DANOL 200

םיחקורה תונקת יפל ןכרצל ןולע

1986- ו"משתה )םירישכת(

אפור םשרמב תבייח וז הפורת

ופוס דע ןולעה תא ןויעב י/ארק

הפורתב י/שמתשת םרטב

תואירבה דרשמ י"ע עבקנ הז ןולע טמרופ

2012ילויב ודי-לע רשואו קדבנ ונכותו

ג"מ 200לונד

תוסומכ

:בכרה

:הליכמ הסומכ לכ

Danazol 200 mg

:םיליעפ יתלב םירמוח

Lactosemonohydrate,maizestarch,talc,magnesium

stearate,gelatin,titaniumdioxide,redironoxide,yellow

iron oxide.

:ליכמ הסומכה לע ספדומה עבצה

Shellac glaze, propylene glycol, black iron oxide.

:וא

Shellac,dehydratedalcohol,propyleneglycol,ammonia

solution, potassium hydroxide, black iron oxide.

:וא

Shellacglaze45%(20%esterfied)inethanol,propyleneglycol,

black iron oxide, ammonium hydroxide 28%.

:וא

Shellac,propyleneglycol,strongammoniasolution,

potassium hydroxide, black iron oxide.

.טרדיהונומ זוטקל ג"מ76.6הליכמ הסומכ לכ

:תיטיופרת הצובק

.תינגורדנא יטנא העפשה לעב יטטניס דיאורטס

:תיאופר תוליעפ

לופיטלביגמהסיזוירטמודנאבלופיטלתדעוימהפורתה

ינשבםדהילכלשתיתשרותתקצבבלופיטלוילנומרוה

.םינימה

?רישכתב שמתשהל ןיא יתמ

תננכתמ,ןוירהבךניהרשאכהפורתבישמתשתלא

."תורהזא"ב םג יאר - הקינימ וא ןוירה

דחאלואלוזאנאדלתושיגרהעודיםאשמתשהלןיא

.הפורתה יביכרממ

אלילאניגוםומידלשהרקמבהפורתבשמתשהלןיא

דוקפתברומחיוקיללשהרקמב,ןחבואמאלוןיקת

הרקמבואהיריפרופלשהרקמבובלהואתוילכה,דבכה

.תורחא תוקצב לש

ת/לבוסךניהואתלבסםאהפורתבשמתשהלןיא

םילודיגיגוסמוא,םיימינפםדישירקואסיזובמורתמ

.םינגורדנאמ םיעפשומש

ינפלאפורבץעוויהלילבמהפורתבשמתשהלןיא

:לופיטה תלחתה

.רחא ןטרס לכ וא דשה ןטרס תוחכונל דשח םייק םא

.המוד לופיטל וא הפורתל רבעב תושיגר התייה םא

בלה:דוקפתביוקילמרבעבתלבסואת/לבוסךניהםא

םדהתכרעמ,ןתשהתכרעמ/הילכה,דבכה,םדילכוא/ו

,תרכוסמ,הובגםדץחלו)'וכוהימטיצילופ,השירקןוגכ(

לכ,םדבםינמושתומרבתוערפה,הנרגימ,היספליפא

.םילזונ תריצא תובקעב רימחהל לוכיש בצמ

?ךלש םוי םויה ייח לע הפורתה עיפשת ךיא

לופיטהתפוקתבםיפירחתואקשמואתונייתותשלןיא

הליחבלםורגללולעלוהוכלאבשומיש-הפורתהםע

.המישנ רצוקל וא

הפישחםעתדחוימתושיגרלםורגלהלולעוזהפורת

הנגהלי/גאדושמשלהפישחמי/ענמיהןכ-לע,שמשל

.)'וכו הנגה תוחשמ ,עבוכ ,םיכורא םידגב( המיאתמ

:תורהזא

ךילע,יהשלכהפורתלואוהשלכןוזמלה/שיגרךניהםא

.הפורתה תליטנ ינפל אפורל ךכ לע עידוהל

עובקיאופרבקעמבתויהלשיהפורתבלופיטהתפוקתב

.דבכ ידוקפת ,םד תוקידב ךורעלו

שמתשהלשי!ןוירהמענמיהלשילופיטהתפוקתב

.םיילאנומרוה אל העינמ יעצמאב

תידיימקיספהלשי,לופיטידכךותןוירהלשהרקמב

.אפורל תונפלו הפורתה תליטנ תא

רישכתבשומישהלעחוודלשיהדבעמתקידבלכינפל

תויתדבעמתואצותביונישלםורגללולעאוהשרחאמהז

.תומיוסמ

