DEPO-PROVERA 150 MG/ ML, SUSPENSION FOR INJECTION,

Main information

  • Trade name:
  • DEPO-PROVERA 150 MG/ ML, SUSPENSION FOR INJECTION,
  • Dosage:
  • 150
  • Pharmaceutical form:
  • Suspension for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DEPO-PROVERA 150 MG/ML, SUSPENSION FOR INJECTION,
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0936/038/001
  • Authorization date:
  • 19-01-2001
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Depo-Provera150mg/ml,SuspensionforInjection

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachpre-filledsyringecontains1mlofsuspensioncontaining150mgofmedroxyprogesteroneacetate.

Forexcipients,see6.1

3PHARMACEUTICALFORM

Suspensionforinjection.

White,sterile,aqueoussuspension.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Asaprogestogen,forparenteraladministration:

Contraception

Depo-Proveraisindicatedforcontraception.

Depo -Proveramayalsobeusedforshort-termcontraceptioninthefollowingcircumstances:

i.Forpartnersofmenundergoingvasectomy,forprotectionuntilthevasectomybecomeseffective.

ii.Inwomenwhoarebeingimmunisedagainstrubella:topreventpregnancyduringtheperiodofactivityofthe

virus.

iii.Inwomenawaitingsterilisation.

Sincelossofbonemineraldensity(BMD)mayoccurinfemalesofallageswhouseMPAinjectionlong-term(See

section4.4Specialwarningsandspecialprecautionsforuse),arisk/benefitassessment,whichalsotakesinto

considerationthedecreaseinBMDthatoccursduringpregnancyand/orlactation,shouldbeconsidered.

Itisofthegreatestimportancethatadequateexplanationsofthelong -termnatureoftheproduct,ofitspossible

side -effectsandoftheimpossibilityofimmediatelyreversingtheeffectsofeachinjectionaregiventopotentialusers

andthateveryeffortismadetoensurethateachpatientreceivessuchcounsellingastoenablehertofullyunderstand

theseexplanations.Patientinformationleafletsaresuppliedbythemanufacturer.Itisrecommendedthatthedoctor

usestheseleafletstoaidcounsellingofthepatient.

Consistentwithgoodclinicalcontraceptivepracticeageneralmedicalaswellasgynaecologicalexaminationshouldbe

undertakenbeforeadministrationofDepo -Proveraandatyearlyintervalsthereafter.

4.2Posologyandmethodofadministration

ThesterileaqueoussuspensionofDepo -Proverashouldbevigorouslyshakenjustbeforeusetoensure

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Dosesshouldbegivenbydeepintramuscularinjectionintotheglutealmuscle.

Contraception

AllpotentialusersofDepo-Proverashouldhaveanegativepregnancytestbeforefirstadministration.

Becauseoftheriskofheavyorprolongedbleedinginsomewomen,thedrugshouldbeusedwithcautioninthe

puerperium.

Therecommendeddoseis150mgofMPAinjectablesuspensionevery3monthsadministeredbyintramuscular

injectionintheglutealmuscle.Theinitialinjectionshouldbegivenduringthefirst5daysaftertheonsetofanormal

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

postpartum.

Forsecondandsubsequentinjections,ifthetimeintervalbetweenIMinjectionsisgreaterthan13weeks,pregnancy

shouldberuledoutbeforeadministeringthenextIMinjection.

Aswithotherhormonalcontraceptives,regularconsiderationshouldbegiventowhethertheprevioustreatmenthas

resultedin:first-timemigraineorunusuallysevereheadaches,visualdisturbances,reappearanceofdepression,

pathologicalchangesinliverfunctiontests.

UseinChildrenandAdolescents

MPAIMisnotindicatedbeforemenarche.

DataregardingtheeffectsofMPAonBMDinadolescentfemales(12-18years)isavailable(see

section5.1PharmacodynamicProperties).OtherthanconcernsaboutlossofBMD,thesafetyandeffectivenessofMPA

IMareexpectedtobethesameforpostmenarchealadolescentandadultfemales.

SwitchingfromotherMethodsofContraception

Whenswitchingfromothercontraceptivemethods,(MPAIMorSC)shouldbegiveninamannerthatensures

continuouscontraceptivecoveragebasedupontheechanismactionofbothmethods,(e.g.,patientsswitchingfromoral

contraceptivesshouldhavetheirfirstinjectionofMPAwithin7daysaftertakingtheirlastactivepill).

