LESCOL 20 MG

עעבקנהזןולעטמרופ " ודילערשואוקדבנונכותותואירבהדרשמי ינויב 2012 .

םיחקורהתונקתיפלןכרצלןולע

) םירישכת ( משתה " ו - 1986

אפורםשרמבתבייחוזהפורת

ארק / שמתשתםרטבופוסדעןולעהתאןויעבי / הפורתבי

לוכסל

20 מ " ג לוכסל

40 מ " ג

תוסומכ תוסומכ

בכרה :

הליכמהסומכלכ :

Fluvastatin (as

sodiumsalt) 20 mg הליכמהסומכלכ :

Fluvastatin (as

sodiumsalt) 40 mg

םיליעפיתלבםיביכרמ :

Magnesiumstearate, sodiumhydrogen carbonate, talc, cellulose microcrystalline,

starch pregelatinised, calciumcarbonate, gelatin, iron oxidered and yellow, titanium

dioxide.

ןיטיצלהיוסתוליכמלוכסלתוסומכ . יגרלאךניהםא / היוסלואםינטובלת , תאלוטילןיא

תוסומכה .

תיטיופרתהצובק :

םיניטטס : םיזנאהיבכעמ HMG-CoA reductase ) דבכבלורטסלוכרוציילשורדהםיזנאה .(

תיאופרתוליעפ :

םדבאוצמלןתינשםיירקיעהםיינמושהםיביכרמהםניהםידירצילגירטולורטסלוכ . לורטסלוכ

לערקיעברצוימ - דבכהידי , ןוזמבםרוקמםדבםידירצילגירטהבורשדועב . לשתוהובגתומר

גוסמלורטסלוכ LDL ) לורטסלוכה ' ערה '( , ואצמנ ץבשובלתלחמלןוכיסבהילעלתורושק . קלחב

םירקמהמ , ר לורטסלוכלשתוהובגתומ ' ער ' תומרבוםידירצילגירטבתינוניבהילעבתוולמםדב

גוסמלורטסלוכלשתוכומנ HDL ) לורטסלוכה ' בוטה ' .( לורטסלוכלשתוהובגתומרדירוהלבושח

ער ' םידירצילגירטו , לורטסלוכהתומרתאתולעהלו ' בוטה ' . םייונישעיצהרבכאפורהיכןכתי

חרואבוהטאידב לעךלשםייחה - לורטסלוכהתאדירוהלתנמ ' ערה ' םידירצילגירטהו , תולעהלו

לורטסלוכהתא ' בוטה ' . הרטמהתגשהלםיקיפסמםניאםייחהןונגסבוהטאידבםייונישםיתיעל .

לוכסלומכףסונלופיטםשוראפורהןכל .

לוכסלתליטנינפל ץלמומ הטאידבליחתהל תלד - לורטסלוכ . לשי ורהםעץעייתה ךכלעךלשאפ .

לוכסלתליטנךלהמבםגהטאידבךישמהלשי .

רישכתבשמתשהלןיאיתמ ?

שמתשהלןיא רישכתב :

תושיגרךלהעודיםא ליעפהרמוחל לואןיטטסבולפ מדחא ה יביכרמ ם לשםיליעפיתלבה הפורתה

ליעלםיעיפומה . תאםאאפורהםעץעייתהלשי / בשוחה / שיגרךניהשת / ה .

תלחמךלשיםא םדבדבכימיזנאלשתרבסומיתלבותיבקעהיילעואהליעפדבכ

תוזנימאסנרט .(

הקינימואןוירהבתאםא .

תוירופהליגבךניהםא , תשמתשמךניהםאאלא יעצמאב ןוירהתעינמלןימא .

ךילאיטנבלרליעלםירקמהמדחאםא , ילשי י לוכסלתחקלילבמאפורהתאעד .

במהפורתבשמתשהלןיא לופיטהתלחתהינפלאפורבץעוויהליל :

LESAPLJUN12 CLV6 REFBPL100512

םא מרבעבתלבס דבכתלחמ . ךרדבועצובידבכידוקפתתוקידב - לופיטהתלחתהינפלללכ

לוכסלב , קודבלידכלופיטהךלהמבםינושןמזיקרפבוןונימתאלעהב תועפות תויוצריתלב .

לבוסךניהםא / תוילכתלחממת .

לבוסךניהםא / אוריתהתטולבבהלחממת די .

ואךלשיםא ב םירירשתולחמלשתיאופרהירוטסיהךתחפשמ .

םינמושתדרוהלרחארישכתתחקלשכםירירשבתויעבךלויהםא .

ךרוצךניהםא / לוהוכלאלשתולודגתויומכת .

רומחםוהיזךלשיםא .

דואמךומנםדץחלךלשיםא ) תרוחרחסלולכלםילוכיםינמיסה , דמועךניהשהשוחת / ת

ףלעתהל .(

הנורחאלתעצפנםא .

דמועךניהםא / חותינרובעלת .

ןוגכםיטילורטקלאבתורומחתוערפהואתורומחתוינירקודנאואתוילובטמתוערפהךלשיםא

םדבןגלשאלשהכומנהמרותנזואמאלתרכוס .

