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05_STAG_DRep_March 2006 /‹#›
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CDA_contr_ methds.__Feb/‹#›
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------=_NextPart_01C64DC3.13C66B50 Content-Location: file:///C:/2C09C636/Long-acting_contraceptives_Darcangues_2006_files/pres.xml Content-Transfer-Encoding: quoted-printable Content-Type: text/xml; charset="utf-8" ------=_NextPart_01C64DC3.13C66B50 Content-Location: file:///C:/2C09C636/Long-acting_contraceptives_Darcangues_2006_files/slide1084.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" Long-acting hormonal contraceptive methods for women - Catherine d’Arcangues
3D"Text
CDA_contr_ methds.__Feb/1
Long-acting hor= monal = co= ntraceptive methods
for women
Catherine d’Arcangues, Ph.D., M.D. =
Department of Reproductive Health and Research
World Health Organization
Training in Reproductive Health Research&= #13;
Geneva, 21 March 2006
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3D"Text
05_STAG_D= Rep_March 2006 /2
Rationale for the development of
long-acting methods of contraception
3D"*"Methods that do not require daily use or interfere with sexual intercourse
[Duration of action: 7 days = ® 7 years]
ŕ  greater use-effectiveness
<= ![if !ppt]>3D"*"Methods with impro= ved pharmacokinetic profile
ŕ reduc= ed side-effects
Note:=   dependence= on health care provider
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3D"Text
05_STAG_D= Rep_March 2006 /2
Schematic representation of expected PK profiles
 of progest= ogens administered by different routes
 and in dif= ferent formulations
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Long-acting hormonal contraceptive methods for women - Catherine d’Arcangues
3D"Text
05_STAG_D= Rep_March 2006 /2
Long-acting methods
3D"*"Injectables
3D"*"Implants
3D"*"Vaginal rings =
3D"*"Transdermal systems
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3D"Text
05_STAG_D= Rep_March 2006 /2
Injectable contraceptive preparations
<= span style=3D'color:#000066;mso-color-index:1'>3D"*"Two-to-three monthly: progestogen-only <= /span>
<= span style=3D'color:#000066;mso-color-index:1;visibility:hidden'>3D"*" =
3D"*"Once-a-month:  progestogen-estrogen combinations
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3D"Text
05_STAG_D= Rep_March 2006 /2
Two-to-three monthly injectables
3D"*"= Depot= -medroxyprogesterone acetate (DMPA)
3D"*"<= span lang=3DEN-GB style=3D'font-size:88%;color:#000066;mso-color-index:1'>Noret= histerone enanthate (NET-EN)
Mec= hanism of action:
ovulation inhibitio= n
= additional effects = on endometrium, tubal function and cervical mucus
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3D"Text
05_STAG_D= Rep_March 2006 /2
Rationale for the development
of combined injectable contraceptives
3D"*"a more regular vaginal bleeding pattern:&= #13;
by ad= ding an estrogen
= 3D"*"faster return to baseline fertility u= pon discontinuation:&#= 13;
throu= gh improved pharmacokinetic profile
Offer to  women an alternative to progestogen-only injectable contraceptives, which ensures:
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3D"Text
05_STAG_D= Rep_March 2006 /2
Idealized pharmacokinetic/pharmacodynamic
p= rofile of a typical combined
m= onthly injectable contraceptive
Adapted from: Fraser and Diczfalusy, 1= 980
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3D"Text
05_STAG_D= Rep_March 2006 /2
Once-a-month combined injectable contraceptives
Main preparations currently available
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05_STAG_D= Rep_March 2006 /2
Percentage of ovulatory cycles after
administration of various monthly injectables
From: Garza-Flore= s, 1991
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05_STAG_D= Rep_March 2006 /2
WHO phase III clinical trials of Cyclofem, Mesigyna
= and DMPA.  Cumulative life table discontinuation rates
p= er 100 women at 12 months
=
Event   Cyclofem      Mesigyna= DMPA
Pregnancy           0                     0.2      0
Bleeding-related reasons      6.3           7.5=    15.5
Amenorrhoea           = 2.1           1.6    12.5 =
Other medical reasons          6.3           6.6=      4.3
Non-medical reasons         15.1         16.6<= span style=3D'mso-tab-count:2;width:15.63%'>    10.1
Lost to follow up        11.4         10.5<= span style=3D'mso-tab-count:2;width:15.63%'>      8.6
Total discontinuations        35.5         36.8<= span style=3D'mso-tab-count:2;width:15.63%'>    41.2
= Woman-months   10 969    10 608 5 429
=
From : WHO, 1986,1988
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3D"Text
05_STAG_D= Rep_March 2006 /2
Pro= portions (%) of women experiencing
different types of bleed= ing patterns.
