ORTHO-GYNEST PESSARIES

Israel - English - Ministry of Health

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Active ingredient:
ESTRIOL 0.5 MG
Available from:
J-C HEALTH CARE LTD
ATC code:
G03CA04
Pharmaceutical form:
PESSARY
Administration route:
VAGINAL
Manufactured by:
CILAG AG, SWITZERLAND
Therapeutic group:
ESTRIOL
Therapeutic indications:
For the treatment of atropic vaginitis and Kraurosis vulvea in post menopausal women and for treatment of pruvitis vulvea and dyspareunia when associated with atrophic vaginal epithelium resulting from estrogen deficiency.
Authorization number:
037812579101
Authorization date:
2010-02-01

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Patient Information leaflet Patient Information leaflet - Hebrew

23-01-2021

ןולעלףיסוהלשי ": עעבקנהזןולעטמרופ " ודילערשואוקדבנונכותותואירבהדרשמי " רשואמןולע ע " רגמי ' לחר

ןמטוג רבמצד 10

1. NAME OF THE MEDICINAL PRODUCT

Trademark

ORTHO-GYNEST ™

Ovules

InternationalNonproprietary Name

Estriol Succinas

Other Names

α-Hydroxyestradiol

2. QUALITATIVE AND QUANTITATIVECOMPOSITION

Estriol 0.5mg

For excipients, see6.1

3. PHARMACEUTICAL FORM

Ovule

3.1. Description of theProduct

ORTHO-GYNESTovules are yellowish-white,torpedoshapedovules.

4. CLINICAL PARTICULARS

4.1. Therapeutic Indications

Treatmentof atrophicvaginitis andkraurosis vulvaeinpostmenopausal

women.

Treatmentof pruritus vulvae anddyspareunia associated withatrophic

vaginalepitheliuminpostmenopausal women.

4.2. Posology and Method of Administration

4.2.1. Adults

ORTHO-GYNESTovules are administeredintravaginally.Theovuleshould

beinsertedhighintothevagina,preferably intheevening.Treatmentcanbe

started any timeafterthemanifestationof atrophicvaginitisorassociated

symptoms(e.g.dyspareunia,pruritus). Therecommendedinitial dose isone

ovule per day.A maintenancedose ofoneovule twice a weekmaybeused

after restorationofthevaginalmucosahas beenachieved.

Attemptstotaperanddiscontinuemedication shouldbemade atthree tosix

monthintervalsfollowingphysicalexamination.

Ifadoseisforgotten,anovule shouldbeinserted as soonasit is realized.

4.2.2. Children

ORTHO-GYNESTovules are not indicatedin children.

4.2.3. Elderly

Patients overtheageof65wereincludedinclinicaltrialswithnodose

adjustment.

4.3. Contraindications

ORTHO-GYNESTovules should not beusedinwomen with:

1.Known orsuspectedpregnancy,or lactation.

2.Malignant tumors ofthebreast.

3.Genital tractor other estrogen-dependentneoplasia.

4.Undiagnosedabnormal genitalbleeding.

5.Activeor pasthistoryofthromboembolic disordersor

thrombophlebitis.

6.Hypersensitivity toany ingredientof thisproduct.

7.Severehepatic orrenaldisease.

8.Porphyria

4.4. Special Warnings and Precautions forUse

Medicalexamination/follow-up

Before starting, andperiodicallyduringestrogenreplacement therapy,itis

recommendedthatthepatientbegiven a thoroughphysicaland

gynecologicalexamination.Acomplete medical andfamilyhistoryshould

be taken. Repeatedbreak-through bleeding,unexpectedvaginalbleeding and

changes noticed duringbreast examinationrequirefurtherevaluation.

A careful appraisalofrisks and benefitshould beundertaken beforethe

initiationoftherapyandduring the continuationoflong-termtreatment.

Endometrial hyperplasia

The riskofendometrialhyperplasiaisnotincreasedwithadaily

administationofORTHO-GYNESTovules, 0.5mgvaginalestriol,in

contrast tooral ortransdermalestrogensadministeredalone for prolonged

periodstowomenwithanintactuterus. It is therefore not necessaryto

combinethe vaginal estrioltherapyregularlywitha progestin.

Break-throughbleedingandspottingmayoccuroccasionally. Ifbreak-

throughbleedingorspottingappearsafter sometimeontherapy,or

continues aftertreatment has beendiscontinued, the reasonshouldbe

investigated, whichmayincludeendometrialbiopsytoexclude endometrial

malignancy.

