1. The Future of Contraception

2. The Future of Contraception
Impact of Generics
Review of new methods
Current
In clinical trial or development
Contraception OTC

3. The Impact of Generics

4. Generics What can be Patented?
The chemical
The combination (dose)
Administration regimen

5. 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

6. New OCPs Extended 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 g EE)
Generic

7. New OCPs Extended Cycle 24/4
LoEstrin 24
YAZ

8. Extended-Cycle OC Trial: Regimens
Formulation
Extended 84/7
Conventional 21/7
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)
Anderson FD. Obstet Gynecol 2002;99(suppl)265; Poster presented at ACOG 50th Annual Clinical
Meeting; May 4-8, 2002; Los Angeles, CA

9. Extended-Cycle OC Trial: Summary
91-day extended-cycle OC regimen is as effective a contraceptive as 28-day OC (>99% 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

10. Lybrel 90 g levonorgestrel 20 g ethinyl estradiol
Take 1 pill every day
No pill free interval
Package insert

11. Efficacy comparable to standard OCPs
Lybrel
Efficacy comparable to standard OCPs

12. Lybrel Month 6 48% no bleeding Month 12 59% no bleeding
20% spotting (no protection)
Package insert

13. Recently Approved 24/4 OCs

14. Recently Approved 24-Day Oral 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
Two 24-day active pill regimens have recently been approved.
These formulations reduce the traditional 7-day pill-free week.
Loestrin® [package insert]. Rockaway, NJ: Warner Chilcott Company, Inc.; February Available at: YAZ® [package insert]. Montville, NJ; Berlex Inc.; December Available at:

15. 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
Nakasima ST, Archer DF, Ellman H. Contraception 2007; 75(1):16

16. 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; 70:190

17. The Newest Implantable: A Single Rod
Etonogestrel subdermal implant 68 mg
Implanon is a 3 year progestin-only subdermal implant containing etonogestrel- the active metabolite of desogestrel. It is inserted between the biceps and triceps in the non-dominant arm. It should be inserted or removed only by those clinicians who have received proper training.

18. Design of ENG Rod 40 mm 2 mm Core: 40% Ethylene vinyl acetate (EVA)
60% Etonogestrel (68 mg)
Implanon is 40 mm in length and 2 mm in diameter. It is composed of a solid core of Evatane with the crystals of etonogestrel imbedded within the core. Surrounding the core is a thin layer of evatane (0.06mm thick) that controls the rate which etonogestrel is released.
Rate-controlling membrane: (0.06 mm)
100% EVA 6

19. ENG Rod Pharmacokinetics
400
300
Etonogestrel (pg/ml)
200
100
Inhibits ovulation
(90 pg/ml)
Serum levels of etenogestrel necessary to inhibit ovulation are achieved within 24 hours of insertion and are maintained well above the minimum level of 90 pg/ml throughout the 3 years of use. 1 2 3 30
120
210
360
Days After Insertion
Davies GC, et al. Contraception. 1993;47:251–261.

20. Contraceptive Efficacy of ENG Rod
Women 2362
Cycles 73,429
Pregnancies 0
Pearl Index (95% CI)
Glasier A. Contraception. 2002;65:29–37.

21. Implant Insertion and Removal Time (Minutes)*
ENG Rod
LNG Implant N
Mean SD
Min-max
670
1.1
0.9
0.03–5.0
665
4.3
2.1
0.83–18.0
Insertion N
Mean SD
Min-max
633
2.6
2.0
0.2–20.0
137
10.2
8.2
1.3–50.0
During the clinical trials a head to head study was done comparing the insertion and removal times of Implanon with Norplant. All clinicians involved were proficient and experienced with the removal and insertion techniques for both subdermal systems. As the data shows, Implanon was about 4 times faster to insert and about 5 times faster to remove.
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. 2000;5(suppl 2):29–34.

22. 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
Because some progestin-only methods cause a decrease in bone over time, a BMD study was done during the clinical trials which compared Implanon with a non- medicated copper IUD. During and at the conclusion of the study, no differences in BMD was noted between the two groups and it was concluded that Implanon has no detrimental effect on bone density. This is primarily due to the fact that although ovulation is effectively inhibited, endogenous estrogen production by the ovaries is not significantly affected.
Beerthuizen R, et al. Hum Reprod. 2000;15:118–122.

