was not

significantly different between the simvastatin andplacebo groups (14 [0.7%] vs. 12 [0.6%]).Elevated

transaminases resulted in the discontinuation of 8 patientsfromtherapy in the simvastatin group

(n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4Swith

normal liver function tests (LFTs) at baseline, 8(0.4%) developed consecutive LFT elevations to >3X

ULN and/or were discontinued due to transaminase elevationsduringthe 5.4 years (median follow-up) of

the study. Among these 8 patients, 5initially developed these abnormalities within the first year. All of the

patients in this study received astarting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.

In 2 controlled clinical studies in1,105patients, the 12-month incidence of persistent hepatic

transaminase elevation without regardtodrugrelationship was 0.9% and 2.1% at the 40- and 80-mg

dose, respectively. No patientsdeveloped persistent liver functionabnormalitiesfollowing the initial

6 months of treatment at a given dose.

It is recommended that liver function tests be performed before the initiationoftreatment,and

thereafter when clinicallyindicated.There have been rare postmarketing reports of fatal and non-fatal

hepatic failure in patients taking statins,including simvastatin. If serious liver injury with clinical symptoms

and/or hyperbilirubinemia or jaundiceoccursduringtreatment with SIMOVIL, promptly interrupt therapy. If

an alternate etiology is not found do not restartSIMOVIL. Note that ALT may emanate from muscle,

therefore ALT rising with CK may indicate myopathy[see Warnings and Precautions (5.1)].

The drug should be used with caution in patients whoconsumesubstantial quantities of alcohol and/or

have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are

contraindications to the use of simvastatin.

As with other lipid-lowering agents, moderate (lessthan 3X ULN) elevations ofserumtransaminases

have been reported following therapy with simvastatin. These changes appeared soon after initiationof

therapy with simvastatin, were often transient,werenotaccompanied by any symptoms and did not

require interruption of treatment.

5.3 Endocrine Function

Increases in HbA1c and fasting serum glucose levelshavebeen reported with HMG-CoA reductase

inhibitors, including SIMOVIL.

HMG-CoA reductase inhibitors as a class raisebloodglucose and in some patients, at high risk of

future diabetes, may produce a level of hyperglycaemiawhere formal diabetes careisappropriate.This

risk, however, is outweighed by the reduction in vascularriskwithstatins and therefore should not be a

reason for stopping statin treatment.Patientsat risk (i.e. those withfasting glucose 5.6 - 6.9 mmol/L,

bodymass index > 30kg/m 2 , raised triglycerides or hypertension)should be monitored both clinically and

biochemically according to national guidelines.

6 ADVERSE REACTIONS

6.1Clinical Trials Experience

Because clinical studies are conducted underwidely varying conditions, adverse reaction rates

observed in the clinical studies of a drug cannot be directlycomparedto rates in the clinical studies of

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

In the pre-marketing controlled clinical studiesand their open extensions (2,423 patients with median

duration of follow-up ofapproximately18months),1.4% of patients werediscontinued due to adverse

reactions.Themost common adverse reactionsthat led to treatment discontinuation were:

gastrointestinal disorders (0.5%), myalgia (0.1%),andarthralgia(0.1%). The most commonly reported

adverse reactions (incidence≥5%) in simvastatin controlled clinical trials were: upper respiratory

infections (9.0%), headache (7.4%), abdominal pain(7.3%), constipation (6.6%), and nausea (5.4%).

Scandinavian Simvastatin Survival Study

In 4S involving 4,444 (age range 35-71years,19% women, 100% Caucasians) treated with

20-40mg/day of SIMOVIL (n=2,221)or placebo (n=2,223) overamedianof 5.4 years, adverse reactions

reported in 2% of patients and at a rate greaterthan placebo are shown in Table 2.

TABLE 2

Adverse Reactions ReportedRegardless of Causalityby 2% of Patients Treated

with SIMOVIL and Greater than Placebo in 4S

SIMOVIL

(N = 2,221)

% Placebo

(N = 2,223)

%

Body as a Whole

Edema/swelling

Abdominal pain 2.7

5.9 2.3

5.8

Cardiovascular SystemDisorders

Atrial fibrillation 5.7 5.1

Digestive System Disorders

Constipation

Gastritis 2.2

4.9 1.6

3.9

Endocrine Disorders

Diabetes mellitus 4.2 3.6

Musculoskeletal Disorders

Myalgia 3.7 3.2

Nervous System/ Psychiatric

Disorders

Headache

Insomnia

Vertigo 2.5

4.0

4.5 2.1

3.8

4.2

Respiratory SystemDisorders

Bronchitis

Sinusitis 6.6

2.3 6.3

1.8

Skin / Skin Appendage Disorders

Eczema 4.5 3.0

Urogenital System Disorders

Infection, urinarytract 3.2 3.1

Heart Protection Study

In the Heart Protection Study (HPS), involving20,536 patients (age range 40-80 years, 25% women,

97% Caucasians, 3% other races) treated withSIMOVIL 40mg/day (n=10,269) or placebo (n=10,267)

overamean of 5 years, only serious adversereactions and discontinuations due to any adverse

reactions were recorded. Discontinuation rates due toadverse reactionswere4.8% in patients treated

with SIMOVIL compared with 5.1% in patientstreatedwith placebo. The incidence of

myopathy/rhabdomyolysis was <0.1% inpatients treated with SIMOVIL.

Other Clinical Studies

In a clinical trial in which 12,064 patients with ahistory of myocardial infarction were treated with

SIMOVIL(meanfollow-up 6.7years), the incidence of myopathy (defined as unexplained muscle

weakness or pain with a serum creatine kinase [CK] >10timesupperlimitof normal [ULN]) in patients on

80mg/day was approximately 0.9% compared with0.02%for patients on 20mg/day. The incidence of

rhabdomyolysis (defined as myopathywith a CK>40timesULN) in patients on 80mg/day was

approximately 0.4% compared with 0%forpatients on 20mg/day. The incidence of myopathy, including

rhabdomyolysis, was highest during thefirstyear and then notably decreased during the subsequent

years of treatment. In this trial, patients were carefullymonitored and some interacting medicinal products

were excluded.

