Department ofReproductive HealthandResearch Department ofReproductive HealthandResearch Department ofReproductive HealthandResearch Long Long Long-acting contraceptive methods Department of reproductivehealth and research Catherine Catherine Catherine d’Arcangues, Ph.D.,M.D. - - acting contraceptive methods acting contraceptive methods World Health Organization World Health Organization World Health Organization Geneva, 24March 2003 Geneva, 24March 2003 Geneva, 24March 2003 d’Arcangues d’Arcangues for women for women for women Département santé et recherche génésiques , Ph.D.,M.D. , Ph.D.,M.D.

CDA_FIGO_SEPT00/1 • • Note: Note: • • Department of reproductivehealth and research ¿ Methods with improvedpharmacokinetic profile [Duration ofaction: 7days with sexualintercourse Methods thatdonot requiredailyuseorinterfere ¿ ¿ Methods with improvedpharmacokinetic profile [Duration ofaction: 7days with sexualintercourse Methods thatdonot requiredailyuseorinterfere ¿ long long reduced side greater use reduced side greater use ¿ ¿ Rationale forthe developmentof Rationale forthe developmentof - - dependance dependance acting methods ofcontraception acting methods ofcontraception - - effectiveness effectiveness - - effects effects on health care provider on health care provider → → éatmn at trcecegénésiques et recherche santé Département 7 years] 7 years]

CDA_FIGO_SEPT/00/2 Department of reproductivehealth and research Schematic representation ofexpectedPKprofiles Schematic representation ofexpectedPKprofiles of of progestogens and indifferentformulations and indifferentformulations administered bydifferent routes administered bydifferent routes éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT/00/3 Department of reproductivehealth and research Long Long • • • • • • • • Transdermal systems Vaginal rings Implants Injectables Transdermal systems Vaginal rings Implants Injectables - - acting methods acting methods éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT/00/4 • • Department of reproductivehealth and research • • Injectable Injectable Once Two Once Two - - to to - - a a - - - - three monthly: three monthly: month: month: progestogen progestogen progestogen contraceptive preparations contraceptive preparations - - - - only estrogen combinations only estrogen combinations éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT/00/5 • • • • Department of reproductivehealth and research Mechanism ofaction: Depot Mechanism ofaction: Norethisterone Depot – – – – Two Two additional effects on ovulation inhibition and cervical mucus additional effects on ovulation inhibition and cervical mucus - - medroxyprogesterone - - to to - - three monthly three monthly enanthate enanthate endometrium endometrium (NET (NET éatmn at trcecegénésiques et recherche santé Département acetate (DMPA) acetate (DMPA) injectables injectables - - , tubalfunction , tubalfunction EN) EN)

CDA_FIGO_SEPT/00/6 • • injectable Offer towomenan alternativetoprogestogen-only • • Department of reproductivehealth and research of combined of combined ¿ discontinuation: faster return tobaselinefertility upon ¿ a moreregular vaginalbleeding pattern: ¿ discontinuation: faster return tobaselinefertility upon ¿ a moreregular vaginalbleeding pattern: through improved pharmacokinetic profile by adding anestrogen through improved pharmacokinetic profile by adding anestrogen Rationale forthe development Rationale forthe development c ontraceptives, which ensures: injectable injectable éatmn at trcecegénésiques et recherche santé Département contraceptives contraceptives

CDA_FIGO_SEPT/00/7 Department of reproductivehealth and research Idealized pharmacokinetic/ Idealized pharmacokinetic/ monthly monthly profile ofatypicalcombined profile ofatypicalcombined injectable injectable Adapted from: Fr éatmn at trcecegénésiques et recherche santé Département contraceptive contraceptive pharmacodynamic pharmacodynamic aser and Diczfalusy, 1980

CDA_FIGO_SEPT/00/8 Mego-E inj Chin Norigyno Mesigyna Lunel Cyclof Topasel Perlut Trade name e c Department of reproductivehealth and research ese t able No l al e em Once Once n 1 - - a a Main preparations currently available Main preparations currently available - - month combined month combined Composition E cap ac Dihy 17 Meges 17 E NET-E E DMPA 25mg+ E 2 2 2 2 valerate 5mg valerate5mg cy enanthat etophenide 150mg+ β α r E -hyd oate 2 drox pionate 5mg 2 3.5 mg N t rol a rox 50mg+ yprog 5 y e 10mg c 0 mg+ pro etate 25 m e ste g e s r tero on éatmn at trcecegénésiques et recherche santé Département injectable injectable e ne g + Chin Chin 7 Latin Ameri I 22 c.,LatinAmerica, Sp Latin Ameri A ndone Af contraceptives contraceptives vailability ain rica a a sia, Thail n c. , c c Ch a, a, Tur ina a nd k ey ,

CDA_FIGO_SEPT/00/9 Department of reproductivehealth and research E DMPA E DMPA E DMPA D For administration of variousmonthly administration of variousmonthly 2 2 2 M Cy Cy Cy m PA ul p p p at Percentage of Percentage of i o n 1 1

D (m 5 25 25 2 ose

2 2 g 5 .5 .5 . ) 5 3 r d mon t r ovulatory eat ovulatory 42 0 0 0 t m h en t éatmn at trcecegénésiques et recherche santé Département 1 s From: G t mon f o 100 24 6 6 cycles after cycles after llo 0 0 t w h a - rza-Flores, 1991 u p injectables injectables 2 n d 100 48 9 7 mo fo l 0 1 l n o t w h -u p

