DEPO-PROVERA

Main information

  • Trade name:
  • DEPO-PROVERA Solution for Injection 150 Mg/Ml
  • Dosage:
  • 150 Mg/Ml
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DEPO-PROVERA Solution for Injection 150 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/175/001
  • Authorization date:
  • 07-04-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Depo-Provera150mg/mlSuspensionforInjection

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontains150mgofmedroxyprogesteroneacetate.

Excipients:

Methylparahydroxybenzoate(E218)

Propylparahydroxybenzoate(E216)

Forafulllistofexcipientsseesection6.1

3PHARMACEUTICALFORM

Suspensionforinjection.

ProductimportedfromBelgium:

White,sterile,aqueoussuspension.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Asaprogestogen,forparenteraladministration:

Contraception

Depo-Proveraisindicatedforcontraception.

Depo-Proveramayalsobeusedforshort-termcontraceptioninthefollowingcircumstances:

Forpartnersofmenundergoingvasectomy,forprotectionuntilthevasectomybecomeseffective.

Inwomenwhoarebeingimmunisedagainstrubella,topreventpregnancyduringtheperiodofactivityofthe

virus.

iii. Inwomenawaitingsterilisation.

Sincelossofbonemineraldensity(BMD)mayoccurinfemalesofallageswhouseMPAinjectionlong-term(See

section4.4Specialwarningsandspecialprecautionsforuse),arisk/benefitassessment,whichalsotakesinto

considerationthedecreaseinBMDthatoccursduringpregnancyand/orlactation,shouldbeconsidered.

Itisofthegreatestimportancethatadequateexplanationsofthelong-termnatureoftheproduct,ofitspossibleside

effectsandoftheimpossibilityofimmediatelyreversingtheeffectsofeachinjectionaregiventopotentialusersand

thateveryeffortismadetoensurethateachpatientreceivessuchcounsellingastoenablehertofullyunderstandthese

explanations.Patientinformationleafletsaresuppliedbythemanufacturer.Itisrecommendedthatthedoctoruses

theseleafletstoaidcounsellingofthepatient.

Consistentwithgoodclinicalcontraceptivepracticeageneralmedicalaswellasgynaecologicalexaminationshouldbe

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4.2Posologyandmethodofadministration

ThesterileaqueoussuspensionofDepo-Proverashouldbevigorouslyshakenjustbeforeusetoensurethatthedose

beinggivenrepresentsauniformsuspensionofDepo-Provera.

Dosesshouldbegivenbydeepintramuscularinjectionintotheglutealmuscle.

Contraception

AllpotentialusersofDepo-Proverashouldhaveanegativepregnancytestbeforefirstadministration.

Becauseoftheriskofheavyorprolongedbleedinginsomewomen,thedrugshouldbeusedwithcautioninthe

puerperium.

Therecommendeddoseis150mgofMPAinjectablesuspensionevery3monthsadministeredbyintramuscular

injectionintheglutealmuscle.Theinitialinjectionshouldbegivenduringthefirst5daysaftertheonsetofanormal

menstrualperiod;within5dayspostpartumifnotbreast-feeding;or,ifexclusivelybreast-feeding,atorafter6weeks

postpartum.

Aswithotherhormonalcontraceptives,regularconsiderationshouldbegiventowhethertheprevioustreatmenthas

resultedin:first-timemigraineorunusuallysevereheadaches,visualdisturbances,reappearanceofdepression,

pathologicalchangesinliverfunctiontests.

UseinChildrenandAdolescents

MPAIMisnotindicatedbeforemenarche.

DataregardingtheeffectsofMPAonBMDinadolescentfemales(12-18years)isavailable(seesection5.1

PharmacodynamicProperties).OtherthanconcernsaboutlossofBMD,thesafetyandeffectivenessofMPAIMare

expectedtobethesameforpostmenarchealadolescentandadultfemales

4.3Contraindications

Depo-Proveraiscontraindicatedinpatientswithahistoryof,orexistentthrombo-embolicdisorders;orattheabove

dosagewithbreastorgenitalcancer(knownorsuspectedtobeoestrogendependent);andinpatientswithaknown

sensitivitytomedroxyprogesteroneacetateoranyingredientofthevehicle.Itsuseiscontra-indicatedinpatientswith

impairedliverfunctionorwithactiveliverdisease,andinpatientswithundiagnosed,vaginalbleeding.