Other adverse reactions reported inclinical trials were: diarrhea,rash, dyspepsia, flatulence, and

asthenia.

Laboratory Tests

Marked persistent increases ofhepatic transaminases have been noted[see Warnings and

Precautions (5.2)]. Elevated alkaline phosphataseand -glutamyl transpeptidase have also been

reported. About 5% of patients had elevations of CK levels of 3or more times the normal value on one or

more occasions. This was attributable to the noncardiac fraction ofCK.[See Warnings and Precautions

(5.1).]

6.2 Post-Marketing Experience

Because the below reactions arereported voluntarily from a population of uncertain size, it is generally

not possible to reliably estimatetheirfrequencyorestablish a causal relationship to drug exposure. The

followingadditionaladverse reactions have been identified during postapproval use of simvastatin:

pruritus, alopecia, a variety of skin changes (e.g.,nodules,discoloration, dryness of skin/mucous

membranes, changes to hair/nails), dizziness, muscle cramps, myalgia, pancreatitis, paresthesia,

peripheralneuropathy,vomiting, anemia, erectile dysfunction, interstitial lung disease, rhabdomyolysis,

hepatitis/jaundice, fatal and non-fatal hepatic failure, and depression.

There have been rare reportsofimmune-mediatednecrotizing myopathy associated with statin use

[see Warnings and Precautions (5.1)].

An apparent hypersensitivity syndrome has been reported rarely which has includedsomeofthe

followingfeatures: anaphylaxis, angioedema, lupuserythematous-like syndrome, polymyalgia

rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia,leukopenia, hemolyticanemia,

positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria,asthenia, photosensitivity, fever,

chills, flushing, malaise, dyspnea,toxicepidermalnecrolysis, erythema multiforme, including Stevens-

Johnson syndrome.

Therehavebeen rare postmarketing reports of cognitiveimpairment (e.g., memory loss, forgetfulness,

amnesia, memory impairment, confusion) associated with statin use. These cognitive issueshavebeen

reportedforall statins. The reports are generallynonserious, and reversible upon statin discontinuation,

with variable times to symptom onset (1 day toyears) and symptom resolution (median of 3 weeks).

7 DRUG INTERACTIONS

7.1Strong CYP3A4 Inhibitors, cyclosporine, or danazol

Strong CYP3A4 inhibitors: Simvastatin, likeseveral other inhibitors of HMG-CoA reductase, is a

substrate of CYP3A4. Simvastatinis metabolized by CYP3A4 but hasno CYP3A4 inhibitory activity;

therefore it is not expected to affect the plasmaconcentrations of other drugsmetabolized by CYP3A4.

Elevated plasma levels of HMG-CoA reductaseinhibitory activity increasesthe risk of myopathy and

rhabdomyolysis, particularlywithhigher doses of simvastatin.[See Warnings and Precautions (5.1)and

Clinical Pharmacology (12.3).]Concomitant use of drugs labeled ashaving a strong inhibitory effect on

CYP3A4 is contraindicated[see Contraindications (4)].If treatment with itraconazole, ketoconazole,

posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with

simvastatin must be suspended during the course of treatment.

Cyclosporine or Danazol: The risk of myopathy,including rhabdomyolysis is increased by concomitant

administration of cyclosporine or danazol. Therefore, concomitant use ofthese drugs is contraindicated.

[see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

7.2Lipid-Lowering Drugs That Can Cause MyopathyWhen Given Alone

Gemfibrozil:Contraindicated with simvastatin[see Contraindications (4) and Warnings and

Precautions (5.1)].

Other fibrates: Caution should be usedwhen prescribing with simvastatin[see Warnings and

Precautions (5.1)].

7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers

The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of

amiodarone, dronedarone, ranolazine, or calcium channelblockers such as verapamil,diltiazem,or

amlodipine[see Dosage and Administration (2.3) and Warnings and Precautions(5.1),andTable3in

Clinical Pharmacology (12.3)].

7.4 Niacin

Cases of myopathy/rhabdomyolysishavebeenobserved with simvastatin coadministered with

lipid-modifying doses ( 1g/day niacin) of niacin-containing products. In particular, caution shouldbeused

when treating Chinese patientswithsimvastatindoses exceeding 20mg/day coadministered with

lipid-modifying doses of niacin-containing products.Because the risk for myopathy is dose-related,

Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of

niacin-containing products.[See Warnings and Precautions (5.1)and Clinical Pharmacology (12.3).]

7.5 Digoxin

In one study, concomitant administration of digoxin with simvastatin resulted in a slightelevationin

digoxinconcentrationsin plasma. Patients taking digoxin should be monitored appropriately when

simvastatin is initiated[see Clinical Pharmacology (12.3)].

7.6 Coumarin Anticoagulants

Intwoclinical studies, one in normal volunteersand the other in hypercholesterolemic patients,

simvastatin 20-40mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin

time, reported as International Normalized Ratio (INR), increased from a baseline of1.7to1.8andfrom

2.6to3.4in the volunteer and patient studies, respectively. With other statins,clinically evident bleeding

and/or increased prothrombin timehasbeenreportedin a few patients taking coumarin anticoagulants

concomitantly. In such patients, prothrombin timeshouldbe determined before starting simvastatin and

frequently enough during early therapy toensure that nosignificantalteration of prothrombin time occurs.

Once a stable prothrombin time has been documented,prothrombintimes can be monitored at the

intervalsusuallyrecommended for patients on coumarin anticoagulants. If the dose of simvastatin is

changedordiscontinued, the same procedure should be repeated. Simvastatin therapy has not been

associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

7.7 Colchicine

Cases of myopathy, including rhabdomyolysis, have been reportedwithsimvastatincoadministered

with colchicine, and caution should be exercisedwhen prescribing simvastatin with colchicine.

8 USE IN SPECIFICPOPULATIONS

8.1 Pregnancy

Pregnancy Category X [See Contraindications (4).]

SIMOVIL is contraindicated in women who are ormay become pregnant. Lipidloweringdrugsofferno

benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal

development. Atherosclerosis is a chronic process,and discontinuation of lipid-lowering drugs during

pregnancyshouldhave little impact on long-term outcomes of primary hypercholesterolemia therapy.