ןטרסבתולחלןוכיסהתאריבגהללולעהפורתבשומישה

.סיזוירטמודנאמ תולבוסה םישנ לצא ,תולחשה

םילוחבםדברכוסהןזאמלעעיפשהללולעלופיטה

.םייתרכוס

שי,המדרהירמוחםעחותינרובעלת/דמועךניהםא

תאריבגהללוכילונד(לונדתליטנלעאפורלחוודל

.)המדרהה ירמוח תוליעפ

שיזוטקללםישיגרהםישנאב,זוטקלליכמרישכתה

.שומישה ינפל אפורה םע ץעייתהל

:תויתפורת-ןיב תובוגת

תורכמנהתופורתללוכ,תפסונהפורתת/לטונךניהםא

התעהזתרמגםאוא,הנוזתיפסותואפורםשרמאלל

ידכלפטמהאפורלחוודלךילע,תרחאהפורתבלופיט

-ןיבתובוגתמםיעבונהתוליעי-יאואםינוכיסעונמל

:תואבהתוצובקהמתופורתיבגלדחוימב,תויתפורת

תופורת,תויוצווכתהואהיספליפאבלופיטלתופורת

,)ןידמוקוןירפרווןוגכ(םדתשירקדגנתופורת,המדרהל

םיילאנומרוהםירישכת,םדץחלתדרוהלתופורת

,)ןורטסגורפ,ןגורטסא,ןורטסוטסט(םירחאםידיאורטסו

,)לתשתייחדתעינמלתופורת(סומילורקטוןירופסולקיצ

,) D ןימטיולשגוס(לודיצלקאפלא,הנרגימדגנתופורת

,)ןיטטסאבולוןיטטסאברוטא,ןיטטסאבמיסןוגכ(םיניטטס

-ןילוסניאואהפהךרדןתמבתרכוסבלופיטלםירישכת

:יאוול תועפות

הבשומישהןמזב,הפורתהלשהיוצרהתוליעפלףסונב

.יאוול תועפות עיפוהל תולולע

תיבלי/הנפואדימאפורלי/הנפולונדתחקלי/קספה

:םיאבה םירקמב דימ םילוחה

תויהלםילוכיךכלםינמיסה-תיגרלאהבוגתתעפוה

,םייתפשבתוחיפנ,המישנבואהעילבבתויעב,החירפ

.ןושלב וא עולב ,םינפב

ולא-תועורזבואתסלב,הזחבץחלואבאכתעפוה

.בל ףקתה לש םינימסת תויהל םילוכי

ה/שחךניהםאדימאפורלי/הנפולונדתחקלי/קספה

לופיטי/ךרטצתוןכתיי-םיאבהםינימסתהמדחא

:ףוחד יאופר

תויעב,הייארבתויעב,הייארבשוטשט;ןגדגדהתלדגה

םורגלתולוכיהדבכבתויעב;עגמהתושדעתבכרהב

קזחשארבאכ;)תבהצ(רועהואםייניעהתבהצהל

םיילגרהואתועורזהתזזהבבאכ;)ילוחתשגרה(הליחבו

םעדחיבהשלוחתשגרה;)םדבשירקמםרגנוןכתיי(

אלוןכתייםתואשםיילגרבואתועורזבהשוחתרסוח

םילוחכםינמיס;)ץבשלעדיעמוןכתיי(זיזהלי/לכות

ןכתיי(תולקברתויםימרגנהםימוהיז,תולקבםימרגנה

עיפומשרחארומחןימסתלכ;)םדבהייעבלעדיעמו

.וריבסהל ה/לוכי ךניאו

םינימסתהמדחאבה/שחךניהםאדימאפורלי/עדוה

:םיאבה

רתירועיש;שארהרעישדוביא;ליגרהמהקזחהנרגימ

הובג(לוקהיונישואלוקבתודירצ,ןורגבאכ;ףוגבוםינפב

םדתעפוה;היספליפאהלשהרמחה;)ליגרהמךומנוא

,רועבתויחופלשואהחירפ;הזחבואןטבבבאכ;ןתשב

.שמשל ותושיגרב וא רועה עבצב יוניש

השענםיאבהםינימסתהמדחאםאאפורלי/עדוה

:םימי המכל לעמ ךשמתמ וא רומח

,הנקא,רועבםימתכ;ןובאיתבהיילעואלקשמבהיילע

םייוניש;תוחיפנואםילזונתריצא;החירפואינמושרוע

הדיריואינימהקשחביוניש,קיתרנבשבוי,ישדוחהרוזחמב

,בגבאכ;רועבהחירפבהוולמההובגםוח;םיידשהלדוגב

,םיקרפמבתוחיפנואבאכ,םירירשבדערותויוצווכתה

תויעבואתרוחרחס,ילוחתשגרה;תועורזבואםיילגרב

;הקמסה;תופייעתשגרה,שארבאכ;לקשמיווישב

קפוד;ליגרהמרתויתונבצעואהדרח,ןואכידתשגרה

תוירופבהדירי;הובגםדץחל,ריהמבלבצק,ריהמבל

.)ערזה תומכב הדירימ םרגנו ןכתיי( רבגה

