The Future of Contraception

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The FutureofContraception
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The Future of Contraception

• Impact of Generics
• Review of new methods
• Current
• In clinical trial or development
• Contraception OTC

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The ImpactofGenerics
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GenericsWhat can be Patented?

1. The chemical
2. The combination (dose)
3. Administration regimen

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Generics

• All current estrogens are off patent
• Drospirenone is still on patent (Yasmin, YAZ)
• New OCPs using other progestins different doses
  or different administration regimens

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New OCPsExtended or No Cycle
Seasonale 84/7 (150 ?g levonorgestrel 30
?g EE Seasonique 84/7 (Seasonale but 7 10 ?g
EE) Lybrel continuous (90 ?g
levonorgestrel 20 ?g EE)
Generic
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New OCPsExtended Cycle 24/4
LoEstrin 24 YAZ
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Extended-Cycle OC Trial Regimens
Regimens
Formulation
150 ?g levonorgestrel/30 ?g ethinyl estradiol
(SEASONALE?) 150 ?g levonorgestrel/30 ?g ethinyl
estradiol (Nordette?) 100 ?g levonorgestrel/20
?g ethinyl estradiol (SEASONALE? Ultra-Lo) 100 ?g
levonorgestrel/20 ?g ethinyl estradiol (Levlite?)
Extended 84/7 Conventional 21/7 Extended
84/7 Conventional 21/7
Anderson FD. Obstet Gynecol 200299(suppl)265
Poster presented at ACOG 50th Annual
Clinical Meeting May 4-8, 2002 Los Angeles, CA
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Extended-Cycle OC Trial Summary

• 91-day extended-cycle OC regimen is as effective
  a contraceptive as 28-day OC (gt99 with perfect
  use) typical use efficacy lower than class
  labeling
• Produces 4 cycles per year compared with 13 with
  28-day cycle OC
• Breakthrough bleeding comparable to 28-day cycle
  OC, especially by 3rd and 4th 91-day cycle

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Lybrel

• 90 ?g levonorgestrel
• 20 ?g ethinyl estradiol
• Take 1 pill every day
• No pill free interval

Package insert
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Lybrel
Efficacy comparable to standard OCPs
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Lybrel

• Month 6 48 no bleeding
• Month 12 59 no bleeding
• 20 spotting (no protection)

Package insert
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Recently Approved 24/4 OCs
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Recently Approved 24-DayOral Contraceptive
Regimens

• Loestrin 24 Fe(norethindrone acetate 1 mg/EE 20
  mcg)
• YAZ (drospirenone 3 mg/EE 20 mcg)
• Each has a dosing regimen of 24 active days of
  hormones followed by 4 hormone-free days

Loestrin package insert. Rockaway, NJ Warner
Chilcott Company, Inc. February 2006. Available
at http//www.loestrin24.com/pdf/pi_loestrin24_fe
.pdf. YAZ package insert. Montville, NJ
Berlex Inc. December 2006. Available at
http//www.berlex.com/html/products/pi/fhc/YAZ_PPI
.pdf
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Loestrin 24 Fe Efficacy

• Norethindrone acetate 1 mg/EE 20 ?g
• Comparative study of 24/4 vs 21/7 of same
  combination
• 24/4 21/7
• Pearl Index 1.82 2.98

Nakasima ST, Archer DF, Ellman H. Contraception
2007 75(1)16
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YAZ Efficacy

• Drospiranone 3 mg/EE 20 ?g
• Non-comparative study
• 11 pregnancies in 11,140 cycles
• Pearl index 1.29
• - Comparable to other OCs

Bachmann et al. Contraception 2004 70190
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The Newest Implantable A Single Rod

• Etonogestrel subdermal implant 68 mg

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Design of ENG Rod
40 mm
2 mm
Core 40 Ethylene vinyl acetate (EVA) 60
Etonogestrel (68 mg)
Rate-controlling membrane (0.06 mm) 100 EVA
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ENG Rod Pharmacokinetics
400
300
200
Etonogestrel (pg/ml)
100
Inhibits ovulation (90 pg/ml)
1
2
3
30
120
210
360
Days After Insertion
Davies GC, et al. Contraception. 199347251261.
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Contraceptive Efficacy of ENG Rod