HepaticInsufficiency

NoclinicalstudieshaveevaluatedtheeffectofhepaticdiseaseonthepharmacokineticsofMPA.However,MPAis

almostexclusivelyeliminatedbyhepaticmetabolismandsteroidhormonesmaybepoorlymetabolizedinpatientswith

severeliverinsufficiency,(seeSection4.3–Contraindications).

RenalInsufficiency

NoclinicalstudieshaveevaluatedtheeffectofrenaldiseaseonthepharmacokineticsofMPA.However,sinceMPA

isalmostexclusivelyeliminatedbyhepaticmetabolism,nodosageadjustmentshouldbenecessaryinwomen

withrenalinsufficiency.

4.3Contraindications

Depo -Proveraiscontraindicatedinpatientswithahistoryof,orexistentthrombo-embolicdisorders;orattheabove

dosagewithbreastorgenitalcancer(knownorsuspectedtobeoestrogendependent);andinpatientswithaknown

sensitivitytomedroxyprogesteroneacetateoranyingredientofthevehicle.Itsuseiscontra-indicatedinpatientswith

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Depo-proveraiscontraindicatedinpatientswithsevereliverdysfunction.

Depo -Proverashouldnotbeusedduringknownorsuspectedpregnancy,eitherfordiagnosisortherapy.

4.4Specialwarningsandprecautionsforuse

Warnings:

LossofBoneMineralDensity(BMD)

UseofDMPAinjectionreducesserumestrogenlevelsandisassociatedwithsignificantlossofBMDasbone

metabolismaccommodatestoalowerestrogenlevel.Bonelossisgreaterwithincreasingdurationofuse,however

BMDappearstoincreaseafterDepo-proveraisdiscontinuedandovarianestrogenproductionincreases.

ThislossofBMDisofparticularconcernduringadolescenceandearlyadulthood,acriticalperiodofboneaccretion.

ItisunknownifuseofDepo-Proverabyyoungerwomenwillreducepeakbonemassandincreasetheriskforfracture

inlaterlife. ( seeSection5.1–PharmacodynamicProperties,ClinicalStudies;BoneMineralDensityStudies).

BoneFracture

Inonestudy(UKretrospectiveGPRDcohortstudy)anincreasedriskoffracturewasseenfollowinguseofDPMA

comparedwithnon-DPMAusers.HowevertheextenttowhichthiseffectwasduetoDPMAorotherlifestylefactorsis

unclear.

DMPAinjectionshouldonlybeusedasalong-term(e.g.,longerthan2years)birthcontrolmethodifotherbirth

controlmethodsareunsuitable.BMDshouldbeevaluatedwhenafemaleneedstocontinuetouseDMPAinjection

longterm.Inadolescentfemales,interpretationofBMDresultsshouldtakeintoaccountpatientageandskeletal

maturity.

Otherbirthcontrolmethodsshouldbeconsideredintherisk/benefitanalysisfortheuseofDMPAinjectioninwomen

withosteoporoticriskfactors.DMPAinjectioncanposeanadditionalriskinpatientswithriskfactorsforosteoporosis

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

osteoporosisorchronicuseofdrugsthatcanreducebonemasssuchasanticonvulsantsorcorticosteroids).Itis

recommendedthatallpatientshaveadequatecalciumandVitaminDintake.

ForfurtherinformationonBMDchangesinbothadultandadolescentfemales,asreportedinrecentclinicalstudies,

refertosection5.1(PharmacodynamicProperties)

MenstrualIrregularity:

Prolongedanovulationwithamenorrhoeaand/orerraticmenstrualpatternsmayfollowtheadministrationofeithera

singleormultiplecontraceptivedosesofDepo-Provera.UnexpectedvaginalbleedingduringtherapywithDMPA

shouldbeinvestigated.

Returntofertility

WomenshouldbecounselledthatthereisapotentialfordelayinreturntofullfertilityfollowinguseofDepo-Provera.

Themediantimetoconceptionforthosewhodoconceiveis10monthsfollowingthelastinjectionwitharangeof4to

31monthsandisunrelatedtothedurationofuse.

Cancerrisks

Studiesinanimalshaveindicatedthatadministrationofveryhighdosesofestrogensand/orprogestogenswillinduce

neoplastictumoursinsomeanimalspecies.

Studiesinanimals,inparticularthedog,havedemonstratedthattheprogestogensincludingprogesteronewillinduce

neoplasticmammarytumours.Recentinvestigationssuggestthatresultsofdosingstudieswithprogestogeninthedog

areirrelevanttothepotentialforsucheffectsinhumanbeings,becauseofdifferencesinmammaryreceptor

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Long-termcase-controlledsurveillanceofDepo-Proverausersfoundnooverallincreasedriskofovarian,liver,or

cervicalcancerandaprolonged,protectiveeffectofreducingtheriskofendometrialcancerinthepopulationofusers.