אלשיאוולתועפותה/שיגרמךניהובשהרקמלכב

ךילעתיללכהךתשגרהביונישלחםאוא,הזןולעבוניוצ

.דימ אפורה םע ץעייתהל

:ןונימ

.דבלב אפורה תוארוה יפל ןונימ

.תצלמומה הנמה לע רובעל ןיא

עבקנשיפכםיבוצקםינמזבוזהפורתבשמתשהלשי

.לפטמה אפורה ידי-לע

הנמלוטילשי,בוצקןמזבוזהפורתלוטילתחכשםא

האבההנמהתליטנלןמזהםא,םלוא.תרכזנשכדימ

לוטילןיאןפואםושב,החכשנשהנמהלעי/גלדבורק

!דחי תונמ יתש

,אלםא,תסווהלשןושארהםויבלופיטהליחתהלץלמומ

.לופיטה תלחתה ינפל ןוירה תלילשל הקידב ךורעל שי

:שומישה ןפוא

.םימ םע התומלשב הפורתה תא עולבל !סועלל ןיא

?לופיטה תחלצהל עייסל י/לכות דציכ

לופיטהקיספהלןיאךתואירבבצמברופישלחםאםג

.אפורה םע תוצעייתה אלל הפורתב

!הלערה י/ענמ

רוגסםוקמברומשלשיתרחאהפורתלכווזהפורת

ךכידי-לעותוקוניתוא/וםידלילשםדיגשיהלץוחמ

.הלערה י/ענמת

,הפורתהןמדליעלבתועטבםאוארתיתנמתלטנםא

תזיראי/אבהו,םילוח-תיבלשןוימרדחלדימי/הנפ

.ךתיא הפורתה

!אפורמ תשרופמ הארוה אללהאקהל םורגל ןיא

איהת/רחאהלוחב,ךתלחמבלופיטלהמשרנוזהפורת

ךינכש,ךיבורקלוזהפורתי/ןתיתלא.קיזהלהלולע

.ךירכמ וא

הנמהותיוותהקודבלשי!ךשוחבתופורתלוטילןיא

.הפורתה ת/לטונ ךניהשםעפ לכב

.םהל ה/קוקז ךניה םא םייפקשמ ביכרהל שי

:הנסחא

הלועהניאשהרוטרפמטב,שביםוקמבןסחאלשי

לע

תופורת,םיצלמומההנסחאה/הזיראהיאנתיפלםג

ךיראתלבלםישלאנ.דבלבתלבגומהפוקתלתורמשנ

ץעוויהלךילע,קפסלשהרקמלכב!רישכתהלשהגופתה

.הפורתה תא ךל קפיסש חקורב

.הזירא התואב תונוש תופורת ןסחאל ןיא

שיםא.רישכתהלעעדימהלכתאללוכאלהזןולע

אנא,המרבדבה/חוטבךניאואיהשלכהלאשךל

.אפורל י/הנפ

1420822276-01:הפורתה םושיר 'סמ

:ןרצי

.הילגנא ,ובלטניס יפונאס

:םושירה לעב

,מ"עב לארשי סיטנווא-יפונאס

.42504הינתנ ,8090ד.ת

DANO CAPS PL SH 270612

PATIENTPACKAGEINSERTINACCORDANCEWITH

THE PHARMACISTS' REGULATIONS

(PREPARATIONS) - 1986

The dispensing ofthis medicine

requires a doctor's prescription

Read this package insert carefully in its entirety

before using this medicine

The format ofthis leaflet was determined

by the Ministry ofHealth and its content

was checked and approved by it in July 2012

Danol 200 mg

Capsules

Composition:

Each capsule contains:

Danazol 200 mg

Inactive ingredients:

Lactosemonohydrate,maizestarch,talc,magnesium

stearate,gelatin,titaniumdioxide,redironoxide,yellow

iron oxide.

The color printed on the capsule contains:

Shellac glaze, propylene glycol, black iron oxide

Shellac,dehydratedalcohol,propyleneglycol,ammonia

solution, potassium hydroxide, black iron oxide

Shellacglaze45%(20%esterfied)inethanol,propylene

glycol, black iron oxide, ammonium hydroxide 28%.