תנזואמהניאשהיספליפאךלשיםא .

שינפלםדתוקידבךלןתייאפורהולאםירקמב לוכסלךלםושרי .

תאלוכסלבשומישהךלהמבםא / חתפמה / ת הליחבןוגכםינמיסואםימוטפמיס , האקה , ןדבוא

ןובאית , רועהואםייניעהלשהבהצה , לובלב , ןואכידואהירופוא , תילטנמהטאה , רורבאלרוביד ,

הנישתוערפה , תולקרתיבתועצפיהואםומידואדער , לשםינמיסתויהלםייושעש יא - תקיפס

דבכ . ידיימןפואבאפורהםערשקרוצילשיהזכהרקמב .

תורהזא :

ףוליחלעהעפשהשיםיניטטסהתצובקלתוכיישהלורטסלוכתומרתדרוהלתושמשמהתופורתל

רכוסלשםירמוחה . ןכל , לוכסלבשומישהךלהמב :

עדויךניהםא / וךלשייכת / תרכוסלשתיאופרהירוטסיהךתחפשמלוא

םא רבגומאמצןוגכםימוטפמיסואםינמיסךלשי , ההובגןתשתקופת , רבגומןובאית

לקשמבהדיריםע , תופייע , םדברכוסלשההובגהמרלשםינמיסתויהלםייושעולא .

ולאםירקמב , אפורהתאעדיילשי .

םימיוסמםירקמב , ןכו ליגלעמםילפוטמב 70 , סימרוגםימייקםאהקודבליושעאפורה ןוכי

םדתוקידבתועצמאבםירירשתולחמל .

ןוירהבתאםא , לוכסלתליטנינפלחקורהואאפורהםעיצעייתה . ןוירהךלהמבלוכסללוטילןיא .

הפורתבשומישהךלהמבןוירהלתסנכנוהדימב , קיספה י אפורלינפולופיטהתא . ךלריבסיאפורה

ןוירהןמזבלוכסלתחיקלבךורכהןוכיסהתא .

לע תוירופהליגבםישנ טוקנל ב הפורתבשומישהךלהמבםיתואנהעינמיעצמא .

הקינימתאםא , לוכסלתליטנינפלחקורהואאפורהםעיצעייתה . ךלהמבלוכסללוטילןיא

הקנה .

שיגרךניהםא / יהשלכהפורתלואוהשלכןוזמלה , הפורתהתליטנינפלאפורלךכלעעידוהלךילע .

תפורתןיבתובוגת תוי :

לטונךניהםא / תפסונהפורתת , םשרמאללתופורתללוכ הנוזתיפסותו , התעהזתרמגםאוא

תרחאהפורתבלופיט , יאואםינוכיסעונמלידכלפטמהאפורלחוודלךילע - םיעבונהתוליעי

תויתפורתןיבתובוגתמ , תואבהתוצובקהמתופורתיבגלדחוימב : ןירופסולקיצ ) הפורת תשמשמה

יוכידל ןוסיחהתכרעמ ( ; רביפ א םיט ) ליזורביפמגןוגכ ( , ואתיניטוקינהצמוח resin לש תוצמוח

הרמ ) תופורת לורטסלוכתומרתדרוהל ' ער '( ;

לוזאנוקולפ ) פורת ה םייתיירטפםימוהיזבלופיטל ( ;

ןיציפמאפיר , ןיצימורתירא ) יגוס נא ט הקיטויבי ( ; ןיאוטינפ ) היספליפאבלופיטלהפורת ( ;

השירקידגונםירישכת ימופןתמב ןירפרווןוגכ ; דימאלקנבילג ) סבלופיטלהפורת ו תרכ ( ;

םיניציכלוק .

לעומשרנשלורטסלוכתדרוהלםירחאםירישכתםעואדבללוכסללוטילןתינ - אפורהידי .

תליטנרחאל resin ) ןימאריטסלוכןוגכ ( , ןיתמהלשי תוחפל 4 תועש לוכסלתליטנינפל .

תועפות יאוול :

הפורתהלשהיוצרהתוליעפלףסונב , עיפוהלתולולעהבשומישהןמזב תועפות יאוול .

תוחיכשיאוולתועפות ) עיפשהלתויושע ןיבלע 1 ל - 10 ךותמ 100 םילפוטמ ( : הנישבםיישק , באכ

שאר , יא - ןטבבתוחונ , ןטביבאכ , הליחב ;

דבכלוםירירשלםיניקתאלםדתוקידביכרע .

אתחאםא רומחןפואבךילעהעיפשמולאיאוולתועפותמרתויו , עדי / אפורהתאי .

דואמתורידניאוולתועפות ) עיפשהלתויושע ךותמדחאםדאמתוחפלע 10,000 םילפוטמ ( :

םיילגרהוםיידיהתופכבהשוחתרסוחואםיצוצקע , השיחהרשוכבהדיריואהערפה .

שמוללהיאוולהתועפותמרתויואתחאםא רומחןפואבךילעהעיפ , הנפ / אפורלי .

