Nelson: Contraceptive Update Contraceptive Update

Nelson: Contraceptive Update
Conflict of Interest Disclosure
Anita L. Nelson, MD
Contraceptive Update
Anita L. Nelson, MD
Grants/
Research
Barr (Duramed),
Bayer Healthcare (Berlex),
Wyeth
Honoraria/
Speakers Bureau
Barr, Bayer, Wyeth
Consultant/
Advisory Board
Barr, Bayer, Wyeth
Harbor-UCLA Medical Center
Anita L. Nelson, MD - 04/10/08 13:40
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A Diabetic Baby
Learning Objectives
At the conclusion of this presentation, the
participant will be able to:
 Counsel patients on the full array of
contraceptive choices, including mechanisms
of action, failure rates, contraindications,
potential side effects and complications, and
non-contraceptive benefits
 Suggest ways of increasing successful
patient utilization of contraceptive methods
 Describe new approaches to older
contraceptive methods
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Anita L. Nelson, MD - 04/10/08 13:40
Tiers of Contraceptive Efficacy
Longer
Term
Importance of
Contraceptive “Fit”
 Contraceptive
“fit” – the safest, most
effective birth control method that will
work well for the user
 A good fit depends upon a woman’s
Implants, IUDs, Monthly Injections
DMPA Injections
Combined
Vaginal Rings, Transdermal Patches
Hormonal
Oral Contraceptive Pills
Male Condoms
Barriers Diaphragms, Withdrawal, FAM, NFP
and
Caps, Female Condoms, Shield
Behaviors
Spermicides
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Individual health profile
 Lifestyle
 Reproductive stage


Preferences
Farrington A. Health & Sexuality. http://www.arph.org/files/H&Sndic2001.pdf
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Nelson: Contraceptive Update
Etonogestrel Contraceptive Implant


Etonogestrel Implant
Efficacy and Mechanism of Action
Single implant rod
(4 cm x 2 mm) made of
ethylene vinyl acetate
0
pregnancies in clinical trials with 58,900
cycles
 Ovulation suppression over time:
Contains 68 mg of
etonogestrel
(3-keto-desogestrel)
 1 year: 0%
1-2 years: 0%
 2-3 years: 3.1%



Effective for 3 years

6 pregnancies in 20,648 cycles

Inhibits ovulation and thickens cervical
mucus

Rapid return of fertility
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 Thickens
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Etonogestrel Implant
 Provided

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Etonogestrel Implant
Rapid Reversibility
unsurpassed contraceptive efficacy
 Etonogestrel
levels undetectable within
1 week1
 > 90% of subjects ovulated within 1 month
post removal2
By ovulation suppression and thickened
cervical mucus
 Very
cervical mucus
low levels of progestin
phase estrogen
 Follicular

 Rare
medical contraindications
 Rapid reversibility
44 of 47 women who were studied with
ultrasound and serum progesterone levels
 Bleeding
patterns better than Norplant
 Weight changes less well tolerated
Anita L. Nelson, MD - 04/10/08 13:40
1. Davies GC, et al. Contraception. 1993;47:251-261
2. Croxatto HB. Contraception. 1998;58(6):91S-97S
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Etonogestrel Implant: Bleeding Patterns
60
Subjects (%)
n=330
40
Side Effect
% of women complaining
Acne
14
Headache
13
Weight gain
10
Mastalgia
9.4
Emotional lability
5
20
0
1-3
4-6
7-9
14
Etonogestrel Implant
Most Common Adverse Side Effects
Infrequent bleeding
Amenorrhea
Prolonged bleeding
Frequent bleeding
US Data
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10-12 13-15 16-18 19-21 22-24
Months
Data on file, Organon Inc. Study Report 069001.
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Urbancsek J. Contraception. 1998;58(6 Suppl):109S-115S
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Nelson: Contraceptive Update
Etonogestrel Implant Insertion Device
WHO Medical Eligibility Criteria 2004
1. A condition for which there is no restriction for the use
of the contraceptive method.
2. A condition where the advantages of using the method
generally outweigh the theoretical or proven risks.
3. A condition where the theoretical or proven risks usually
outweigh the advantages of using the method.
CU-IUD LNG-IUS
Init Cont Init Cont
Nulliparous
2
2
Postabortal 1st trimester
1
1
Multiple risk factors for MI
1
2
Hypertension
1
2
Migraine with aura
1
2
3
Past PID – subsequent IUP
1
1
1
1
Past PID – no subsequent IUP 2
2
2
2
Increased risk of STI
2/3 2
2/3
2
HIV
2
2
2
2
Prescribing Information. 2003
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http://www.who.int/reproductive-health/publications/RHR_00_2_medical_eligibility_criteria_3rd/index.htm
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Copper T 380
Copper T 380 IUD
Net cumulative rates (%)
by year
1
2
3
4
7
10
2.3
2.7
Pregnancy
0.7 1.0
1.6 1.8
Expulsion
5.7 8.2
9.8 11.0 11.9 14.2
Bleeding/pain 11.9 21.7 28.7 32.2 41.6 50.0
Other medical 2.5 4.6
events
6.2 7.9 9.3 10.1
Prescribing Information. 2005
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IUD Issues: Infection
 Interference
and IUD use: confined to early weeks
 Farley’s reports from multinational studies:
with sperm transport from cervix
to fallopian tube
 Inhibition of sperm capacitation or survival
9/1000 cases of PID
 Infection confined to first 20 days




