CDA_contr_ methds.__Feb/1 contraceptive methods contraceptive methods Long-acting hormonal Long-acting hormonal Department of Reproductive Department of Reproductive Catherine d Catherine d Training inReproductiv Training inReproductiv for women for women World Health Organization World Health Organization Geneva, 21March2006 Geneva, 21March2006 ’ ’ Arcangues, Ph.D.,M.D. Arcangues, Ph.D.,M.D. e e Healthand Healthand Health Research Health Research Research Research 05_STAG_DRep_March 2006 /2 Note: long-acting methods ofcontraception ¯ [Duration ofaction: 7days with sexualintercourse Methods thatdonot requiredailyuseorinterfere Methods with improvedpharmacokinetic profile ¯ Rationale forthe developmentof greater use-effectiveness reduced side-effects dependence on healthcare provider → 7 years] 05_STAG_DRep_March 2006 /3 Schematic representation ofexpectedPKprofiles of progestogens and indifferentformulations administered bydifferent routes 05_STAG_DRep_March 2006 /4 Long Long Transdermal systems Vaginal rings Implants Injectables - - acting methods acting methods 05_STAG_DRep_March 2006 /5 Injectable Injectable Once-a-month: progestogen-estrogen Two-to-three monthly: contraceptive preparations contraceptive preparations combinations progestogen-only 05_STAG_DRep_March 2006 /6 Mechanism ofaction: Norethisterone enanthate Depot-medroxyprogesterone acetate(DMPA) – – Two Two ovulation inhibition function and cervicalmucus additional effectsonendometrium, tubal - - to to - - three monthlyinjectables three monthlyinjectables (NET-EN) 05_STAG_DRep_March 2006 /7 only injectable Offer towomenan alternativetoprogestogen- of combined of combined a moreregular vaginalbleeding pattern: ► discontinuation: faster return tobaselinefertility upon ► Rationale forthe development Rationale forthe development through improved pharmacokinetic profile by adding anestrogen contraceptives, which ensures: injectable injectable contraceptives contraceptives 05_STAG_DRep_March 2006 /8 Idealized pharmacokinetic/ Idealized pharmacokinetic/ monthly monthly profile ofatypical combined profile ofatypical combined Adapted from: F injectable injectable r aser and Diczfalusy, 1980 contraceptive contraceptive pharmacodynamic pharmacodynamic 05_STAG_DRep_March 2006 /9

Mego-E injectable No1 Chin Norigynon Mesigyna Lunel Cyclofem Topase Perlut Trade n Once Once ese le al l

- - a a a me Main preparations currently available Main preparations currently available - - month combined month combined E c acetophenide 150mg+ Dihydroxypr 17 Megestr 17 E NET-E E DMPA 2 E Com a 2 2 2 2 valerate5mg valerate5mg cypionate5mg enant pr β α E - o h a 2 yd p 3. N te 250 o r osit 5 50 h o 5 mg l a mg+ ate 10m xyprogesterone c o mg + etate 25 mg+ mg gesterone ion

+ injectable injectable g

7 A Lat Indonesia, Thailand 22 c.,LatinAmerica, Sp Lat Chin Chin Avail contraceptives contraceptives ain i i f n A n A rican a a

m m a bili eri eri c. , c c Chin a a ty , ,

Turkey

a , 05_STAG_DRep_March 2006 /10 administration of variousmonthlyinjectables administration of variousmonthlyinjectables E DM E DM DMPA Form E DM 2 2 2 Cy Cy Cy Percentage of Percentage of PA PA PA u p p p l a