LESAPLJUN12 CLV6 REFBPL100512

םישנאלשןטקרפסמבועיפוהשתורחאיאוולתועפות , העודיהניאתקיודמהןתוחיכשםלוא :

היצנטופמיא .

רבדהםא רומחןפואבךילעעיפשמ , אפורהתאעדי .

תועפות יאוול תדחוימתוסחייתהתובייחמה :

דואמתורידנואתורידניאוולתועפות : יבאכ םירירש , םירבסומיתלבםירירשתשלוחואתושיגר

םינמיסתווהלםייושע םימדקומ ל פ םירירשהלשרומחקורי תאקיספיאפורהםאעונמלןתינש

לפםעלופיטה ו תירשפאהתוריהמבןיטטסב . תופסונתופורתםעםגואצמנולאיאוולתועפות

וזהצובקמ ) םיניטטס .(

תופייע הליגראל םוחוא , ןווג םייניעבורועבבהבהצ , ןתשהלשההכןווג ) תקלדלשםינמיס

דבכה ( ; ןוגכתוירועתובוגתלשםינמיס רועבהחירפ , תדפרס , תוימומדא , דרג , תוחיפנ הלש םינפ ,

םייפעפע ו ה םייתפש ; רועבתוחיפנ , המישניישק , תרוחרחס ) הרומחתיגרלאהבוגתלשםינמיס ( ;

יגרהמתולקרתיבהעיצפואםומיד ל ) םינמיס הרפסמבהדירילש םדבתויסט ( ; רועבםירוזא

לוגסואםודאעבצב ) לםינמיס ד םדהילכבתקל ( ; תיתקלדהמודאהחירפ , םינפברקיעב , ןכתי

תופייעיווילב , םוח , הליחב , ןובאיתדוביא ) תבאזתיומדהבוגתלשםינמיס ( ; ןטבבםידחםיבאכ

הנוילעה ) לםינמיס התקלד בלבל ( – עדי / י תא ה אפור דימ !

שיגרמךניהובשהרקמלכב / אוולתועפותה יוצאלשי הזןולעבונ , ךתשגרהביונישלחםאוא

תיללכה , דימאפורהםעץעייתהלךילע .

ןונימ :

דבלבאפורהתארוהיפלןונימ .

תצלמומההנמהלערובעלןיא .

לופיטלךתבוגתלםאתהב עאפורה ןונימהתאדירוהלואתולעהליוש .

רת ליגלתחתמםידלילותוקוניתלללכךרדבתדעוימהניאוזהפו 18 הנש .

לעעבקנשיפכםיבוצקםינמזבוזהפורתבשמתשהלשי - לפטמהאפורהידי .

הפורתלוטילתחכשםא וז בוצקןמזב , תרכזנשכדימהנמלוטילשי . עבראמתוחפוראשנוהדימב

האבההנמלדעתועש , קלוהחכשנשהנמהלעגלדלשי הנמהתאתח ה האב בוצקהןמזב . ןיא

דחיבתונמיתשלוטיל החכשנשהנמלעתוצפלידכ ! תועטבתלטנםא רתיתנמ הנפ / י דימ אפורל

לפטמה . קקדזתיכןכתי / יאופרלופיטלי .

שומישהןפוא :

סועללןיא ! תאעולבלשי ןתומלשבתוסומכה , םימסוכםע .

החוראילבואםעלוכסלתחקלןתינ .

שי הנישהינפלואברעבלוכסלתוסומכתחקל .

ךבצמתאאפריאללוכסל , ובטולשלרוזעיךא . ןכל , תוארוהלםאתהבלוכסללוטילךישמהלשי ,

לורטסלוכהלשתוכומנתומרלערומשלידכ ' ערה ' . םינמושהתומרלשתויתרגשתוקידבעצבלשי

םדב , ךתומדקתהתארטנלידכ . ורתילערומשלידכ לופיטהתונ , לוכסללוטילקיספהלןיא , אלא

אפורהתארוהב .

ענמ / הלערהי !

וםידלילשםדיגשיהלץוחמרוגסםוקמברומשלשיתרחאהפורתלכווזהפורת / תוקוניתוא

לעו - ידי ענמתךכ / הלערהי .

הפורתהןמדליעלבתועטבםא , הנפ / תיבלשןוימרדחלדימי - םילוח , אבהו / פורתהתזיראי ה

ךת .

האקהלםורגלןיא אפורמתשרופמהארוהאלל !

ךתלחמבלופיטלהמשרנוזהפורת ; רחאהלוחב / קיזהלהלולעאיהת .

תלא י ןת / י ךיבורקלוזהפורת , ךירכמואךינכש .

ךשוחבתופורתלוטילןיא ! לשי הנמהותיוותהקודב םעפלכב לטונךניהש / ת הפורת .

קוקזךניהםאםייפקשמביכרהלשי / םהלה .

הנסחא :

ןסחאלשי לתחתמ - 25º C ידכ םוחמןגהל . תוחלמןגהלידכתירוקמההזיראברומשלשי .