Otherwarnings and precautions

Thefollowingwarnings andprecautionsarebasedonexposureto

systemicallyadministeredestrogens and/orprogestins.Theextenttowhich

thesewarnings andprecautionsapplyto vaginally administeredestriolis

unknown.

Breastcancer

Estrogenandestrogen/progestintherapyinpostmenopausal womenhas

been associatedwithan increasedriskofbreastcancer. Intheconjugated

equineestrogens andmedroxyprogesterone acetate(CE/MPA)substudy

oftheWomen’s Health Initiativestudy(WHI), a 26% increase of

invasivebreastcancer(38 vs 30per 10,000woman-years) after an

averageof5.2yearsoftreatment was observedinwomenreceiving

CE/MPAcomparedtowomen receivingplacebo. Theincreasedriskof

breast cancerbecameapparentafter 4years onCE/MPA. Thewomen

reportingprior postmenopausaluseofestrogens and/orestrogenwith

progestinhadahigher relativeriskforbreast cancer associatedwith

CE/MPA than thosewho had never usedthesehormones.

Epidemiologicstudieshavereportedanincreasedriskofbreast cancerin

association withincreasingdurationofpostmenopausaltreatment with

estrogenswith orwithoutaprogestin.This associationwas reanalyzed in

original datafrom51studiesthatinvolved variousdosesand types of

estrogens,with orwithoutprogestins. Inthereanalysis, anincreasedrisk

ofhaving breast cancerdiagnosedbecameapparentafter 5years of

continued treatment,andsubsidedafter treatmenthadbeendiscontinued

for 5years or longer. Somelaterstudieshavesuggested that

postmenopausaltreatment withestrogens andprogestin increase therisk

ofbreastcancermore thantreatmentwithestrogenalone.Breastcancer

foundin new orcurrent usersofhormone replacement therapymaybe

morelikelytobelocalizedtothe breastthanthose innon-users.

Ovarian cancer

Longterm(atleast 5 years)use ofestrogen-only hormonereplacement

therapy (HRT)products inhysterectomizedwomenhasbeen associated

withan increasedriskof ovariancancerinsomeepidemiological studies.

Itisuncertainwhether long-termuseofcombinedHRTconfersa

differentriskthanestrogen-onlyproducts.

Venous thromboembolism

HRTis associatedwithahigherrelativeriskof developingvenous

thromboembolism(VTE), i.e.deep vein thrombosisorpulmonary

embolism.One randomizedcontrolledtrialandepidemiologicalstudies

foundatwo-tothreefoldhigher riskforuserscomparedwithnon-users.

For non-users,itisestimatedthatthe number ofcases of VTEthatwill

occur overa5yearperiodisabout3per1000womenaged50to59years

and8per1000womenaged between60to 69years. Itisestimatedthat

inhealthywomenwhouseHRTfor5 years,thenumberof additional

casesof VTEovera5yearperiodwill bebetween2 and6(bestestimate

=4)per 1000womenaged50 to59 yearsandbetween5 and 15(best

estimate= 9)per 1000womenaged60to69years.The occurrence of

suchanevent ismorelikelyinthefirstyear ofHRT thanlater.

GenerallyrecognizedriskfactorsforVTEincludeapersonalhistoryor

familyhistoryofthromboembolicdisorders, obesity(BMI

>30kg/m2) andsystemiclupus erythematosus (SLE).There isno

consensusabout the possible role of varicose veins inVTE.

Patients with ahistoryofVTEorknown thrombophilic stateshave an

increasedriskofVTE.HRT mayaddtothis risk.Personalorstrong

familyhistoryofrecurrent thromboembolismorrecurrentspontaneous

abortions shouldbe investigatedin ordertoexclude athrombophilic

predisposition. Untila thoroughevaluationofthrombophilicfactors has

been madeoranticoagulant treatmentinitiated, useof HRT insuch

patientsshould beviewedas contraindicated.Those womenalready on

anticoagulanttreatmentrequirecarefulconsiderationofthe benefit-risk

ofuseofHRT.

The riskofVTEmaybe temporarily increased withprolonged

immobilization, major traumaor major surgery.As in allpostoperative

patients, scrupulous attentionshouldbegiventoprophylacticmeasuresto

prevent VTE following surgery.Where prolongedimmobilizationis

likelytofollowelectivesurgery,particularlyabdominalororthopaedic

surgeryto thelowerlimbs,considerationshould be given to temporarily

stoppingHRT fourtosixweeks earlier,ifpossible. Treatment shouldnot

berestarted until the woman iscompletelymobilized.