Shellac,propyleneglycol,strongammoniasolution,

potassium hydroxide, black iron oxide.

Each capsule contains lactose monohydrate 76.6 mg.

Therapeutic group:

A synthetic steroid with antiandrogenic properties.

Therapeutic activity:

Thismedicineisintendedforthetreatmentof

endometriosisamenabletohormonalmanagement,

andforthetreatmentofhereditaryangioedemain

both females and males.

When should the preparation not be used?

Donotusethismedicineifyouarepregnant,planning

tobecomepregnantorbreastfeeding-seealso

“Warnings”.

Donotuseifthereisaknownsensitivitytodanazol

or to any ingredients ofthe medicine.

Donotusethismedicineincaseofabnormaland

undiagnosedvaginalbleeding,incaseofseverely

impairedfunctionoftheliver,kidneysorheart,and

in case ofporphyria, or ifthere are other edemas.

Donotusethismedicineifyouhavesufferedorare

sufferingfromthrombosisorinternalbloodclots,or

from androgen dependent tumors.

Donottakethismedicinewithoutconsulting

a doctor before starting treatment:

Ifthereissuspiciontothepresenceofbreastcanceror

any other cancer.

Ifyouhaveexperiencedsensitivitytothismedicineor

to similar treatment in the past.

Ifyousufferorhavesufferedinthepastfromimpaired

functionofthe:heartand/orbloodvessels,liver,

kidneys/urinarytract,bloodsystem(e.g.coagulation,

polycythemia,etc.)andhypertension,fromdiabetes,

epilepsy,migraine,bloodlipidleveldisturbances,any

conditionthatmaybeaggravatedasaresultoffluid

retention.

How will this medicine affect your daily life?

Donotdrinkwinesorotheralcoholicbeveragesduring

treatmentwiththismedicine;useofalcoholmaycause

nausea or shortness ofbreath.

Thismedicinemaycausespecialsensitivityupon

exposuretothesun;therefore,avoidexposuretothe

sunandtakeappropriateprotectivemeasures(long

garments, a hat, sun screening creams, etc.).

Warnings:

Ifyouaresensitivetoanytypeoffoodormedicine,

inform your doctor before commencing treatment.

Duringtreatmentwiththismedicine,youshouldbe

underregularmedicalfollow-upandbloodandliver

functions tests should be performed.

Duringtreatmentwiththismedicine,avoidpregnancy!

Use a non-hormonal contraceptive method.

Shouldpregnancyoccurwhileundertreatmentwith

thismedicine,stoptreatmentimmediatelyandrefer

to your doctor.

Priortoundergoinganylaboratorytestsyoushould

notifythatyouaretakingthismedicineasitmaycause

changes in the results ofcertain laboratory tests.

Useofthismedicinemayincreasetheriskofovarian

cancer in women suffering from endometriosis.

Treatmentmayaffectthesugarbalanceintheblood

ofdiabetic patients.

Ifyouareabouttoundergosurgeryinvolvinganesthesia,

informthedoctorthatyouaretakingDanol(Danolcan

increase the action ofanesthetics).

Thismedicinecontainslactose,peoplesensitiveto

lactose should consult the doctor before use.

Drug interactions:

Ifyouaretakinganotherdrug,includingnon-prescription

medicinesandfoodsupplements,orifyouhavejust

finishedtreatmentwithanothermedicine,inform

theattendingdoctor,inordertopreventhazardsor

lackofefficacyarisingfromdruginteractions.Thisis

especiallyimportantformedicinesbelongingtothe

followinggroups:medicinesfortreatmentofepilepsy

orconvulsions,anesthetics,anticoagulants(e.g.:

warfarinandCoumadin),antihypertensives,hormonal

medicationsandothersteroids(testosterone,estrogen,

progesterone),cyclosporineandtacrolimus(medicines

migrainemedications,alfacalcidol(atypeofvitaminD),

statins(e.g.:simvastatin,atorvastatinandlovastatin),oral

medicinesforthetreatmentofdiabetesorinsulin-in

diabetespatientstheinsulindosagemaysometimes

have to be increased.

Side effects:

Inadditiontothedesiredeffectofthemedicine,adverse

reactionsmayoccurduringthecourseoftakingthis

medicine.

StoptakingDanolandrefertothedoctorimmediately

orproceedtothehospitalimmediatelyinthe

following cases:

Onsetofanallergicreaction-thesignscanberash,

problemsswallowingorbreathing,swellingofthelips,

face, throat or tongue.

Onsetofpainortightnessinthechest,jaworarms-

these can be symptoms ofheart attack.