study of 975 women in 1996:
Viable sperm scarce in fallopian tubes of IUD
users
 Inhibition
of fertilization: no normally dividing
fertilized ova in tubes or uterus
 Not an abortifacient
No cases of PID
 U.S.
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Copper Intrauterine Devices
Mechanisms of Action
 PID
 Finnish
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studies:
“PID” rate 1/1000
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Nelson: Contraceptive Update
Copper T 380 IUD: Comparison of
Old And New FDA-Approved Labels
Condition of Ova Recovered From
Fallopian Tubes at Ovulation
Group
Control
Old Label
New Label
Recommended
Indicated
for women who for IUC
for up to
1. Have had at
10 years
least one child
2. Are in a stable,
mutually
monogamous
relationship
3. Have had no
history of PID
Uncertain Or
Normal
No
Abnormal
Develop- DevelopDevelopment
ment
ment
10
3
7
0
9
5
Lippes loop
0
3
1
TCu 200
0
2
3
Progestin IUD
0
4
1
All IUDs
Alvarez F, et al. Fertil Steril. 1988;49(5):768-73
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Previous label












New FDA-approved label
Pregnancy or suspicion of pregnancy
Distorted uterine cavity
Acute PID or history of PID

Postpartum endometritis or infected
abortion in past 3 months
Uterine or cervical cancer or
unresolved abnormal Pap smear
Genital bleeding of unknown source
Untreated acute cervicitis or vaginitis
Wilson’s disease
Allergy to copper
Patient or partner with multiple
partners
Increased susceptibility to infection
(AIDS, leukemia, etc)
Genital actinomycosis
Current IUD in place








Pregnancy or suspicion of pregnancy
Distorted uterine cavity
Acute PID or current behavior
suggesting a high risk for PID
Postpartum or postabortal
endometritis in the past 3 months
Known or suspected uterine or
cervical malignancy
Genital bleeding of unknown etiology
Mucopurulent cervicitis
Wilson’s disease
Allergy to any component
IUD
14,122
Vasectomy
13,898
Implants
13,813
Injections
13,373
Oral Contraceptives
Previously placed IUD that has not
been removed
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LNG IUS Typical Use
Failure Rates (Pearl Index)
 First
32 mm
12,879
8,933-12,239
Trussell J, et al. Am J Public Health. 1995;85:494-503
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Levonorgestrel-Releasing
Intrauterine System (LNG IUS)
year
 5-year cumulative
0.14%
0.71%
 Meta-analysis
of comparative clinical trials
showed no differences in efficacy compared
to copper IUDs with ≥ 250 mm2 copper
Steroid
reservoir
Levonorgestrel
20 mcg/day
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Birth Control Method $ Saved Over 5 Years
Barriers, Spermicides,
Withdrawal

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Estimates of Cost Savings for Various Methods
of Birth Control for a Fertile, Sexually Active
Woman Over a Five-Year Period
Contraindications: Label Comparison

Key Messages
Appropriate for
1. Nulliparous women
2. Women without a
relationship
requirement
3. Women who have
had PID in the past
but current behavior
does not make them
high risk for PID
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Anderson K, et al. Contraception. 1994;49:56
Luukkainen T, et al. Contraception. 1987;36:169
French RS, et al. Br J Obstet Gynecol. 2000;107:1218-25
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Nelson: Contraceptive Update
LNG IUS Plasma Concentrations
of Levonorgestrel
LNG IUS:
Menstrual Cycle Changes

Months 1-4: increased days of spotting and
bleeding (mean 1st month 16-17 days of spotting)

After 6 months: average 1 day bleeding per
month with some residual, unpredictable spotting

By 12 months: mean bleeding days = 0; 80% had
1-3 days of spotting; 90% reduction in blood loss
in women with menorrhagia;  hemoglobin 0.4
Amenorrhea: 20% by 12 months; 30% by 24
months; 60% by 12 years

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Menstrual blood loss (mL)
LNG IUS: Treatment for
Heavy Bleeding
400
0
300
-25
200
-50
100
-75
-100
0
3
Before
treatment
6
LNG IUS
Prostaglandin Synthetase Inhibitor
Tranexamic Acid (antifibrinolytic agent)
12
Months of use
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Milsom I, et al. Am J Obstet Gynecol. 1991;164(3):879-83
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Women Canceling
Hysterectomy
60
P ercent
“Surgery reduces menstrual bleeding at
one year more than medical treatments,
but levonorgestrel IUS appears equally
beneficial in improving quality of life and
may control bleeding as effectively as
conservative surgery over the long term”
50
40
30
20
10
0
LNG IUS
Marjoribanks, et al. Cochrane Database Syst Rev. 2003
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LNG IUS as
Alternative to Hysterectomy
Menorrhagia:
Conclusion from Trial Data
Comparing LNG-IUS to Surgery
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Menorrhagia Medical Therapy:
Bleeding Reduction with LNG-IUS
vs NSAID and Tranexamic Acid
Andersson and Rybo. Br J Obstet Gynaecol. 1990;97:690
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Medical Therapies
Lahteenmaki, et al. BMJ. 1998;316:1122-6
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Nelson: Contraceptive Update
LNG IUS Versus Hysterectomy:
Outcomes and Costs

 Dose:
150 mg every 11-13 weeks
 Highly effective with consistent and correct
use
236 women age 35-49 with menorrhagia


Depo Medroxyprogesterone
Acetate (DMPA)
Randomized to hysterectomy versus LNG-IUS
5-year follow-up