IfVTEdevelopsafter initiatingtherapy,ORTHO-GYNESTovules

shouldbediscontinued.Patientsshouldbetoldto contact their doctors

immediately when theyare awareofapotential thromboembolic

symptom (e.g.,painful swellingofa leg,suddenpaininthe chest,

dyspnoea).

Coronaryarterydisease(CAD)

Thereisnoevidencefrom randomizedcontrolledtrialsof

cardiovascular benefit withcontinuous combinedconjugatedestrogens

andmedroxyprogesteroneacetate (MPA). Largeclinicaltrialsshoweda

possibleincreased riskofcardiovascular morbidity inthefirstyearof

use and no benefitthereafter.For otherHRT productsthereareasyet

no randomized controlled trialsto dateexamining benefitin

cardiovascularmorbidity ormortalityin women withoutevidenceof

ischemic heart disease.

Stroke

One large randomizedclinical trial[Women’sHealth Initiative (WHI)

trial] foundanincreasedriskofstrokein healthywomen during

treatmentwithcontinuouscombinedconjugatedestrogensandMPA.

Forwomen whodonot useHRT, itis estimatedthat thenumberof

casesofstrokethat will occur overa 5 year period is about 3per 1000

womenaged50to59 years and11per 1000womenaged60 to69

years.Itisestimated thatforwomenwhouse conjugated estrogens and

MPAfor 5 years,the numberofadditionalcases willbebetween 0 and

3(best estimate=1)per1000users aged50to59years andbetween1

and9(best estimate= 4)per1000usersaged60to69.It isunknown

whetherthe increasedriskalsoextends toother HRTproducts.

Dementia

There is no conclusiveevidenceforimprovement ofcognitivefunction.

There issomeevidencefromtheWHI trial ofincreased risk of

probabledementiainwomen who start using continuouscombined

conjugatedequine estrogen(CEE)and medroxyprogesteroneacetate

(MPA) afterthe age of65.Itis unknownwhether thefindings applyto

youngerpost-menopausalwomenorother HRT products.

Other Conditions

Appropriate monitoring is recommendedinpatients with migraineor

severeheadache,hypertension, cardiacimpairment, systemiclupus

erythematosus,epilepsy,diabetesmellitus,history ofcholestatic

jaundice,disturbancesorimpairmentof liver or kidneyfunction,

endometriosis, leiomyoma, mastopathy,or a familyhistoryof breast

cancer.

ORTHO-GYNESTovulesarenottobeusedas contraception.

KeepORTHO-GYNEST ovulesawayfromchildrenand pets.

4.5. Interactions with Other Medicinal Productsand Other

Forms ofInteraction

Drugs whichinducemicrosomalliverenzymeactivitymayalterestrogen

metabolism.Examplesofsuchdrugs arebarbiturates,hydantoins,

carbamazepine,meprobamate, phenylbutazone, bosentan,rifampicin,

rifabutin and certain non-nucleoside reversetranscriptaseinhibitors (e.g.

nevirapine andefavirenz). 15

Ritonavirandnelfinavir, althoughknownasstronginhibitors,bycontrast

exhibitinducingpropertieswhenused concomitantly withsteroidhormones.

DrugmetabolismmaybeaffectedbySt.John’s Wortpreparations

(HypericumperforatumL.),which inducecertaincytochrome

P450isoenzyme inthe liver(e.g., CYP 3A4)aswellas P-gylcoproteins.)

Withvaginaladministration,thefirstpass effectinthe liver is avoided and

thus, estriolgivenintravaginallymightbeless affectedbyenzymeinducers

than oral hormones,however unscheduledbleeding might stilloccur.

Estrogen-containing oralcontraceptiveshavebeenshown tosignificantly

decreaseplasmaconcentrationsoflamotriginewhenco-administereddueto

induction oflamotrigine glucuronidation. Thismayreduce seizure control.

Although thepotential interaction betweenestrogen-containinghormone

replacementtherapy and lamotrigine has notbeenstudied,it isexpectedthat

asimilar interaction exists, whichmay leadtoa reductioninseizurecontrol

among women takingboth drugstogether. Therefore,dosageadjustmentof

lamotrigine maybenecessary.