There are no adequate and well-controlled studies ofuse with SIMOVIL during pregnancy; however,

there are rare reports of congenital anomalies in infants exposed to statinsin utero. Animal reproduction

studies of simvastatin in rats and rabbitsshowedno evidence of teratogenicity. Serum cholesterol and

triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential

for fetal development. Becausestatinsdecreasecholesterol synthesis and possiblythe synthesis of other

biologically active substances derived from cholesterol, SIMOVIL may cause fetal harmwhen

administered to a pregnant woman. If SIMOVIL isusedduring pregnancy or if the patient becomes

pregnant while taking this drug, the patient shouldbe apprised of the potential hazard to the fetus.

There are rare reports of congenital anomalies following intrauterine exposure to statins. Inareview 1

of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another

structurally related statin,the incidences of congenitalanomalies, spontaneous abortions, and fetal

deaths/stillbirths did not exceedthose expected in the general population. However, the study was only

able to exclude a 3- to 4-foldincreasedriskofcongenital anomalies over the background rate. In 89% of

these cases, drug treatment was initiated prior to pregnancy and was discontinuedduringthefirst

trimester when pregnancy was identified.

Simvastatin was not teratogenic in rats or rabbitsat doses (25, 10 mg/kg/day, respectively)that

resulted in 3 times the human exposure based on mg/m 2 surface area. However, in studies with another

structurally-related statin, skeletal malformations were observed in rats and mice.

Women of childbearing potential, who requiretreatment with SIMOVIL for a lipid disorder, should be

advisedtouse effective contraception. For women trying to conceive, discontinuation of SIMOVIL should

be considered. If pregnancy occurs, SIMOVIL should be immediately discontinued.

8.3 Nursing Mothers

Itisnot known whether simvastatin is excretedin human milk. Because a small amount of another

druginthisclassis excreted in human milk and because of the potential for serious adverse reactions in

nursing infants, women taking simvastatin should notnurse their infants. A decision should be made

whether to discontinue nursing or discontinue drug, takingintoaccountthe importance of the drug to the

mother[see Contraindications (4)].

8.5 Geriatric Use

Of the 2,423 patients who receivedSIMOVIL in Phase IIIclinicalstudies and the 10,269 patients in the

Heart Protection Study who received SIMOVIL,363 (15%) and 5,366 (52%), respectively were≥65 years

old. In HPS, 615 (6%) were≥75 years old. No overalldifferencesin safety or effectivenesswere

observed between these subjectsandyounger subjects, and other reported clinical experience has not

identified differences in responses between the elderlyand younger patients, butgreater sensitivity of

Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillanceof Lovastatin and Simvastatin

Exposure During Pregnancy,Reproductive Toxicology, 10(6):439-446, 1996.

some older individuals cannot be ruled out. Since advancedage(≥65 years) is a predisposing factor for

myopathy, SIMOVIL should be prescribed with caution in the elderly.[See Clinical Pharmacology(12.3).]

Apharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be

approximately 45% higher in elderly patients between70-78 years of age compared with patients

between 18-30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering

efficacy was at least as great inelderlypatients compared with youngerpatients, and SIMOVIL

significantly reduced total mortality and CHD mortalityinelderly patients with a history of CHD. In HPS,

52% of patients wereelderly(4,891 patients 65-69 years and 5,806 patients 70 years or older). The

relativerisk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization

procedures, and stroke were similar in older and younger patients[seeClinical Studies (14.1)]. In HPS,

among 32,145 patients entering the active run-in period, there were 2 cases of

myopathy/rhabdomyolysis; thesepatientswereaged 67 and 73. Of the 7 cases of

myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at

baseline),ofwhom one was over 75. There wereno overall differences in safety between older and

younger patients in either 4S or HPS.

Because advanced age (≥65 years) is a predisposing factorformyopathy, including rhabdomyolysis,

SIMOVIL should be prescribed with caution in theelderly. In a clinical trial of patients treated with

simvastatin 80 mg/day, patients≥65yearsof age had an increasedrisk of myopathy, including

rhabdomyolysis, compared topatients <65 years of age.[See Warnings and Precautions (5.1) and

Clinical Pharmacology (12.3).]

8.6 Renal Impairment

Caution should be exercised when SIMOVILisadministered to patients with severe renal impairment.

[See Dosage and Administration (2.6).]

8.7 Hepatic Impairment

SIMOVIL is contraindicated in patients withactiveliverdisease which may include unexplained

persistentelevations in hepatic transaminase levels[see Contraindications (4) and Warnings and

Precautions (5.2)].

10 OVERDOSAGE

Significant lethality was observed in mice after a single oraldoseof9g/m 2 . No evidence of lethality

was observed in rats or dogs treated with doses of 30 and 100g/m 2 , respectively. No specificdiagnostic

signs were observed in rodents. At these doses theonlysigns seen in dogs were emesis and mucoid

stools.

A few cases of overdosage withSIMOVILhavebeenreported; the maximum dose taken was 3.6g.

All patients recovered without sequelae. Supportive measures should be taken in the event of an

overdose. The dialyzability of simvastatin and itsmetabolites in man is not known at present.

11 DESCRIPTION

SIMOVIL(simvastatin)is a lipid-lowering agent that is derived synthetically from a fermentation

product ofAspergillus terreus.After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed

to the corresponding -hydroxyacid form. This is an inhibitorof 3-hydroxy-3-methylglutaryl-coenzyme A

(HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, whichisan

early and rate-limiting step in thebiosynthesis of cholesterol.

Simvastatin is butanoicacid,2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-

hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1 ,3,7,8(2S * ,4S * ),-8a ]]. The empirical

formula of simvastatin is C

and its molecular weight is 418.57. Its structural formula is:

Simvastatin is a white tooff-white,nonhygroscopic,crystalline powder that is practically insoluble in

water, and freely soluble in chloroform, methanol and ethanol.

Tablets SIMOVIL for oral administration containeither 10mg, 20mg, or 40mg of simvastatin and the

followinginactive ingredients: ascorbic acid, citricacid, hydroxypropyl cellulose, hypromellose, iron

oxides, lactose hydrous, magnesiumstearate, microcrystalline cellulose, pregelatinized starch, talc,and

titanium dioxide. Butylated hydroxyanisole is added as a preservative.