No difference in Health-related Quality Of Life

42% of LNG-IUS users underwent hysterectomy


 Typical
use first-year failure
rate: 7.4%
 Very convenient and private
 Special clinical applications
Discounted Indirect and Direct Costs
LNG-IUS
$2817 95% CI ($2222-3530)
Hysterectomy $4660 95% CI ($4014-5180)
Hurskainen R, et al. JAMA. 2004;291:1456-63
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First year : 0.25-0.3%
Five-year cumulative : 0.9%
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DMPA: Clinical Applications
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DMPA Issues

 Sickle
cell anemia
 Mental retardation
Side effects:
Menstrual irregularities tend toward
amenorrhea with time
 Slow return to fertility (10 months average
delay to conception)

 Breast
feeding
 Seizure disorders
 Concerns:
Weight gain (1-3 kg with long-term use)
 Low estrogen levels (bone density effects)


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New Developments in DMPA
 Contributions
Study
Year
Mainwaring
1995
22
None
Moore
1995
50
None
Taneepanichskul 1999
to reducing adolescent
 Weight
changes
 Other issues: diabetes, chlamydia, and
HIV susceptibility
 Quick start
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low-dose formulation
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DMPA and Weight Change:
Recent Observational Studies
pregnancy
 Labeling changes
 New
Removes incentive for condom use
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Weight Change
100
None
Danli
2000 1994
None
Pelkman
2001
20
None
Polaneczky
1996
125
+3.3±8.6 lb
Risser
1999
130
+3.0±4.5 lb
Espey
2000
306
+5 lb
Templeman
2000
133
+9.8±10.5 lb
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6
N
Mainwaring R et al. Contraception. 1995;51:149-3
Moore LL. Contraception. 1995;52:215-9
Taneepanichskul S et al. Contraception. 1999;59:301-3
Danli S et al. Contraception. 2000;62:15-8
Pelkman CL et al. Am J Clin Nutr. 2001;73:19-26
Polaneczky M et al. Fam Plan Perspect. 1996;38:174-8
Risser WL et al. J Adolesc Health. 1999;24:433-6
Espey E et al. Contraception. 2000;62:55-8
Templeman C et al. J Pediatr Adolesc Gynecol. 2000;13:45-6
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Nelson: Contraceptive Update
DMPA: 2004 Black Box Warning
Recommendations Since
Publication of Black Box Warning
Women who use Depo-Provera Contraceptive
Injection may lose significant bone mineral density.
Bone loss is greater with increasing duration of use
and may not be completely reversible.
It is unknown if use of Depo-Provera Contraceptive
Injection during adolescence or early adulthood, a
critical period of bone accretion, will reduce peak
bone mass and increase the risk for osteoporotic
fracture in later life.
Depo-Provera Contraceptive Injection should be used
as a long-term birth control method (e.g. longer than
2 years) only if other birth control methods are
inadequate.
The current evidence on DMPA use and skeletal health
indicates that concerns regarding BMD should not restrict
initiation or continuation of DMPA use in adults or teens.
 Because the clinical implications of dual energy X-ray
absorptiometry testing in premenopausal women are not
well established, DXA assessment is not recommended for
DMPA users.
 Because the safety of bisphosphonates in reproductive-age
women is not established, such medications should not be
prescribed to current or former DMPA users.
 Adequate calcium intake should be encouraged, but this
recommendation applies for all women regardless of
contraceptive use.
DMPA use and skeletal health. ACOG Today. 2005;49(10):9

FDA. 11/17/2004
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DMPA
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DMPA Administration Flow Sheet
Yes LMP  5 days? No
of action immediate if DMPA given in
first 5 days of menstrual cycle

Negative
Yes
If given after that period, must use back-up
method for at least 7 days
Offer EC
rates may be lower than
reported clinical trials due to system barriers
Unprotected IC since LMP?
No
UCG Pregnancy Test Positive
Unprotected IC  5 days?
 Continuation

Yes
Inject DMPA
 Onset
No
No DMPA
Advise that UCG not conclusive,
but DMPA should not affect fetus
No Patient desires DMPA now?
Yes
Inject DMPA
Advise use of
backup method
for 7 days
Offer barrier method for 14 days
Teens have high discontinuation rates and
stop-start pattern of use
Yes Menses < 14 days? No
Inject DMPA
Positive Repeat UCG Negative
Repeat UCG
in 2-3 weeks
if IC < 2 weeks
No DMPA
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
66
DMPA-SC: Treatment for Endometriosis Pain
DMPA-SC
 Highly
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effective contraceptive option
0 pregnancies in 20,607 woman-cycles
of exposure
Immediate suppression of ovulation
 Efficacy not affected by BMI

 Safe
and well tolerated
Similar safety profile to DMPA-IM
 Similar bleeding pattern to DMPA-IM
 Improved tolerability profile versus
DMPA-IM

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Prescribing Information. 2005
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Nelson: Contraceptive Update
DMPA Support
 Patient
Oral Contraceptive Pills
Support Toll-free Line
 Safe
1-866-554-DEPO (3376)
 24 hours/day, 7 days/week
 English or Spanish

 Health


 Failure
rate with consistent and correct use
< 1%
 Typical first year failure rate is 8%
 Rapidly reversible:
Care Provider Support Toll-free Line
1-877-HCP-DEPO (427-3376)
 Patient
and well-tested -- the gold standard:
47 years of clinical experience in US
 Best studied medication in history