Months 6-9 of a one year = diary
From: Fraser,1994; Sang et al, 1995; Coutinho et al, 1997<= /i>
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3D"Text
05_STAG_D= Rep_March 2006 /2
Mechanisms of progestin-induced
e= ndometrial bleeding
3D"*"Abnormal angiogene= sis ® neovascular formations, increased microvascular density, redu= ced smooth muscle a-actin, deficient microvascular basement membrane, dilated surface vessels. <= /span><= ![if !ppt]>3D"*"Infiltration, proliferation and activation of leukocytes and mast = cells ® expression and activation of growth factors, cytokines and proteases (MMPs), degra= dation of extra-cell= ular matrix. Abnor= mal epithelium with reduced cytokeratin  formation or deposition ® less likely to contain micro-hemorrhages.
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05_STAG_D= Rep_March 2006 /2
12-months life-table d/c rates for medical reasons in
 multicentre trials of DMPA, NET-EN and Cyclofem
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3D"Text
CDA_contr_ methds.__Feb/15
Metabolic effects of DMPA and NET-= EN
<= span style=3D'font-size:75%;text-shadow:auto'>= 3D"*"   Small degree of insulin resistance
<= span style=3D'font-size:63%;text-shadow:auto'>= 3D"*"   Moderate unfavourable lipid changes.
In epidemiological studies: no increased risk of =
stroke, VTE or AMI in healthy women BUT increased
<= b> risk of stroke in those with hypertension
<= span style=3D'font-size:63%;text-shadow:auto'>= 3D"*"   No quantitative effect on milk production,
     some changes in milk composition
<= span style=3D'font-size:63%;text-shadow:auto'>= 3D"*"   No measurable effect on breast-fed infants
     (growth, hypothalamic-pituitary gonadal axis)
<= span style=3D'font-size:63%;text-shadow:auto'>= 3D"*"   Delayed return of fertility= after use discontinuation     
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3D"Text
05_STAG_D= Rep_March 2006 /16
Metabo= lic effects
of Cyclofem and Mesigyna<= /b>
Minor lipid changes= , which revert promptly at discontinuation 3D"*"Minor hemostatic changes, which revert promptly at discontinuation
<= span style=3D'color:#000066;mso-color-index:1'>3D"*"No significant change in glucose metabolism
<= span style=3D'color:#000066;mso-color-index:1'>3D"*"No studies on their effect on lactation
3D"*"Delay in the return to fertility during 3 months after d/c
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3D"Text
05_STAG_D= Rep_March 2006 /16
Return of ovulation and fertility
after prolonged use of different methods
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3D"Text
05_STAG_D= Rep_March 2006 /16
DMPA use and risk of STIs
3D"*"5 cross-sectional studies and 3 prospective studies
3D"*"No increased risk of infection w= ith gonorrhoea, trichomoniasis, syphilis, herpes or HPV.
3D"*"Two studies found an increased r= isk of chlamydial infection with DMPA use (hazard ratios of 4.3 and 1.6, respectiv= ely) but this could be due to differential STI exposure among the study gro= ups.