• Women 2362
• Cycles 73,429
• Pregnancies 0
• Pearl Index (95 CI) 0-0.09

Glasier A. Contraception. 2002652937.
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Implant Insertion and Removal Time (Minutes)
ENG Rod
LNG Implant
N Mean SD Min-max
670 1.1 0.9 0.035.0
665 4.3 2.1 0.8318.0
Insertion
N Mean SD Min-max
633 2.6 2.0 0.220.0
137 10.2 8.2 1.350.0
Removal
Insertion time time needed for incision (if
any) and placement removal time time needed
for anesthesia, incision, and removal. Mascarenhas
L. Eur J Contracept Reprod Health Care.
20005(suppl 2)2934.
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Bone Mineral Density and ENG Rod

• Head-to-head study of ENG rod with non-medicated
  IUD (copper)
• No differences in BMD changes between 2 groups
• Authors concluded that although ENG rod is a
  progestin-only method, no bone loss occurs during
  use

Beerthuizen R, et al. Hum Reprod. 200015118122.
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Etonogestrel/Ethinyl Estradiol Vaginal Ring
Vaginal Ring
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Etonogestrel/Ethinyl Estradiol Vaginal Ring

• Progestin Etonogestrel 120 µg/day
• Estrogen Ethinyl estradiol 15 µg/day
• Worn for three out of four weeks
• Self insertion removal
• Pregnancy rate 0.65 per 100 womanyears

Roumen FJ, et al. Hum Reprod. 200116(3)469-475.
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Patient Management
Vaginal Ring

• Patient inserts ring and it is supposed to
  remain in the vagina for 3 weeks
• Ring is removed during the fourth week, menstrual
  period should begin
• If ring is removed or slips out of place for gt 3
  hrs, back-up contraception is necessary for 7
  days

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Summary
Vaginal Ring

• Good cycle control
• Irregular bleeding was rare (2.6 - 6.4 of
  evaluable cycles)
• Withdrawal bleeding occurred (97.9 - 99.4 of
  evaluable cycles)
• Compliance with the regimen was met in 90.8 of
  cycles

Roumen FJ, et al. Hum Reprod. 200116(3)469-475.
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Application of the Transdermal Patch on Abdomen
Contraceptive Patch
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Equivalence of Sites EE Results
Contraceptive Patch
100
75
Abdomen
Arm
EE Serum Concentration (pg/mL)
50
Buttock
Torso
25
0
0
1
2
3
4
5
10
7
8
9
6
Days
Skee D, et al. Clin Pharm Ther. 200067159.
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NGMN and EE LevelsPatch vs OC
Contraceptive Patch
2.1
150
Patch EE
Patch NGMN
1.8
125
EE
NGMN
1.5
100
Reference Range
EE Serum Concentration (pg/mL)
NGMN Serum Concentration (ng/mL)
1.2
75
Patch Removed
.9
50
.6
25
.3
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Days
Noncomparative data
Abrams L, et al. Contraception. 200164287-294.
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Comparative Randomized, Controlled Trial Data
Efficacy (pregnancies per 100 woman-years)
Contraceptive Patch
Pearl Indices
Cycles (n)
Pregnancies (n)
Overall Pearl
Method Pearl

5240
5
1.24
0.99
Patch
OC
4167
7
2.18
1.25

User failure plus method failure Failure when
taken as directed
Audet M, et al. JAMA. 20012852347-2354.
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Mean Proportion of Participants Cycles With
Perfect Compliance
Contraceptive Patch
N Total Cycles of Cycles
Patch 811 5141 88.2
OC 605 4134 77.7
(plt.001)
Audet M, et al. JAMA. 20012852347-2354.
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Compliance by Age Group
Contraceptive Patch
Compliant Cycles
Plt0.001
Plt0.001
Plt0.001
Plt0.008
Plt0.006
Plt0.005
Age (years)
Archer D, et al. Fertil Steril. 200176S20.
Abstract O-50.
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Distribution of Pregnancies by Baseline Body
Weight Deciles (n3319 subjects)