Information Website
www.birthcontrolresources.com

Only 2 week average delay in fertility
 Extensive
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


Paul Brenner, M.D.
Professor, OB-GYN
USC

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Anita L. Nelson, MD - 04/10/08 13:40
based, case control study
 4,575 women with breast cancer
 4,685 control women
 Current users: RR = 1.0 (0.8-1.3)
 Former users: RR = 0.9 (0.8-1.0)
 No consistent increases with increasing
estrogen dose or duration of use
 No association with family history of
breast cancer or young initiation
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Non-Contraceptive Health Benefits
of Oral Contraceptives
 Population
Marchbanks PA, et al. N Engl J Med. 2002;346:2025-32
71
Holt fount higher failure rates in women > 154 lbs
 No consistent does relatedness
Not clear if failure related to obesity or behaviors
ACOG advises that women over the age of 35
with a BMI ≥ should not use estrogen containing
hormonal methods
British authorities prohibit use of COCs in woman
with BMI > 40
1. Holt VL, et al. Obstet Gynecol. 2005;105(1):46-52
2. Holt VL, et al. Obstet Gynecol. 2002;99(5 Pt 1):820-7
3.Obstet Gynecol. 2006;107(6):1453-72.
Oral Contraceptives and the Risk of
Breast Cancer for Women of Age 35-64
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Weight Issues and Combination
Hormonal Contraception
“Birth control pills are not
dangerous, but there are dangerous
women out there. Find them and
keep them away from the pill, and
the pill will do its work well.”
Anita L. Nelson, MD - 04/10/08 13:40
non-contraceptive benefits
Anita L. Nelson, MD - 04/10/08 13:40
Proven Reduction in Risk:
Ovarian Cancer

Cardiovascular Disease



Endometrial Cancer
Pelvic Inflammatory
Disease

Uterine Fibroids
Endometriosis

Rheumatoid Arthritis

Ectopic Pregnancy

Benign Breast Disease
Menorrhagia


Dysmenorrhea
Iron Deficiency Anemia

Low Bone Density

75
Anita L. Nelson, MD - 04/10/08 13:40
8
Possible Reduction in Risk:

Adapted from: Ory HW.
Fam Plann Perspect.
1982;14:182-4
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Nelson: Contraceptive Update
Incidence of Events Commonly
Attributable to OC Use
60
Data displayed as:
Triphasic
N (%) Norgestimate/EE
(N=228)
Headache
42 (18.4)
Nausea
29 (12.7)
Dysmenorrhea
23 (10.1)
Breast pain
21 ( 9.2)
Abdominal pain
13 ( 5.7)
Back pain
13 ( 5.7)
Vomiting
8 ( 3.5)
Breast enlargement
6 ( 2.6)
Emotional lability
6 ( 2.6)
Weight gain
5 ( 2.2)
50
Tri-NGM
40
30
Placebo
20
10
0
0
1
2
3
4
5
6
Cycle
Both groups had daily hygiene.
Cycles 2-6: P<0.0001
Redmond et al. Obstet Gynecol. 1997;89:615-22
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New Developments in OCs
 Change

 New

in placebo pills
Symptoms
Pelvic pain
Headaches
Breast
tenderness
Bloating/swelling
Use of pain
medications
start/utilization patterns
Extended/continuous use
 365
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products
pill product
Quick start protocols
 24/4 regimens

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Hormone-Withdrawal Symptoms
in OC Users
Placebo pills replaced by low-dose EE
 84/7
Placebo
(N=234) p-value
48 (20.5) 0.639
21 ( 9.0) 0.231
21 ( 9.0) 0.752
11 ( 4.7) 0.067
9 ( 3.9) 0.270
8 ( 3.4) 0.597
6 ( 2.6) 0.597
3 ( 1.3) 0.333
1 ( 0.4) 0.065
5 ( 2.1) 1.000
Redmond et al.
Contraception. 1999;60:81-5
Percent Lesion Reduction
Reduction in Total Acne Lesions
Hormone
HormoneTreatment % Free %
(21 days)
(7 days) p-value
21
70
<0.001
53
70
<0.001
19
58
<0.001
16
43
38
69
<0.001
<0.001
Sulak P, et al. Obstet Gynecol. 2000;95:261–6
79
Anita L. Nelson, MD - 04/10/08 13:40
LH/FSH: Comparing 7 and
3 or 4-day HFI
CU 06-29-08 Kaiser
80
Ovarian response for 7 versus
4 or 3-day HFI
10
90
7-day HFI
3- or 4-day HFI
Pos t hoc com p ar is o n o f cycle s
diffe r * p < 0.05 ** p < 0.01
8
M e ans for 2 cycle s in 12 s ubje cts
7-day HFI
3- or 4- day HFI
Pos t hoc com par is ons be tw e e n cycle s
* p < 0.05 ** p < 0.01
80
70
60
pg/mL
mIU/mL
6
**
4
**
**
**
50
40
**
30
**
**
**
2
*
20
**
10
**
0
OC
1
2
3
4
5
6
7
OC
OC
1
2
3
4
5
6
7
0
OC
OC
LH
1
2
3
4
5
Es tr adiol
Willis SA, et al. Contraception 2006;74(2):100-3
Anita L. Nelson, MD - 04/10/08 13:40
6
7
OC
OC
1
2
3
4
5
6
7
OC
FSH
CU 06-29-08 Kaiser
Inhibin-B
Willis SA, et al. Contraception 2006;74(2):100-3
81
Anita L. Nelson, MD - 04/10/08 13:40
9
CU 06-29-08 Kaiser
82
Nelson: Contraceptive Update
Treatment of PMDD with 24/4
drospirenone with 20 mcg EE
Baseline
Treatment
OC
Placebo
OC
Placebo
pvalue
Depression
9.7
9.7
4.0
4.6
.005
Mood swings
8.3
8.5
3.3
4.5
<.001
Symptoms
Composite Hyperkalemia Outcomes
 Ingenix study
 Cases of hyperkalemia