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3D"Text
05_STAG_D= Rep_March 2006 /16
DMPA use and HIV acquisition
3D"*"4 cohort studies and 14 cross-sec= tional studies give inconsistent results:
15 find no association
3 find a positive association
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3D"Text
05_STAG_D= Rep_March 2006 /16
DMPA used by HIV+ women
=
=
= 3D"*"No evidence that DMPA use affect= s HIV disease progression= (one study)
= 3D"*"Three studies gave inconsistent results re. a possible association between DMPA use and HIV and HSV sheddin= g
= 3D"*"Few data on possible interaction= between DMPA and anti-retroviral drugs
------=_NextPart_01C64DC3.13C66B50 Content-Location: file:///C:/2C09C636/Long-acting_contraceptives_Darcangues_2006_files/master36_image029.png Content-Transfer-Encoding: base64 Content-Type: image/png iVBORw0KGgoAAAANSUhEUgAAAA8AAABYAQMAAAAQkz9GAAAAAXNSR0ICQMB9xQAAAAZQTFRFAAAA AABmAbZ9ogAAAAF0Uk5TAEDm2GYAAAAJcEhZcwAACDYAAAg0Ab6QHjwAAAAZdEVYdFNvZnR3YXJl AE1pY3Jvc29mdCBPZmZpY2V/7TVxAAAASklEQVQoz42OUQrAMAhDnxW3a/foK5a4FjpYyIckMQq/ cScHLghou17uHGYG5YfiSTS4LNMi5fY3YFpvWbgmI+k6aiqsr+LjwxMerGABZtPrA2kAAAAASUVO RK5CYIJ= ------=_NextPart_01C64DC3.13C66B50 Content-Location: file:///C:/2C09C636/Long-acting_contraceptives_Darcangues_2006_files/slide1104.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" Long-acting hormonal contraceptive methods for women - Catherine d’Arcangues
3D"Text
05_STAG_D= Rep_March 2006 /16
Pharmacokinetic COC-ARV
drug interactions
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>No data
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>?Ł
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%;color:#CC0000;mso-color-index:3'>Delavi= rdine
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>No change
<= span style=3D'font-family:"Wingdings 3";mso-ascii-font-family:Arial;mso-bidi-fo= nt-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;mso-char-type: symbol'>Ł
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;color:#CC0000; mso-color-index:3'>Efavirenz
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>No change
<= span style=3D'font-family:"Wingdings 3";mso-ascii-font-family:Arial;mso-bidi-fo= nt-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;mso-char-type: symbol'>¤ 
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;color:#CC0000; mso-color-index:3'>Nevirapine 
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%'>Non-nucleo= side reverse transcriptase inhibitors
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>No change
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>No data
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;color:#CC0000; mso-color-index:3'>Saquinavir
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>No data
<= span style=3D'font-family:"Wingdings 3";mso-ascii-font-family:Arial;mso-bidi-fo= nt-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;mso-char-type: symbol'>Ł
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;color:#CC0000; mso-color-index:3'>Indinavir
<= span style=3D'font-family:"Wingdings 3";mso-ascii-font-family:Arial;mso-bidi-fo= nt-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;mso-char-type: symbol'>¤
<= span style=3D'font-family:"Wingdings 3";mso-ascii-font-family:Arial;mso-bidi-fo= nt-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;mso-char-type: symbol'>Ł
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;color:#CC0000; mso-color-index:3'>Amprenavir
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>No data
<= span style=3D'font-family:"Wingdings 3";mso-ascii-font-family:Arial;mso-bidi-fo= nt-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;mso-char-type: symbol'>Ł
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;color:#CC0000; mso-color-index:3'>Atazanavir