Ameta-analysisin1996from54epidemiologicalstudiesreportedthatthereisaslightincreasedrelativeriskofhaving

breastcancerdiagnosedinwomenwhoarecurrentlyusinghormonalcontraceptives.Theobservedpatternofincreased

riskmaybeduetoanearlierdiagnosisofbreastcancerinhormonalcontraceptiveusers,biologicaleffectsora

combinationofboth.Theadditionalbreastcancersdiagnosedincurrentusersofhormonalcontraceptivesorinwomen

whohaveusedtheminthelasttenyearsaremorelikelytobelocalisedtothebreastthanthoseinwomenwhonever

usedhormonalcontraceptives.Breastcancerisrareamongwomenunder40yearsofagewhetherornottheyuse

hormonalcontraceptives.Inthemeta-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

disappearsduringthecourseofthe10yearsafterstoppingIPuse,suchthatby10yearsthereappearstobenoexcess.

Theevidencesuggeststhatcomparedwithnever-users,among10,000womenwhouseIPsforupto5yearsbutstopby

age20,therewouldbemuchlessthan1extracaseofbreastcancerdiagnosedupto10yearsafterwards.Forthose

stoppingbyage30after5yearsuseoftheIP,therewouldbeanestimated2-3extracases(additionaltothe44casesof

breastcancerper10,000womeninthisagegroupneverexposedtooralcontraceptives).Forthosestoppingbyage40

after5year’suse,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

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Physiciansshouldbeawarethatpathologistsshouldbeinformedofthepatient'suseofDepo-Proveraifendometrialor

endocervicaltissueissubmittedforhistologicalexamination.Theresultsofcertainlaboratorytestsmaybeaffectedby

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

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

test,metyraponetest,liverfunctionteststhyroidfunctiontestsandsexhormonebindingglobulin.Coagulationtest

valuesforprothrombin(FactorII),andFactorsVII,VIII,IXandXmayincrease.

Theeffectsofmedroxyprogesteroneacetateonlipidmetabolismhavebeenstudiedwithnoclearimpactdemonstrated.

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

densitylipoprotein(HDL)cholesterolhavebeenobservedinstudies.

Thedrugshouldbeusedwithcautioninpatientswithcardiovascularorrenaldisease,asthmaorepilepsybecauseofthe

potentialproblemoffluidretentioninsomepatients.

Weightgain

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.

Asthisproductcontainsmethylparahydroxbenzoteandpropylparahydroxybenzoate,itmaycauseallergicreactions

(possiblydelayed),andexceptionally,bronchospasm.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

AminoglutethimideadministeredconcurrentlywithDepo-Proveramaysignificantlydepressthebioavailabilityof

Depo-Provera.Usersofhigh-doseMPAshouldbewarnedofthepossibilityofdecreasedefficacywiththeuseof

aminoglutethimide.Interactionswithothermedicinaltreatments(includingoralanticoagulants)haverarelybeen

reported,butcausalityhasnotbeendetermined.Thepossibilityofinteractionshouldbeborneinmindinpatients

receivingconcurrenttreatmentwithotherdrugs

4.6Fertility,pregnancyandlactation

Pregnancy

MPAiscontraindicatedinwomenwhoarepregnant.

Somereportssuggestanassociationbetweenintrauterineexposuretoprogestationaldrugsinthefirsttrimesterof

pregnancyandgenitalabnormalitiesinmaleandfemalefoetuses.

Infantsfromunintentionalpregnanciesthatoccur1-2monthsafterinjectionofMPAinjectablesuspensionmaybeatan

increasedriskoflowbirthweight,which,inturn,isassociatedwithanincreasedriskofneonataldeath.

ThisriskislowaspregnancieswhileonMPAareuncommon.

IfMPAisusedduringpregnancy,orifthepatientbecomespregnantwhileusingthisdrug,thepatientshouldbe

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Childrenexposedtomedroxyprogesteroneacetateinuteroandfollowedtoadolescence,showednoevidenceofany

adverseeffectsontheirhealthincludingtheirphysical,intellectual,sexualorsocialdevelopment.

Lactation

MPAanditsmetabolitesareexcretedinbreastmilk.Thereisnoevidencetosuggestthatthispresentsanyhazardtothe

nursingchild.