8.2
8.4
3.7
4.7
<.001
Overwhelmed
6.8
7.3
2.8
3.3
<.001
13.4
13.3
7.4
8.6
<.001
Physical
Yonkers KA, et al. Obstet Gynecol. 2005;106(3):492-501
CU 06-29-08 Kaiser
2.
83
0.33
0.5
1.0
2.0
3.0
4.0
CU 06-29-08 Kaiser
88
Extended OC Applications:
Control of Menstrual Cycle Timing
For Convenience
Incidence Rate Ratio –
Yasmin versus Other OCs (95% CI)
0.25
Data on file, Bayer HealthCare Pharmaceuticals, Inc.; Pharmacoepidemiology
and Drug Safety, 2006; 15: S1-S316.
Dinger JC et al. Contraception 2007; 75: 344–354.
Anita L. Nelson, MD - 04/10/08 13:40
Ingenix Study:
Similar Hyperkalemia-Related Events
0.2
study
No higher risk of arrhythmia for women
using Yasmin® compared with other
OCs2
EURAS = European Active Surveillance; OC = Oral contraceptive.
1.
Anita L. Nelson, MD - 04/10/08 13:40
Composite hyperkalemia outcomes similar1
 EURAS

Anger
1 reported case in Yasmin® users (22,429)
4 cases in the other OC users1 (44,858)
5.0
Syncope
Arrhythmia
Hyperkalemia
0
 Honeymoons
Other Electrolyte Disturbance
Dialysisa
Myocardial Infarctiona
 Business
0
0
 Travel
0
Hospitalization with Hyper/Hypokalemiaa
Death
meetings
 Sporting
0.1
 Military
campaigns
 Examinations
 Life
events
Composite Hyperkalemiab
Some outcomes may be continuations of pre-existing conditions.
a
No rate ratio calculated as no case in Yasmin cohort.
b
Composite hyperkalemia outcome comprised of chart-confirmed cases of arrhythmia, syncope,
electrolyte disturbance, hyperkalemia, and myocardial infarction.
Data on File, Bayer HealthCare Pharmaceuticals Inc.; Pharmacoepidemiology and Drug Safety, 2006; 15: S1-S316.
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
89
Anita L. Nelson, MD - 04/10/08 13:40
Extended Cycle OC Trial: Scheduled
Withdrawal Bleeding/Spotting Days
30
25
25
Median Number of
Unscheduled
Bleeding/Spotting
Days per Year
20
36
15
10
5
20
15
26
10
13
5
10
0
0
Seasonale®
Seasonale®
Nordette®
Anderson FD, et al. Contraception. 2003;68:89-96
Anita L. Nelson, MD - 04/10/08 13:40
90
Extended Cycle OC Trial:
Unscheduled Bleeding/Spotting Days
30
Median Number of
Scheduled
Withdrawal
Bleeding Days
Per Year
CU 06-29-08 Kaiser
Nordette®
Anderson FD, et al. Contraception. 2003;68:89-96
CU 06-29-08 Kaiser
91
Anita L. Nelson, MD - 04/10/08 13:40
10
CU 06-29-08 Kaiser
92
Nelson: Contraceptive Update
Extended Cycle OC Trial: Median Days
of Breakthrough Bleeding/Spotting
Cumulative Amenorrhea
with Extended OC
12
Days per Cycle
10
8
6
12
4
6
6
2
4
0
Days:
1–84
Cycle:
1
92–175
2
183–266
3
274–357
4
Data on file, Barr Research
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
Data on file, Wyeth Pharmaceuticals Inc.
93
Anita L. Nelson, MD - 04/10/08 13:40
Oral Contraceptives: Quick Start
CU 06-29-08 Kaiser
Quick Start Versus First Day Start
 With
conventional start of OCs, up to 25% of
women do not start their pills due to:
Quick First Day
(n=63)
(n=41)
Mean days bleeding and spotting1
Pregnancy
 Change in method
 Confusion about pill instructions
 Fear of possible side effects

 Quick
94
Mean # bleeding/spotting episodes1
Mean length of bleeding/spotting free1
Number of pills missed in 90 days1
start with OCs protocol
Percent
Start with first pill in pack
 Provide backup method for 7 days
 Provide EC if indicated
satisfied1
18.9
19.4
3.7
3.8
17.4
17.2
1.7
1.8
93.6
95.1
72%
56%

