The Future of Contraception. Impact of Generics Review of new methods –Current –In clinical...
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Transcript of The Future of Contraception. Impact of Generics Review of new methods –Current –In clinical...
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