הזיראהיאנתיפלםג / םיצלמומההנסחאה , דבלבתלבגומהפוקתלתורמשנתופורת . בלםישלאנ

רישכתהלשהגופתהךיראתל ! קפסלשהרקמלכב , פורתהתאךלקפיסשאפורבץעוויהלךילע ה .

הזיראהתואבתונושתופורתןסחאלןיא .

לכותדציכ / לופיטהתחלצהלעייסלי ?

LESAPLJUN12 CLV6 REFBPL100512

לוכסל 20 מ " ג : 069062820200

לוכסל 40 מ " ג : 069072820300

ןרציה : פסיטרבונ א סהקיטיוצמר . א . , דרפס , אהמראפסיטרבונרובע יי ג ' י , לזב , ץיווש .

םושירהלעב : גייאססיורסהמראפסיטרבונ ' י , חר ' םחש 36 , חתפ - קת ו הו .

עעבקנהזןולעטמרופ " ודילערשואוקדבנונכותותואירבהדרשמי ינויב 2012 .

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF MEDICINAL PRODUCT

Lescol 20 mgcapsules, hard

Lescol 40 mgcapsules, hard

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance: fluvastatin (as fluvastatin sodium)

Lescol 20 mgcapsules:

One capsule contains 21.06 mgfluvastatin sodiumequivalent to 20 mgfluvastatin free acid.

Lescol 40 mgcapsules:

One capsule contains 42.12 mgfluvastatin sodiumequivalent to 40 mgfluvastatin free acid.

Excipient: For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Capsule, hard

Lescol 20 mgcapsules:

Cap: Strong reddish brown opaque .

Body: Pale yellow opaque; imprint: XU 20 mg(red ink) .

Lescol 40 mgcapsules:

Cap: Strong reddish brown opaque .

Body: Orange yellow opaque; imprint: XU 40 mg(red ink) .

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Reduction of elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides

and increase of HDL cholesterol in patients withprimaryhypercholesterolemia and primarymixed

dyslipidemia (Fredrickson types IIA and II B) inwhomdietarymeasures have proved insufficiently

effective.

4.2Posology and method of administration

Adults

Prior to initiating treatment with Lescol, patientsshould be placed on a standard cholesterol-lowering

diet, which should be continued during treatment.

Starting and maintenance doses should be individualized according to the baseline LDL-C levels and

the treatment goal to be accomplished.

The recommended dosing range is 20 to 80 mg/day.For patients requiring LDL-C reduction to a goal

of < 25%a starting dose of 20 mgmaybe used as one capsule in the evening. For patients requiring

LDL-C reduction to a goal of≥25%, the recommended starting dose is 40 mgas one capsule in the

evening. The dose maybe uptitrated to 80 mgdaily, administered as one 40 mgcapsule given twice

daily(one in the morning and one in the evening).

LES API JUN12 CL V7 REF CDS 100512

The maximumlipid-lowering effect with a given dose is achieved within 4 weeks. Dose adjustments

should be made at intervals of 4 weeks or more.

Lescol is efficacious in monotherapy. When Lescol isused in combination with cholestyramine or

other resins, it should be administered at least 4 hours after the resin to avoid significant interaction

due to binding of the drug to the resin. In cases where coadministration with a fibrate or niacin is

necessary,the benefit and the risk of concurrent treatment should be carefullyconsidered (for use with

fibrates or niacin see section 4.5).

Paediatric population

Lescol is not indicated in the paediatric population.

Renal Impairment

Lescol is cleared bythe liver, with less than 6% ofthe administered dose excreted into the urine.

The pharmacokinetics of fluvastatin remain unchangedin patients with mild to severe renal insuffi-

ciency.

No dose adjustments are therefore necessaryin these patients.

Hepatic Impairment

Lescol is contraindicated in patients with active liverdisease, or unexplained, persistent elevations in

serumtransaminases (see sections 4.3, 4.4 and 5.2).

Elderly population

No dose adjustments are necessaryin this population.

Method of administration

Lescol capsules can be taken with or without meals and should be swallowed as whole with a glass of

water.

4.3 Contraindications

Lescol is contraindicated:

- in patients with known hypersensitivityto fluvastatin or anyof the excipients listed in section

6.1.

- in patients with active liver disease, or unexplained, persistent elevations in serumtransami-

nases (see sections 4.2, 4.4 and 4.8).

- during pregnancyand breast-feeding (see section 4.6).

4.4Special warnings and precautions for use

Excipient

Lescol 20mg and 40mg capsules contain soyalecithin which might be a source of soyaprotein and

should therefore not be taken in patients allergic to soyaor peanut due to the risk of hypersensitivity

reactions.

Liver function

Postmarketingcasesof fatal and non-fatal hepaticfailures have been reported with somestatins

including Lescol. Although acausalrelationshipwithLescol treatment has not been determined,

patients should be advised to reportanypotentialsymptomsor signs of hepatic failure (e.g. nausea,

vomiting, loss of appetite, jaundice, impaired brain function, easybruising orbleeding),andtreatment

discontinuation should be considered.