23. Etonogestrel/Ethinyl Estradiol Vaginal Ring
The etonogestrel/EE ring is a flexible, soft, transparent ring with an outer diameter of 54 mm and a cross section of 4 mm
The etonogestrel/EE vaginal ring is a new, highly effective contraceptive method recently approved by the FDA

24. 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 woman–years
This ring releases 120 µg of the progestin etonogestrel, formerly 3-keto-desogestrel, and 15 µg of the estrogen ethinyl estradiol per day
It can be easily inserted and removed by the woman herself, and is intended to be used for one cycle consisting of 3 weeks of continuous ring use and a 1 week ring-free period
A total of six pregnancies were reported during treatment, giving it a Pearl Index of 0.65
Roumen FJ, et al. Hum Reprod. 2001;16(3):
Suggested Core Slide

25. Vaginal Ring
Patient Management
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 > 3 hrs, back-up contraception is necessary for 7 days
The ring must be kept in place for three consecutive weeks
Remove the ring three weeks after insertion on the same day of the week as it was inserted, and at about the same time
Your menstrual period will usually start two to three days after the ring is removed and may not have finished before the next ring is inserted. To continue to be protected from pregnancy, you must insert the ring one week after the last one was removed, even if your menstrual bleeding has not stopped
It should be noted that the ring can be expelled from the vagina while removing a tampon, moving the bowels, straining, or with severe constipation
If the ring slips out and it has been out less than three hours, you should still be protected from pregnancy. The ring should be re-inserted as soon as possible. If it has been out of the vagina for more than three hours, you may not be protected from pregnancy. You must use an additional method of birth control, such as male condoms or spermicide, until the ring has been in place for seven days in a row

26. Summary Good cycle control
Vaginal Ring
Summary
Good cycle control
Irregular bleeding was rare (2.6% - 6.4% of evaluable cycles)
Withdrawal bleeding occurred (97.9% % of evaluable cycles)
Compliance with the regimen was met in 90.8% of cycles
This study demonstrated that the ring is an effective method of contraception with good cycle control. It is easy to use, well-tolerated and well- accepted by users
The ring has a good bleeding profile. Irregular bleeding occurred in only 2.6% – 6.4% of the cycles. The irregular bleeding that occurred consisted mainly of spotting only; breakthrough bleeding was reported in only 0.4% – 1.1% of the cycles
Compliance to the regimen was high (90.8%)
Roumen FJ, et al. Hum Reprod. 2001;16(3):
Suggested Core Slide

27. Application of the Transdermal Patch on Abdomen
Contraceptive Patch
Application of the Transdermal Patch on Abdomen
The patch (ORTHO EVRA™) is beige in color, very thin, and pliable
The patch can be applied to the buttocks, upper outer arm, lower abdomen (shown), or upper torso (not the breasts)
No makeup, creams, lotions, powders, or other topical products should be applied to the skin area where the patch is or will be applied
The patch is comprised of three layers – a backing layer, a middle layer, and a release liner – this is referred to as a matrix system
In this system, the hormones are actually in the middle layer with the adhesive
Suggested Core Slide

28. Equivalence of Sites: EE Results
Contraceptive Patch
Equivalence of Sites: EE Results
100 75
Abdomen
Arm
EE Serum Concentration (pg/mL) 50
Buttock
Torso
A pharmacokinetics study was conducted to determine the therapeutic equivalence of the patch on four different application sites
The absorption of norelgestromin (NGMN), 17-deacetylnorgestimate and ethinyl estradiol (EE) was determined to be therapeutically equivalent for application on the abdomen, arm, buttock, and torso 25 1 2 3 4 5 6 7 8 9 10
Days
Skee D, et al. Clin Pharm Ther. 2000;67:159.
Suggested Core Slide

29. NGMN and EE Levels Patch vs OC*
Contraceptive Patch
NGMN and EE Levels Patch vs OC*
150
Patch EE
2.1
Patch NGMN
125
1.8 EE
NGMN
100
1.5
EE Serum Concentration (pg/mL)
Reference Range 75
NGMN Serum Concentration (ng/mL)
1.2
Patch Removed 50 .9
Delivers constant levels of NGMN and EE compared to the peaks and troughs of OCs
Delivers NGMN 150 μg/day and EE 20 μg/day to the systemic circulation
Following application, the patch delivers steady-state levels of norelgestromin and EE throughout the wear period
The reference range was established based on the systemic exposure of norgestimate and EE in subjects taking ORTHO-CYCLEN
This illustration shows patch data overlaid with data from oral dosing. One can see the peaks and troughs associated with oral administration versus steady-state delivery 25 .6 .3 1 2 3 4 5 6 7 8 9 10 11 12
Days
Abrams L, et al. Contraception. 2001;64:
*Noncomparative data
Suggested Core Slide