StoptakingDanolandrefertothedoctorimmediately

ifyouexperienceoneofthefollowingsymptoms-you

may need urgent medical treatment:

Enlargementoftheclitoris;blurringofvision,vision

problems,problemswearingcontactlenses;liver

problemsthatcancauseyellowingoftheeyesorskin

(jaundice);severeheadacheandnausea(feelingsick);

painwhenmovingthearmsorlegs(maybecausedby

abloodclot);feelingweaktogetherwithnumbnessin

thearmsorlegswhichyoumaynotbeabletomove

(mayindicateastroke);bruisingthatoccursmoreeasily,

infectionsthatoccurmoreeasily(mayindicateablood

problem);anyotherseveresymptomthatoccurand

cannot be explained.

Notifythedoctorimmediatelyifyouexperienceone

ofthe following symptoms:

Strongermigrainethanusual;scalphairloss;excessive

hairinessonthefaceandbody;sorethroat,hoarsenessor

changeofvoice(higherorlowerthanusual);worsening

ofepilepsy;bloodintheurine;painintheabdomen

orchest;skinrashorblistering,changesinskincolor

or sensitivity to the sun.

Notifythedoctorifoneofthefollowingsymptoms

becomes worse or lasts longer than a few days:

Weightgainorincreasedappetite;spotsontheskin,acne,

oilyskinorrash;retentionoffluidsorbloating;changes

inthemenstrualcycle,vaginaldryness,changeinlibido

ordecreasedbreastsize;highfeveraccompaniedby

skinrash;backpain,musclecrampsandtwitching,

painorswellingofthejoints,legsorarms;feelingsick,

dizzinessorbalanceproblems;headache,feelingtired;

flushing;feelingdepressed,anxiousormorenervous

thanusual;rapidpulse,fastheartbeat,highblood

pressure;decreasedfertilityinmen(maybecausedby

a reduction in the amount ofsperm).

Ifyouexperiencesideeffectsnotmentionedinthis

leaflet,orifthereisachangeinyourgeneralhealth,

consult the doctor immediately.

Dosage:

Dosage is according to doctor's instructions only.

Do not exceed the recommended dosage.

Thismedicineistobetakenatspecifictimeintervals

as determined by the attending doctor.

Ifyouforgettotakethismedicineatthespecifiedtime,

takethedoseassoonasyouremember,butifitisalmost

timeforthenextdose,skipthemisseddose.Nevertake

two doses together!

Itisrecommendedtostarttreatmentonthefirstdayof

menstruation.Ifnot,atesttoruleoutpregnancyshould

be carried out before starting treatment.

Directions for use:

Donotchew!Swallowthemedicinewholewith

water.

Howcanyoucontributetothesuccessofthe

treatment?

Evenifthereisanimprovementinyourhealth,donot

discontinueuseofthismedicinewithoutconsulting

your doctor.

Avoid poisoning!

Thismedicine,andallothermedicines,mustbestoredin

asafeplaceoutofthereachofchildrenand/orinfants,

to avoid poisoning.

Ifyouhavetakenanoverdose,orifachildhasaccidentally

swallowedthemedicine,proceedimmediatelytoa

hospitalemergencyroomandbringthepackageofthe

medicine with you.

Donotinducevomitingunlessexplicitlyinstructedto

dosobyadoctor!Thismedicinehasbeenprescribed

forthetreatmentofyourailment;inanotherpatient

itmaycauseharm.Donotgivethismedicinetoyour

relatives, neighbors or acquaintances.

Donottakemedicinesinthedark!Checkthelabeland

thedoseeachtimeyoutakeyourmedicine.Wearglasses

ifyou need them.

Storage:

Storeinadryplaceatatemperaturenotexceeding

30°C.

Evenifkeptintheiroriginalcontainerandstoredas

recommended,medicinesmaybekeptforalimited

periodonly.Pleasenotetheexpirydateofthemedicine!

Incaseofdoubt,consultthepharmacistwhodispensed

the medicine to you.

Donotstoredifferentmedicationsinthesame

package.

Thisleafletdoesnotcontainalltheinformationabout

yourmedicine.Ifyouhaveanyquestionsorarenot

sure about anything, ask your doctor.

License number:1420822276-01

Manufacturer:

Sanofi Synthélabo, UK.

Registration holder:

sanofi-aventis Israel ltd.,

P.O. Box 8090, Netanya 42504.