CDA_FIGO_SEPT/00/10 Event Pregnancy Bleeding Amenorrhoea Other medical reasons Non Lost tofollow up Total discontinuations Woman Event Pregnancy Bleeding Amenorrhoea Other medical reasons Non Lost tofollow up Total discontinuations Woman Department of reproductivehealth and research - - medical reasons medical reasons - - months and DMPA.Cumulative lifetablediscontinuationrates months and DMPA.Cumulative lifetablediscontinuationrates - - related reason related reason WHO phaseIIIclinical trialsof WHO phaseIIIclinical trialsof per 100womenat12 months per 100womenat12 months s s 10 969 10 969 Cyclofem Cyclofem 15.1 11.4 35.5 15.1 11.4 35.5 0 6.3 2.1 6.3 0 6.3 2.1 6.3 éatmn at trcecegénésiques et recherche santé Département 10 608 10 608 Mesigyna Mesigyna 36.8 36.8 16.6 10.5 16.6 10.5 0.2 7.5 1.6 6.6 0.2 7.5 1.6 6.6 Cyclofem Cyclofem From :WHO, 1986,1988 , , Mesigyna Mesigyna DMPA 5 429 DMPA 5 429 15.5 12.5 10.1 41.2 15.5 12.5 10.1 41.2 0 4.3 8.6 0 4.3 8.6

CDA_FIGO_SEPT/00/11 DMPA Mesigyna Cyclofem Untreated Group Department of reproductivehealth and research 3 893 802 766 311 Proportions (%)of womenexperiencing Proportions (%)of womenexperiencing ( n) different typesof bleedingpatterns. different typesof bleedingpatterns. Months 6 Months 6 rrhoea Ameno- 1.3 1.1 1.3 37.0 I bleeding n frequent 2.8 5.4 2.9 24.8 - - 9 ofaoneyeardiary 9 ofaoneyeardiary From: Fraser,1994; Sang etal, 1995; Coutinho Frequent bleeding 2 0 4 8.3 .8 .1 .9 éatmn at trcecegénésiques et recherche santé Département bleeding Irregular 5.4 25.4 24.8 2 7.7 bleeding Prolonged 9.4 9.9 12.6 1 7.3 et al, 1997 63.3 61.3 90.1 6.4 pattern Regular

CDA_FIGO_SEPT/00/12 • • • • • • or deposition cytokines andproteases( cellular matrix. dilated surfacevessels. Abnormal epithelium with reduced mast cells Infiltration, proliferationandactivation ofleukocytes and increased Abnormal angiogenesis α or deposition cytokines andproteases( cellular matrix. dilated surfacevessels. Abnormal epithelium with reduced mast cells Infiltration, proliferationandactivation ofleukocytes and increased Abnormal angiogenesis α - - actin, deficient actin, deficient Department of reproductivehealth and research Mechanisms of progestin Mechanisms of progestin microvascular microvascular → → expression andactivationof growth factors, → expression andactivationof growth factors, → endometrial bleeding less likely tocontain micro less likely to contain micro endometrial bleeding microvascular microvascular → → density, reducedsmooth muscle density, reducedsmooth muscle MMPs MMPs neovascular neovascular basement membrane, basement membrane, éatmn at trcecegénésiques et recherche santé Département ), degradation ofextra ), degradation ofextra cytokeratin cytokeratin formations, formations, - - induced induced - - hemorrhages hemorrhages formation formation - - . .

CDA_FIGO_SEPT/00/13 Woman-months Hypertension Decreased libido Headaches Dizziness Fatigue Anxiety/depression Weight gain Abdominal discomfort Department of reproductivehealth and research 12 12 multicentre trialsof DMPA,NET multicentre trialsof DMPA,NET - - months life months life T O AL - - table d/cratesformedical reasonsin table d/cratesformedical reasonsin DMPA 20,550 0 1 0.7 2 1 0.5 0 2.1 8 .9 .1 .3 .2 .9 .7 éatmn at trcecegénésiques et recherche santé Département NET-EN 10,361 - 0.6 0.6 2.0 1.6 0 0.9 0 1 9.3 - EN and EN and .9 .7 .6 Cyclofem Cyclofem Cyclofem 10,969 0 0.3 1 1 0 0.8 1.5 6 - .1 .2 .2 .4 .3

CDA_FIGO_SEPT/00/14 • • • • • • • • • • • • • • • Department of reproductivehealth and research risk ofstrokeinthose withhypertension stroke, VTEorAMI in healthywomenBUT In epidemiological studies: noincreasedriskof risk ofstrokeinthose withhypertension stroke, VTEorAMI in healthywomenBUT In epidemiological studies: noincreasedriskof risk ofstrokeinthose withhypertension) stroke, VTEorAMI in healthywomenBUTincreased In epidemiological studies: noincreasedriskof Delayed return of fertility No measurable effectonbreast No quantitative effectonmilk production, Moderate unfavourable lipidchanges. Delayed return of fertility No measurable effecton breast No quantitative effectonmilk production, Moderate unfavourable lipidchanges. Delayed return of fertility No measurable effecton breast-fed infants No quantitative effectonmilk production, Moderate unfavourable lipidchanges. Small degreeofinsulin resistance (growth, hypothalamic some changes inmilkcomposition Small degreeofinsulin resistance Small degreeofinsulin resistance (growth, hypothalamic some changes inmilkcomposition (growth, hypothalamic-pituitary gonadal some changes inmilkcomposition Metabolic effects ofDMPAandNET Metabolic effects ofDMPAandNET Metabolic effects ofDMPAandNET-EN - - pituitary pituitary after use discontinuation after use discontinuation a fter use discontinuation éatmn at trcecegénésiques et recherche santé Département - - fed infants fed infants gonadal gonadal ) ) axis) axis) axis) increased increased - - EN EN