30. Contraceptive Patch
Comparative Randomized, Controlled Trial Data: Efficacy (pregnancies per 100 woman-years)
Pearl Indices
Cycles
(n)
Pregnancies
(n)
Overall
Pearl*
Method
Pearl**
Patch
5240 5
1.24
0.99
Data published in JAMA demonstrate the efficacy data are reported as the Pearl Indices
Comparing the total Overall Pearl to the Method Pearl, one can infer that there were few patch failures associated with poor user compliance
A contraceptive with high compliance would be associated with an overall failure rate (method plus user failure) that is very similar to the method failure alone, as seen with the transdermal patch
In the patch group, 4 method-failure pregnancies and 1 user-failure pregnancy occurred among 811 women treated for 5240 cycles
In the OC group, comprised of a triphasic LNG, 4 method-failure and 3 user-failure pregnancies occurred among 605 women treated for 4167 cycles
While the numerical differences in Pearl Indices are not statistically significant, this demonstrates that the transdermal contraceptive system is a highly effective method of contraception
Additional evidence that better compliance contributed to the low probability of pregnancy with the patch is seen from analysis of 6-cycle data, a treatment duration all participants were to complete. After 6 cycles, the overall probability of pregnancy with the patch was half that of the OC (0.6% vs 1.2%) while the method failure probability of pregnancy was nearly the same (0.4% vs 0.6%) OC
4167 7
2.18
1.25
*User failure plus method failure
**Failure when taken as directed
Audet M, et al. JAMA. 2001;285:
Suggested Core Slide

31. Mean Proportion of Participants’ Cycles With Perfect Compliance
Contraceptive Patch
Mean Proportion of Participants’ Cycles With Perfect Compliance N
Total Cycles
% of Cycles
Patch
811
5141
88.2* OC
605
4134
77.7
An important finding in a randomized, controlled trial was that use of the transdermal contraceptive system resulted in statistically better compliance than with the OC comparator
Improved compliance may be due to the simple weekly dosing schedule
This is important because while OCs have failure rates in clinical trials around 1%, Trussell, et al., estimate that actual use failure rates can be as high as 7% with OCs
Since incorrect and inconsistent use of contraception can lead to higher pregnancy rates – it is hoped that the improved compliance profile of the patch will result in improved “actual use” efficacy in broad usage
Perfect compliance was defined as 21 consecutive days of drug-taking during a 28-day cycle
For the transdermal system, each patch had to be worn for exactly 7 days, for three consecutive weeks
*(p<.001)
Audet M, et al. JAMA. 2001;285:
Suggested Core Slide

32. Compliance by Age Group
Contraceptive Patch
Compliance by Age Group
% Compliant Cycles
P<0.001
P<0.001
P<0.001
P<0.008
P<0.006
P<0.005
Usage of the patch resulted in increased compliance across all age groups
Compliance rates were similar for all age groups using the patch, whereas the rates varied among the age groups for OCs
Therefore, the increased compliance seen with the patch is a potential benefit to a wide range of women
Age (years)
Archer D, et al. Fertil Steril. 2001;76:S20. Abstract O-50.
Suggested Core Slide

33. Distribution of Pregnancies by Baseline Body Weight Deciles (n=3319 subjects)
Decile Weight Pregnancies Range (kg) Total
1 <52 1
<55 2
<58 0
<60 0
<63 2
<66 0
<69 1
<74 0
<80 2
10 80 7
85 – 90 1
> 90 5
While patch is highly efficacious for the vast majority of women, the patch may be less efficacious in women >198 lbs.
This phenomenon was also seen with Norplant but no data is available for other hormonal methods. The NIH is currently funding a study to look at the impact of weight on contraceptive efficacy.
5 pregnancies among the 83 subjects with body weight  90 kg (198 lbs) (3% of study population)
10 pregnancies among the subjects with body weight  198 lbs. were uniformly distributed
90 kg (threshold) supported by statistical analyses
Zieman et al., Fertil Steril 2001; vol. 76:S19
(abst O-48)

34. Comparative Data: Most Common Adverse Events
Contraceptive Patch
Comparative Data: Most Common Adverse Events
Patch (N=812)
OC (N=605)
Overall
Treatment Limiting
Breast discomfort
19%
1.0% 6%
0.2%
Headache
22%
1.5%
0.3%
Application site reaction
20%
2.6% NA
Nausea
1.8%
18%
0.8%
Abdominal pain 8%
Dysmenorrhea
13%
10%
Overall, the patch is well-tolerated with mild, transient side effects similar to OCs
There were no unexpected adverse events in either treatment group
With the exception of mild-to-moderate application site reactions, the types of adverse events were similar between the patch and OC. More patients experienced slight breast discomfort on the patch vs. OCs, but only in the first two cycles
For the patch and OC, approximately 2% of participants reported a serious adverse event – these events were generally similar between treatment groups
Audet M, et al. JAMA. 2001;285:
Suggested Core Slide