• Decile Weight Pregnancies Range (kg) Total
• 1 lt52 1
• 2 52 - lt55 2
• 3 55 - lt58 0
• 4 58 - lt60 0
• 5 60 - lt63 2
• 6 63 - lt66 0
• 7 66 - lt69 1
• 8 69 - lt74 0
• 9 74 - lt80 2
• 10 ?80 7
• 80 - 85 1
• 85 90 1
• gt 90 5

Zieman et al., Fertil Steril 2001 vol. 76S19
(abst O-48)
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Comparative Data Most Common Adverse Events
Contraceptive Patch
Patch (N812) Patch (N812) OC (N605) OC (N605)
Overall Treatment Limiting Overall Treatment Limiting
Breast discomfort 19 1.0 6 0.2
Headache 22 1.5 22 0.3
Application site reaction 20 2.6 NA NA
Nausea 20 1.8 18 0.8
Abdominal pain 8 0.2 8 0.3
Dysmenorrhea 13 1.5 10 0.2
Audet M, et al. JAMA. 20012852347-2354.
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IUDs

• Have low increased risk of infection
• Are not major or independent cause of PID
• Do not increase risk of ectopic pregnancy
• Do not cause infertility after removed
• Are NOT abortifacients

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Mirena

• Releases 20 µg/day of LNG in vitro for the first
  year and about half that amount by the fifth
  year of use
• Long-term reversible method
• Early spotting, anemia
• Reduction in menstrual blood loss
• Low systemic levels of LNG

Steroidreservoir
Steroidreservoir
32 mm
32 mm
Levonorgestrel 20 mcg/day
Levonorgestrel 20 mcg/day
MIRENA Package Insert.
MIRENA Package Insert.
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Levonorgestrel IUS Efficacy
Intrauterine System

• Overall failure rate 0.1 per 100 women
• Gross cumulative five-year failure rate is 0.7
  per 100 women

Luukkainen T, et al. Contraception.
198736169-179. Mirena Package Insert.
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IUD
Labeling change for CuT 380A (2005)

• Use by nulliparous women now allowed
• History of PID no longer a contraindication
• Woman must be in a stable (rather than
  mutually monogamous) relationship

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Essure

• Soft, flexible micro-insert
• The Essure procedure is performed by a trained
  gynecologist and is an alternative to surgical
  sterilization
• Essure is 99.8 effective in preventing
  pregnancy
• Another method of birth control must be used for
  at least three months after the procedure

Uterus
Cervix
ESSURE Package Insert.
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Pop Council Ring

• Nestorone / Ethynyl Estradiol
• Wear for 3 weeks
• Remove for 1 week
• Reinsert (13 cycles)

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(No Transcript)
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Hormone
Azospermic
Asian Caucasian
TE 91 60
TE DMPA 96 59
19NT DMPA 98 67
Waites, GMH. British Medical Bulletin
199349210-221
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Effective, Reversible, Safe Contraceptives
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Comparison of New Contraceptive Methods
Overview
Monthly Injectable Implant IUS Ring Patch
Efficacious Yes Yes Yes Yes Yes
Office visits 1 Month Insertion removal Insertion removal Prescription Prescription
Easily reversible Yes Yes Yes Yes Yes
Dosing frequency 1 month 3-5 yrs 5 yrs Every 4 weeks Weekly
User-controlled No No No Yes Yes
Discreet Yes Sometimes Yes Yes Sometimes
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Contraception OTC
Emergency Contraception
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HollyMead, Institute for Womens Policy Research.
Publication A126, 2001.
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HollyMead, Institute for Womens Policy Research.
Publication A126, 2001.
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HollyMead, Institute for Womens Policy Research.
Publication A126, 2001.
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HollyMead, Institute for Womens Policy Research.
Publication A126, 2001.
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HollyMead, Institute for Womens Policy Research.
Publication A126, 2001.
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HollyMead, Institute for Womens Policy Research.
Publication A126, 2001.
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What Happens to My Agency

• ? Pt volume
• ? Cost of OTC items
• Focus on provider assisted methods
• IUC, Implant, Injection
• ? Ring and Patch