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>No data
<= span style=3D'font-family:"Wingdings 3";mso-ascii-font-family:Arial;mso-bidi-fo= nt-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;mso-char-type: symbol'>¤ <= /div>
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;color:#CC0000; mso-color-index:3'>Lopinavir/ritonavir
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>No data
<= span style=3D'font-family:"Wingdings 3";mso-ascii-font-family:Arial;mso-bidi-fo= nt-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;mso-char-type: symbol'>¤ <= /div>
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;color:#CC0000; mso-color-index:3'>Ritonavir
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>No data
<= span style=3D'font-family:"Wingdings 3";mso-ascii-font-family:Arial;mso-bidi-fo= nt-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;mso-char-type: symbol'>¤
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%;color:#CC0000;mso-color-index:3'>Nelfin= avir
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%'>Protease inhibitors
<= span style=3D'font-family:"Times New Roman";mso-ascii-font-family:Arial;mso-bid= i-font-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:32%;display:none'>=
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";font-size:64%;color:#ED119E'>ARV levels
<= span style=3D'font-family:"Times New Roman";mso-ascii-font-family:Arial;mso-bid= i-font-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:43%;display:none'>=
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;color:#ED119E'= >Contraceptive steroid levels
<= span style=3D'font-family:"Times New Roman";mso-ascii-font-family:Arial;mso-bid= i-font-family: "Times New Roman";mso-hansi-font-family:Arial;font-size:32%;color:#006600; display:none'>
<= span style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bidi-font-famil= y: "Times New Roman";mso-hansi-font-family:Arial;font-size:64%;color:#006600'= >ARV
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3D"Text
05_STAG_D= Rep_March 2006 /16
DMPA and bone metabolism
= 3D"*"Between the ages o= f 25 and 45, slight acceleration of bone metabolism= with bone resorption that is not fully compensa= ted by bone formation, reversible upon discontinuation and witho= ut any apparent long-term effect.
= 3D"*"In adolescents, sl= ow down of the normal bone mass accumulation.=   Current research focuses on <= span lang=3DEN-GB style=3D'font-size:88%;color:#000066;mso-color-index:1'>the i= mpact on adult bone mass and long-term risks. =
3D"*"Few data on the peri-menopause.
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3D"Text
CDA_contr_ methds.__Feb/23
DMPA discontinued
DMPA Non-user
<= span lang=3DEN-GB style=3D'font-family:"Times New Roman";font-size:78%;color:bl= ack; mso-special-format:lastCR;display:none'>
DMPA current user
0.94
0.96
0.98
1
1.02
1.04
1.06
1.08
1.1
0
12
18
24
30
36
Spine
0.84
0.86
0.88
0.9
0.92
0.94
0.96
0.98
0
6
12
18
24
30
36
Total Hip
3D"Text
BMD (g/cm2)
Month of Follow-up
Month of Follow-up
Source: Scholes et al, 2002
<= b>Changes in bone mineral density among 182 DMPA users and 258 non-users, 18-39 years old
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3D"Text
CDA_contr_ methds.__Feb/23
D= MPA
<= span style=3D'mso-special-format:bullet;mso-bullet-image:"image004\.png";color:= #CC0000; font-size:50%'>3D"*"= First registered for this indication in 1967 =
3D"*"<= b>Currently registered in over 70 countries, <= b>including 10 EC countries and the USA
3D"*"<= b>Currently used by over 10 million women <= b> worldwide
3D"*"<= b>Approved by the US Food and Drug <= b>Administration (USFDA) in 1982
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3D"Text
05_STAG_D= Rep_March 2006 /25
Relative risks = of 5 neoplasms in women
who have ever used DMPA
WHO Collaborative Study