Infantsexposedtomedroxyprogesteroneviabreastmilkhavebeenstudiedfordevelopmentalandbehaviouraleffects

topuberty.Noadverseeffectshavebeennoted.

4.7Effectsonabilitytodriveandusemachines

Notrelevant.

4.8Undesirableeffects

PatientsreceivingDepo -Proveramaybesubjecttotheside-effectsnormallyassociatedwiththeuseofprogestogens.

Inaddition,itislikelythatsomeorallofthefollowingeffectsmayoccur:

Genitourinary

Delayinreturntonormalmenstrualcyclingandtransientinfertilitylastingupto18monthsoroccasionallylongermay

occurfollowingcontinuoustreatmentwithDepo -Provera.

Depo -Proveramaybeexpectedtocausedisruptionofthenormalmenstrualcycle.Irregular,prolonged,decreasedor

heavyvaginalbleedingorspottingmaybeexperiencedduringthefirsttwoorthreecyclesoftreatment.Thefrequency

ofoccurrenceofbleedingusuallydecreaseswithsubsequentinjections.Afteroneyearoftreatmentsomewomenare

amenorrhoeic.

BODYSYSTEM EVENT

Infectionsandinfestations vaginitis

Immunesystemdisorders Hypersensitivityreactions(e.g.,anaphylaxis&

anaphylactoidreactions,angioedema)

Endocrinedisorders Prolongedanovulation

Gastrointestinaldisorders Abdominalpainordiscomfort,bloating,nausea

Hepato-biliary Jaundice,

Metabolic&Nutritiondisorders Weightchange,fluidretention

Psychiatricdisorders Depression,decreasedlibido,anorgasmia,insomnia,

nervousness,

NervousSystemdisorders Convulsions,dizziness,headache,somnolence,

migraine,

Vasculardisorders Thromboembolicdisorders,hotflashes,

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

nohairgrowth

Musculoskeletalandconnectivetissueandbone

disorders Arthralgia,backache,,legcramps,osteoporosis*

Reproductivesystemanbreastdisprders Abnormaluterinebleeding(irregular,increase,

decrease),amenorrhea,leukorrhea,pelvicpain,

galactorrhea,mastodynia,tenderness

General disorders and administration site

conditions Fatigue,asthenia,injection-sitereactions,lossofbone

mineraldensity,

Eyedisorders Sudden,partialorcompletelossofvision,protopsis,

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*Inpostmarketingexperience,therehavebeenrarecasesofosteoporosisincludingosteoporoticfracturesreportedin

patientstakingMPAIM.

4.9Overdose

Nopositiveactionisrequiredotherthancessationoftherapy.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Parenteralmedroxyprogesteroneacetateisalongactingprogestationalsteroid.Itexertsanti-oestrogenic,anti-

androgenicandantigonadotrophiceffects.

BMDChangesinAdultWomen

Inacontrolled,clinicalstudyadultwomenusingMPAinjection(150mgIMforupto5years)showedspineandhip

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.PleaserefertoTable1belowfor

furtherdetails.

AfterstoppinguseofMPAinjection(150mgIM),therewaspartialrecoveryofBMDtowardbaselinevaluesduring

the2-yearpost-therapyperiod.After2yearsofftreatment,theBMDdeficithaddecreasedtoapproximately2.1%at

thespineandhip.AlongerdurationoftreatmentwasassociatedwithaslowerrateofBMDrecovery.(seeSection4.4

–Specialwarningsandprecautionsforuse).

Table1.MeanPercentChangefromBaselineinBMDinAdultsbySkeletalSiteandCohortafter5Yearsof

TherapywithMedroxyprogesteroneacetate150mgIMandafter2YearsPost-Therapyor7Yearsof

Observation(Control)

*Thetreatmentgroupconsistedofwomenwhoreceivedmedroxyprogesteroneacetateinjection(150mgIM)for5

yearsandthecontrolgroupconsistedofwomenwhodidnotusehormonalcontraceptionforthistimeperiod.

**ThetreatmentgroupconsistedofwomenwhoreceivedmedroxyprogesteroneacetateInjection(150mgIM)for5

yearsandwerethenfollowedupfor2yearspost-useandthecontrolgroupconsistedofwomenwhodidnotuse

Miscellaneous Moonfacies,pyrexia

Investigations Decreasedglucosetolerance,disturbedliverfunction

Time

Study Spine TotalHip FemoralNeck

Medroxyprogesterone

acetate Control Medroxyprogesterone

acetate Control Medroxyprogesterone

acetate Control

years* n=33

-5.38% n=105

0.43% n=21

-5.16% n=65

0.19% n=34

-6.12% n=106

-0.27%

years** n=12

-3.13% n=60

0.53% n=7

-1.34% n=39

0.94% n=13

-5.38% n=63

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BMDChangesinAdolescentFemales(12-18years)

Anopen-labelnon-randomizedclinicalstudyofMPAinjectable(150mgIMevery3monthsforupto240weeks[4.6

years])inadolescentfemales(12-18years)forcontraceptionalsoshowedasignificantdeclineinBMDfrombaseline.