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action

Simvastatin is a prodrug and ishydrolyzed to itsactive -hydroxyacid form, simvastatin acid, after

administration.Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)

reductase, the enzyme that catalyzes the conversionof HMG-CoA to mevalonate, an early and rate

limiting step in the biosynthetic pathway for cholesterol. In addition,simvastatin reduces VLDL and TG

and increases HDL-C.

12.2 Pharmacodynamics

Epidemiological studies have demonstrated that elevatedlevelsof total-C, LDL-C, as well as

decreased levels of HDL-Careassociatedwiththe development of atherosclerosis and increased

cardiovascular risk. Lowering LDL-C decreases thisrisk. However, the independent effect of raising

HDL-CorloweringTGonthe risk of coronary and cardiovascular morbidity and mortality has not been

determined.

12.3 Pharmacokinetics

Simvastatin is a lactone that is readily hydrolyzedin vivoto the corresponding -hydroxyacid, a potent

inhibitor of HMG-CoA reductase. Inhibition of HMG-CoAreductase is the basis for an assay in

pharmacokinetic studies of the -hydroxyacid metabolites (active inhibitors) and, following base

hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin.

Following an oral dose of 14 C-labeled simvastatin in man, 13%ofthe dose was excreted in urine and

60% in feces. Plasma concentrations oftotal radioactivity (simvastatin plus 14 C-metabolites) peaked at 4

hours and declined rapidly to about 10% of peak by12 hours postdose. Since simvastatin undergoes

extensivefirst-pass extraction in the liver, the availability of the drugto the general circulation is low

(<5%).

Both simvastatin and its -hydroxyacid metabolite are highly bound (approximately95%)tohuman

plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-

derived radioactivity crossed the blood-brain barrier.

The major active metabolites ofsimvastatin present in human plasma are the -hydroxyacid of

simvastatin and its 6 -hydroxy, 6-hydroxymethyl, and 6-exomethylene derivatives. Peak plasma

concentrations of both active and total inhibitors wereattained within 1.3 to 2.4 hours postdose. While the

recommended therapeutic dose range is 5 to 40mg/day,there was no substantial deviation from linearity

of AUC of inhibitors in the generalcirculation with an increase in dose to as high as 120mg. Relative to

the fasting state, the plasma profile of inhibitors was not affected when simvastatinwasadministered

immediately before an American Heart Association recommended low-fat meal.

Ina study including 16 elderlypatients between 70 and 78 yearsof age who received SIMOVIL

40mg/day, the mean plasma level of HMG-CoAreductase inhibitory activity was increased approximately

45%compared with 18 patients between 18-30 years of age. Clinical study experience in the elderly

(n=1522), suggests that there were no overall differences in safety betweenelderly and younger patients

[see Use in Specific Populations (8.5)].

Kinetic studies with another statin,having a similar principal route ofelimination, have suggested that

foragivendose level higher systemic exposuremay be achieved in patients with severe renal

insufficiency (as measured by creatinine clearance).

Although the mechanism is not fully understood, cyclosporine has beenshown to increase the AUC of

statins. The increase in AUC for simvastatin acidis presumably due, in part, to inhibition of CYP3A4.

The risk of myopathy is increased byhigh levels of HMG-CoA reductaseinhibitory activity in plasma.

Inhibitors of CYP3A4 can raise the plasma levelsof HMG-CoA reductase inhibitory activity and increase

the risk of myopathy[see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

TABLE 3

Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure

Coadministered Drug

or Grapefruit Juice Dosing of Coadministered

Drug or Grapefruit Juice Dosing of

Simvastatin Geometric Mean Ratio

(Ratio*with /without

coadministered drug)

No Effect = 1.00

AUC C

max

Contraindicated with simvastatin[see Contraindications (4) and Warnings and Precautions (5.1)]

Telithromycin † 200 mg QD for 4 days 80 mg simvastatin acid ‡

simvastatin 12

8.9 15

5.3

Nelfinavir † 1250 mg BID for 14 days 20 mg QD for 28

days simvastatin acid ‡

simvastatin

6

6.2

Itraconazole † 200 mg QD for 4 days 80 mg simvastatin acid ‡

simvastatin 13.1

13.1

Posaconazole 100 mg (oral suspension)

QD for 13 days

200 mg (oral suspension)

QD for 13 days 40 mg

40 mg simvastatin acid

simvastatin

simvastatin acid

simvastatin 7.3

10.3

8.5

10.6 9.2

9.4

9.5

11.4

Gemfibrozil 600 mg BID for 3days 40 mg simvastatin acid

simvastatin 2.85

1.35 2.18

0.91

Avoid grapefruitjuice with simvastatin[see Warnings and Precautions (5.1)]

Grapefruit Juice §

(high dose) 200 mL of double-strength

60 mg single dose simvastatin acid

simvastatin 7

16

Grapefruit Juice §

(lowdose) 8 oz (about 237mL) of

single-strength # 20 mg single dose simvastatin acid

simvastatin 1.3

1.9

Avoid taking with >10 mg simvastatin, based on clinical and/orpost-marketing experience[see Warnings and Precautions (5.1)]

Verapamil SR 240 mg QD Days1-7 then

240 mg BID on Days8-10 80 mg on Day10 simvastatin acid

simvastatin 2.3

2.5 2.4

2.1

Diltiazem 120 mg BID for 10 days 80 mg on Day10 simvastatin acid

simvastatin 2.69

3.10 2.69

2.88

Diltiazem 120 mg BID for 14 days 20 mg on Day14 simvastatin 4.6 3.6

Dronedarone 400 mg BID for 14 days 40 mg QD

For 14 days simvastatin acid

simvastatin 1.96

3.90 2.14

3.75

Avoid taking with >20 mg simvastatin, based on clinical and/orpost-marketing experience[see Warnings and Precautions (5.1)]

Amiodarone 400 mg QD for 3 days 40 mg on Day3 simvastatin acid

simvastatin 1.75

1.76 1.72

1.79

Amlodipine 10 mg QD x10 days 80 mg on Day10 simvastatin acid

simvastatin 1.58

1.77 1.56

1.47

Ranolazine SR 1000 mg BID for 7 days 80 mg on Day1 and

Days6-9 simvastatin acid

simvastatin 2.26

1.86 2.28

1.75

No dosing adjustments required forthe following:

Fenofibrate 160 mg QD X14 days 80 mg QD on Days

8-14 simvastatin acid

simvastatin 0.64

0.89 0.89

0.83

Niacin

extended-release Þ 2 g single dose 20 mg single dose simvastatin acid

simvastatin 1.6

1.4 1.84

1.08

Propranolol 80 mg single dose 80 mg single dose total inhibitor

activeinhibitor 0.79

0.79 ↓from

33.6 to

21.1

ng·eq/mL

↓from

7.0 to 4.7

ng·eq/mL

Results based on a chemicalassayexcept results with propranolol as indicated.