Depo-Proverashouldnotbeusedduringknownorsuspectedpregnancy,eitherfordiagnosisortherapy

4.4Specialwarningsandprecautionsforuse

Warnings:

LossofBoneMineralDensity

UseofMPAinjectionreducesserumestrogenlevelsandisassociatedwithsignificantlossofBMDasbone

metabolismaccommodatestoalowerestrogenlevel.ThislossofBMDisofparticularconcernduringadolescenceand

earlyadulthood,acriticalperiodofboneaccretion.Bonelossisgreaterwithincreasingdurationofuseandmaynotbe

completelyreversibleafterdiscontinuationofMPA.ItisunknownifuseofMPAinjectionbyadolescentsandyoung

adultwomenwillreducepeakbonemassandincreasetheriskforosteoporoticfractureinlaterlife.Inbothadultand

adolescentfemales,thedecreaseinBMDappearstobeatleastpartiallyreversibleafterMPAinjectionisdiscontinued

andovarianestrogenproductionincreases.

MPAinjectionshouldonlybeusedasalong-term(e.g.,longerthan2years)birthcontrolmethodifotherbirthcontrol

methodsareunsuitable.BMDshouldbeevaluatedwhenafemaleneedstocontinuetouseMPAinjectionlongterm.In

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Otherbirthcontrolmethodsshouldbeconsideredintherisk/benefitanalysisfortheuseofMPAinjectioninwomen

withosteoporoticriskfactors.MPAinjectioncanposeanadditionalriskinpatientswithriskfactorsforosteoporosis

(e.g.,metabolicbonedisease,chronicalcoholand/ortobaccouse,anorexianervosa,strongfamilyhistoryof

osteoporosisorchronicuseofdrugsthatcanreducebonemasssuchasanticonvulsantsorcorticosteroids).

ItisrecommendedthatallpatientshaveadequatecalciumandVitaminDintake.

ForfurtherinformationonBMDchangesinbothadultandadolescentfemales,asreportedinrecentclinicalstudies,

refertosection5.1(PharmacodynamicProperties)

MenstrualIrregularity

Prolongedanovulationwithamenorrhoeaand/orerraticmenstrualpatternsmayfollowtheadministrationofeithera

singleormultiplecontraceptivedosesofDepo-Provera.UnexpectedvaginalbleedingduringtherapywithMPAshould

beinvestigated.

Returntofertility

WomenshouldbecounselledthatthereisapotentialfordelayinreturntofullfertilityfollowinguseofDepo-Provera.

Themediantimetoconceptionforthosewhodoconceiveis10monthsfollowingthelastinjectionwitharangeof4to

31monthsandisunrelatedtothedurationofuse.

Cancerrisks

Studiesinanimalshaveindicatedthatadministrationofveryhighdosesofoestrogensand/orprogestogenswillinduce

neoplastictumoursinsomeanimalspecies.

Studiesinanimals,inparticularthedog,havedemonstratedthattheprogestogensincludingprogesteronewillinduce

neoplasticmammarytumours.Recentinvestigationssuggestthatresultsofdosingstudieswithprogestogeninthedog

areirrelevanttothepotentialforsucheffectsinhumanbeings,becauseofdifferencesinmammaryreceptor

susceptibilityandresponse.

Long-termcase-controlledsurveillanceofDepo-Proverausersfoundnooverallincreasedriskofovarian,liver,or

cervicalcancerandaprolonged,protectiveeffectofreducingtheriskofendometrialcancerinthepopulationofusers.

Ameta-analysisin1996from54epidemiologicalstudiesreportedthatthereisaslightincreasedrelativeriskofhaving

breastcancerdiagnosedinwomenwhoarecurrentlyusinghormonalcontraceptives.Theobservedpatternofincreased

riskmaybeduetoanearlierdiagnosisofbreastcancerinhormonalcontraceptiveusers,biologicaleffectsora

combinationofboth.Theadditionalbreastcancersdiagnosedincurrentusersofhormonalcontraceptivesorinwomen

whohaveusedtheminthelasttenyearsaremorelikelytobelocalisedtothebreastthanthoseinwomenwhonever

usedhormonalcontraceptives.