t i on Dose

12.5 2.5 12.5 5 (mg) 5 25 25 3 ovulatory ovulatory r d treatm mo 42 100 0 0 0 nth ent 1 From: s t follow mont cycles after cycles after 60 60 24 G a h rza-Flores, - up 2 n 1991 d f 90 100 71 48 month o llow-up 05_STAG_DRep_March 2006 /11 and DMPA.Cumulative lifetablediscontinuationrates Total discontinuations Other medical reasons6.3 Non Lost tofollow up Amenorrhoea Pregnancy Bleeding Event Woman Other medical reasons6.3 Total discontinuations Non Lost tofollow up and DMPA.Cumulative lifetablediscontinuationrates Amenorrhoea Pregnancy Bleeding Woman Event WHO phaseIIIclinical trialsof WHO phaseIIIclinical trialsof - - medical reasons medical reasons - - - - months months related reasons6.3 related reasons6.3 per 100womenat12 months per 100womenat12 months Cyclofem 10 969 Cyclofem 10 969 35.5 11.4 35.5 11.4 15.1 15.1 2.1 0 2.1 0 10 608 10 608 Mesigyna Mesigyna 36.8 10.5 16.6 36.8 10.5 16.6 Cyclofem Cyclofem 6.6 1.6 0.2 7.5 6.6 1.6 0.2 7.5 From :WHO, 1986,1988 , , Mesigyna Mesigyna 5 429 5 429 DMPA DMPA 41.2 12.5 10.1 15.5 41.2 12.5 10.1 15.5 8.6 4.3 0 8.6 4.3 0 05_STAG_DRep_March 2006 /12 Proportions (%) ofwomenexperiencing Proportions (%) ofwomenexperiencing DM Mesi C Un Group (n) y cl treat different types ofbleedingpatterns. different types ofbleedingpatterns. P o g A f y

em n e a d Months 6 Months 6

766 3 893 311 802 r A r m hoea 1. 1. 1. 37. eno- 0 3 3 1

- - blee Infr 9 ofaoneyear diary 9 ofaoneyear diary e 2. 2. 5. 24. ding q ue 8 From: Fraser,1994; Sanget 9 8 4 nt ble Fr e e q 4. 8. 0. 2. ding ue 9 3 1 8 nt

ble Irr e 5. e 27. 24. 25. gular ding al, 1995;Coutinho 7 8 4 4

ble Pr olonged e 9. 9. 17. 12. ding 3 6 9 4

et al,1997

63. pa R 90. 61. e

6. tte gular

4 3 1 3 r n

05_STAG_DRep_March 2006 /13 Mechanisms ofprogestin Mechanisms ofprogestin dilated surfacevessels. α increased microvascular deposition Abnormal epithelium withreduced cytokeratin mast cells Infiltration, proliferation andactivationofleukocytes Abnormal angiogenesis cellular matrix. cytokines and proteases(MMPs), degradationofextra- -actin, deficientmicrovascular endometrial bleeding endometrial bleeding → → e less likely tocontain micro-hemorrhages. xpression and activationofgrowth factors, → density, reducedsmooth muscle neovascular b asement membrane, f ormations, - - induced induced formation or 05_STAG_DRep_March 2006 /14

Woman-months 20,550 Hy Decreased libido Headache Dizziness 1.2 Fatigue 0.9 Anxiet Weight gain Abdominal discomfort 12 12 multicentre trialsof DMPA,NET multicentre trialsof DMPA,NET pertension 0.5 - - months life months life y / depression 0.7 s 2.3 T O A L - - table d/cratesformedical reasonsin table d/cratesformedical reasonsin DMPA NET-EN 0.9 2.1 1.1 8 .7 - - EN and EN and 10,361 0.9 0.7 9.3 1.6 2.0 0.9 0.6 1.6 0.6 Cyclofem Cyclofem Cy 10,969 clofem 0.3 1.2 1.2 6.3 0.8 0.4 1.5 0.1 -

CDA_contr_ methds.__Feb/15 Metabolic effects ofDMPAandNET Metabolic effects ofDMPAandNET Moderate unfavourablelipid changes. Delayed returnoffertili No measurable effectonbreast No quantitative Moderate unfavourablelipid changes. Delayed returnoffertili No measurable effectonbreast No quantitative Small degreeofinsulinresistance (growth, hypothalamic Small degreeofinsulinresistance some changes in (growth, hypothalamic some changes in stroke, VTEorAMIinhealthy womenBUT In epidemiologicalstudi risk ofstrokeinthosewith hypertension stroke, VTEorAMIinhealthy womenBUT In epidemiologicalstudi risk ofstrokeinthosewith hypertension effectonmil effectonmil mil mil k k composition composition - - ty ty pi pi es: noincreasedriskof es: noincreasedriskof tuitar after use discontinuation tuitar after use discontinuation k k production, production, y y - - fed infants fed infants gonadal gonadal axis) axis) increased increased - - EN EN 05_STAG_DRep_March 2006 /16 after d/c Delay inthe return to fertilityduring 3 months No studies ontheireffect onlactation No significant changeinglucose metabolism promptly atdiscontinuation Minor hemostatic discontinuation Minor lipidchanges, whichrevertpromptlyat of of Cyclofem Cyclofem Metabolic effects Metabolic effects c hanges, whichrevert and and Mesigyna Mesigyna after prolonged useofdifferentmethods