CDA_FIGO_SEPT00/15 • • • • • • • • • • Delay inthereturn tofertility during 3months afterd/c No studies on their effect onlactation No significant changeinglucose metabolism Minor discontinuation Minor lipidchanges, whichrevertpromptlyat discontinuation Delay inthereturn tofertility during 3months afterd/c No studies on their effect onlactation No significant changeinglucose metabolism Minor discontinuation Minor lipidchanges, whichrevertpromptlyat discontinuation Department of reproductivehealth and research hemostatic hemostatic of of Cyclofem Cyclofem Metabolic effects Metabolic effects changes, which revertpromptly at changes, which revertpromptly at and and éatmn at trcecegénésiques et recherche santé Département Mesigyna Mesigyna

CDA_FIGO_SEPT/00/16 Method OC IUD DMPA Cyclofem Department of reproductivehealth and research after prolongeduse ofdifferentmethods after prolongeduse ofdifferentmethods Return ofovulation andfertility Return ofovulation andfertility 437 125 796 70 n M edian timeto conception (months) 3.0 4.5 5.5 5.5 éatmn at trcecegénésiques et recherche santé Département at oneyear(%) conception rate Cumulative 75.8 76.2 84.9 8 2.9

CDA_FIGO_SEPT/00/17 • • • • Department of reproductivehealth and research To date,one studysuggestsa 3 HIV transmissionmay be number ofHIV of HIV+ DMPAusers. More research needed or maybe HIV transmissionmay be To date,one studysuggestsa 3 number ofHIV of HIV+ DMPAusers. More research needed or maybe vaginal thinning, prolonged vaginalbleeding, cervical mucus thickening vaginal thinning, prolonged vaginalbleeding, cervical mucus thickening hindered hindered - DMPA andHIV - DMPA andHIV infected cellsin thevaginal secretions infected cellsin thevaginal secretions through: through: immunosuppression immunosuppression promoted promoted éatmn at trcecegénésiques et recherche santé Département - - unsterilised unsterilised fold increase inthe fold increase inthe through: through: , , needles needles

CDA_FIGO_SEPT/00/18 • • • • • • Department of reproductivehealth and research Few data onthe the effects on adult bone massand long mass accumulation. Current researchfocuses on In adolescents, slowdownof thenormalbone long upon discontinuation andwithoutanyapparent fully compensated by boneformation,reversible of bonemetabolism withboneresorptionthatisnot Between theages of 25and45,slightacceleration Few data onthe the effects on adult bone massand long mass accumulation. Current researchfocuses on In adolescents, slowdownof thenormalbone long upon discontinuation andwithoutanyapparent fully compensated by boneformation,reversible of bonemetabolism withboneresorptionthatisnot Between theages of 25and45,slightacceleration - - term effect. term effect. DMPA andbone metabolism DMPA andbone metabolism peri peri - - menopause. menopause. éatmn at trcecegénésiques et recherche santé Département - - term risks. term risks.

CDA_FIGO_SEPT/00/19 • • • • • • • • • • • • Department of reproductivehealth and research Currently used byover10million womenworldwide Currently registered inover70countries,including Currently used byover10million womenworldwide Currently registered inover70countries,including Currently used byover10million womenworldwide Currently registered inover70countries,including First registeredfor this indicationin1967 First registeredfor this indicationin1967 (USFDA) in1982 10 ECcountriesand theUSA First registeredfor this indicationin1967 (USFDA) in1982 10 ECcountriesand theUSA (USFDA) in1982 10 ECcountriesand theUSA Approved bytheUSFoodand DrugAdministration Approved bytheUSFoodand DrugAdministration Approved bytheUSFoodand DrugAdministration DMPA DMPA DMPA éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT00/20 * Controls matched withcases by age,centre and year ofentry intostudy Cervix Breast Liver Ovary Endometrium Cancer Site Department of reproductivehealth and research Relative risksof 5 Relative risksof 5 who haveeverused DMPA who haveeverused DMPA Cases WHO Collaborative Study Number ofSubjects WHO Collaborative Study 224 869 2,009 122 57 Controls* 1,781 9,583 1 939 290 1,890 neoplasms neoplasms éatmn at trcecegénésiques et recherche santé Département Adjusted RelativeRisk 1.21 1.07 0.21 1.1 1 .0 in women in women (95% CI) ( (0.96-1.52) (0.06-0.79) 0.96-1.29) (0.6-1.8) (0.4-2.8)