3 month compliance in teens
1. Westhoff CW, et al. Fertil Steril. 2003;79:322-9
2. Lara-Torre E, Schroeder B. Contraception. 2002;66:81-5
Westhoff CW, et al. Fertil Steril. 2003;79:322-9
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
95
Anita L. Nelson, MD - 04/10/08 13:40
Percentage of Pill Users, By Behavior
Related to Effective Contraceptive Use
%
98.6
98.0
88.8
61.3
41.7
19.6
13.0
CU 06-29-08 Kaiser
96
60
Diary
50
Electronic
device
40
30
60
50
40
30
20
20
10
10
0
0 1 2 >2
0 1 2 >2
1 2 >2
Cycle 3
Cycle 2
Cycle 1
Potter L, et al. Fam Plann Perspect. 1996;28:154-8
Oakley et al, Fam Plann Perspect, 1991;23(4):150-4
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
Oral Contraceptive Compliance:
Number of Active Pills Missed
Percentage of Women (%)
Behavior
Never took others’ pills
Always took pills in same order
Took all pills
Always used backup method as needed
Took pill every day
Took pill every day, always at same time
Took pill correctly every day
(n=77,116)2
97
Anita L. Nelson, MD - 04/10/08 13:40
11
0
CU 06-29-08 Kaiser
98
Nelson: Contraceptive Update
Contraceptive
Patch:
Distribution of
Pregnancies
by Baseline
Body Weight
Deciles
(n=3319 subjects)
Application of Contraceptive Patch on Abdomen
Body Weight
Weight
Total
Decile
Range (kg) Pregnancies
1
<52
1
2
52 - <55
2
3
55 - <58
0
4
58 - <60
0
5
60 - <63
2
6
63 - <66
0
7
66 - <69
1
8
69 - <74
0
9
74 - <80
2
10
>80
7
Zieman M, et al.
Fertil Steril.
2002;77(2
Suppl 2):S13-8
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
99
% Compliant Cycles
100
74.4
85.2
79.8
Day 1 to day 84
88.3
91.6
82.6
Median bleeding-spotting days
84.8
67.7
60
40
P<0.001
P<0.001
P<0.001
P<0.008
P<0.006
1
>90
5
CU 06-29-08 Kaiser
101
Extended Use of Contraceptive Patch
OC
89.3
88.3
88.2
87.7
80
1
85 - 90
Anita L. Nelson, MD - 04/10/08 13:40
Contraceptive Patch:
Compliance by Age Group
Patch
80 - 85
P<0.005
Extended Cyclic
(n=155) (n=80)
P
14
16
.407
Median bleeding-spotting
episodes
2
3
< .001
Median bleeding days
6
14
< .001
Median bleeding episodes
1
3
< .001
12
1
< .003
20
0
18-19
20-24
25-29
30-34
35-39
> 40
Age (years)
Amenorrhea (%)
Archer D, et al. Contraception. 2004;69(3):189-95
Anita L. Nelson, MD - 04/10/08 13:40
Stewart FH, et al. Obstet Gynecol. 2005 Jun;105(6):1389-96
CU 06-29-08 Kaiser
104
Anita L. Nelson, MD - 04/10/08 13:40
Contraceptive Patch: Bold Warning
CU 06-29-08 Kaiser
110
VTE Risk of Patch vs OCs
The pharmacokinetic (PK) profile for the
ORTHO EVRA® patch is different from the PK
profile for oral contraceptives in that it has
higher steady state concentrations and lower
peak concentrations. AUC and average
concentration at steady state for ethinyl
estradiol (EE) are approximately 60% higher in
women using ORTHO EVRA® compared with
women using an oral contraceptive containing
EE 35 µg. In contrast, peak concentrations for
EE are approximately 25% lower in women
using ORTHO EVRA®. FDA. 11/10/2005, 9/20/2006
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser

124 newly diagnosed, idiopathic cases of VTE

OR comparing the contraceptive patch to
norgestimate-35 EE OC was 0.9 (95% CI 0.5–1.6)

The age-adjusted VTE incidence rate ratio (IRR) for
current use of the contraceptive patch vs.
norgestimate-35 was 1.0 (95% CI 0.7–1.5)

Conclusion: Risk of nonfatal VTE for contraceptive
patch is similar to the risk for OCs containing 35
mcg ethinyl estradiol and norgestimate.
Jick S, et al. Contraception. 2007; 76(1):4-7
111
Anita L. Nelson, MD - 04/10/08 13:40
12
CU 06-29-08 Kaiser
113
Nelson: Contraceptive Update
VTE Risk of Patch vs OCs
 Second
Contraceptive Vaginal Ring
study included chart review
 Very
 OR
for current users of contraceptive patch
compared to current users of norgestimate35 EE OC was 2.2 (95% CI 1.3-3.8)
 Flexible
 Conclusion:
Increased risk of VTEs for
current users of contraceptive patch
compared to current users of OCs containing
35 mcg ethinylestradiol and norgestimate
 Transparent
 Outer
diameter: 54 mm
 Thickness: 4 mm
 One ring per cycle: 3 weeks ring-in
1 week ring-free
 Longer
follow-up for VTE, heart attack and
stroke has been requested by FDA
Cole J. Obstet Gynecol. 2007; 109(2):339-46
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
low dose
120 mcg/day etonogestrel
 15 mcg/day ethinyl estradiol

114
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
115
Contraceptive Vaginal Ring
Placement
Contraceptive Vaginal Ring
Advantages