1

טמרופ ןולע הז עבקנ י"ע דרשמ תואירבה ונכותו קדבנ רשואו לירפאב 2012

S UMMARY OF PRODUCT CHARACTERISTICS

1. T RADE N AMEOF M EDICINAL P RODUCT

Danol 200mg Capsules

2. Q UALITATIVE AND Q UANTITATIVE C OMPOSITION

Each capsule contains 200mg of danazol

Also contains 76.6 mg of lactose monohydrate

For a full list of excipients see 6.1

3. P HARMACEUTICAL F ORM

Capsule

4. C LINICAL P ARTICULARS

4.1 Therapeutic Indications

Danol capsules are recommended for:

Treatment of endometriosis amenable to hormonal management.

Treatment of Hereditary angioedema.

4.2 Posologyand Method of Administration

Adults:

Danolcapsules should be given as a continuous course, dosage being adjusted according to the severity of

the condition and the patient's response. A reduction in dosage once a satisfactory response has been

achieved may prove possible. In fertile females, Danolcapsules should be started during menstruation,

preferably on the first day, to avoid exposing a pregnancytoitspossible effects. Where doubt exists,

appropriatechecksshouldbe made to exclude pregnancybefore starting medication. Females of child-

bearing age should employ non-hormonal contraception throughout the course of treatment.

In endometriosis the recommended dosage is 200mg to 800mgdailyin a course of treatment lasting

normally three to six months. Dosage should be increased if normal cyclical bleeding still persistsaftertwo

months therapy, a higher dosage (not exceeding 800mgper day) may also be needed for severe disease.

For the prophylaxis of hereditary angioedema the recommended initial dose is 200mg two or three times a

day until the desired initial response is obtained; thenthemaintenancedosage is determined by decreasing

the initial dosage by 50% or less at intervals ofonetothreemonths or longer, depending on frequency of

attacks prior totreatment.

Following a favourable response to Danol, the lowesteffective maintenance dose should be soughtfora

continuous preventive treatment.

Daily dosage may be increased by up to 200mg if conditionis not controlled at lower doses.

Elderly: Danol is not recommended.

Children: Danol is not recommended.

The capsules are for oral administration.

4.3 Contra-Indications

1. Pregnancy

2. Breast feeding

3. Markedly impaired hepatic, renal or cardiac function

2

4. Porphyria

5. Active thrombosis or thromboembolicdisease and a history of such events

6. Androgen dependent tumour

7. Undiagnosed abnormal genital bleeding.

8. Hypersensitivity to danazol or to any of the excipients.

4.4 Special Warnings and Special Precautions for Use

4.4.1 Special Warnings

Intheevent of virilisation, Danolshould be withdrawn. Androgenic reactions generally prove reversible, but

continued use of Danol afterevidenceofandrogenicvirilisation increases the risk of irreversible androgenic

effects.

Danol should be stopped if any clinically significantadverseevent arises, and particularly if there is

evidence of papilloedema, headache, visualdisturbances or othersignsorsymptoms of raised intracranial

pressure,jaundiceor other indication of significanthepatic disturbance, thrombosis or thromboembolism.

Whilst a course of therapy may need to be repeated,care should be observed as nosafetydataare

available in relation to repeated courses of treatment over time. The long-termriskof 17-alkylated steroids

(includingbenignhepatic adenomata, peliosis hepatisand hepatic carcinoma), should be considered when

danazol, which is chemically related to those compounds, is used.

Data, from two case-control epidemiological studies,werepooledto examine the relationship between

endometriosis, endometriosistreatments and ovarian cancer. These preliminary results suggest that

the use of danazol might increase the baseline risk of ovarian cancer in - patients treatedfor

endometriosis.

Patients with rare hereditary problems of galactoseintolerance, the Lapp lactase deficiency orglucose-

galactose malabsorption should not take this medicine.

4.4.2 Precautions

In view of its pharmacology, known interactionsand side effects, particular care should be observedwhen

using Danol in patients with hepatic or renaldisease,hypertension or other cardiovascular disease and in

any state which may be exacerbatedby fluid retention as well as in diabetes mellitus, polycythaemia,

epilepsy, lipoprotein disorder, and in those who haveshownmarkedor persistent androgenic reaction to

previous gonadal steroid therapy.

Caution is advised in patients with migraine.

Until more is known, caution is advised in theuse of Danol in the presence of known or suspected

malignant disease (see also contra-indications). Before treatment initiation, the presence ofhormone–

dependent carcinoma should be excluded at least by careful clinical examination, as well asifbreast

nodules persist or enlarge during danazol treatment.

In addition to clinical monitoring in all patients,appropriate laboratory monitoring should be considered

which may include periodic measurement ofhepaticfunction and haematological state. For long-term

treatment(>6 months) or repeated coursesof treatment, biannual hepatic ultrasonography is

recommended.

Danazol should be initiated during menstruation. Aneffective, non-hormonalmethod of contraception

should be employed (see Section 4.2 and 4.6 Pregnancy and Lactation).