Breastcancerisrareamongwomenunder40yearsofagewhetherornottheyusehormonalcontraceptives.Inthe

meta-analysistheresultsforinjectableprogestogens(1.5%ofthedata)and

progestogenonlypills(0.8%ofthedata)didnotreachsignificancealthoughtherewasnoevidencethattheydiffered

fromotherhormonalcontraceptives.Whilstthebackgroundriskofbreastcancerincreaseswithage,theexcessnumber

ofbreastcancerdiagnosesincurrentandrecentinjectableprogestogen(IP)usersissmallinrelationtotheoverallrisk

ofbreastcancer,possiblyofsimilarmagnitudetothatassociatedwithcombinedoralcontraceptives.However,forIPs,

theevidenceisbasedonmuchsmallerpopulationsofusers(lessthan1.5%ofthedata)andislessconclusivethanfor

combinedoralcontraceptives.

Itisnotpossibletoinferfromthesedatawhetheritisduetoanearlierdiagnosisofbreastcancerinever-users,the

biologicaleffectsofhormonalcontraceptives,oracombinationofreasons.

ThemostimportantriskfactorforbreastcancerinIPusersistheagewomendiscontinuetheIP;theoldertheageat

stopping,themorebreastcancersarediagnosed.Durationofuseislessimportantandtheexcessriskgradually

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Theevidencesuggeststhatcomparedwithnever-users,among10,000womenwhouseIPsforupto5yearsbutstopby

age20,therewouldbemuchlessthan1extracaseofbreastcancerdiagnosedupto10yearsafterwards.Forthose

stoppingbyage30after5yearsuseoftheIP,therewouldbeanestimated2-3extracases(additionaltothe44casesof

breastcancerper10,000womeninthisagegroupneverexposedtooralcontraceptives).Forthosestoppingbyage40

after5yearsuse,therewouldbeanestimated10extracasesdiagnosedupto10yearsafterwards(additionaltothe160

casesofbreastcancerper10,000never-exposedwomeninthisagegroup).

Itisimportanttoinformpatientsthatusersofallhormonalcontraceptivesappeartohaveasmallincreaseintheriskof

beingdiagnosedwithbreastcancer,comparedwithnon-usersofhormonalcontraceptives,butthatthishastobe

weighedagainsttheknownbenefits.

Patientsreceivingtreatmentwithprogestogensshouldbekeptunderregularsurveillance.

Averylowincidenceofanaphylactoidreactionshasbeenreported.

Patientswithahistoryofendogenousdepressionshouldbecarefullymonitored.Somepatientsmaycomplainof

premenstrual-typedepressionwhileonDepo-Proveratherapy.

Precautions:

Medicationshouldnotbereadministeredpendingexaminationifthereisasuddenpartialorcompletelossofvisionor

ifthereisasuddenonsetofproptosis,diplopia,ormigraine,jaundiceorpathologicalchangesinliverfunctiontests.If

examinationrevealspapilledemaorretinalvascularlesions,medicationshouldnotbereadministered.

Adecreaseinglucosetolerancehasbeenobservedinsomepatientstreatedwithprogestogens.Themechanismforthis

decreaseisobscure.Forthisreason,diabeticpatientsshouldbecarefullyobservedwhilereceivingprogestogen

therapy.

Rarecasesofthrombo-embolismhavebeenreportedwithuseofDepo-Provera.Shouldthepatientexperience

pulmonaryembolism,cerebrovasculardiseaseorretinalthrombosiswhilereceivingDepo-Provera,thedrugshouldnot

bereadministered.

Physiciansshouldbeawarethatpathologistsshouldbeinformedofthepatient'suseofDepo-Proveraifendometrialor

endocervicaltissueissubmittedforhistologicexamination.Theresultsofcertainlaboratorytestsmaybeaffectedby

theuseofDepo-Provera.Theseincludeplasma/urinarygonadotrophinlevels(e.g.LHandFSH),plasmaprogesterone

levels,urinarypregnanediollevels,plasmaoestrogenlevels(inthefemale),plasmacortisollevels,glucosetolerance

test,metyraponetest,liverfunctiontests,thyroidfunctiontestsandsexhormonebindingglobulin.Coagulationtest

valuesforprothrombin(FactorII),andFactorsVII,VIII,IXandXmayincrease.

Theeffectsofmedroxyprogesteroneacetateonlipidmetabolismhavebeenstudiedwithnoclearimpactdemonstrated.