A monthly method
 Easily inserted by the woman

Discreet
 Lowest EE dose (15 µg/day)
 Constant serum concentrations

Avoids GI interference with absorption
Avoids hepatic first-pass metabolism

Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
No incorrect way to insert
contraceptive vaginal ring
116
Anita L. Nelson, MD - 04/10/08 13:40
60
50
40
30
20
10
0
40
2000
Etonogestrel
1500
1000
Ethinyl estradiol
500
5
10
15
10.7
6.3
3.1
4.3
5.4 5
1.1
0
n=16
CU 06-29-08 Kaiser
11
10.1
4
1.9
1
Timmer & Mulders. Clin Pharmacokinet. 2000;39:233-42
Anita L. Nelson, MD - 04/10/08 13:40
30 EE/150 LNG
NuvaRing
Irregular
Bleeding 20
(%)
10
20
Number of days after insertion
38.8
30
0
0
117
Contraceptive Vaginal Ring
versus 30 mcg OC: Cycle Control
Etonogestrel
(pg/mL)
Ethinyl estradiol
(pg/mL)
Contraceptive Vaginal Ring
Pharmacokinetics
CU 06-29-08 Kaiser
Metabolic studies
118
Anita L. Nelson, MD - 04/10/08 13:40
13
2
3
Cycle
4
5
6
CU 06-29-08 Kaiser
120
Nelson: Contraceptive Update
Quick Start Ring vs Pill: Bleeding Patterns
84-day
Reference Period
Bleeding-spotting
days
Bleeding-only days
Spotting-only days
Bleeding-spotting
episodes
Bleeding-spotting
episode days
Bleeding-spottingfree interval days
Ring
Pill
(n = 78 ) (n = 78) Diff.
Contraceptive Vaginal Ring:
Extended Use (Off Label)
95% CI
14.5
19.2
4.7
2.1,7.3
28 d
9.1
5.4
11.9
7.3
2.8
1.9
1.1,4.5
0.18,3.7
2.4
3.0
0.58 0.24,0.92
6.0
6.5
0.50 -0.28,1.2
21.2
19.0
-2.2 -4.3,-0.03
Total bleeding days
First 90 days
7
Last 90 days
8
Total bleeding/spotting days
First 90 days
15
Last 90 days
17
Completers
77%
CU 06-29-08 Kaiser
121
Cervical cytology
Vaginal cytology
 Low incidence of shift of
normal to abnormal
Anita L. Nelson, MD - 04/10/08 13:40
0
3.5
9
11
72%
17
7
62%
12
14
59%
CU 06-29-08 Kaiser
122
Contraceptive Vaginal Ring
Local Effects
 Interaction
Colposcopy/ Vaginoscopy
 The frequency of normal to
abnormal changes was low
 A similar number of subjects
showed abnormal to normal
changes in microbiology and
colposcopy
 No abnormal findings
 Ulcerations,
 Acetowhite epithelium
 Erythema
 Laceration
CU 06-29-08 Kaiser
4
2
Anita L. Nelson, MD - 04/10/08 13:40
Contraceptive Vaginal Ring
Local Effects
Leukorrhea/Vaginal Flora
 Leukorrhea - 6 % of
patients per year
 No significant normal to
abnormal or abnormal to
normal change in flora
4
6
Miller L, et al. Obstet Gynecol. 2005;106:473-82
Westhoff C, et al. Obstet Gynecol. 2005 Jul;106(1):89-96
Anita L. Nelson, MD - 04/10/08 13:40
Median Days
48 d 91 d 364 d


Spermicides/water-based formulation: No

Anti-mycotics/oil-based formulation:
Interaction most likely caused by formulation

No effects on efficacy and safety
Decrease in recurrence of BV
Anita L. Nelson, MD - 04/10/08 13:40
The Male Condom
Yes, but:

Impact on infection

123
with vaginal medications
CU 06-29-08 Kaiser
124
“Ten months ago, I would have
called this (the condom) an
invention of the devil, but now
I find that its inventor must
have been a man of good will ...”
Jacques Casanova, 1758
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
128
Anita L. Nelson, MD - 04/10/08 13:40
14
CU 06-29-08 Kaiser
129
Nelson: Contraceptive Update
Male Condom
Polyurethane Condom

Typical first year failure rate: 17%; range 2-20%

Advantages:


Male participation

Protects well against STDs

Inexpensive

Cervical dysplasia reduced

Readily available
Special applications:

Premature ejaculation

Antisperm antibody

Female allergy to sperm
Kost K, et al. Contraception. 2008;77(1):10-21
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
130
Polyurethane
Latex
Breakage & slippage, 1997
8.5%
1.6%
Breakage & slippage, 1990
10.5%
1.7%
Breakage
66/1804
7/1882
Slippage
6/1804
1/1882
Uncorrected pregnancy rate
4.6 (2.6)
6.1 (1.0)
Corrected pregnancy rate
5.3 (3.1)
6.5 (1.2)
Anita L. Nelson, MD - 04/10/08 13:40
Male Condoms: Sizes



 Sensitivity,
texture, extra strength,
desensitizing, pleasure producing,
flavor/scent, color, lubrication
 Desensitizing condoms with “climax control
lubricant featuring benzocaine that helps
prolong sexual pleasure and aids in
prevention of premature ejaculation” (Durex
Performax, Trojan Extended Pleasure)
Beyond7, Studded Beyond 7, Exotica Snugger Fit,
LifeStyles Snugger Fit, Trojan Ultra Fit
Larger size—more headroom

Trojan Ultra Pleasure, Trojan Very Sensitive,
Bareback, Trojan Her Pleasure, Midnight Desire,
Pleasure Plus, LifeStyles Xtra Pleasure, Inspiral,
Durex Enhanced Pleasure, LifeStyles Natural Feeling
Larger size—roomy from top to bottom

Maxx, Trojan Large, Magnum XL, Magnum,
Durex Maximum, LifeStyles Large, Avanti, Crown,
Trojan Supra
Anita L. Nelson, MD - 04/10/08 13:40
132
Male Condoms:
Other Characteristics
Snug fitting