The lowest effective dose of Danol should always be sought.

4.5 Interactions with other medicinal products and other forms of Interaction

Anti-convulsant therapy: Danol may affect theplasma level of carbamazepine and possibly the patient's

response to this agent and to phenytoin. With phenobarbitone itis likely that similar interaction would occur.

3

Anti-diabetic therapy: Danol can cause insulin resistance.

Oral anti-coagulant therapy: Danol can potentiate the action of warfarin.

Anti-hypertensive therapy: Possibly through promotionoffluid retention, Danolcan oppose the action of

anti-hypertensive agents.

Cyclosporin and tacrolimus: Danol canincreasetheplasma level of cyclosporin and tacrolimus, leading to

an increase of the renal toxicity of these drugs.

Concomitant steroids: Although specific instances have not been described, itis likely that interactions will

occur between Danol and gonadal steroid therapy.

Migraine therapy: Danol may itself provoke migraineand possibly reduce the effectiveness ofmedicationto

prevent that condition.

Ethyl alcohol: Subjective intolerance in the form of nausea and shortness of breath has been reported.

Alpha calcidol: Danol may increase the calcaemic responseinprimary hypoparathyroidism necessitating a

reduction in dosage of this agent.

Interactions with laboratory function tests:Danazol treatment may interferewithlaboratory

determination of testosterone or plasma proteins (See also section4.8 Undesirable effects)

Statins: The risk of myopathyand rhabdomyolysis is increased byconcomitant administration of

danazol with statins metabolised by CYP3A 4 suchas simvastatin, atorvastatin and lovastatin.

4.6 Pregnancyand Lactation

There is epidemiological and toxicologicalevidenceof hazard in human pregnancy. Danazol is known to be

associated with the risk ofvirilisationtothefemalefoetus if administered during human pregnancy. Danazol

should not be used during pregnancy. Women ofchildbearing age should be advised to use an effective,

non-hormonal,methodof contraception. If the patient conceives during therapy, danazol should be

stopped.

Danazol has the theoretical potentialforandrogeniceffects in breast-fed infants and therefore either

danazol therapy or breast-feeding should be discontinued.

4.7 Effects on Abilityto Drive and Use Machines

Danol has no or negligible influence onthe ability to drive and use machines.

4.8Undesirable Effects

Blood and lymphatic system disorders

Increase in red cell and platelet count. Reversible polycythaemia, leucopoenia, thrombocytopenia,

eosinophilia and splenic peliosis.

Endocrine disorders

Androgenic effects:

Acne, weight gain, increased appetite, seborrhoea, hirsutism, hair loss, voice change, which may take

the form of hoarseness, sore throat or of instability or deepening of pitch. Hypertrophy of the clitoris,

fluid retention.

Other endocrine effects:

Menstrual disturbances in the form of spotting,alteration of the timing of the cycle and amenorrhoea.

Flushing, vaginal dryness, changes in libido,vaginal irritation and reduction in breast size.

Modest reduction in spermatogenesis.

Metabolism and nutrition disorders

4

Increased insulin resistance, increase in plasma glucagon, mild impairment of glucose tolerance.

Increase in LDL cholesterol, decrease in HDL cholesterol, affecting all subfractions, and decrease in

apolipoproteins AI and AII.

Induction of aminolevulinic acid(ALA) synthetase, and reduction in thyroid binding globulin, T4, with

increased uptake of T3 but without disturbance ofthyroid stimulating hormone or free levothyroxine

index.

Psychiatric disorders

Emotional lability, anxiety,depressed mood and nervousness.

Nervous system disorders

Dizziness, headache, vertigo, benign intracranial hypertension, migraine.

Aggravation of epilepsy,carpal tunnel syndrome.

Eye disorders

Visual disturbances such as blurring of vision, difficulty in focusing, difficultyin wearing contact lenses

and refraction disorders requiring correction.

Respiratory,thoracic and mediastinal disorders

Pleuritic pain, interstitial pneumonitis.

Gastrointestinal disorders

Nausea, epigastric pain.

Cardiac disorders

Hypertension, palpitations and tachycardia.

Thrombotic events including sagittal sinus, cerebrovascular thrombosis as well as arterial thrombosis.

Myocardial infarction.

Hepatobiliarydisorders

Isolated increases in serum transaminase levels, cholestatic jaundice, benign hepatic adenomata and

pancreatitis. Peliosis hepatitis as well as malignanthepatic tumour observed with long term use.

Skin and subcutaneous tissue disorders

Rashes, which may be maculopapular, petechial orpurpuric and may be accompanied by fever or may

take an urticarial form and may be accompanied by facial oedema. Sun-sensitive rash.