05_STAG_DRep_March 2006 /17 after prolonged useofdifferentmethods

Method OC IUD DM Cyclofem Return ofovulation andfertility Return ofovulation andfertility PA

437 125 796 70 n Median timeto con (months) c 3.0 4.5 5.5 5.5 ep ti on con at one Cumu c ept 84.9 75.8 76.2 82.9 year (%)

i lative on ra te 05_STAG_DRep_March 2006 /18 among thestudy groups. could bedue todifferential STI exposure ratios of 4.3 and1.6,respectively) butthis chlamydial infectionwith DMPA use(hazard Two studies foundanincreased riskof trichomoniasis, syphilis, herpesorHPV. No increasedrisk ofinfectionwithgonorrhoea, studies 5 cross-sectional studiesand3prospective DMPA useand riskof DMPA useand riskof STIs STIs 05_STAG_DRep_March 2006 /19 DMPA use DMPA use studies giveinconsistent results 4 c ohort studiesand 14cross-sectional – – 3 findapositive association 15 findno association and and HIV acquisition HIV acquisition : 05_STAG_DRep_March 2006 /20 re. apossible association between Three studiesgave inconsistentresults disease progression (onestudy) No evidencethat DMPAuseaffectsHIV between DMPA and anti-retroviral drugs Few data onpossibleinteraction DMPA use andHIVHSV shedding DMPA DMPA used used by HIV+ by HIV+ women women 05_STAG_DRep_March 2006 /21 Delavirdine Efavirenz Nevirapine Non-nucleoside reversetranscriptaseinhibitors Saquinavir Indinavir Amprenavir Atazanavir Lopinavir/ritonavir Ritonavir Nelfinavir Protease inhibitors ARV Pharmacokinetic COC Pharmacokinetic COC drug interactions drug interactions Contraceptive steroidlevels ?

† No data

† † †

- - ARV ARV ARV levels No data No change No change No change No data † No data No data No data No data 05_STAG_DRep_March 2006 /22 Few data onthe peri-menopause. risks. the impact onadultbonemass andlong-term mass accumulation. Current researchfocuses on In adolescents, slowdownof thenormalbone apparent long-term effect. reversible upondiscontinuation andwithoutany not fullycompensated byboneformation, of bonemetabolism withboneresorptionthatis Between theages of 25and45,slightacceleration DMPA andbone metabolism DMPA andbone metabolism CDA_contr_ methds.__Feb/23

BMD (g/cm2) Changes inbonemineral densityamong182DMPA 0. 0. 0. 1. 1. 1. 1. 1. 98 02 04 06 08 94 96 1 1 users and258non-users, 18-39yearsold 0 DMPA Non- 1 Month ofFoll 2 1 82 Spine use r ow 43 -up DMPA disconti 0 3 6 n ued 0. 0. 0. 0. 0. 0. 0. 0. 98 84 86 88 92 94 96 9 0 DMPA currentuser 6 M Source: Scholes onth ofFoll 12 Total Hip 18 ow 24 -up e t al,2002 30 36 CDA_contr_ methds.__Feb/24 First registeredfor thisindicationin1967 Administration (USFDA) in1982 Approved by the USFood and Drug Currently usedbyover10 million women including 10ECcountries andtheUSA Currently registered inover70countries, worldwide Administration (USFDA) in1982 Approved by the USFood and Drug Currently usedbyover10 million women including 10ECcountries andtheUSA Currently registered inover70countries, First registeredfor thisindicationin1967 worldwide DMPA DMPA DMPA 05_STAG_DRep_March 2006 /25 Cervix Breast Liver Ovar Endometrium Cancer Site Numb Relative risksof 5 Relative risksof 5 y

who haveeverused DMPA who haveeverused DMPA WHO Collaborative Study WHO Collaborative Study Cases * Controls matchedwithcases byage 869 122 224