As with other lipid-lowering agents, it is recommended that liver function tests be performed before

the initiation of treatment and at 12 weeks following initiation of treatment or elevation in dose and

periodicallythereafter in all patients. Should anincrease in aspartate aminotransferase or alanine

aminotransferase exceed 3 times the upper limit of normal and persist, therapyshould be discontinued.

In veryrare cases, possiblydrug-related hepatitiswas observed that resolved upon discontinuation of

treatment.

Caution should be exercised when Lescol is administered to patients with a historyof liver disease or

heavyalcohol ingestion.

Skeletal muscle

LES API JUN12 CL V7 REF CDS 100512

Myopathyhas rarelybeen reported with fluvastatin. Myositis and rhabdomyolysis have been reported

veryrarely. In patients with unexplained diffuse myalgias, muscle tenderness or muscle weakness,

and/or marked elevation of creatine kinase (CK)values, myopathy,myositis or rhabdomyolysis have

to be considered. Patients should therefore be advised to promptlyreport unexplained muscle pain,

muscle tenderness or muscle weakness, particularlyif accompanied bymalaise or fever.

Creatine kinase measurement

There is no current evidence to require routine monitoring of plasma total CK or other muscle enzyme

levels in asymptomatic patients on statins. If CKhas to be measured it should not be done following

strenuous exercise or in the presence of anyplausible alternative cause of CK increase as this makes

the value interpretation difficult.

Before treatment

As with all other statins physicians should prescribefluvastatin with caution in patients with predis-

posing factors for rhabdomyolysis and its complications. A creatine kinase level should be measured

before starting fluvastatin treatment in the following situations:

- Renal impairment

- Hypothyroidism

- Personal or familial historyof hereditarymuscular disorders

- Previous historyof muscular toxicitywith a statin or fibrate

- Alcohol abuse

- Sepsis

- Hypotension

- Trauma

- Major surgery

- Severe metabolic, endocrine or electrolyte disorders

- Uncontrolled epilepsy

- In elderly(age > 70 years), the necessityofsuch measurement should be considered, accord-

ing to the presence of other predisposing factors for rhabdomyolysis

In such situations, the risk of treatment should beconsidered in relation to the possible benefit and

clinical monitoring is recommended. If CK levelsare significantlyelevated at baseline (> 5x ULN),

levels should be re-measured within5 to 7 dayslater to confirmthe results. If CK levels are still

significantlyelevated (> 5x ULN) at baseline, treatment should not be started.

Whilst on treatment

If muscular symptomslike pain, weakness or crampsoccur in patients receiving fluvastatin, their CK

levels should be measured. Treatment should be stopped if these levels are found to be significantly

elevated (> 5x ULN).

If muscular symptomsare severe and cause dailydiscomfort, even if CK levels are elevated to≤5x

ULN, treatment discontinuation should be considered.

Should the symptomsresolve and CK levels returnto normal, then re-introduction of fluvastatin or

another statin maybe considered at the lowest dose and under close monitoring.

The risk of myopathyhas been reported to be increased in patients receiving immunosuppressive

agents (including ciclosporin), fibrates, nicotinic acid or erythromycin together with other HMG-CoA

reductase inhibitors. Isolated cases of myopathyhavebeen reported post-marketing for concomitant

administration of fluvastatin with ciclosporin and fluvastatin with colchicines. Lescol should be used

with caution in patients receiving such concomitant medicine (see section 4.5).

Use of statins and effects on glucose metabolism

Increased glycosylated hemoglobin (HbA1C) and/orfasting plasma glucose levels were observed in

patients with HMG-CoA reductase inhibitors (statins). New onset of diabetes mellitus was also re-

ported in patients with risk factors for diabetes mellitus.

4.5Interaction with other medicinal products and other forms of interaction

Fibrates and niacin

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Concomitant administration of fluvastatin with bezafibrate, gemfibrozil, ciprofibrate or niacin (nico-

tinic acid) has no clinicallyrelevant effect on the bioavailabilityof fluvastatin or the other lipid-

lowering agent. Since an increased risk of myopathyand/or rhabdomyolysis has been observed in

patients receiving HMGCoA reductase inhibitors together with anyof these molecules, the benefit and

the risk of concurrent treatment should be carefullyweighed and these combinations should onlybe

used with caution (see section 4.4).

Colchicines

Myotoxicity, including muscle pain and weakness andrhabdomyolysis, has been reported in isolated

cases with concomitant administration of colchicines.The benefit and the risk of concurrent treatment

should be carefullyweighed and these combinations should onlybe used with caution (see section

4.4).

Ciclosporin

Studies in renal transplant patients indicate that thebioavailabilityof fluvastatin (up to 40 mg/day) is

not elevated to a clinicallysignificant extent in patients on stable regimens of ciclosporin. The results

fromanother studyin which 80 mgfluvastatin was administered to renal transplant patients who were

on stable ciclosporin regimen showed that fluvastatin exposure (AUC) and maximumconcentration

(Cmax) were increased 2-fold compared to historical data in healthysubjects. Although these increas-

es in fluvastatin levels were not clinicallysignificant, this combination should be used with caution.

Starting and maintenance dose of fluvastatin shouldbe as low as possible when combined with ciclos-

porin.