CDA_FIGO_SEPT/00/21 Department of reproductivehealth and research Setting: NewZealand (entirecountry) 1,768 cases and13,905controls 1,768 cases and13,905controls Setting: NewZealand (entirecountry) 1,768 cases and13,905controls Setting: NewZealand (entirecountry) DMPA usedby 14.1%cases and 14.2%controls DMPA usedby 14.1%cases and 14.2%controls DMPA usedby 14.1%cases and 14.2%controls DMPA andBreast Cancer(1) DMPA andBreast Cancer(1) DMPA andBreast Cancer(1) Thailand (3centres) Thailand (3centres) Thailand (3centres) Mexico (1centre) Kenya (1centre) Mexico (1centre) Kenya (1centre) Mexico (1centre) Kenya (1centre) éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT00/22 Maximum increaseinriskattributable toDMPA: previously increased inwomenwhobegan use>5years Risk didnotincrease withdurationofuseandwasnot exposure, inwomen <35yearsatdiagnosis;smalln Risk increasedduring first4yearsafterinitial RR (95%CI)inever usersofDMPA=1.1(0.97 Maximum increaseinriskattributable toDMPA: previously increased inwomenwhobegan use>5years Risk didnotincrease withdurationofuseandwasnot exposure, inwomen <35yearsatdiagnosis;smalln Risk increasedduring first4yearsafterinitial RR (95%CI)inever usersofDMPA=1.1(0.97 Maximum increaseinriskattributable toDMPA: previously increased inwomenwhobegan use>5years Risk didnotincrease withdurationofuseandwasnot exposure, inwomen <35yearsatdiagnosis;smalln Risk increasedduring first4yearsafterinitial RR (95%CI)inever usersofDMPA=1.1(0.97- Department of reproductivehealth and research 3.2 3.2 3.2 - DMPA andBreast Cancer(2) DMPA andBreast Cancer(2) DMPA andBreast Cancer(2) - - 4.5 cases per100 000women 4.5 cases per100 000women 4 .5 cases per100 000women-years éatmn at trcecegénésiques et recherche santé Département - - years years - - 1.4) 1.4) 1 .4)

CDA_FIGO_SEPT00/23 > 60 25-60 13-24 1-12 0 of use Months Department of reproductivehealth and research DMPA andInvasive DMPA andInvasive WHO Collaborative Study WHO Collaborative Study C Number ofSubjects 26 17 50 58 7 ases 82 Cervical Cancer Cervical Cancer Controls 127 86 92 216 5,184 éatmn at trcecegénésiques et recherche santé Département Squamous Squamous Relative Risk 0 1.4 (0.9 –2.2) 1.2 (0.7–2.0) 1 .6 (0.4 –1.1) .4 (1.0-2.0) (95% CI) Cell Cell 1 .0

CDA_FIGO_SEPT/00/24 Department of reproductivehealth and research DMPA andCervical Carcinoma DMPA andCervical Carcinoma DMPA andCervical Carcinoma Pap smear frequency age, number of pregnancies, use ofOC, used DMPA 23.3% casesand15.4% controlshadever 1,217 casesand8,956 controls Setting: Mexico,Thailand RR (CI95%) =1.43(1.22 Pap smear frequency age, number of pregnancies, use ofOC, RR (CI95%) =1.43(1.22 used DMPA 23.3% casesand15.4% controlshadever 1,217 casesand8,956 controls Setting: Mexico,Thailand used DMPA 23.3% casesand15.4% controlshadever 1,217 casesand8,956 controls Setting: Mexico,Thailand Pap smear frequency age, number of pregnancies, use ofOC, RR (CI95%) =1.43(1.22- éatmn at trcecegénésiques et recherche santé Département - - 1.67) adjusted for 1.67) adjusted for 1 .67) adjusted for

in situ in situ in situ

(1) (1)

(1)

CDA_FIGO_SEPT00/25 situ suggest that ifDMPAincreases theriskofcervical CA cervical cancer andDMPAin thissamestudy,the findings Since norelationship wasestablishedbetweeninvasive with timesincefirst andlastuse. The riskincreased with durationofusebutdecreased The riskincreased with durationofusebutdecreased situ suggest that ifDMPAincreases theriskofcervical CA cervical cancer andDMPAin thissamestudy,the findings Since norelationship wasestablishedbetweeninvasive with timesincefirst andlastuse. The riskincreased with durationofusebutdecreased situ suggest that ifDMPAincreases theriskofcervical CA cervical cancer andDMPAin thissamestudy,the findings Since norelationship wasestablishedbetweeninvasive with timesincefirst andlastuse. Department of reproductivehealth and research : : : ------DMPA andCervical Carcinoma DMPA andCervical Carcinoma DMPA andCervical Carcinoma cervical lesions induced byDMPA donot this isareversible effect,or cervical lesions induced byDMPA donot this isareversible effect,or c t progress to invasive disease progress to invasive disease progress to invasive disease his isareversible effect,or ervical lesions inducedby DMPA donot éatmn at trcecegénésiques et recherche santé Département in situ in situ in situ (2) (2) (2) in in in

