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

The Futureof

Contraception

The Futureof

Contraception

The Future of Contraception

• Impact of Generics

• Review of new methods– Current– In clinical trial or development

• Contraception OTC

The Impactof

Generics

The Impactof

Generics

GenericsWhat can be Patented?

1. The chemical

2. The combination (dose)

3. Administration regimen

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

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)

Gen

eric

New OCPsExtended Cycle 24/4

LoEstrin 24

YAZ

Extended-Cycle OC Trial: Regimens

Extended 84/7

Conventional 21/7

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)

Regimens Formulation

Anderson FD. Obstet Gynecol 2002;99(suppl)265; Poster presented at ACOG 50th Annual ClinicalMeeting; May 4-8, 2002; Los Angeles, CA

• 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

Extended-Cycle OC Trial: Summary

Lybrel

• 90 g levonorgestrel• 20 g ethinyl estradiol

Take 1 pill every day

No pill free interval

Package insert

Lybrel

Efficacy comparable to

standard OCPs

Lybrel

Month 6 48% no bleeding

Month 12 59% no bleeding

20% spotting (no

protection)Package insert

Recently Approved 24/4 OCs

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

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

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

The Newest Implantable: A Single Rod

• Etonogestrel subdermal implant 68 mg

Design of ENG Rod

Rate-controlling membrane: (0.06 mm)100% EVA

40 mm

2 mm

Core: 40% Ethylene vinyl acetate (EVA)60% Etonogestrel (68 mg)

Davies GC, et al. Contraception. 1993;47:251–261.

400

1 2 3 30 120 210 360

100

200

300

Days After Insertion

Eto

no

ge

str

el (

pg

/ml)

Inhibits ovulation(90 pg/ml)

ENG Rod Pharmacokinetics

Contraceptive Efficacy of ENG Rod

Women 2362

Cycles 73,429

Pregnancies 0

Pearl Index (95% CI) 0-0.09

Glasier A. Contraception. 2002;65:29–37.

Implant Insertion and Removal Time (Minutes)*

Insertion

Removal

NMeanSDMin-max

NMeanSDMin-max

6701.10.90.03–5.0

6332.62.00.2–20.0

6654.32.10.83–18.0

13710.28.21.3–50.0

ENG ENG Rod LNG LNG Implant

*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.

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. 2000;15:118–122.

Etonogestrel/Ethinyl Estradiol Vaginal Ring

Vaginal Ring

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

Roumen FJ, et al. Hum Reprod. 2001;16(3):469-475.

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

Vaginal Ring

Summary

• 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. 2001;16(3):469-475.

Vaginal Ring

Application of the Transdermal Patch on Abdomen

Contraceptive Patch

100

107 8 90 1 2 3 4 5 60

25

50

75

AbdomenAbdomen

ArmArm

ButtockButtock

TorsoTorso

Equivalence of Sites: EE ResultsE

E S

eru

m C

on

cen

trat

ion

(p

g/m

L)

Days

Contraceptive Patch

Skee D, et al. Clin Pharm Ther. 2000;67:159.

Days

EE

Ser

um

Co

nce

ntr

atio

n (

pg

/mL

)

2.1

1.8

1.5

1.2

.9

.6

150

125

100

75

50

25

NG

MN

Ser

um

Co

nce

nt r

atio

n (

ng

/mL

)

.300 1 2 3 4 5 6 7 8 9 10 11 12

Patch EEPatch NGMN

EE

NGMN

Patch Removed

Reference Range

NGMN and EE LevelsPatch vs OC*

*Noncomparative dataAbrams L, et al. Contraception. 2001;64:287-294.

Contraceptive Patch

Comparative Randomized, Controlled Trial Data: Efficacy

(pregnancies per 100 woman-years)

Patch

OC

Cycles(n)

5240

4167

Pregnancies(n)

5

7

OverallPearl*

1.24

2.18

MethodPearl**

0.99

1.25

*User failure plus method failure**Failure when taken as directed

Audet M, et al. JAMA. 2001;285:2347-2354.

Pearl Indices

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

*(p<.001)

Audet M, et al. JAMA. 2001;285:2347-2354.

Contraceptive Patch

Compliance by Age Group

Archer D, et al. Fertil Steril. 2001;76:S20. Abstract O-50.

Contraceptive Patch

91.688.389.388.388.287.7

84.882.6

85.279.8

74.467.7

0102030405060708090

100

18-19 20-24 25-29 30-34 35-39 > 40

Patch OC

P<0.001 P<0.001 P<0.001 P<0.008 P<0.006 P<0.005

Age (years)

% C

om

plia

nt

Cyc

les

Distribution of Pregnancies by Baseline Body Weight Deciles (n=3319 subjects)

Decile Weight Pregnancies Range (kg) Total

1 <52 12 52 - <55 23 55 - <58 04 58 - <60 05 60 - <63 26 63 - <66 07 66 - <69 18 69 - <74 09 74 - <80 2

10 80 780 - 85 185 – 90 1

> 90 5Zieman et al., Fertil Steril 2001; vol. 76:S19 (abst O-48)

Comparative Data: Most Common Adverse Events

Patch (N=812) OC (N=605)

OverallTreatment 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. 2001;285:2347-2354.

Contraceptive Patch

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

Mirena®

MIRENA® Package Insert.

Levonorgestrel 20 mcg/day

Steroidreservoir

32 m

m

• 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

MIRENA® Package Insert.

Levonorgestrel 20 mcg/day

Steroidreservoir

32 m

m

Levonorgestrel IUS: Efficacy

• 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. 1987;36:169-179.Mirena Package Insert.

Intrauterine System

IUD

• Use by nulliparous women now allowed

• History of PID no longer a contraindication

• Woman must be in a “stable” (rather than “mutually monogamous”) relationship

Labeling change for CuT 380A (2005)

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

ESSURE® Package Insert.

Uterus

Cervix

Pop Council Ring

• Nestorone / Ethynyl Estradiol

• Wear for 3 weeks

• Remove for 1 week

• Reinsert (13 cycles)

Asian Caucasian

TE 91 60

TE + DMPA 96 59

19NT + DMPA 98 67

Waites, GMH. British Medical Bulletin 1993;49:210-221

Hormone % Azospermic

Effective, Reversible, Safe Contraceptives

IUSVaginal RingSpermicide

ImplantInjectableBarrier

DMPAPatchOral Contraceptives

3 mos. +1 wk – 1 moDaily or with Intercourse

Frequency of Use

Combination of estrogen and progestin

Comparison of New Contraceptive Methods

Monthly Injectable

Implant IUS Ring Patch

Efficacious Yes Yes Yes Yes Yes

Office visits 1 MonthInsertion &

removalInsertion &

removalPrescription Prescription

Easily reversible

Yes Yes Yes Yes Yes

Dosing frequency

1 month 3-5 yrs 5 yrsEvery 4 weeks

Weekly

User-controlled

No No No Yes Yes

Discreet Yes Sometimes Yes Yes Sometimes

Overview

Contraception OTC

Emergency Contraception

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

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

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

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

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

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

What Happens to My Agency

Pt volume

Cost of OTC items

Focus on provider assisted methods: IUC, Implant, Injection

? Ring and Patch