Bothincreasesanddecreasesintotalcholesterol,triglycerides,low-densitylipoprotein(LDL)cholesterol,andhigh-

densitylipoprotein(HDL)cholesterolhavebeenobservedinstudies.

Thedrugshouldbeusedwithcautioninpatientswithcardiovascularorrenaldisease,asthmaorepilepsybecauseofthe

potentialproblemoffluidretentioninsomepatients.

ThereisatendencyforwomentogainweightwhileonDepo-Proveratherapy.Studiesindicatethatoverthefirst1-2

yearsofuse,averageweightgainwas5-8lbs.Womencompleting4-6yearsoftherapygainedanaverageof14-16.5

lbs.Thereisevidencethatweightisgainedasaresultofincreasedfatandisnotsecondarytoananaboliceffectorfluid

retention.

Aswithanyintramuscularinjection,especiallyifnotadministeredcorrectly,thereisariskofabscessformationatthe

siteofinjection,whichmayrequiremedicalorsurgicalintervention.

Theoreticalevidencesuggeststhatuseofprogesteronesshouldbeinterruptedforanintervaltopermitreturntonormal

hypothalamo-pituitary-gonadalfunction.Whileitisnotyetpossibletostateevenaprovisionallyacceptableinterval,

anyprescribershouldbearthismatterinmindwhenorganisingprolongeduseofsuchagents.

Asthisproductcontainsmethylparahydroxybenzoateandpropylparahydroxybenzoate,itmaycauseallergicreactions

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

AminoglutethimideadministeredconcurrentlywithDepo-Proveramaysignificantlydepressthebioavailabilityof

Depo-Provera.Usersofhigh-doseMPAshouldbewarnedofthepossibilityofdecreasedefficacywiththeuseof

aminoglutethimide.

Interactionswithothermedicinaltreatments(includingoralanticoagulants)haverarelybeenreported,butcausalityhas

notbeendetermined.Thepossibilityofinteractionshouldbeborneinmindinpatientsreceivingconcurrenttreatment

withotherdrugs

4.6Pregnancyandlactation

Pregnancy

MPAiscontraindicatedinwomenwhoarepregnant.

Somereportssuggestanassociationbetweenintrauterineexposuretoprogestationaldrugsinthefirsttrimesterof

pregnancyandgenitalabnormalitiesinmaleandfemalefetuses.

Infantsfromunintentionalpregnanciesthatoccur1-2monthsafterinjectionofMPAinjectablesuspensionmaybeatan

increasedriskoflowbirthweight,which,inturn,isassociatedwithanincreasedriskofneonataldeath.The

attributableriskislowbecausepregnancieswhileonMPAareuncommon.

IfMPAisusedduringpregnancy,orifthepatientbecomespregnantwhileusingthisdrug,thepatientshouldbe

appraisedofthepotentialhazardtothefetus.

Childrenexposedtomedroxyprogesteroneacetateinuteroandfollowedtoadolescence,showednoevidenceofany

adverseeffectsontheirhealthincludingtheirphysical,intellectual,sexualorsocialdevelopment..

Lactation

MPAanditsmetabolitesareexcretedinbreastmilk.Thereisnoevidencetosuggestthatthispresentsanyhazardtothe

nursingchild.Infantsexposedtomedroxyprogesteroneviabreastmilkhavebeenstudiedfordevelopmentaland

behaviouraleffectstopuberty.Noadverseeffectshavebeennoted.

4.7Effectsonabilitytodriveandusemachines

Notapplicable

4.8Undesirableeffects

PatientsreceivingDepo-Proveramaybesubjecttotheside-effectsnormallyassociatedwiththeuseofprogestogens.In

addition,itislikelythatsomeorallofthefollowingeffectsmayoccur.

Genitourinary

Delayinreturntonormalmenstrualcyclingandtransientinfertilitylastingupto18monthsoroccasionallylongermay

occurfollowingcontinuoustreatmentwithDepo-Provera.

i.Depo-Proveramaybeexpectedtocausedisruptionofthenormalmenstrualcycle.Irregular,prolonged,decreasedor

heavyvaginalbleedingorspottingmaybeexperiencedduringthefirsttwoorthreecyclesoftreatment.Thefrequency

ofoccurrenceofbleedingusuallydecreaseswithsubsequentinjections.Afteroneyearoftreatmentsomewomenare

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*Inpostmarketingexperience,therehavebeenrarecasesofosteoporosisincludingosteoporoticfracturesreportedin

patientstakingMPAIM.