CDA_FIGO_SEPT00/26 • • • Improved pharmacokinetic profile: Improved pharmacokinetic profile: • • • • • • Improved pharmacokinetic profile: Department of reproductivehealth and research Monolithic Biodegradable Controlled particle size distribution Controlled particle size distribution Monolithic Biodegradable Controlled particle size distribution: Monolithic macrocrystals: Biodegradable microspheres: Injectables Injectables Injectables combined foronce , 17 norethisterone, combined foronce progesterone, 17 norethisterone, combined foronce-a-monthadministration progesterone, 17-beta- norethisterone, , progesterone D D D MPA, MPA, MPA, levonorgestrel levonorgestrel macrocrystals macrocrystals microspheres microspheres - - - norgestimate norgestimate Developments (1) - - Developments (1) D beta beta - - a a evelopments (1) - - month administration month administration - - butanoate butanoate butanoate , estradiol, estradiol, : : éatmn at trcecegénésiques et recherche santé Département , progesterone , progesterone : : : :

CDA_FIGO_SEPT00/27 • Safer deliverysystem : Department of reproductivehealth and research Safer deliverysystem : • ( disposable syringes Provision of in non ( disposable syringes Provision of in non Uniject Uniject Injectables Injectables - - reusable reusable , , Soloshot Soloshot Cyclofem Cyclofem ) ) - - Developments (2) Developments (2) éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT/00/28 Department of reproductivehealth and research Implantable contraceptives Implantable contraceptives Implantable contraceptives éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT00/29 Jadelle *Sino-implants Domestic No.IandIInot shownaregeneric versionsof **Same progestin with adifferent name. Elcometrine Nestorone Levonorgestrel Levonorgestrel Department of reproductivehealth and research Progestin Tradename respectively, available inChina. Implantable contraceptives forwomen ** ** a c. Uniplant Elcometrine Nestorone Implanon Jadelle Norplant * * Six capsules Single capsule Single capsule Single rod Single rod Two rods éatmn at trcecegénésiques et recherche santé Département U nits Duration Norplant and of action From: Croxatto 1 y 6 mo 2 y 3 y 5 y 7 y 2001

CDA_FIGO_SEPT/00/30 Department of reproductivehealth and research

34 mm Norplant 2.4 mm 36 mg crystals free Silastic medical Silastic tubing adhesive LNg in copolymer embedded éatmn at trcecegénésiques et recherche santé Département 75 crystals mg Jadelle 2.4 mm From: Croxatto

43 mm 2001

CDA_FIGO_SEPT/00/31 Department of reproductivehealth and research serum LNG ng/mL 0.1 0.2 0.3 0.4 0 Serum leveloflevonorgestrel inwomen 012 z using Norplantfor8 years zz 34 Years z z 56 éatmn at trcecegénésiques et recherche santé Département z z 78 From: Diaz etal1987 z

CDA_FIGO_SEPT/00/32 Serum LNG pg/mL 200 400 600 800 0 Department of reproductivehealth and research Contraceptive threshold WEEKS { z 23 Serum levelsoflevonorgestrel inwomen { z { z 4 { DU z 12 using NorplantorJadelle RA { z TION OF TREAT { z 34 { z { z 56 MONTHS { z éatmn at trcecegénésiques et recherche santé Département MENT 78 z { From: Croxatto { z 9 JADELLE NORPLANT 10 11 et al1991 { 12 z

CDA_FIGO_SEPT/00/33 • • • • Department of reproductivehealth and research Efficacy: Mechanism ofaction: Efficacy: Mechanism ofaction: luteal mostly ovulationinhibition cervical mucusthickening luteal mostly ovulationinhibition cervical mucusthickening - highest rates inwomen<25 y/oor>70kg 5 7 - highest rates inwomen<25 y/oor>70kg 5 7 year cumulative pregnancyrate: 1.1per100 year cumulative pregnancy rate: 1.9 per100 year cumulative pregnancyrate: 1.1per100 year cumulative pregnancy rate: 1.9 per100 For Norplant For Norplant phase abnormalities phase abnormalities Norplant and Norplant and : : éatmn at trcecegénésiques et recherche santé Département Jadelle Jadelle

CDA_FIGO_SEPT/00/34 From Population Council, 1990 Department of reproductivehealth and research 60-69 kg 50-59 kg Cumulative gross pregnancyratesper100 Cumulative gross pregnancyratesper100 < 50kg > 70kg Weight Norplant Norplant R R Rate users through5years users through5years 8.5 0.2 5.0 3.4 éatmn at trcecegénésiques et recherche santé Département 1 0 2 0 SE .4 .9 .3 .2

CDA_FIGO_SEPT/00/35 Total discontinuation Total adverse Other medical Menstrual From Sivin, 1990 Department of reproductivehealth and research Discontinuation resulting fromadverseexperiences: Discontinuation resulting fromadverseexperiences: Gross annualrateper 100 Gross annualrateper 100 19.0 15.1 6.0 9 123 .1 22.6 13.5 5 7.9 .6 éatmn at trcecegénésiques et recherche santé Département 20.8 Norplant Year Norplant 4.1 4 9.0 .9 2 4 3 7 3.3 4 R R .0 . .3 3 users users 2 5.1 2 8.0 2.4 5 .9