† Results could be representativeofthe following CYP3A4 inhibitors: ketoconazole,erythromycin, clarithromycin, HIV protease inhibitors, and

nefazodone.

‡ Simvastatin acid refers to the -hydroxyacid of simvastatin.

§ The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not beenstudied.

Double-strength: one can of frozenconcentrate diluted with one can of water. Grapefruit juicewas administered TID for 2days, and 200mL

together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day3.

# Single-strength: one can offrozen concentrate diluted with 3cans of water. Grapefruit juice was administered withbreakfastfor 3days, and

simvastatin was administered in the evening on Day3.

BecauseChinese patients havean increased risk for myopathywith simvastatincoadministered with lipid-modifying doses ( 1 gram/day

niacin) of niacin-containing products, and the risk is dose-related, Chinese patientsshould not receive simvastatin 80 mg coadministered with

lipid-modifying doses ofniacin-containing products[see Warnings and Precautions (5.1) and Drug Interactions (7.4)].

In a study of 12healthyvolunteers,simvastatinatthe 80-mg dose had no effect on the metabolism of

theprobe cytochrome P450 isoform 3A4 (CYP3A4)substrates midazolamand erythromycin. This

indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is notexpected to affect the

plasma levels of other drugs metabolized by CYP3A4.

Coadministrationofsimvastatin (40 mg QD for 10days) resulted in an increase in the maximum mean

levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of25,100,and

400mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8times

higher than the mean human plasma drug level, respectively (as total inhibitory activity basedonAUC)

after an 80-mg oral dose. Liver carcinomas weresignificantly increased in high-dose femalesandmid-

and high-dose males with a maximum incidence of 90%in males. The incidence of adenomas of the liver

was significantly increased in mid- and high-dosefemales. Drug treatment also significantly increased the

incidence of lung adenomas in mid- and high-dose males and females. Adenomas of theHarderiangland

(aglandofthe eye of rodents) weresignificantly higher in high-dose micethan in controls. No evidence of

a tumorigenic effect was observed at 25 mg/kg/day.

Inaseparate 92-week carcinogenicity study in mice at doses up to 25mg/kg/day, no evidence of a

tumorigenic effect was observed (mean plasma druglevelswere 1 times higher than humans given

80 mg simvastatin as measured by AUC).

In a two-year study in rats at 25mg/kg/day, therewasa statistically significant increase in the

incidenceofthyroidfollicular adenomas in female ratsexposed to approximately 11 times higher levels of

simvastatin than in humans given 80 mgsimvastatin (as measured by AUC).

A second two-year rat carcinogenicity studywith doses of 50 and 100mg/kg/dayproduced

hepatocellular adenomas and carcinomas (in femaleratsat both doses and in males at 100mg/kg/day).

Thyroid follicular cell adenomas were increased in males and females at both doses;thyroidfollicularcell

carcinomas were increased in females at 100mg/kg/day. The increased incidence of thyroid neoplasms

appears to be consistent with findings from other statins.These treatment levels represented plasma

drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times(females)themean

human plasma drug exposure after an 80 milligram daily dose.

No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with orwithoutrat

or mouse liver metabolic activation. In addition,noevidenceofdamageto genetic material was noted in

anin vitroalkalineelutionassay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an

in vitrochromosome aberration study in CHO cells, or anin vivochromosomal aberration assay in mouse

bone marrow.

There was decreased fertility in male rats treatedwith simvastatin for 34 weeks at 25mg/kg body

weight (4 times the maximum human exposure level,based on AUC,inpatients receiving 80mg/day);

however, this effect was not observed during a subsequentfertilitystudy in which simvastatin was

administered at this same dose level to male ratsfor 11 weeks (the entire cycle of spermatogenesis

including epididymal maturation). No microscopic changeswere observed in the testes of rats from either

study.At180mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking

80mg/day based on surfacearea,mg/m 2 ), seminiferous tubule degeneration (necrosis and loss of

spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased

spermatogenesis, spermatocytic degeneration and giant cell formation at 10mg/kg/day, (approximately 2

times the human exposure, based on AUC,at 80mg/day). Theclinicalsignificance of these findings is

unclear.

13.2Animal Toxicologyand/or Pharmacology

CNSToxicity

Opticnervedegeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at

180mg/kg/day, a dose that produced mean plasmadrug levels about 12 times higher than the mean

plasma drug level in humans taking 80 mg/day.

A chemically similar drug in this class alsoproduced optic nerve degeneration (Wallerian degeneration

of retinogeniculate fibers) in clinically normal dogsina dose-dependent fashion starting at 60mg/kg/day,

a dose that produced mean plasma drug levels about 30timeshigherthanthe mean plasma drug level in

humans taking the highest recommended dose (as measuredby total enzyme inhibitoryactivity).This

samedrugalso produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell

chromatolysisindogstreated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug

level similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema,mononuclearcell

infiltration of perivascular spaces, perivascular fibrindepositsand necrosis of small vessels were seen in

dogs treated with simvastatin at a dose of360mg/kg/day, a dose that produced mean plasma drug levels

that were about 14 times higher than the mean plasmadrug levels in humanstaking80mg/day.Similar

CNS vascular lesions have been observed withseveral other drugs of this class.