* Controls matched with cases by age, centre and year of entry into study
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3D"Text
CDA_contr_ methds.__Feb/26
DM= PA and Breast Cancer (1)
Setting:  New Zealand (entire country) <= /span>
               Thailand (3 centres) =
                Kenya (1 centre)
                Mexico (1 centre)
1,768 cases and 13,905 controls&#= 13;
DMPA used by 14.1% cases and 14.2% controls
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3D"Text
CDA_contr_ methds.__Feb/26
DMPA and Breast Cancer (2)
RR (95% CI) in = ever users of DMPA =3D 1.1 (0.97 - 1.4)
Ri= sk increased during first 4 years after initial ex= posure, in women < 35 years at diagnosis; small n
Ri= sk did not increase with duration of use and was not increased in women who began use > 5 years pr= eviously
Maximum increas= e in risk attributable to DMPA:
  3.2 - 4.5 cases per 100 000 women-years   =
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3D"Text
05_STAG_D= Rep_March 2006 /28
DMPA and Invasi= ve Squamous Cell
Cervical Cancer
WHO Collaborative Study
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3D"Text
CDA_contr_ methds.__Feb/29
DMPA and Cervical Ca= rcinoma in situ <= /span>(1)
Setting:  Mexico , Thailand
<= span style=3D'mso-tab-count:1;width:10.91%'> 1,217 cases and 8,956 controls
<= span style=3D'mso-tab-count:1;width:10.01%'> 23.3% cases and 15.4% contr= ols had ever
<= span style=3D'mso-tab-count:1;width:10.91%'> used DMPA
<= span style=3D'mso-tab-count:1;width:9.46%'> RR (CI 95%) =3D 1.43 (1.22 -= 1.67) adjusted for
<= span style=3D'mso-tab-count:1;width:10.49%'> age, number of pregnancies,= use of OC,
<= span style=3D'mso-tab-count:1;width:10.91%'> Pap smear frequency<= /div>
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3D"Text
CDA_contr_ methds.__Feb/29
DM= PA and Cervical Carcinoma in situ (2= )
T= he risk increased with duration of use but decreased
w= ith time since first and last use.
= Since no relationship was established between invasive cervical cancer and DMPA in this same study, the findings suggest that if DMPA increases the risk of <= span style=3D'position:absolute;top:57.75%;left:3.55%;width:95.69%;height:6.0%'= >cervical CA in situ:=
<= span style=3D'mso-spacerun:yes'>       -  this is a reversible effect, or
<= span style=3D'mso-spacerun:yes'>       -  cervical lesions induced by DMPA do not
<= span style=3D'mso-spacerun:yes'>           progress to invasive disease&= #13;
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3D"Text
CDA_contr_ methds.__Feb/29
Implantable contraceptives<= /div>
------=_NextPart_01C64DC3.13C66B50 Content-Location: file:///C:/2C09C636/Long-acting_contraceptives_Darcangues_2006_files/master37_image043.png Content-Transfer-Encoding: base64 Content-Type: image/png iVBORw0KGgoAAAANSUhEUgAAAA8AAABUAQMAAABnUf89AAAAAXNSR0ICQMB9xQAAAAZQTFRFAAAA AABmAbZ9ogAAAAF0Uk5TAEDm2GYAAAAJcEhZcwAACDYAAAg0Ab6QHjwAAAAZdEVYdFNvZnR3YXJl AE1pY3Jvc29mdCBPZmZpY2V/7TVxAAAAQ0lEQVQY052NUQoAIAhDl2Jeu6Mng0nUXw+RqVOBX4w5 gaBORuEMU3mzMGhI5mJq19WxQzeudz31411ThkFPSMdzSmyHQAEY53ufOgAAAABJRU5ErkJggk== ------=_NextPart_01C64DC3.13C66B50 Content-Location: file:///C:/2C09C636/Long-acting_contraceptives_Darcangues_2006_files/slide1115.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" Long-acting hormonal contraceptive methods for women - Catherine d’Arcangues
3D"Text
05_STAG_D= Rep_March 2006 /32
Progestin           Trade= name           Units             Duration
                                               =                                  of action
Levonorgestrel =
Levonorgestrel =
Etonogestrel=
Norplant*
Jadelle*
Implanon
Six capsules
Two rods
Single rod
7 y
5 y
3 y
*Sino-implants Domesti= c No. I and II not shown are generic versions of Norplant and Jadelle respective= ly, available in China.
