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The Future of Contraception

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Presentation on theme: "The Future of Contraception"— Presentation transcript:

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

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