CDA_FIGO_SEPT/00/36 No. Women- A Irregular Regular Adapted from Shoupe m e of Department of reproductivehealth and research norrhe w o y e men Bleeding patterns(%) of ar Bleeding patterns(%) of a most frequentcategory foreachyear s most frequentcategory foreachyear during 5yearsofuse, assignedto during 5yearsofuse, assignedto e t al., 1991 198.0 7.1 6 2 215 6.3 6.6 123 127.9 4 5 138 5 0.0 4.7 .3 éatmn at trcecegénésiques et recherche santé Département Norplant Norplant 101.9 39.9 53.5 Year 115 6.6 R R 6 2 6 users users 5 77 8.1 6.8 4 .1 8 .8 34.9 3 6 46 7.5 2.5 5 0

CDA_FIGO_SEPT/00/37 Department of reproductivehealth and research Adverse effects withNorplantuse Adverse effects withNorplantuse (other thanmenstrual disorders) (other thanmenstrual disorders) Mood changes Dizziness Hair loss / hirsutism Acne Weight gain Headache Symptom éatmn at trcecegénésiques et recherche santé Département % 4-11 3-22 4-22 10 -30 1-9 2-5 users

CDA_FIGO_SEPT/00/38 Department of reproductivehealth and research • • • • • • • • - - - Vaginal bleeding patterns: exposure (women> 70kgwereexcluded) No pregnanciesobserved in5629yearsof More consistentovulation inhibition EVA rodreleasing etonogestrel - - - Vaginal bleeding patterns: exposure (women> 70kgwereexcluded) No pregnanciesobserved in5629yearsof More consistentovulation inhibition EVA rodreleasing etonogestrel 30% infrequent bleeding 10 30 30% infrequent bleeding 10 30 - - - - 20% prolonged bleeding 40% amenorrhea throughout 3years 20% prolonged bleeding 40% amenorrhea throughout 3years Implanon Implanon éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT/00/39 • • • • Department of reproductivehealth and research • • • • Note: within normal range Liver function: elevated Clotting and in someusers Carbohydrate metabolism: mildinsulinresistance Lipid effects:small or none. Note: within normal range Liver function: elevated Clotting and in someusers Carbohydrate metabolism: mildinsulinresistance Lipid effects:small or none. (Norplant, (Norplant, Metabolic effects ofimplants Metabolic effects ofimplants No studies in women at risk Predictive value questionable No studies in women at risk Predictive value questionable fibrinolytic fibrinolytic Jadelle Jadelle systems: minor changes systems: minor changes bilirubin bilirubin éatmn at trcecegénésiques et recherche santé Département , , Implanon Implanon in somewomen, in somewomen, ) )

CDA_FIGO_SEPT/00/40 • • • • Department of reproductivehealth and research No effecton: Potential beneficial effects: No effect on: Potential beneficial effects: decreased riskof connective tissue disorders revovery ovarian cyst enlargement anemia bone density decreased riskofpelvic inflammatorydisease connective tissue disorders revovery ovarian cyst enlargement anemia bone density decreased riskof decreased riskofpelvic inflammatorydisease and lowergenitaltract infection and lowergenitaltract infection Safety ofNorplant (1) Safety ofNorplant (1) of fertility of fertility ectopic ectopic éatmn at trcecegénésiques et recherche santé Département pregnancy pregnancy

CDA_FIGO_SEPT/00/41 Department of reproductivehealth and research • • • • No studies largeenoughtoassess effecton: evaluation: Potential adverseeffects thatneedfurther No studies largeenoughtoassess effecton: evaluation: Potential adverseeffects thatneedfurther diabetes HIV/AIDS cancer hormonal side increased riskofgallbladder disease increased riskofhypertension cardio diabetes HIV/AIDS cancer cardio hormonal side increased riskofgallbladder disease increased riskofhypertension Safety ofNorplant (2) Safety ofNorplant (2) - - vascular disease vascular disease - - effects effects éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT/00/42 • • • • - Infants breast Breast - Infants breast Breast ------Department of reproductivehealth and research absorb about 100 no effecton infantgrowthand development with Norplant: slight year (?) eye infections and skin conditions duringthe first experience longerperiods ofamenorrhea after weaning,bleeding patternsameasinnon nursing users no effectonbonemetabolism absorb about 100 no effecton infantgrowthand development with Norplant: slight year (?) eye infections and skin conditions duringthe first experience longerperiods ofamenorrhea after weaning,bleeding patternsameasinnon nursing users no effectonbonemetabolism Contraceptive implants andlactation - Contraceptive implants andlactation - feeding womenusing Norplant: feeding womenusing Norplant: - - fed bywomen usingNorplant or fed bywomen usingNorplant or ng ng ↑ ↑ /day ofprogestogen /day ofprogestogen in mild respiratory diseases, in mild respiratory diseases, éatmn at trcecegénésiques et recherche santé Département Implanon Implanon - - : :

CDA_FIGO_SEPT/00/43

-Other -Rashing -Itching -Pain LOCA E INFECTION X Department of reproductivehealth and research P L U complications during thefirstyearofNorplantuse L RE complications during thefirstyearofNorplantuse S A C 2674 womenin19 centres in7countries 2674 womenin19 centres in7countries Percentage ofwomen withinsertionsite TION Percentage ofwomen withinsertionsite From: Klavon Al l Centres 0. 0. 1. 2. 4.7 0. 0. % 3 3 9 2 4 8 and Grubb, 1990 éatmn at trcecegénésiques et recherche santé Département Individual Centres % R 0 0 0 –18.0 –3. –3. a n g 0 0 e