From: Croxatto 2001
Implantable contraceptives for women
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3D"Text
05_STAG_D= Rep_March 2006 /32
Silastic medical&#= 13;
adhesive
Silastic tubing
LNg=
2.4= mm
3D"Text
34 mm
36 = mg
Nor= plant
   Jad= elle
75 = mg
2.4= mm
3D"Text
43 mm
free <= /div>
crystals
crystals
embedded
in copolymer
From: Croxatto 2001
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3D"Text
05_STAG_D= Rep_March 2006 /32
l
l
l
 
l
l
l
l
l
0
0.1
0.2
0.3
0.4
0
1
2
3
4
5
6
7
8
Years
 serum LNG ng/mL=
From: Diaz et al 1987
<= b>Serum level of levonorgestrel in women <= b>using Norplant for 8 years
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3D"Text
05_STAG_D= Rep_March 2006 /32
ˇ
ˇ
l
l
ˇ
1
2
3
4
5
6
Durat= ion of treatment
3D"Text
Serum LNG pg/mL
0
200
400
600
800
2
3
4
Weeks
Months
9
7
8
10
11
12
NORPLANT
JADELLE
Contraceptive threshold
ˇ
l
ˇ
ˇ
ˇ
l
l
l
l
l
ˇ
ˇ
l
l
ˇ
ˇ
l
From: Croxatto et al 1991
l
ˇ
<= b>Serum levels of levonorgestrel in women <= b>using Norplant or Jadelle
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3D"Text
05_STAG_D= Rep_March 2006 /32
Norplant and Jadelle
3D"*"Mechanism of actio= n: = ;
         mostly ovulation inhibition
         luteal phase abnormalities
         cervical mucus thickening
3D"*"Efficacy: = ;
5 year cumulative pregnancy rate: 1.1 per 100
highest rates in women < 25 y/o or > 70 kg
-<= span style=3D'mso-spacerun:yes'>  For Norplant: = ;
7 year cumulative pregnancy rate: 1.9 per 100
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3D"Text
05_STAG_D= Rep_March 2006 /32
Cumulative gross pregnancy rates per 100
NorplantR users throu= gh 5 years
From Population Council, 1990
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3D"Text
05_STAG_D= Rep_March 2006 /32
Discontinuation resulting from adverse experiences:
Gross annual rate per 100 NorplantR users
From Sivin, 1990
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05_STAG_D= Rep_March 2006 /32
Bleeding patter= ns (%) of NorplantR users
during 5 years of use, assigned to
most frequent category for each year
Adapted from Shoupe et al., 1991
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05_STAG_D= Rep_March 2006 /32
Adverse effects with Norplant use
(other than menstrual disorders)
<= span style=3D'mso-tab-count:1;width:8.12%'> Symptom % users =
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3D"Text
05_STAG_D= Rep_March 2006 /32
Implanon
<= span style=3D'font-size:81%;color:#CC0000;mso-color-index:3'><= ![if !ppt]>3D"*"EVA rod releasing etonogestrel
<= span style=3D'font-size:81%;color:#CC0000;mso-color-index:3'><= ![if !ppt]>3D"*"More consistent ovulation inhibition
<= ![if !ppt]>3D"*"No pregnancies obs= erved in 5629 years of exposure (women > 70kg were excluded)&= #13;
<= span style=3D'font-size:81%;color:#CC0000;mso-color-index:3'><= ![if !ppt]>3D"*"Vaginal bleeding patterns:
<= span lang=3DEN-GB style=3D'font-size:81%;color:#CC0000;mso-color-index:3'> -  30-40% amenorrhea throughout 3 years
<= span lang=3DEN-GB style=3D'font-size:81%;color:#CC0000;mso-color-index:3'> -  30% infrequent bleeding
<= span lang=3DEN-GB style=3D'font-size:81%;color:#CC0000;mso-color-index:3'> -  10-20% prolonged bleeding
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3D"Text
05_STAG_D= Rep_March 2006 /32
Metabolic effe= cts of implants
(Norplant, Jadelle, Implanon)
<= ![if !ppt]>3D"*"Lipid effects: sma= ll or none.