2,009 57 er of Subj Controls* neoplasms neoplasms 9,583 1,781 11,890

939 290 ect s

, centreand yearof Adj 1.21 0.21 1.07 1.1 1.0 u ste in women in women (95 d Relativ % (0.96-1.29) (0.96-1.52) (0.06-0.79) entry into study CI) (0.6-1.8) (0.4-2.8) e Risk CDA_contr_ methds.__Feb/26 1,768 cases and13,905controls DMPA usedby 14.1%cases and 14.2%controls Setting: NewZealand (entirecountry) DMPA usedby 14.1%cases and 14.2%controls 1,768 cases and13,905controls Setting: NewZealand (entirecountry) DMPA andBreast Cancer(1) DMPA andBreast Cancer(1) Thailand (3centres) Thailand (3centres) Mexico (1 centre) Kenya (1centre) Mexico (1 centre) Kenya (1centre) CDA_contr_ methds.__Feb/27 Maximum increase inriskattributable toDMPA: previously not increased inwomenwhobegan use>5years Risk didnotincrease withdurationofuseandwas exposure, inwomen < 35yearsatdiagnosis;smalln Risk increasedduring first4yearsafterinitial RR (95%CI)ineverusers ofDMPA=1.1(0.97- DMPA andBreast Cancer(2) DMPA andBreast Cancer(2) 3.2 - 4 .5 cases per100 000women-years 1 .4) 05_STAG_DRep_March 2006 /28 > 60 25- 13- 1-12 0 782 of use Mo DMPA andInvasive DMPA andInvasive 60 24 nth s

WHO Collaborative Study WHO Collaborative Study

Cervical Cancer Cervical Cancer Cases Num 58 26 17 50 b er o f Subj Controls

5,184 Squamous Squamous 216

127 ect 86 92 s

Relativ 1.4 (0.9 –2 1.2 (0.7–2.0) 0.6 (0.4–1.1) 1.4 (1.0 (95 Cell Cell 1.0 % e CI) - 2.0) Risk .

2) CDA_contr_ methds.__Feb/29 DMPA andCervical Carcinoma DMPA andCervical Carcinoma Pap smear frequency age, number ofpregnancies, useofOC, RR (CI95%) =1.43(1.22 used DMPA 23.3% casesand15.4% controlshadever 1,217 casesand8,956 controls Setting: Mexico,Thailand Pap smear frequency age, number ofpregnancies, useofOC, RR (CI95%) =1.43(1.22 used DMPA 23.3% casesand15.4% controlshadever 1,217 casesand8,956 controls Setting: Mexico,Thailand - - 1.67) adjusted for 1.67) adjusted for in situ in situ (1) (1) CDA_contr_ methds.__Feb/30 The riskincreased with durationofusebutdecreased cervical CA the findings suggestthatifDMPA increasesthe riskof invasive cervicalcancer andDMPAinthissamestudy, Since norelationship wasestablishedbetween with timesincefirst andlastuse. cervical CA the findings suggestthatifDMPA increasesthe riskof invasive cervicalcancer andDMPAinthissamestudy, Since norelationship wasestablishedbetween with timesincefirst andlastuse. The riskincreased with durationofusebutdecreased DMPA andCervical Carcinoma DMPA andCervical Carcinoma - - - - this isareversible effect,or cervical lesions induced byDMPA donot this isareversible effect,or cervical lesions induced byDMPA donot progress toinvasive disease progress toinvasive disease in situ in situ : : in situ in situ (2) (2) CDA_contr_ methds.__Feb/31 Implantable contraceptives Implantable contraceptives 05_STAG_DRep_March 2006 /32 and Jadelle *Sino-implants Domestic No.IandIInot shownaregeneric versionsof Implantable contraceptives forwomen Progestin Levonorgestrel Etonogestrel Levonorgestrel respectively, availablein China. T Implanon Jadelle Norplant radename * * Single rod Two rods Six capsules Units Duration From: Croxatto 3 y 5 y 7 y of action Norplant 2001 05_STAG_DRep_March 2006 /33