Therewerecataracts in female rats after twoyears of treatment with 50 and 100mg/kg/day (22 and

25 times the human AUC at 80mg/day,respectively)and in dogs after three months at 90mg/kg/day

(19 times) and at two years at 50 mg/kg/day (5 times).

14 CLINICAL STUDIES

14.1Clinical Studies in Adults

Reductions in Risk of CHD Mortality and Cardiovascular Events

In 4S, the effect of therapy with SIMOVIL on total mortality was assessed in 4,444patientswithCHD

and baseline total cholesterol 212-309mg/dL (5.5-8.0mmol/L). In this multicenter, randomized,double-

blind,placebo-controlled study, patients were treated with standard care, including diet, and either

SIMOVIL20-40mg/day(n=2,221) or placebo (n=2,223)for a median duration of5.4 years. Over the

course of the study, treatment with SIMOVIL led tomean reductions in total-C, LDL-C and TGof25%,

35%, and 10%, respectively, and a meanincreaseinHDL-C of 8%. SIMOVIL significantly reduced the

risk of mortality by 30%(p=0.0003, 182 deaths in the SIMOVILgroup vs 256 deaths in the placebo

group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths).

There was no statistically significant differencebetween groups in non-cardiovascular mortality. SIMOVIL

significantly decreased theriskofhaving major coronary events (CHD mortality plus hospital-verified and

silent non-fatal myocardial infarction [MI]) by34%(p<0.00001,431 vs 622 patients with one or more

events). The risk of having a hospital-verifiednon-fatal MI was reduced by 37%. SIMOVIL significantly

reduced the risk for undergoing myocardial revascularization procedures (coronary arterybypassgrafting

or percutaneous transluminal coronary angioplasty)by 37% (p<0.00001, 252 vs 383 patients). SIMOVIL

significantly reduced the risk of fatalplusnon-fatal cerebrovascular events (combined stroke and

transientischemic attacks) by 28% (p=0.033, 75vs 102 patients). SIMOVIL reduced the risk of major

coronaryeventsto a similar extentacross the range of baseline totaland LDL cholesterol levels. Because

there were only 53 female deaths,theeffectofSIMOVIL on mortality in women could not be adequately

assessed. However, SIMOVIL significantly lessened the risk of havingmajorcoronary events by 34% (60

vs 91 women with one or more event). The randomization was stratified byangina alone (21% of each

treatment group) or a previous MI. Because there were only 57 deaths among the patientswithangina

aloneatbaseline,the effect of SIMOVIL on mortality in this subgroup could not be adequately assessed.

However, trends in reduced coronary mortality, majorcoronary events and revascularization procedures

were consistent between this group andthetotalstudycohort. Additionally, SIMOVIL resulted in similar

decreasesin relative risk for total mortality, CHD mortality, and major coronaryevents in elderly patients

(≥65 years), compared with younger patients.

The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study

with a mean duration of 5 years conducted in20,536 patients (10,269 on SIMOVIL40mgand10,267on

placebo). Patients were allocated to treatment using a covariate adaptive method 2 which took into

account the distribution of 10 important baselinecharacteristicsof patients already enrolled and

minimized the imbalance of thosecharacteristics across the groups.Patientshad a mean age of 64 years

(range 40-80 years), were 97% Caucasian andwereathigh risk of developing a major coronary event

because of existing CHD (65%), diabetes(Type2, 26%; Type 1, 3%),history of stroke or other

cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertensioninmales≥65 years

(6%). At baseline, 3,421 patients (17%)hadLDL-Clevels below 100mg/dL, of whom 953 (5%) had LDL-

D.R. Taves, Minimization: a newmethod of assigning patients totreatment and control groups. Clin. Pharmacol. Ther. 15 (1974),

pp. 443-453

C levels below 80mg/dL; 7,068 patients (34%) had levels between 100 and130mg/dL;and10,047

patients (49%) had levels greater than 130 mg/dL.

The HPS results showed that SIMOVIL 40mg/daysignificantly reduced: total and CHD mortality; non-

fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 4).

TABLE 4

Summaryof Heart Protection StudyResults

Endpoint

SIMOVIL

(N=10,269)

n (%) † Placebo

(N=10,267)

n (%) † Risk Reduction

(%) (95%CI) p-Value

Primary

Mortality1,328 (12.9) 1,507 (14.7) 13 (6-19)p=0.0003

CHD mortality 587 (5.7) 707 (6.9) 18 (8-26) p=0.0005

Secondary

Non-fatal MI 357 (3.5) 574 (5.6) 38 (30-46) p<0.0001

Stroke 444 (4.3) 585 (5.7) 25 (15-34) p<0.0001

Tertiary

Coronaryrevascularization 513 (5) 725 (7.1) 30 (22-38) p<0.0001

Peripheral and other non-coronary

revascularization 450 (4.4) 532 (5.2) 16 (5-26) p=0.006

n = number of patients with indicated event

Two composite endpoints were defined in order tohavesufficient events to assess relative risk

reductions across a range of baseline characteristics (see Figure 1). A composite of majorcoronary

events (MCE) was comprised ofCHD mortality and non-fatal MI (analyzed by time-to-first event; 898

patients treated with SIMOVILhad events and 1,212patientsonplacebo had events). A composite of

major vascular events (MVE) was comprised of MCE,stroke and revascularization procedures including

coronary, peripheral and other non-coronary procedures(analyzed by time-to-first event; 2,033 patients

treated with SIMOVIL had eventsand2,585 patients on placebo had events). Significant relative risk

reductionswere observed for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001).

Treatment with SIMOVIL produced significant relativerisk reductions for all components ofthecomposite

endpoints. The risk reductions produced by SIMOVIL inbothMCE and MVE were evident and consistent

regardless of cardiovascular disease related medicalhistory at study entry (i.e., CHD alone; or peripheral

vascular disease, cerebrovascular disease, diabetesortreated hypertension, with or without CHD),

gender, age, creatinine levels up to the entry limitof2.3mg/dL, baseline levels of LDL-C, HDL-C,

apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or

calcium channel blockers), smoking status, alcoholintake, or obesity. Diabetics showed risk reductions

for MCE and MVE due to SIMOVIL treatment regardlessofbaselineHbA1c levels or obesity with the

greatest effects seen for diabetics without CHD.