<= ![if !ppt]>3D"*"Carbohydrate metab= olism: mild insulin resistance in some users <= ![if !ppt]>3D"*"Clotting and fibrinolytic systems: minor changes <= ![if !ppt]>3D"*"Liver function: el= evated bilirubin in some women, within normal range
Note:  Predictive value questionable
No studies in women at risk=
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3D"Text
05_STAG_D= Rep_March 2006 /32
Safety of Norplant (1)
<= span style=3D'font-size:88%;color:#000066;mso-color-index:1'><= ![if !ppt]>3D"*"Potential benefici= al effects:
decreased risk of ectopic pregnancy
decreased risk of pelvic inflammatory
     disease and lower genital tract infection
<= span style=3D'font-size:88%;color:#000066;mso-color-index:1'><= ![if !ppt]>3D"*"No effect on: =
bone density
anaemia
ovarian cyst enlargement= 3;
recovery of fertility <= /span>
connective tissue disorders=
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3D"Text
05_STAG_D= Rep_March 2006 /32
Safety of Norplant (2)
3D"*"Potential adverse effects that need further evaluation:
increased risk of hypertension
increased risk of gallbladd= er disease
hormonal side-effects <= /span>
<= span style=3D'font-size:81%;color:#000066;mso-color-index:1'><= ![if !ppt]>3D"*"No studies large e= nough to assess effect on:
cardio-vascular disease = ;
cancer
HIV/AIDS
diabetes
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3D"Text
05_STAG_D= Rep_March 2006 /32
Contraceptive implants and lactation
<= span style=3D'font-size:75%;color:#000066;mso-color-index:1'><= ![if !ppt]>3D"*"Breast-feeding wom= en using Norplant:
- experience longer periods of amenorrhea - after weaning, bleeding pattern same as in non- nursing users
- no effect on bone metabolism
<= span style=3D'font-size:75%;color:#000066;mso-color-index:1'>3D"*"Infants breast-fed= by women using Norplant or Implanon:
- absorb about 100 ng/day of progestogen
- no effect on infant growth and development =
- with Norplant: slight ­ in mild respiratory diseases, eye infections and skin cond= itions during the first year (?)
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3D"Text
05_STAG_D= Rep_March 2006 /32
Percentage of w= omen with insertion site
complications during the first year of Norplant use<= /b>
2674 women in 19 centres in 7 countries
From:  Klavon and Grubb, 1990
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3D"Text
05_STAG_D= Rep_March 2006 /32
From: Klavon and Grubb, 1990
* Fol= low-up interval and the inclusive days post-insertion were: 1-month (days 1-60),&= #13;
3-mon= th days (61-136), 6-month (days 137-273), and 12-month (days 274-456).
Occurences of Insertion Site Infection and Implant Expulsion, by Follow-up Interval
2
3
2
2
4
5
5
N=3D17
Follow-up interval
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3D"Text
CDA_contr_ methds.__Feb/48
= Lessons learnt from Norplant as a delivery s= ystem
Positive attributes
- long duration of action; no action required from user for 5 y.