Lescol capsules (40 mgfluvastatin) had no effecton the bioavailabilityof ciclosporin when co-

administered.

Warfarin and other coumarin derivatives

In healthyvolunteers, the use of fluvastatin andwarfarin (single dose) did not adverselyinfluence

warfarin plasma levels and prothrombin times compared to warfarin alone.

However, isolated incidences of bleeding episodes and/or increases prothrombin times have been

reported veryrarelyin patients on fluvastatin receiving concomitant warfarin orother coumarin deriv-

atives. It is recommended that prothrombin times are monitored when fluvastatin treatment is initiated,

discontinued, or the dosage changes in patientsreceiving warfarin or other coumarin derivatives.

Rifampicin

Administration of fluvastatin to healthyvolunteers pre-treated with rifampicin (rifampin) resulted in a

reduction of the bioavailabilityof fluvastatin byabout 50%. Although at present there is no clinical

evidence that fluvastatin efficacyin lowering lipid levels is altered, for patients undertaking long-term

rifampicin therapy(e.g. treatment of tuberculosis),appropriate adjustment of fluvastatin dosage may

be warranted to ensure a satisfactoryreduction in lipid levels.

Oral antidiabetic agents

For patients receiving oral sulfonylureas (glibenclamide (glyburide), tolbutamide) for the treatment of

noninsulin- dependent (type 2) diabetes mellitus (NIDDM), addition of fluvastatin does not lead to

clinicallysignificant changes in glycaemic control.In glibenclamide-treated NIDDM patients (n=32),

administration of fluvastatin (40 mgtwice dailyfor 14 days) increased the mean Cmax, AUC, and t½

of glibenclamide byapproximately50%, 69%, and 121%, respectively.Glibenclamide (5 to 20 mg

daily) increased the mean Cmax and AUC of fluvastatin by44% and 51%, respectively.In this study

there were no changes in glucose, insulin, and C-peptide levels. However,patients on concomitant

therapywith glibenclamide (glyburide) and fluvastatin should continue to bemonitored appropriately

when their fluvastatin dose is increased to 80 mgper day.

Bile acid sequestrants

Fluvastatin should be administered at least 4 hours after the resin (e.g. cholestyramine) to avoid a

significant interaction due to drug binding of the resin.

Fluconazole

Administration of fluvastatin to healthyvolunteerspre-treated with fluconazole (CYP 2C9 inhibitor)

resulted in an increase in the exposure and peak concentration of fluvastatinbyabout 84% and 44%.

LES API JUN12 CL V7 REF CDS 100512

Although there was no clinical evidence that the safetyprofile of fluvastatin was altered in patients

pretreated with fluconazole for 4 days, caution should be exercised when fluvastatin is administered

concomitantlywith fluconazole.

Histamine H2-receptor antagonists and proton pump inhibitors

Concomitant administration of fluvastatin with cimetidine, ranitidine or omeprazole results in an

increase in the bioavailabilityof fluvastatin, which, however, is of no clinical relevance.

Phenytoin

The overall magnitude of the changes in phenytoinpharmacokinetics during co-administration with

fluvastatin is relativelysmall and not clinicallysignificant. Thus routine monitoring of phenytoin

plasma levels is sufficient during co-administration with fluvastatin.

Cardiovasular agents

No clinicallysignificant pharmacokinetic interactionsoccur when fluvastatin is concomitantlyadmi-

nistered with propranaolol, digoxin, losartan, clopidogrel or amlodipine. Based on the pharmacokinet-

ic data, no monitoring or dosage adjustments are required when fluvastatin is concomitantlyadminis-

tered with these agents.

Itraconazole and erythromycin

Concomitant administration of fluvastatin withthe potent cytochromeP450 (CYP) 3A4 inhibitors

itraconazole and erythromycin has minimal effects on the bioavailabilityof fluvastatin. Given the

minimal involvement of this enzymein the metabolismof fluvastatin, it is expected that other

CYP3A4 inhibitors (e.g. ketoconazole, ciclosporin)are unlikelyto affect the bioavailabilityof fluvas-

tatin.

Grapefruit juice

Based on the lack of interaction of fluvastatin withother CYP3A4 substrates, fluvastatin is not ex-

pected to interact with grapefruit juice.

4.6Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential have to use effective contraception.

If a patient becomes pregnant while takingLescol, therapyshould be discontinued.

Pregnancy

There is insufficient data on the use of fluvastatin during pregnancy.

Since HMG-CoA reductase inhibitors decrease the synthesis of cholesterol and possiblyof other

biologicallyactive substances derived fromcholesterol, theymaycause foetal harmwhen adminis-

tered to pregnant women. Therefore, Lescol iscontraindicated during pregnancy(see section 4.3).

Breastfeeding

Based on preclinical data, it is expected that fluvastatin is excreted into human milk. There is insuffi-

cient information on the effects of fluvastatin in newborns / infants.

Lescol is contraindicated in breastfeeding women (see section 4.3).

4.7Effects on ability to drive and use machines

No studies on the effects on the abilityto drive and use machines have been performed.

4.8 Undesirable effects

The most commonlyreported adverse reactions aremild gastrointestinal symptoms, insomnia and

headache.