Figure 1

The Effects of Treatment withSIMOVIL on Major Vascular Events and Major CoronaryEvents in HPS

Characteristics

N Placebo

Placebo Major VascularEvents Major CoronaryEvents

Incidence(%)

ZOCOR Incidence(%)

ZOCOR

Favors

Favors

Favors

Favors

ZOCOR

Placebo

ZOCOR

Placebo

All patients 19.8 8.7 25.2 11.8 20,536

Without CHD 16.1 5.1 20.8 8.0 7,150

WithCHD 21.8 10.7 27.5 13.9 13,386

Diabetesmellitus 20.2 9.4 25.1 12.6 5,963

Without CHD 13.8 5.5 18.6 8.4 3,982

WithCHD 33.4 17.4 37.8 21.0 1,981

Without diabetes mellitus 19.6 8.5 25.2 11.5 14,573

Peripheralvasculardisease 26.4 10.9 32.7 13.8 6,748

Without CHD 24.7 7.0 30.5 10.1 2,701

WithCHD 27.6 13.4 34.3 16.4 4,047

Cerebrovasculardisease 24.7 10.4 29.8 13.3 3,280

Without CHD 18.7 5.9 23.6 8.7 1,820

WithCHD 32.4 16.2 37.4 19.0 1,460

Gender

Female 14.4 5.2 17.7 7.8 5,082

Male 21.6 9.9 27.6 13.1 15,454

Age (years)

40to< 65 16.9 6.2 22.1 9.2 9,839

65to< 70 20.9 9.5 27.2 13.1 4,891

70 23.6 12.4 28.7 15.2 5,806

LDL-cholesterol(mg/dL)

100 16.4 7.5 21.0 9.8 3,421

100to< 130 18.9 7.9 24.7 11.9 7,068

130 21.6 9.7 26.9 12.4 10,047

HDL-cholesterol(mg/dL)

35 22.6 10.2 29.9 14.4 7,176

35to< 43 20.0 8.9 25.1 11.7 5,666

Baseline

N = number of patients ineachsubgroup. The inverted triangles are point estimatesof the relativerisk, with their 95% confidence intervals

represented as a line. The area ofatriangle is proportional to the number of patients with MVE or MCE in the subgroup relative to the number with

MVE or MCE, respectively, in the entirestudypopulation. The vertical solid line represents a relativerisk ofone.Thevertical dashed line represents

the point estimate of relativerisk in the entire studypopulation.

Angiographic Studies

In the Multicenter Anti-AtheromaStudy, the effect of simvastatinonatherosclerosis was assessed by

quantitative coronary angiography in hypercholesterolemicpatientswith CHD. In this randomized,

double-blind, controlled study, patients were treatedwithsimvastatin20mg/day or placebo. Angiograms

were evaluated at baseline, twoand four years. The co-primarystudy endpoints were meanchangeper-

patientinminimumand mean lumen diameters, indicating focal and diffuse disease, respectively.

SIMOVIL significantly slowed the progression of lesions as measuredin the Year 4 angiogram by both

parameters, as well as by change in percent diameterstenosis. In addition, simvastatin significantly

decreased the proportion of patients with newlesions and with new total occlusions.

Modifications of Lipid Profiles

Primary Hyperlipidemia (Fredrickson type lla and llb)

SIMOVIL has been shown to be effective in reducing total-C and LDL-C in heterozygousfamilialand

non-familialformsofhyperlipidemia and in mixed hyperlipidemia. Maximal to near maximal response is

generally achieved within 4-6weeks and maintainedduring chronic therapy. SIMOVIL consistently and

significantlydecreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; SIMOVIL also

decreased TG and increased HDL-C (see Table 5).

TABLE 5

Mean Response in Patients with PrimaryHyperlipidemia and Combined (mixed) Hyperlipidemia

(Mean Percent Change from Baseline After 6 to 24 Weeks)

TREATMENT

N

TOTAL-C

LDL-C

HDL-C

Lower Dose Comparative Study ‡

(Mean % Change at Week 6)

SIMOVIL5 mg q.p.m.

SIMOVIL10 mg q.p.m.

109

110

-19

-23

-26

-30

10

12

-12

-15

Scandinavian Simvastatin Survival Study §

(Mean % Change at Week 6)

Placebo

SIMOVIL20 mgq.p.m.

2223

2221

-1

-28

-1

-38

0

8

-2

-19

Upper Dose Comparative Study ||

(Mean % Change Averaged at

Weeks 18 and 24)

SIMOVIL40 mg q.p.m.

SIMOVIL80 mg q.p.m. ¶

433

664

-31

-36

-41

-47

9

8

-18

-24

Multi-Center Combined Hyperlipidemia Study ††

(Mean % Change at Week 6)

Placebo

SIMOVIL40 mg q.p.m.

SIMOVIL80 mg q.p.m.

125

123

124

1

-25

-31

2

-29

-36

3

13

16

-4

-28

-33

† median percent change

‡ mean baseline LDL-C 244 mg/dL andmedian baseline TG 168 mg/dL

§ mean baseline LDL-C 188 mg/dL andmedian baseline TG 128 mg/dL

|| mean baseline LDL-C 226 mg/dL andmedian baseline TG 156 mg/dL

21% and 36% median reduction in TG in patients with TG 200 mg/dL and TG >200 mg/dL,respectively. Patients with TG >350 mg/dL were

excluded

†† mean baseline LDL-C 156 mg/dL andmedian baseline TG 391 mg/dL.

Hypertriglyceridemia (Fredrickson type lV)

The results of a subgroupanalysisin74patientswith typelV hyperlipidemia from a 130-patient,

double-blind, placebo-controlled, 3-period crossover study are presented in Table 6.