35. 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

36. Levonorgestrel 20 mcg/day
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
Steroid reservoir
Steroid reservoir
32 mm
32 mm
Research conducted since 1970 into several hormonally medicated intrauterine systems led to the development of the levonorgestrel intrauterine system (LNG IUS), which is licensed in 25 countries and was approved for use as a intrauterine contraceptive in the U.S. by the FDA in December, (In other countries, it is also approved for the treatment of menorrhagia.)
As shown here, this polyethylene system consists of a T-shaped frame that is 32 mm in diameter. The polyethylene is compounded with barium sulfate, making it radiopaque.
A “sleeve” or reservoir on the vertical stem of the T-body contains 52 mg of levonorgestrel dispersed in polydimethylsiloxane. It is covered by a silicone rate-limiting surface membrane.
A monofilament, polyethylene thread attached to the end of the vertical stem is provided for purposes of removing the IUS.
The LNG IUS releases 20 µg/day of LNG in vitro for the first year and about half that amount by the fifth year of use.
Levonorgestrel 20 mcg/day
Levonorgestrel 20 mcg/day
MIRENA® Package Insert.
MIRENA® Package Insert.

37. Levonorgestrel IUS: Efficacy
Intrauterine System
Levonorgestrel IUS: Efficacy
Overall failure rate 0.1 per 100 women
Gross cumulative five-year failure rate is 0.7 per 100 women
Safety and efficacy of LNG IUS was studied in two large clinical trials
In study sites that had evaluable data and informed consent, 1169 women (18 to 35 years of age at enrollment) used the LNG IUS for up to 5 years
Reported pregnancy rates for one year were less than or equal to 0.2 and the 5-year cumulative rate was approximately Due to limitations of available data, a precise estimate of the pregnancy rate is not possible
Nonetheless, the LNG IUS is a highly effective, long-term method of birth control
Luukkainen T, et al. Contraception. 1987;36:
Mirena Package Insert.

38. 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

39. 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.

40. Nestorone / Ethynyl Estradiol Wear for 3 weeks Remove for 1 week
Pop Council Ring
Nestorone / Ethynyl Estradiol
Wear for 3 weeks
Remove for 1 week
Reinsert (13 cycles)
One reason we want to improve successful contraceptive use is because contraception saves lives!
As you can see, there are significant morbidity and mortality consequences associated with unintended pregnancy in the United States.
This is another reason why all pregnancies should be planned pregnancies.

42. Hormone % Azospermic Asian Caucasian TE 91 60 TE + DMPA 96 59
19NT + DMPA 98 67
Waites, GMH. British Medical Bulletin 1993;49:

43. Effective, Reversible, Safe Contraceptives
IUS
Vaginal Ring
Spermicide
Implant
Injectable
Barrier
DMPA
Patch
Oral Contraceptives
3 mos. +
1 wk – 1 mo
Daily or with Intercourse
Frequency of Use
Combination of estrogen and progestin
One common feature of these newer methods is that they are used for an extended duration and therefore, are not associated with intercourse and do not require daily attention
The new methods offer a variety of different dosing regimens (weekly, monthly, etc.)
Options include methods that deliver combination estrogen and progestin as well as progestin only

44. Comparison of New Contraceptive Methods
Overview
Comparison of New Contraceptive Methods
Monthly Injectable
Implant
IUS
Ring
Patch
Efficacious
Yes
Office visits
1 Month
Insertion & removal
Insertion & removal
Prescription
Easily reversible
Dosing frequency
1 month
3-5 yrs
5 yrs
Every 4 weeks
Weekly
User-controlled No
Discreet
Sometimes
New contraceptive options offer women and clinicians flexibility in choosing a method that suits the woman’s needs
There are a variety of characteristics by which contraceptive methods are evaluated
Women and providers have new options available to them, and these methods are now in the form of new delivery systems. Hopefully with expanded choices, women can find a method that suits their particular lifestyle

45. Emergency Contraception
Contraception OTC
Emergency Contraception

46. HollyMead, Institute for Women’s Policy Research
HollyMead, Institute for Women’s Policy Research. Publication # A126, 2001.

47. HollyMead, Institute for Women’s Policy Research
HollyMead, Institute for Women’s Policy Research. Publication # A126, 2001.

48. HollyMead, Institute for Women’s Policy Research
HollyMead, Institute for Women’s Policy Research. Publication # A126, 2001.

49. HollyMead, Institute for Women’s Policy Research
HollyMead, Institute for Women’s Policy Research. Publication # A126, 2001.

50. HollyMead, Institute for Women’s Policy Research
HollyMead, Institute for Women’s Policy Research. Publication # A126, 2001.

51. HollyMead, Institute for Women’s Policy Research
HollyMead, Institute for Women’s Policy Research. Publication # A126, 2001.

52. What Happens to My Agency
 Pt volume
 Cost of OTC items
Focus on provider assisted methods:
IUC, Implant, Injection
? Ring and Patch