Adverse drug reactions (Table 1) are listed byMedDRA systemorgan class. Within each systemorgan

class, the adverse drug reactions are ranked byfrequency,with the most frequent first. Within each

frequencygrouping, adverse drug reactions are presented in order of decreasing seriousness. In addi-

tion, the corresponding frequencycategory,usingthe following convention (CIOMS III) is also

provided for each adverse drug reaction: verycommon (≥1/10); common (≥1/100, <1/10); uncommon

LES API JUN12 CL V7 REF CDS 100512

(≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); veryrare (<1/10,000), not known (cannot be estimated

fromthe available data).

Table 1 Adverse drug reactions

System organ class Frequency Adverse reactions

Blood and lymphatic system

disorders Veryrare Thrombocytopenia

Immune system disorders

Rare Hypersensitivityreactions (rash, urticaria)

Veryrare Anaphylactic reaction

Psychiatric disorders CommonInsomnia

Nervous system disorders

Common Headache

Veryrare Paresthesia, dysesthesia, hypoesthesia also known to

be associated with the underlying hyperlipidaemic

disorders

Vascular disorders Veryrare Vasculitis

Gastrointestinal disorders

Common Nausea, abdominal pain, dyspepsia

Veryrare Pancreatitis

Hepatobiliary disorders Veryrare Hepatitis

Skin and subcutaneous

tissue disorders

Veryrare

Angioedema, face oedemaand other skin reactions

(e.g. eczema, dermatitis, bullous exanthema)

Musculoskeletal and connec-

tive tissue disorders

Rare Myalgia, muscular weakness, myopathy

Veryrare Rhabdomyolysis, lupus erythematosus like syn-

drome, myositis

Reproductive system and

breast disorders Not known* Erectile dysfunction

Investigations

Common Blood creatine phosphokinase increased, blood

transaminases increased

* Based on post-marketing experience with Lescol via spontaneous case reports and literature cases.

Because these reactions are reported voluntarily fromapopulation of uncertain size,it is not possible to

reliablyestimate their frequencywhich istherefore categorised as notknown.

Laboratoryfindings

Biochemical abnormalities of liver function have been associated with HMG-CoA reductase inhibitors

and other lipid-lowering agents. Based on pooled analyses of controlled clinical trials confirmed

elevations of alanine aminotransferase or aspartateaminotranferase levels to more than 3 times the

upper limit of normal occurred in 0.2% on Lescol capsules 20 mg/day, 1.5% to 1.8% on Lescol cap-

sules 40 mg/dayand in 2.7% to 4.9% on twice dailyLescol capsules 40 mg. The majorityof patients

with these abnormal biochemical findings were asymptomatic. Marked elevations of CK levels to

more than 5x ULN developed in a verysmall number of patients (0.3 to 1.0%).

4.9 Overdose

To date there has been limited experience with overdose of fluvastatin. Specific treatment is not

available for Lescol overdose. Should an overdose occur, the patient should be treated symptomatical-

lyand supportive measures instituted, as required. Liver function tests and serumCK levels should be

monitored.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: HMG-CoA reductase inhibitors, ATC code: C10A A04

Fluvastatin, a fullysynthetic cholesterol-lowering agent, is a competitive inhibitor of HMG-CoA

reductase, which is responsible forthe conversion of HMG-CoA to mevalonate, a precursor of sterols,

LES API JUN12 CL V7 REF CDS 100512

including cholesterol. Fluvastatin exerts its main effectin the liver and is mainlya racemate of the two

erythro enantiomers of which one exerts the pharmacological activity. The inhibition of cholesterol

biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors

and therebyincreases the uptake of LDL particles. The ultimate result of these mechanismsis a reduc-

tion in the plasma cholesterol concentration.

Lescol reduces total-C, LDL-C, Apo B, and triglycerides, and increases HDL-C in patients with

hypercholesterolaemia and mixed dyslipidaemia.

In 12 placebo-controlled studies in patients with TypeIIa or IIb hyperlipoproteinaemia, Lescol alone

was administered to 1,621 patients in dailydose regimens of 20 mg, 40 mgand 80 mg(40 mgtwice

daily) for at least 6 weeks duration. In a 24-week analysis, dailydoses of 20 mg, 40 mgand 80 mg

produced dose-related reductions in total-C, LDL-C, Apo B and in triglycerides and increases in HDL-

C (see Table 2).

Therapeutic response is well established withintwo weeks, and a maximumresponse is achieved

within four weeks. After four weeks of therapy,the median decrease in LDL-C was 38% and at week

24 (endpoint) the median LDL-C decrease was 35%. Significant increases in HDL-C were also ob-

served.