- near-zero order release of minimal d= ose required: minimal metabolic changes, go= od reversibility but reduced efficacy in heavier women
Specific requirements
- provider training= for careful insertion and removal, and for careful counselling
- adaptation of health services; planning of removals
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3D"Text
CDA_contr_ methds.__Feb/48
Lessons learnt from Norplant
as a delivery system=
Controversies
<= span style=3D'mso-special-format:bullet;mso-bullet-image:"image004\.png";color:= #CC0000; font-size:50%'>3D"*"= coercive use by providers/target-driven national family planning programmes
<= span style=3D'mso-special-format:bullet;mso-bullet-image:"image004\.png";color:= #CC0000; font-size:50%'>3D"*"<= span lang=3DEN-GB style=3D'font-size:88%;text-shadow:auto;color:#000066;mso-col= or-index: 1'>financing, including free insertion and payment for early removal
3D"*"m= isuse by judiciary system and politicians
3D"*"c= lass action suits in the USA and the UK = ;
3D"*"=
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3D"Text
CDA_contr_ methds.__Feb/48
Contraceptive vaginal rings=
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3D"Text
05_STAG_D= Rep_March 2006 /51
Placing/removing the vaginal ring
Contraceptive vaginal rings
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3D"Text
CDA_contr_ methds.__Feb/52
3D"*"=    <= /span>relea= sing estrogen                     + progestogen         (3 weeks in/1 week out)
        NUVARING
3D"*"=    <= /span>relea= sing                progesterone (continuous use over 3
 months)                  
   PROGERING
CONTRACEPTIVE  VAGINAL RINGS
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05_STAG_D= Rep_March 2006 /53
NUVARING
(120 mg/= day etonogestrel + 15 mg/= day EE)
Serum concentration-time curves
<= span lang=3DFR style=3D'font-family:"Times New Roman";font-size:78%;mso-special= -format: lastCR;display:none'>
Timmer & Mulders, 2000.
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05_STAG_D= Rep_March 2006 /53
NUVARING
 Maximum estrad= iol concentration and follicular
diameter during normal and extended use
Source: Mulders & Dieben, 2001
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3D"Text
05_STAG_D= Rep_March 2006 /53
NUVARING - Phase III clinical trials
<= span style=3D'font-size:75%;color:#000066;mso-color-index:1'><= ![if !ppt]>3D"*"Pearl index of 0.7= 7 (CI: 0.37-1.41) with perfect use,
1.18 with actual use in clin= ical trial setting 
<= ![if !ppt]>3D"*"Withdrawal bleedin= g when expected (2-4 days after ring removal) in 98.5 % cycles, lasting 4-5 days.
<= span style=3D'font-size:75%;color:#000066;mso-color-index:1'><= ![if !ppt]>3D"*"Breakthrough bleeding/spotting in 5.5 % of all cycles.
<= span style=3D'font-size:75%;color:#000066;mso-color-index:1'><= ![if !ppt]>3D"*"Complaints of horm= onal side-effects: 3-6 %
<= ![if !ppt]>3D"*"Device-related eve= nts (foreign body sensation, coital pb, expulsion): 4.4 %&= #13;<= ![if !ppt]>3D"*"No adverse effect = on cervical or vaginal cytology during one year of use.&#= 13;
<= span style=3D'font-size:75%;color:#000066;mso-color-index:1'><= ![if !ppt]>3D"*"Minimal effects on lipid, CHO and hemostatic variables.
3D"Text
05_STAG_D= Rep_March 2006 /53
PROGERING
 (15® 5 mg/day progesterone, over 3 months)
Pre-= registration study
3D"*"285 ring users vs = 262 CuT380A IUD users, all nursing women =
<= span style=3D'font-size:75%;color:#000066;mso-color-index:1'><= ![if !ppt]>3D"*"one year follow-up= : no pregnancy in either group
<= ![if !ppt]>3D"*"breast-feeding and infant growth similar in both groups = <= ![if !ppt]>3D"*"mean duration or amenorrhea: 12 months in ring users vs 6 months = in IUD users some = early discontinuations among ring users because of discomf= ort or ring expulsion
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3D"Text
05_STAG_D= Rep_March 2006 /53
Transdermal systems
3D"*"
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