34 mm Norplant 2.4 mm crystals 36 mg free Silastic medical Silastic tubing adhesive LNg in copolymer embedded crystals 75 mg 2.4 mm Jadelle From: Croxatto

2001 43 mm 05_STAG_DRep_March 2006 /34 Serum leveloflevonorgestrel

serum LNG ng/mL 0.1 0.2 0.3 0.4 0 using Norplant for 8years 0 O 1 OO 2 3 Years O 4 O 567 O O i O n women 8 From: Diaz etal1987 05_STAG_DRep_March 2006 /35 Serum LNG pg/mL Serum levelsof levonorgestrel 200 400 600 800 0 Contraceptive threshold Weeks { O 23 { using Norplant or Jadelle O { O 4 Duration oftreatment { O 12 { O { O 34 { O { O 56 M onths { O 78 { O { O 9 JADELLE NORPLANT in women 10 From : Croxatto 11 { 12 O et al1991 05_STAG_DRep_March 2006 /36 Efficacy Mechanism ofaction cervical mucusthickening luteal mostly ovulationinhibition 7 year cumulative pregnancy rate: 1.9per 100 - highest rates inwomen<25 y/oor>70kg 5 yearcumulative pregnancy rate:1.1per100 For Norplant : phase abnormalities Norplant and Norplant and : : Jadelle Jadelle 05_STAG_DRep_March 2006 /37 Cumulative gross pregnancyratesper100 Cumulative gross pregnancyratesper100 60-6 50-5 < 50 > 70 Weight Norplant Norplant

9 k 9 k kg kg g g

R R users through5 years users through5 years Rate SE 0.2 5.0 3.4 8.5 2.3 From Population Council,1990 0.2 1.4 0.9

Discontinuation resulting fromadverseexperiences: Discontinuation resulting fromadverseexperiences: 05_STAG_DRep_March 2006 /38 Total discontinuatio Total adverse Ot Menst

Gross annualrate per100 her medical Gross annualrate per100 rual

n

15.1 19.0 22.6 6.0 9.1 1 2

13.5 5.6 7.9

Norplant Norplant 20.8 Year 4. 9. 4. 3

0 1 9 R From Sivin, 1990 R 23.3 3.3 7.3 4.0 4 users

users 22.4 2.9 8.0 5.1 5

05_STAG_DRep_March 2006 /39 No. of Women- Amenorrh Irregular 66.3 Regular Bleeding patterns (%)of Bleeding patterns (%)of most frequentcategory foreachyear most frequentcategory foreachyear w during 5yearsof use,assignedto during 5yearsof use,assignedto o y e men ea ars

198.0 7.1 26.6 215 1 2

127.9 40.0 54.7 138 5.3

Adapted from Shoupe Norplant 101.9 Norplant 39.9 53.5 Year 115 6.6 3

6 28.1 66. 5.1 77 4

8 8 .8 R R

et al.,1991 users users 34 37.5 62. 46 0 5

5 .9

05_STAG_DRep_March 2006 /40 Adverse effects withNorplantuse Adverse effects withNorplantuse (other thanmenstrual disorders) (other thanmenstrual disorders)