4.9Overdose

Nopositiveactionisrequiredotherthancessationoftherapy.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Parenteralmedroxyprogesteroneacetateisalongactingprogestationalsteroid.Itexertsanti-oestrogenic,anti-

androgenicandantigonadotrophiceffects.

BMDChangesinAdultWomen

Inacontrolled,clinicalstudyadultwomenusingMPAinjection(150mgIM)forupto5yearsshowedspineandhip

meanBMDdecreasesof5-6%,comparedtonosignificantchangeinBMDinthecontrolgroup.ThedeclineinBMD

wasmorepronouncedduringthefirsttwoyearsofuse,withsmallerdeclinesinsubsequentyears.Meanchangesin

lumbarspineBMDof–2.86%,-4.11%,-4.89%,-4.93%and-5.38%after1,2,3,4and5years,respectively,were

observed.MeandecreasesinBMDofthetotalhipandfemoralneckweresimilar.

AfterstoppinguseofMPAinjection(150mgIM),therewaspartialrecoveryofBMDtowardbaselinevaluesduring

the2-yearpost-therapyperiod.AlongerdurationoftreatmentwasassociatedwithaslowerrateofBMDrecovery.

BMDChangesinAdolescentFemales(12-18years)

Preliminaryresultsfromanongoing,open-labelclinicalstudyofMPAinjectable(150mgIMevery12weeksforupto

5years)inadolescentfemales(12-18years)alsoshowedthatMPAIMusewasassociatedwithasignificantdeclinein

BMDfrombaseline.ThemeandecreaseinlumbarspineBMDwas4.2%after5years;meandecreasesforthetotalhip

andfemoralneckwere6.9%and6.1%,respectively.Incontrast,mostadolescentgirlswillsignificantlyincreasebone

densityduringthisperiodofgrowthfollowingmenarche.Preliminarydatafromasmallnumberofadolescentshave

BODYSYSTEM EVENT

Genitourinary Abnormaluterinebleeding(irregular,increase,decrease),

amenorrhea,leukorrhea,pelvicpain,prolonged

anovulation,vaginitis,decreasedlibido,anorgasmia.

Breast Galactorrhea,mastodynia,tenderness

CentralNervousSystem Convulsions,depression,dizziness,fatigue,headache,

insomnia,nervousness,somnolence

Gastrointestinal/Hepatobiliary Abdominalpainordiscomfort,bloating,disturbedliver

function,jaundice,nausea

Metabolic&Nutritional Decreasedglucosetolerance,weightchange,fluid

retention

Cardiovascular Thromboembolicdisorders

Skin&MucousMembranes Acne,hirsutism,pruritus,rash,urticaria,alopeciaorno

hairgrowth

Allergy Hypersensitivityreactions(e.g.anaphylaxisand

anaphylactoidreactions,angioedema)

Musculoskeletal Arthralgia,asthenia,backache,injection-sitereactions,leg

cramps,lossofbonemineraldensity,osteoporosis*

Ocular Sudden,partialorcompletelossofvision,protopsis,

diplopia,migraine,papilloedemaorretinalvascular

lesions.

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5.2Pharmacokineticproperties

Thedrugisabsorbedreadily,metabolisedintheliverinitiallytoprogesteronewhichisrapidlydistributedtobinding

sites,andtopregnanediolandexcretedthereafterinurine.

5.3Preclinicalsafetydata

Nonestated.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

ExcipientspresentintheproductimportedfromBelgium

Polysorbate80

Methylparahydroxybenzoate(E218)

Propylparahydroxybenzoate(E216)

Macrogol3350

Sodiumchloride

Waterforinjections

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Donotfreeze.

6.5Natureandcontentsofcontainer

1mlpre-filleddisposablesyringeconsistingofaTypeI(Ph.Eur.)glassbarrelwithabutylrubberstopperandtipcap

containing1mlofsuspension.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Donotmixwithotheragents.Forsingleuseonly.Discardanyunusedcontents.

7ParallelProductAuthorisationHolder

PCOManufacturingLimited

Unit10,AshbourneBusinessPark

Rath

Ashbourne

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8ParallelProductAuthorisationNumber

PPA0465/175/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation: 07April2006

10DATEOFREVISIONOFTHETEXT

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