TABLE 6

Six-week, Lipid-lowering Effects of Simvastatin in Type lV Hyperlipidemia

Median Percent Change (25 th and 75 th percentile) from Baseline †

TREATMENT

N

Total-C

LDL-C

HDL-C

TG

VLDL-C

Non-HDL-C

Placebo

74

+2

(-7, +7)

+1

(-8, +14)

+3

(-3, +10)

-9

(-25, +13)

-7

(-25, +11)

+1

(-9, +8)

SIMOVIL 40

mg/day

74

-25

(-34, -19)

-28

(-40, -17)

+11

(+5, +23)

-29

(-43, -16)

-37

(-54, -23)

-32

(-42, -23)

SIMOVIL 80

mg/day

74

-32

(-38, -24)

-37

(-46, -26)

+15

(+5, +23)

-34

(-45, -18)

-41

(-57, -28)

-38

(-49, -32)

† The median baseline values (mg/dL) for thepatients in this studywere: total-C = 254,LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and

non-HDL-C = 215.

Dysbetalipoproteinemia (Fredrickson type lll)

The results of a subgroup analysisin7patientswith typelll hyperlipidemia (dysbetalipoproteinemia)

(apo E2/2) (VLDL-C/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover

study are presented in Table 7.

TABLE 7

Six-week, Lipid-lowering Effects of Simvastatin in Type lll Hyperlipidemia

Median Percent Change (min, max)from Baseline †

TREATMENT

N

Total-C

LDL-C + IDL

HDL-C

TG

VLDL-C+IDL

Non-HDL-C

Placebo

7

-8

(-24, +34)

-8

(-27, +23)

-2

(-21, +16)

+4

(-22, +90)

-4

(-28, +78)

-8

(-26, -39)

SIMOVIL 40 mg/day

7

-50

(-66, -39)

-50

(-60, -31)

+7

(-8, +23)

-41

(-74, -16)

-58

(-90, -37)

-57

(-72, -44)

SIMOVIL 80 mg/day

7

-52

(-55, -41)

-51

(-57, -28)

+7

(-5, +29)

-38

(-58, +2)

-60

(-72, -39)

-59

(-61, -46)

† The median baseline values (mg/dL) were: total-C = 324, LDL-C= 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.

Homozygous Familial Hypercholesterolemia

In a controlled clinical study, 12 patients15-39 years of age with homozygous familial

hypercholesterolemia received simvastatin 40mg/day in a single dose orin3divideddoses,or

80mg/day in 3 divided doses. In 11 patients withreductions in LDL-C, the mean LDL-C changes for the

40- and 80-mg doses were 14% (range 8% to 23%, median 12%) and 30% (range 14% to 46%, median

29%), respectively. One patient had an increase of 15%in LDL-C. Another patient with absentLDL-C

receptor function had an LDL-C reduction of 41% with the 80-mg dose.

Endocrine Function

In clinical studies, simvastatin did notimpairadrenal reserve or significantly reduce basal plasma

cortisol concentration. Small reductions from baselineinbasal plasma testosterone in men were

observed in clinical studies with simvastatin, an effect also observed with otherstatins and the bile acid

sequestrant cholestyramine. There was no effect onplasmagonadotropin levels. In a placebo-controlled,

12-week study there was no significanteffect of simvastatin 80mg on the plasma testosterone response

to human chorionic gonadotropin. In another 24-weekstudy, simvastatin 20-40mghadnodetectable

effectonspermatogenesis. In 4S, in which 4,444 patients were randomized to simvastatin 20-40mg/day

or placebo for a median duration of5.4 years, the incidence of malesexualadverseevents in the two

treatmentgroupswas not significantly different. Because of these factors, the small changes in plasma

testosterone are unlikely to be clinicallysignificant.The effects, if any, on the pituitary-gonadal axis in pre-

menopausal women are unknown.

16 HOW SUPPLIED/STORAGE AND HANDLING

No. 8146— Tablets SIMOVIL 10mg are peach, oval,film-coated tablets, coded MSD 735 on one side

and plain on the other. They are suppliedas follows: blisters of 30 tablets.

No. 8147— Tablets SIMOVIL 20mg are tan, oval,film-coated tablets, coded MSD740 on one side

and plain on the other. They are suppliedas follows: blisters of 30 tablets.

No. 8148— Tablets SIMOVIL 40mg are brick red,oval, film-coated tablets, coded MSD749 on one

side and plain on the other. They are supplied as follows: blisters of 30 tablets.

Storage

Store below 30°C.

17 PATIENT COUNSELING INFORMATION

Patients should be advised to adhere to their National Cholesterol Education Program(NCEP)-

recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.

Patientsshould be advised about substances theyshould not take concomitantlywith

simvastatin[see Contraindications (4) and Warnings and Precautions(5.1)]. Patients should also

be advised to inform other healthcare professionals prescribing a newmedicationorincreasing

the dose of an existing medication that theyare taking SIMOVIL.

17.1 MusclePain

All patients starting therapy with SIMOVIL should be advised oftherisk of myopathy, including

rhabdomyolysis,and told to report promptly anyunexplained muscle pain, tenderness or weakness

particularly if accompanied by malaise or fever orif these muscle signs or symptoms persist after

discontinuing SIMOVIL.Patients using the 80-mg dose should be informed that the risk of

myopathy,including rhabdomyolysis, is increased with use of the 80-mg dose.The risk of

myopathy, including rhabdomyolysis, occurring with use of SIMOVIL is increased whentakingcertain

types of medication or consuming grapefruit juice.Patients should discuss all medication, both

prescription and over the counter, with their healthcare professional.

17.2 LiverEnzymes

It is recommended that liver function testsbeperformed before the initiation of SIMOVIL, and

thereafter when clinically indicated. All patientstreated with SIMOVIL should be advised to report

promptly any symptoms that may indicate liverinjury, including fatigue, anorexia, right upperabdominal

discomfort, dark urine or jaundice.

17.3 Pregnancy

Women of childbearing age should be advised to use aneffective method of birth controltoprevent

pregnancy while using SIMOVIL. Discuss futurepregnancy plans with your patients, and discuss when to

stop taking SIMOVIL if they are trying to conceive. Patients should be advisedthatiftheybecome

pregnant they should stop taking SIMOVILand call their healthcare professional.

17.4 Breastfeeding

Womenwhoare breastfeeding should not use SIMOVIL. Patients who have a lipid disorder and are

breastfeeding should be advised to discuss the options with their healthcare professional.

Manufactured by: Merck Sharp & Dohme B.V., Haarlem, Holland

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

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

and approved in December 2012.