4.6 Pregnancyand Lactation

TheuseofORTHO-GYNESTovulesiscontraindicated inpregnancyor

lactation.

4.7 Effects on AbilitytoDrive and Use Machines

There is no informationoneffectsofORTHO-GYNEST ovules on the

abilityto driveand use machines.

4.8 Adverse Effects

Inadouble-blind, placebocontrolledclinicaltrialof30womentreated with

ORTHO-GYNEST ovules thefollowingundesirableeffects werereported in

theestriolovule treatmentgroupmore frequentlythanintheplacebogroup:

Breast pain,micturitionfrequencyincreased, vaginal discharge,cystitis, leg

pain,pre-menstrualtension, lower abdominalpain, palpitationsand

depression.

Other adverse eventswhichhavebeenreportedinassociation with

estrogen/progestintreatmentare:

Estrogen-dependent neoplasmsbenignand malignant; e.g.endometrial

cancer; breast cancer*.

Venous thromboembolism**

Myocardialinfarctionandstroke

Gallbladder diseaseandliver adenoma

Aggravationofepilepsy

Skin and subcutaneous tissuedisorders: chloasma; erythemamultiforme;

erythemanodosum;vascular purpura,urticaria,angioedema

Probable dementia(seesection4.4)

Ifsuchevents occur, ORTHO-GYNEST ovules should bediscontinued

immediately.

* The riskofbreastcancer increases withthenumber ofyears ofHRT

intake.According to datafromepidemiological studies- 51epidemiological

studiesperformedduringthe1970stotheearly1990sandreportedinare-

analysis, andfrommorerecentstudies- thebestestimate ofthe risk for

womennot usingHRT isabout 45womeninevery 1000 womento have

breast cancerdiagnosed betweenthe ages50to 70 years.Itisestimatedthat,

amongthosewith current or recent useof HRT,thetotal numberof

additionalcasesoverthesameagerangewillbebetween1and3(best

estimate=2)extra casesper 1000womenhavingusedHRT for 5years,

between 3and9(best estimate = 6) extracasesper 1000womenhavingused

HRT for10yearsandbetween5and20(best estimate =12)extracases per

1000 women havingused HRTfor 15years. The numberofadditionalcases

ofbreastcancerisbroadly similar forwomenbetween 45and 65who start

HRT irrespectiveofageatstartof HRT(seesection 4.4).

** Venousthromboembolism,i.e. deeplegorpelvic venous thrombosisand

pulmonaryembolismare morefrequent amongHRTusers thanamong

non-users.For further information,see section4.3 Contraindicationsand

4.4SpecialWarningsandPrecautionsfor Use.

4.9Overdose

Symptomsof overdoseofestrogentherapymayincludebreastpainor

tenderness,nausea,break-throughbleeding, abdominal crampsand/or

bloating.Vaginal lavage shouldbeconsidered.If accidental ingestionof

large quantities ofthe product occurs,anappropriatemethodofgastric

emptyingmaybeconsidered.

5. PHARMACOLOGICAL PROPERTIES

Chemistry

The estrogenic component inORTHO-GYNEST ovules is estriol.Itis a

white tocreamywhitepowderchemicallydescribedasEstra-

1,3,5,(10)-trien-3,16 α,17β-triol.Ithas a molecular formulaofC

and

amolecular weightof 288.38. The structuralformulais:

5.1Pharmacodynamic Properties

Estriol, a weak estrogen,isanaturalmetabolite of estradiol, thepredominant

estrogen. Estriolexertsestrogenicitybybindingtoestrogenreceptors,

presentin the femalegenital tract. 19 However, the final outcomes in different

tissues may differ from thoseof estradiol,as the intracellularsignaling

processes seemdistinct.

Oral or vaginalestriol, similartoestradiol,corrects lowered proliferationand

abnormalphysiology in theatrophicvaginalepithelium seenin estrogen

deficientstates, suchasafternatural orsurgicalmenopause.Studiesofthe

endometriumupon ORTHO-GYNEST ovulesrarelyshowminor signsof

proliferation inpreviouslyatrophicendometria.