Inflammatory erythematosus nodules, changes in skin pigmentation, exfoliative dermatitis and

erythema multiforme.

Musculoskeletal and connective tissue disorders

Backache and muscle cramps which can be severe, with elevation of creatine phosphokinase levels.

Muscle tremors, fasciculation, limb pain, joint pain and joint swelling.

Renal and urinarydisorders

Haematuria with prolonged use in patients with hereditary angioedema.

General disorders and administration site conditions

Fatigue.

4.9. Overdose

Available evidence suggests thatacute overdosage would be unlikely to give rise to immediate serious

reaction.

5

In the case of acute overdose,considerationshould be given to reducing the absorption of the drug with

activated charcoal and the patient should be keptunder observation in case of any delayed reactions.

5. P HARMACOLOGICAL P ROPERTIES

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: sex hormones and modulators of the genital system, antigonadotropins

and similar agents, ATC code: G03XA01

Danazol, 17a-pregna-2,4-dien-20-yno(2,3-d)-isoxazol-17-ol, is a synthetic steroid derived from ethisterone.

Its pharmacological properties include:

1. Relatively marked affinity for androgen receptors, less marked affinity forprogesteronereceptors

and least affinity for oestrogen receptors.Danazolis a weak androgen but in addition

antiandrogenic, progestogenic, antiprogestogenic,oestrogenic and antioestrogenic actions have

been observed.

2. Interference with the synthesis of gonadal steroids, possibly byinhibition of theenzymesof

steroidogenesis, including 3 βhydroxysteroid dehydrogenase,17βhydroxysteroid dehydrogenase,

17 hydroxylase, 17, 20lyase,11 βhydroxylase, 21 hydroxylase and cholesterol side chain cleavage

enzymes, or alternatively by inhibition ofthe cyclic AMP accumulation usually induced by

gonadotrophic hormones in granulosa and luteal cells.

3. Inhibition of the mid-cycle surge of FSH and LHas well as alterations in the pulsatilityofLH.

Danazol can also reduce the mean plasma levels of these gonadotrophins after the menopause.

4. A wide range of actions on plasmaproteins, including increasing prothrombin, plasminogen,

antithrombinIII, alpha-2 macroglobulin, C1 esterase inhibitor, and erythropoietin and reducing

fibrinogen, thyroid binding and sex hormone bindingglobulins. Danazol increases the proportion

and concentration of testosterone carried unbound in plasma.

5. Thesuppressive effects of danazol on the hypothalmic-pituitary-gonadal axis are reversible,

cyclical activity reappearing normallywithin 60-90 days after therapy.

5.2 Pharmacokinetic Properties

Danazol is absorbed from thegastrointestinal tract, peak plasmaconcentrations of 50-80ng/ml being

reached approximately 2-3 hours after dosing. Comparedtothe fasting state, the bioavailability has been

showntoincrease3 fold when the drug is taken with ameal with a high fat content. It is thought that food

stimulates bile flow which facilitates the dissolution and absorption of danazol, a highly lipophilic compound.

Theapparent plasma elimination half life of danazol ina single dose is approximately 3-6 hours. With

multiple doses this may increase to approximately 26 hours.

Noneofthe metabolites of danazol, which have been isolated, exhibits pituitary inhibiting activity

comparable to that of danazol.

Few data on excretion routes and rates exist. In the monkey 36% of a radioactivedosewasrecoverablein

the urine and 48% in the faeces within 96 hours.

5.3 Preclinical SafetyData

Therearenopre-clinical data of relevance to the prescriber which are additional to that already

included in other sections of the SPC.

6. P HARMACEUTICAL P ARTICULARS

6.1 List of Excipients

Capsule

6

Maize starch

Lactose monohydrate

Talc

Magnesium stearate

Capule Shell

Gelatin

Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (E172)

Black Ink which contains:

Shellac Glaze ,Propylene glycol,Blackiron oxide, Ammonium hydroxide.

OR

Shellac, Dehydrated alcohol, Propylene glycol, Ammonia solution, Potassium hydroxide, Black iron

oxide.

OR

Shellac glaze 45% (20 esterfied) in ethanol, propylene glycol, black iron oxide (E172), ammonium

hydroxide 28%.

OR

Shellac, propylene glycol, strong ammonia solution, potassium hydroxide,black iron oxide (E 172).

6.2 Special Precautions for Storage

Store in a dry place below 30◦C

7. Manufacturer

Sanofi-Synthelabo Ltd

Guildford

Surrey GU1 4YS

UK

8. License Holder

Sanofi-aventis Israel ltd. POB 8090 Netanya 42504