Amongsubjectswhoreceived>4injections/60-weekperiod,themeandecreaseinlumbarspineBMDwas-2.1%

after240weeks;meandecreasesforthetotalhipandfemoralneckwere-6.4%and-5.4%,respectively.Basedon

meanchanges,post-treatmentfollow-upshowedthatlumbarspineBMDrecoveredtobaselinelevelsapproximately1

yearaftertreatmentwasdiscontinuedandthathipBMDrecoveredtobaselinelevelsapproximately3yearsafter

treatmentwasdiscontinued.Incontrast,unmatched,untreatedsubjectsshowedmeanBMDincreasesat240weeksof

6.4%,1.7%and1.9%forlumbarspine,totalhipandfemoralneck,respectively.(seeSection4.4–Specialwarnings

andprecautionsforuse).

Bonefracture

AretrospectivecohortstudyusingdatafromtheGeneralPracticeResearchDatabase(GPRD)reportedthatwomen

usingMPAinjections(DMPA),haveahigherriskoffracturecomparedwithcontraceptiveuserswithnorecordeduse

ofDMPA(incidentrateratio1.41,95%CI1.35-1.47forthefiveyearfollow-upperiod);itisnotknownifthisisdueto

DMPA,ortootherrelatedlifestylefactorswhichhaveabearingonfracturerate.Bycontrast,inwomenusingDMPA,

thefractureriskbeforeandafterstartingDMPAwasnotincreased(relativerisk1.08,95%CI0.92-1.26).Importantly,

thisstudycouldnotdeterminewhetheruseofDMPAhasaneffectonfractureratelaterinlife.

5.2Pharmacokineticproperties

Thedrugisabsorbedreadily,metabolisedintheliverinitiallytoprogesteronewhichisrapidlydistributedtobinding

sites,andtopregnanediolandexcretedthereafterinurine.

Absorption:Followingintramuscularadministration,MPAisslowlyreleased,resultinginlow,butpersistentlevelsin

thecirculation.Immediatelyafterintramuscularinjectionof150mg/mlMPA,plasmalevelswere1.7±0.3nmol/l.Two

weekslater,levelswere6.8±0.8nmol/l.Meantimetopeakisapproximately4to20daysfollowinganintramuscular

dose.Serummedroxyprogesteroneacetatelevelsgraduallydeclineandremainrelativelyconstantatabout1ng/mlfor

2-3months.Circulatinglevelscanbedetectedforaslongas7to9monthsfollowinganintramuscularinjection.

Distribution:MPAisapproximately90to95%proteinbound.Volumeofdistributionisreportedas20+3liters.

Medroxyprogesteroneacetatecrossestheblood-brain-barrier,andtheplacentalbarrier.Lowlevelsof

medroxyprogesteroneacetatehavebeendetectedinbreastmilkoflactatingwomenadministered150mgof

medroxyprogesteroneacetatebytheIMroute.

Metabolism:MPAismetabolizedintheliver.

Elimination:Theeliminationhalf-lifefollowingsingleintramuscularinjectionisabout6weeks.Medroxyprogesterone

acetateisprimarilyexcretedinthefaeces,viabiliarysecretion.Approximately30%ofanintramusculardoseis

secretedintheurineafter4days.

5.3Preclinicalsafetydata

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Methylparahydroxybenzoate(E218)

Macrogol

Polysorbate80

Propylparahydroxybenzoate(E216

Sodiumchloride

Waterforinjections

Sodiumhydroxide

Hydrochloricacid

6.2Incompatibilities

Nonestated.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

C.Donotfreeze.

6.5Natureandcontentsofcontainer

1mlpre-filleddisposablesyringeconsistingofaTypeI(Ph.Eur.)glassbarrelwithabutylrubberstopperandtipcap

containing1mlofsuspension.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Donotmixwithotheragents.

Forsingleuseonly.

Discardanyunusedcontents.

7MARKETINGAUTHORISATIONHOLDER

PharmaciaIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19January1996

Dateoflastrenewal:19January2006

10DATEOFREVISIONOFTHETEXT

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