Clinicaltrial information

Signs ofestrogenic stimulation ofthe vaginal epithelium was alreadynoted

after7daysofdaily treatmentwithORTHO-GYNESTovulesinastudy

including50subjects withvaginal atrophy.Thematurationindexshoweda

26%increase ofthe superficial cells and a52%decrease ofbasaland

parabasal cellsattheendofthefirst week.Improvement was sustainedover

7 ormore weeks ina total of70 patients studied intwo clinical trials. 5,21

Alleviationofassociatedsymptoms(e.g.dyspareunia,urethralsymptoms)

wasfirst observedafter 4weeks ofdailytreatmentwithORTHO-GYNEST

ovules ina totalof110women infour clinicaltrialsand further

improvement wasseenover subsequent months.

5.2 Pharmacokinetic Properties

Absorption

Estriol isreadily absorbedfollowing intravaginalapplication.Peakplasma

estriol concentrationsaregenerally observedwithin 2 hoursfollowing

intravaginal applicationandremainelevatedfor 6hours.Systemic

bioavailabilityofvaginal administration isbetter thanafter oral

administration. Intravaginalapplicationof onemgestriolin women with

senileatrophyof the vaginal epitheliumresults in serumlevelssimilarto

thoseseenafteroraladministrationof10mgestriol.

Peakplasma estriollevels, mean(SD),were450(113) pmol/Landwere

similar in womenwhowere recumbentoractive. Upon continuoususe for

three months, therewere nosignificantchanges inplasmalevelsof estriol,

estroneorestradiolindicatingnotrendtowardaccumulationduring this

period.

Distribution

Estriol circulateswiththeblood,about14% free,8%boundto sexhormone-

bindingglobulin(SHBG)andthe restboundtoalbumin.

Metabolism

Primarymetabolitesofestriol includethe16-alpha-glucuronide,3-

glucuronide,3-sulfateand 3-sulfate-16-alpha-glucuronide.

Excretion

Morethan95% ofestriolisexcretedintheurine, predominantlyintheform

ofglucuronides.

5.3 Preclinical SafetyData

Estriol (E3)isanendogenic estrogenthatinman occursas theproductof

estroneand estradiolmetabolism; hence, the physiologic productionof

estriol isconsiderable.Ascomparedwiththeprimaryestrogens,estradiolor

estrone, estriol inbiologicaltestsystemsexhibitslowerbiologicalactivityby

abouta power often,withanoralLD

inratsinexcessof2000mg/kg.

Preclinicalsafetyevaluationswere conductedandincluded local tolerability,

single andrepeateddose toxicityupto28daysindogsandmonkeys, and

reproductivestudiesin ratswheredosingtookplace eitherbefore matingor

duringvarioustimesduring gestation.Mutagenicityandcarcinogenicity

parametershavealsobeenevaluated, however, moresoinlightofendogenic

steroid hormones ratherthanestriol alone.

Results fromthese evaluationsshowedthatthe productwas welltolerated

locallyand causednovaginal irritation.Single dose toxicityindicates very

lowacutetoxicitywith a widemarginofsafety. Repeateddose studies

showedeffectsfocused primarilyonthe genitals,while reproductivestudies

showedeffects suchasfeminization ofmalefetusesorreduced littersize.

Carcinogenicityeffects,asis withpotentestrogens, showedthe ability to

inducemammarytumorsinmice. Evaluationofmutagenicityresultsis

difficult to interpret atbest,giventheinherenthormonaleffects athigh

concentrations andtheassociateddisturbedhormonebalanceofthe

organism.In conclusion,allof these observationsareto beexpected

followingtreatmentwithcomparativelyhigh doses ofapotent estrogen,and

aregenerallyrelatedtoanexaggeratedpharmacological effectandindicate

littlerelevancetothe proposedclinical useofthisproduct.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Benzoic acid

Butylated hydroxytoluene

Polyethyleneglycol400

Polyethyleneglycol1000

Sorbitanmonostearate

HardfatType E(WhitepsolS55)

6.2. Incompatibilities

ORTHO-GYNESTovules haveacomponentthatmaydamagerubber

diaphragmsorlatexcondoms,andmayreducetheir efficacy. Thus,

ORTHO-GYNEST ovules shouldnotbeusedwith latexcondomsorrubber

diaphragms.

6.3. Special Precautions for Storage

Donot storeabove25°C

6.4. Nature and Contents of Container

StandardPVC/PE moulds, containing5or15ovules.

6.5. Instructions for Use and Handling

Must keepoutofreachofchildren.

7.MANUFACTURER

Cilag AG,Schaffhausen,Switzerland

9. REGISTRATIONHOLDAER

J-CHealthCareLtd.,KibbutzShefayim,60990

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