Acne Weight gain Headache Mood ch Dizzines Hair loss Symptom s anges / hirsutism % 4-11 1-9 10 -30 3-22 4-22 2-5 users 05_STAG_DRep_March 2006 /41 - - - Vaginal bleedingpatterns: exposure (women> 70kg wereexcluded) No pregnanciesobserved in5629yearsof More consistentovulation inhibition EVA rodreleasingetonogestrel 1 3 30% infrequent bleeding 0-20% prolonged bleeding 0-40% amenorrhea throughout 3years Implanon Implanon 05_STAG_DRep_March 2006 /42 Metabolic effects ofimplants (Norplant, Metabolic effects ofimplants (Norplant, changes Clotting andfibrinolytic resistance insome users Carbohydrate metabolism: mildinsulin Lipid effects:small or none. women, within normalrange Liver function: elevatedbilirubin insome Note: No studies inwomen atrisk Predictive value questionable Jadelle Jadelle systems: minor , , Implanon Implanon ) ) 05_STAG_DRep_March 2006 /43 No effecton: Potential beneficial effects: bone density decreased riskofpelvic inflammatory decreased riskofectopic pregnancy connective tissue disorders recovery offertility ovarian cyst enlargement anaemia disease andlower genital tractinfection Safety ofNorplant (1) Safety ofNorplant (1) 05_STAG_DRep_March 2006 /44 No studies largeenoughtoassess effecton: evaluation: Potential adverseeffects thatneedfurther hormonal side-effects increased riskofgallbladder disease increased riskofhypertension diabetes HIV/AIDS cancer cardio-vascular disease Safety ofNorplant (2) Safety ofNorplant (2) 05_STAG_DRep_March 2006 /45 Contraceptive implantsandlactation Contraceptive implantsandlactation Breast-feeding women usingNorplant: - Infants breast-fed bywomenusing NorplantorImplanon: - - - - - e n nursing users n w a a year (?) eye infections and skinconditions during thefirst xperience longerperiods ofamenorrhea fter weaning,bleeding patternsameasinnon- o effecton infant growthanddevelopment o effectonbonemetabolism bsorb about 100ng/dayofprogestogen ith Norplant: slight ↑ in mildrespiratory diseases, 05_STAG_DRep_March 2006 /46 complications during thefirstyearofNorplantuse complications during thefirstyearofNorplantuse

LOC EXPLUSION INFEC % 2674 womenin19 centresin7countries 2674 womenin19 centresin7countries Percentage ofwomen withinsertionsite Percentage ofwomen withinsertionsite A -Pain -Other -Rashing -Itching L R T ION E A

C TION

All Centres 0.3 0.3 1.9 2.2 4.7 0.4 0.8

%

From: Kl Individual Centres avon 0 0 –3.0 0 –3.0 and Grubb, 1990 – R a 18.0

n g e

05_STAG_DRep_March 2006 /47 Occurences Occurences

Percentage of total occurrences 10 20 30 40 50 60 70 0 3-month days (61-136),6-month (days * Follow-up intervalandthe N=17 Expulsion, byFollow Expulsion, byFollow 1 - m o n of InsertionSiteInfection andImplant of InsertionSiteInfection andImplant 5 t h inclusive days post-inserti Follow-up interval 4 3 Inf -m o e n 5 c t 137-273), and12-mo h t ion E x - - puls on were:1-mon 2 6 up Interval up Interval -m o From: Klavon n ion nth (days 274-456). 2 th th (days1-60), and Grubb, 1990 1 3 2 -m o n 2 t h CDA_contr_ methds.__Feb/48 Specific requirements - - - - Positive attributes Specific requirements - - - - Positive attributes adaptation ofhealth services; planning ofremovals long durationofaction; noactio near provider training forcarefulinsertion andremoval, for adaptation ofhealth services; planning ofremovals long durationofaction; noactio near provider training forcarefulinsertion andremoval, for heavier women metabolic changes,good reversibilitybutreducedefficacyin careful counselling heavier women metabolic changes,good reversibilitybutreducedefficacyin careful counselling Lessons learnt fromNorplantas Lessons learnt fromNorplantas - - zero orderreleaseofminimal doserequired:minimal zero orderreleaseofminimal doserequired:minimal a deliverysystem a deliverysystem n requiredfromuserfor 5y. n requiredfromuserfor 5y. CDA_contr_ methds.__Feb/49 Controversies Controversies Lessons learnt fromNorplant class actionsuits inthe USA and theUK misuse by judiciarysystemand politicians payment for earlyremoval financing, includingfreeinsertion and coercive usebyproviders/target national familyplanning programmes class actionsuits inthe USA and theUK misuse by judiciarysystemand politicians payment for earlyremoval financing, includingfreeinsertion and coercive usebyproviders/target national familyplanning programmes as adeliverysystem - - driven driven CDA_contr_ methds.__Feb/50 Contraceptive vaginalrings Contraceptive vaginalrings 05_STAG_DRep_March 2006 /51 Contraceptive vaginal rings Placing/removing t he vaginal ring CDA_contr_ methds.__Feb/52 releasing releasing estrogen (continuous useover3 progesterone (3 weeksin/1weekout) + progestogen months) CONTRACEPTIVE VAGINALRINGS PROGERING NUVARING 05_STAG_DRep_March 2006 /53 1 1 200 600 400 800 Serum concentration Serum concentration (120 (120 0 0 1 3 µ µ g/day etonogestrel+ 15 g/day etonogestrel+ 15 E 5 t on oge 7 s N t r o e 9 l ( r m NUVARING p NUVARING 11 a g l / us m N l u ) 13 e m b e 1 r of 5 da 17 y s a 19 f t e r 21 day 2