CDA_FIGO_SEPT/00/44 Percentage of total occurrences 10 20 30 40 50 60 70 Department of reproductivehealth and research 0 3-month days(61-136), 6-month (days * Follow-up intervalandthe Occurences Occurences 1- N=17 mo n 5 t h Expulsion, byFollow Expulsion, byFollow of InsertionSiteInfection andImplant of InsertionSiteInfection andImplant inclusive days post-inserti From: Klavon 3 - 4 Inf m o Follow-up interval e n 137-273), and 12-mo c 5 t t h ion and Grubb, 1990 éatmn at trcecegénésiques et recherche santé Département E on were:1-mon x 6- puls 2 mo nth (days 274-456). - - up Interval up Interval n i 2 on t h th (days1-60), 1 2- 3 mo n 2 t h

CDA_FIGO_SEPT/00/45 - Specific requirements - Positive attributes - - - - - Specific requirements - Positive attributes Positive attributes - - Specific requirements - - near adaptation ofhealth services; planning ofremovals heavier women metabolic changes,good reversibilitybutreducedefficacyin near adaptation ofhealth services; planning ofremovals heavier women metabolic changes,good reversibilitybutreducedefficacyin n a heavier women metabolic changes,good reversibilitybutreducedefficacyin long durationofaction; noactionrequiredfromuserfor5y. long durationofaction; noactionrequiredfromuserfor5y. provider training forcarefulinsertion andremoval, and for long durationofaction; noactionrequiredfromuserfor5y. provider training forcarefulinsertion andremoval, and for careful counselling provider training forcarefulinsertion andremoval, and for careful counselling careful counselling daptation ofhealth services; planning ofremovals ear-zero orderrelease ofminimaldoserequired: Department of reproductivehealth and research - - zero orderreleaseof minimaldoserequired: zero orderreleaseof minimaldoserequired: Lessons learnt fromNorplantasa Lessons learnt fromNorplantasa Lessons learnt fromNorplantasa delivery system delivery system delivery system éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT00/46 • • • • Controversies Controversies • • • • • • • • Controversies Department of reproductivehealth and research class actionsuits inthe USA and theUK financing, includingfreeinsertion andpayment coercive usebyproviders/target misuse by judiciarysystemand politicians class actionsuits inthe USA and theUK financing, includingfreeinsertion andpayment coercive usebyproviders/target misuse by judiciarysystemand politicians class actionsuits inthe USA and theUK financing, includingfreeinsertion andpayment coercive usebyproviders/target-driven national misuse by judiciarysystemand politicians family planningprogrammes for earlyremoval family planningprogrammes for earlyremoval family planningprogrammes for earlyremoval Lessons learnt fromNorplantasa Lessons learnt fromNorplantasa Lessons learnt fromNorplantasa delivery system delivery system delivery system éatmn at trcecegénésiques et recherche santé Département - - driven national driven national

CDA_FIGO_SEPT00/47 Department of reproductivehealth and research Implantable contraceptives forwomen Implantable contraceptives forwomen • • nestorone isnotabsorbedorally. Infants are notexposedtosteroids as suitable for breast Nestorone nestorone isnotabsorbedorally. Infants are notexposedtosteroids as suitable for breast Nestorone under development under development - - releasing singleimplant, releasing singleimplant, - - feeding women. feeding women. éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT/00/48 Department of reproductivehealth and research Contraceptive vaginal rings Contraceptive vaginal rings Contraceptive vaginal rings éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT00/49 Department of reproductivehealth and research Contraceptive vaginal rings Placing/removing the éatmn at trcecegénésiques et recherche santé Département v aginal ring

CDA_FIGO_SEPT/00/50 • • • • releasing a releasing estrogen releasing a releasing estrogen + progestogen progestogen months) (continuous useover3 (3 weeksin/1weekout) (3 weeksin/1weekout) months) (continuous useover3 progestogen + progestogen Department of reproductivehealth and research CONTRACEPTIVE VAGINALRINGS NUVARING NUVARING PROGERING PROGERING éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT00/51 Department of reproductivehealth and research 1200 1600 400 800 0 0 Serum concentration Serum concentration (120 (120 1 3 E µ µ 5 t onoges g/day etonogestrel+ 15 g/day etonogestrel+ 15 7 N t r o el ( 9 r m pg/ 11 a l NUVARING NUVARING us m N u l ) 13 e m b e 15 r of da 17 y s a 19 f t e r 21 day 21 ins éatmn at trcecegénésiques et recherche santé Département e - 23 - r s t time curves ion time curves 25 E µ µ x E 27 t t e h g/day EE) g/day EE) Timmer nde iny 29 l es d us t r adiol ( 31 & e

Mulders, 2000. 33 pg/ m 35 l ) 0 10 20 30

CDA_FIGO_SEPT/00/52 Department of reproductivehealth and research Maximum Maximum diameter duringnormal andextendeduse

Serum estradiol (pmol/l) diameter duringnormal andextendeduse 100 150 200 50 0 -7 estradiol estradiol 0 F o lli c u la 7 N NUVARING NUVARING r di o r m am al concentration andfollicular T concentration andfollicular u e i s t m er e e 1 ( 4 d ays) éatmn at trcecegénésiques et recherche santé Département 21 Se r u m E E x 2 t e nde 2 8 d us e Source: Mulders 35 10 0 2 4 6 8