CU 06-29-08 Kaiser
CU 06-29-08 Kaiser
 Spermicidally
lubricated condoms
134
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
135
136
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
137
Recently Introduced Condoms
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
15
Nelson: Contraceptive Update
Female Barrier Methods
Failure Rates
Perfect Use
Users
Lea’s Shield
 Single
size, cup shaped
silicone device covering cervix
Typical
 No
5.2-6.9
16-18
11.4
16-20
fitting needed
walls stabilize
 One-way valve allows exit
for cervical secretions and air
no difference
6
18-21
 No
unknown
3
21-25
Nulliparous Parous
Diaphragm
no difference
Cervical Cap
8.8
Spermicide
Female
Condom
26.4
Anita L. Nelson, MD - 04/10/08 13:40
All
Use
CU 06-29-08 Kaiser
 Vaginal
vacuum needed
 Posterior end thicker to fill fornix
 Loop
143
on anterior end to facilitate removal
Anita L. Nelson, MD - 04/10/08 13:40
FemCap
CU 06-29-08 Kaiser
145
Contraceptive Sponge
 Approved
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
by FDA in 1983, withdrawn in
1994, and reapproved in 2005
 Disposable polyurethane foam disk
containing 1 gram N-9
 Single use device
moistened and placed high
in vault to cover cervix
 Mechanisms of action:
spermicide (24 hours) plus
device absorbs semen
and blocks cervix
147
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
148
CU 06-29-08 Kaiser
150
THE EVENING AFTER THE DAY FOLLOWING
THE MORNING AFTER THE NIGHT BEFORE PILL
EMERGENCY CONTRACEPTION
Cycle Beads
 Color
coded string of beads helps women
identify days of cycle pregnancy is likely
and unlikely
Anita L. Nelson, MD - 04/10/08 13:40
CU 06-29-08 Kaiser
149
Anita L. Nelson, MD - 04/10/08 13:40
16
Nelson: Contraceptive Update
WHO EC Study: Single Dose Vs Two
Doses Used Within 120 Hours
LNG-only EC
Single-dose Versus 2-dose Regimens
2 doses 1 dose
0.75 mg 1.5 mg
Pregnancies
7/560
4/600
Effectiveness
86.8%
92.9%
Headaches
14.5%
21.3%
Breast tenderness
8.8%
12.9%
Arowojolu AO, et al. Contraception. 2002;66:269-73
151
Pregnancy Rate
1.0%
3.1%
1.8%
0.5%
0.0%
13-24
25-36
37-48
49-60
61-72
CU 06-29-08 Kaiser
153
women
 Ovulation (day 0) calculated from LH, E2 and
P4 levels obtained just prior to EC ingestion
 Cycle day of IC derived from patient history
 No pregnancies occurred when IC occurred
day -5 to day -2 and EC taken before or on
day 0
Number
 All
pregnancies occurred when IC was day -1
to day 0 and EC was day +2
Luteal
Unknown
3-4 pregnancies expected, 3 occurred
Novikova N, et al. Contraception 2007;75:112-8
CU 06-29-08 Kaiser
CU 06-29-08 Kaiser
CU 06-29-08 Kaiser
152
156
Women in Cycle Phase
Follicular Periovulatory Luteal
41
30
20
Percent believing they are in phase
Follicular
39%
13%
Periovulatory
17%
23%
4-5 pregnancies expected, 0 occurred
Anita L. Nelson, MD - 04/10/08 13:40
21/1359
Cycle Phase: Endocrinological vs
Patient Estimate
 99

1.5%
Anita L. Nelson, MD - 04/10/08 13:40
LNG EC Mechanisms of Action

Mifepristone (10 mg)
1. Ortiz ME, et al. Hum Reprod. 2004;19:1352-6
2. von Hertzen H, et al. Fam Plann Perspect. 1996;28:52-7,88
3. Gemzell-Danielsson K, et al. Hum Reprod Update. 2004;10:341-8
Piaggio G, et al. Lancet. 1999;353:721
Anita L. Nelson, MD - 04/10/08 13:40
24/1356
monkey: LNG EC inhibited or delayed
ovulation. Once fertilization had taken place,
EC did not prevent establishment of
pregnancy 1
 Human: LNG administered during luteul
phase did not cause significant endometrial
changes 2
 Human: LNG EC blocks or delays ovulation,
due either to prevention or delay of LH surge,
rather than inhibiting implantation 3
2.6%
0-12
1.8%
 Cebus
4.1%
1.5%
2 doses LNG (0.75 mg x 2)
LNG EC Mechanisms of Action
WHO Pooled Data (Yuzpe and LNg), 1998
2.0%
20/1356
Anita L. Nelson, MD - 04/10/08 13:40
How Long After the Morning After?
3.0%
1.5%
von Hertzen H, et al. Lancet. 2002;360:1803-10
CU 06-29-08 Kaiser
4.0%
Single dose LNG (1.5 mg)
differences seen in nausea, vomiting, headache,
or change in onset of next menses.
differences seen in nausea, vomiting, dizziness,
lower abdominal pain, or heavy menses.
5.0%
#
Pregnancies
● No
● No
Anita L. Nelson, MD - 04/10/08 13:40
Pregnancy
Rates
39%
5%
53%
11%
7%
18%
68%
17%
Novikova N, et al. Contraception 2007;75:112-8
157
Anita L. Nelson, MD - 04/10/08 13:40
17
CU 06-29-08 Kaiser
158