ins 1 e 2 r s t 3 - - ion time curves time curves 2 5 E E x 2 t t e 7 h µ µ in nde y Timmer g/day EE) g/day EE) 2 l e 9 d us s t r adio 31 e

l

( & Mulders, 2000. 33 pg/ m 35 l ) 0 10 20 30 05_STAG_DRep_March 2006 /54 Maximum estradiol concentrationandfollicular Maximum estradiol concentrationandfollicular diameter duringnormal andextendeduse diameter duringnormal andextendeduse

Serum estradiol (pmol/l) 200 100 150 50 0 -7 0 F o l lic u NUVARING NUVARING l 7 ar N diam o rm al T u et i s m er e e 1 ( 4 d ay s) 2 1 Se Source: Mulders ru m E E x 2 t ende 28 d us e

35 &

Dieben, 2001 10 0 2 4 6 8

Follicular diameter (mm) 05_STAG_DRep_March 2006 /55 NUVARING NUVARING Breakthrough bleeding/spotting in5.5%ofallcycles. removal) in98.5%cycles, lasting4-5days. Withdrawal bleedingwhen expected(2-4daysafterring 1.18 withactualusein clinicaltrialsetting Pearl indexof0.77(CI: 0.37-1.41)withperfectuse, Minimal effectson lipid,CHO andhemostatic one yearof use. No adverse effectoncervicalorvaginal cytologyduring expulsion): 4.4 % Device-related events(foreignbody sensation,coitalpb, Complaints ofhormonal side-effects:3-6% - - Phase III Phase III clinical clinical variables. trials trials 05_STAG_DRep_March 2006 /56 groups breast-feeding andinfant growthsimilarinboth one yearfollow-up:no pregnancyineithergroup nursing women 285 ringusersvs because ofdiscomfort orring expulsion some early discontinuationsamong ringusers users vs mean duration oramenorrhea:12 monthsinring (15 (15 → → 5 mg/dayprogesterone, over3months) 5 mg/dayprogesterone, over3months) 6 monthsin IUDusers Pre Pre PROGERING PROGERING - - registration study registration study 262 CuT380AIUDusers, all 05_STAG_DRep_March 2006 /57 Transdermal Transdermal systems systems 05_STAG_DRep_March 2006 /58 20 cm maintained over 7 days(+2 days assafety window blood levels reachsteadystatein <48hoursandare norgestimate)+ 20 releasing 150 – – – inner, clear polyesterliner,peeled offbeforeuse contraceptive steroids middle layerthatcontains anadhesiveandthetwo outer polyethelene+polyester 2 (4.5 cmside),three-layered patch: Transdermal Transdermal µ ORTHO ORTHO g/day norelgestromin µ g/day EE - - EVRA EVRA systems systems protective layer (active metabolite of ) 05_STAG_DRep_March 2006 /59 following application ofEVRAfor7and10days Mean norelgestromin

17d-NGM Conc. (ng/mL) 0. 0. 0. 0. 1. 2 4 6 8 2 1 0 0 1 2 3 4 5 6 7 Time 8 9 10 (days) serum levels(ng/ml) 11 12 13 14 Therapeut 15 16 range 17 18 ic 19 20 05_STAG_DRep_March 2006 /60 Differences withOCin randomizedclinicaltrials: Same mechanismofaction asthecombinedOC. – – – – – patch partial orcompletedetachment needing for thisreason) application sitereaction in20%users(2.6%d/c better compliance(88% vs dysmenorrhea reason. breast discomfort (19%vs replacement patch:5% ORTHO ORTHO (14% vs - - 10%) EVRA EVRA 6%). 1%d/c forthis 77%)