Table 2 Median percent change in lipid parameters from baseline to week 24

Placebo-controlled studies (Lescol)

Total-C TG LDL-C Apo B HDL-C

Dose N % ΔN % ΔN % ΔN % ΔN% Δ

All patients

Lescol 20 mg 1 747 -17 747 -12 747 -22 114 -19 747 +3

Lescol 40 mg 1 748 -19 748 -14 748 -25 125 -18 748 +4

Lescol 40 mgtwice daily 1 257 -27 257 -18 257 -36 232 -28 257 +6

Baseline TG≥200 mg/dl

Lescol 20 mg 1 148 -16 148 -17 148 -22 23 -19 148 +6

Lescol 40 mg 1 179 -18 179 -20 179 -24 47 -18 179 +7

Lescol 40 mgtwice daily 1 76 -27 76 -23 76 -35 69 -28 76 +9

Datafor Lescolfrom12 placebo-controlled trials

5.2 Pharmacokinetic Properties

Absorption

Fluvastatin is absorbed rapidlyand completely(98%) after oral administration of a solution to fasted

volunteers. In a fed state, the substance is absorbed at a reduced rate.

Distribution

Fluvastatin exerts its main effect in the liver, which is also the main organ for its metabolism.The

absolute bioavailabilityassessed fromsystemic blood concentrations is 24%. The apparent volume of

distribution (Vz/f) for the drug is 330 litres. More than 98% of the circulating drug is bound to plasma

proteins, and this binding is not affected either bythe concentration of fluvastatin, or bywarfarin,

salicylic acid or glyburide.

Biotransformation

Fluvastatin is mainlymetabolised in the liver.The major components circulating in the blood are

fluvastatin and the pharmacologicallyinactive N-desisopropyl-propionic acid metabolite. The hydrox-

ylated metabolites have pharmacological activitybut do not circulate systemically. There are multiple,

alternative cytochromeP450 (CYP450) pathwaysforfluvastatin biotransformation and thus fluvasta-

tin metabolismis relativelyinsensitive to CYP450 inhibition.

Fluvastatin inhibited onlythe metabolismof compoundsthat are metabolised byCYP2C9. Despite the

potential that therefore exists for competitive interaction between fluvastatin and compounds that are

CYP2C9 substrates, such as diclofenac, phenytoin,tolbutamide and warfarin, clinical data indicate

that this interaction is unlikely.

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Elimination

Following administration of 3H-fluvastatin to healthyvolunteers, excretion of radioactivityis about

6% in the urine and 93% in the faeces, and fluvastatinaccounts for less than 2% of the total radioactiv-

ityexcreted. The plasma clearance (CL/f) for fluvastatin in man is calculated to be 1.8 ± 0.8 l/min.

Steady-state plasma concentrations show no evidence of fluvastatin accumulation following adminis-

tration of 80 mgdaily. Following oral administration of 40 mgLescol, the terminal disposition half-

life for fluvastatin is 2.3 ±0.9 hours.

Characteristics in patients

Plasma concentrations of fluvastatin do not varyasa function of either age or gender in the general

population. However, enhanced treatment responsewas observed in women and in elderlypeople.

Since fluvastatin is eliminated primarilyvia the biliaryroute and is subject to significant presystemic

metabolism,the potential exists for drug accumulation in patients with hepatic insufficiency(see

sections 4.3 and 4.4).

Children and adolescents

No pharmacokinetic data in children are available.

5.3Preclinical Safety Data

The conventional studies, including safetypharmacology, genotoxicity, repeated dose toxicity, carci-

nogenicityand toxicityon reproduction studies did not indicate other risks for the patient than those

expected due to the pharmacological mechanismofaction. A varietyof changes were identified in

toxicitystudies that are common to HMG-CoA reductase inhibitors. Based on clinical observations,

liver function tests are alreadyrecommended (see section 4.4). Further toxicityseen in animals was

either not relevant for human use or occurred atexposure levels sufficientlyin excess of the maximum

human exposure indicating little relevance to clinicaluse. Despite the theoretical considerations

concerning the role of cholesterol in embryodevelopment, animal studies did not suggest an embryo-

toxic and teratogenic potential of fluvastatin.

6. PHARMACEUTICAL PARTICULARS

6.1List of excipients

Lescol 20 mg and 40 mg capsules:

Capsule content:

Magnesiumstearate

Sodiumhydrogen carbonate

Talc

Cellulose microcrystalline

Pregelatinised starch

Calciumcarbonate

Capsule shell:

Cap:

Titaniumdioxide (E 171)

Iron oxide red (E 172)

Gelatin

Body:

Iron oxide red (E 172)(lescol 20)

Iron oxide yellow (E 172)

Titaniumdioxide (E 171)

Gelatin

Iron oxide

Imprint:

Iron oxide red (E 172)

Shellac

Butyl alcohol

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Purified water

Lecithin (soya) (E 322)

Dimethylpolysiloxane (E 900) (AntifoamDC 1510 (Food grade))

Industrial methylated spirit

6.2 Incompatibilities

None.

6.3 Shelf-life

3 years.

6.4Special precautions for storage

Store below 25°C. Capsules should be leftin the blister pack until required for use.6.5 Nature and

contents of container

PA/AL/PVC blisters.

6.5Special precautions for disposal and other handling

No special requirements.

Manufacturer:

Novartis Pharmaceutica SA, Spain

For Novartis PharmaAG, Basel, Switzerland

License Holder:

Novartis PharmaServices AG

36 ShachamSt., Petach-Tikva.