Follicular diameter (mm) & Dieben, 2001

CDA_FIGO_SEPT/00/53 • • • • • • • • • • • • • • expulsion): 4.4% Minimal effects on lipid, CHO and one year ofuse. No adverse effect oncervical orvaginal cytology during Device Complaints ofhormonalside Breakthrough bleeding/spotting in5.5%ofallcycles. Withdrawal bleeding whenexpected(2 Pearl indexof0.77 (CI:0.37 removal) in98.5% cycles,lasting4 1.18 withactualuse inclinicaltrialsetting expulsion): 4.4% Minimal effects on lipid, CHO and one year ofuse. No adverse effect oncervical orvaginal cytology during Device Complaints ofhormonalside Breakthrough bleeding/spotting in5.5%ofallcycles. Withdrawal bleeding whenexpected(2 Pearl indexof0.77 (CI:0.37 removal) in98.5% cycles,lasting4 1.18 withactualuse inclinicaltrialsetting Department of reproductivehealth and research NUVARING NUVARING - - related events (foreignbody sensation, coital related events (foreignbody sensation, coital - - Phase III Phase III - - - - 1.41) withperfectuse, 1.41) withperfectuse, effects: 3 effects: 3 éatmn at trcecegénésiques et recherche santé Département hemostatic hemostatic - - 5 days. 5 days. clinical clinical - - - - 6 % 6 % 4 daysafterring 4 daysafterring variables. variables. trials trials pb pb , ,

CDA_FIGO_SEPT/00/54 • • • • • • • • • • Department of reproductivehealth and research because ofdiscomfort or ringexpulsion some earlydiscontinuations among ringusers users mean duration oramenorrhea: 12monthsinring breast one yearfollow 285 ringusers nursing women groups because ofdiscomfort or ringexpulsion some earlydiscontinuations among ringusers users mean duration oramenorrhea: 12monthsinring breast one yearfollow 285 ringusers nursing women groups (15 (15 vs vs - - feeding and infantgrowthsimilar inboth feeding and infantgrowthsimilar inboth → → 6 months in IUDusers 6 months in IUDusers 5 mg/dayprogesterone, over3months) 5 mg/dayprogesterone, over3months) Pre Pre vs vs - - up: nopregnancyin eithergroup up: nopregnancyin eithergroup PROGERING PROGERING - - registration study registration study 262 CuT380AIUD users, all 262 CuT380AIUD users, all éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT/00/55 Department of reproductivehealth and research Transdermal Transdermal éatmn at trcecegénésiques et recherche santé Département systems systems

CDA_FIGO_SEPT/00/56 • • • • • • of norgestimate)+ 20 maintained over 7days(+2 daysas safety window) blood levelsreach steady statein <48hours andare releasing 150 20 cm of norgestimate)+ 20 maintained over 7days(+2 daysas safety window) blood levelsreach steady statein <48hours andare releasing 150 20 cm – – – Department of reproductivehealth and research – – – inner, clear polyesterliner,peeled offbeforeuse contraceptive middle layerthatcontains anadhesiveandthetwo outer inner, clear polyesterliner,peeled offbeforeuse contraceptive steroids middle layerthatcontains anadhesiveandthetwo outer 2 2 (4.5 cmside),three (4.5 cmside),three polyethelene+polyester polyethelene+polyester Transdermal Transdermal µ µ g/day g/day ORTHO ORTHO µ µ norelgestromin g/day EE g/day EE - - - - EVRA EVRA layered patch: layered patch: systems systems éatmn at trcecegénésiques et recherche santé Département protective layer protective layer (active metabolite (active metabolite

CDA_FIGO_SEPT/00/57 Department of reproductivehealth and research following application ofEVRAfor7and10days

17d-NGM Conc. (ng/mL) Mean norelgestromin 0. 0. 0. 0. 1. 6 8 2 2 4 0 1 0 1 2 3 4 5 6 7 8 Time 9 10 (days) s 11 erum levels(ng/ml) 1 2 éatmn at trcecegénésiques et recherche santé Département 1 3 14 1 Therapeutic 5 16 range 17 1 8 1 9 20

CDA_FIGO_SEPT/00/58 • • • • Differences withOC inrandomizedclinicaltrials: Same mechanism of actionasthecombinedOC. Differences withOC inrandomizedclinicaltrials: Same mechanism of actionasthecombinedOC. – – – – – Department of reproductivehealth and research – – – – – dysmenorrhea breast discomfort (19% replacement patch:5% patch partial orcompletedetachment needing reason) application sitereactionin20% users(2.6%d/cfor this better compliance(88% reason) application sitereactionin20% users(2.6%d/cfor this better compliance(88% dysmenorrhea breast discomfort (19% replacement patch:5% patch partial orcompletedetachment needing ORTHO ORTHO (14% (14% vs vs 10%) 10%) vs vs vs vs - - 6%). 1% d/cfor thisreason. 6%). 1% d/cfor thisreason. EVRA 77%) EVRA 77%) éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT/00/59 Department of reproductivehealth and research éatmn at trcecegénésiques et recherche santé Département

CDA_FIGO_SEPT/00/60