Transcript Diapositive 1

XIIème JLGO
Liège, 24-25 septembre 2009
Contraception orale avec extension
ou continue :
l’aménorrhée serait-elle la règle ?
David Serfaty, Paris
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
COCs and 7-day hormone interval (1)
« …When oral contraceptives (OCs) were first
introduced during the 1960s, the 28-day cycle
[21 days of active pills and a 7-day hormone-free
interval (HFI)] was designed not necessarily based on
scientific evidence but rather with the intention of
mimicking women’s natural monthly menstrual cycles
to make OC use more acceptable and provide
reassurance of the absence of pregnancy… »
M.A. Vandever et al. Contraception, 2008 ; 77 : 162-170
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
COCs and 7-day hormone interval (2)
« …This steroidal regimen has proven to be
effective in preventing pregnancy. However,
evidence is accumulating that modifications of
the HFI each cycle or modifications of the time
between HFI may be beneficial… »
Modified from M.A. Vandever et al. Contraception, 2008 ; 77 : 162-170
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Plan
Part I
- Shortening the pill free interval
Part II
- Extended or continuous cycle
versus cyclic use of COCs
Part III
- To bleed or not to bleed ?
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Part - I Shortening
the pill free interval
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Shortening the pill free interval (1)
Although the traditional dosing regimen, 21 active pills and 7
placebo pills reduces many symptoms women suffer with
spontaneous cycles, hormone withdrawal symptoms often
occur during the 7-day hormone-free interval. Shortening the
pill free interval may suppress ovarian activity more
effectively. As consequences efficacy and cycle control can be
improved even in users of ultra-low OCs (for example users
of 15gEE pills).
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Shortening the pill free interval (2)
This concept may aid in decreasing many of adverse
symptoms that women may experience during the seven-day
hormone-free interval: headache, PMS, dysmenorrhea,
prolonged menstrual flow…
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Some pills with short hormone-free
interval (1)





Melodia®, Minesse® = 24 x GTD 60 g + EE 15 g + 4 placebo pills
Yaz®
= 24 x DRSP 3 mg + EE 20 g + 4 placebo pills
Loestrin 24 Fe®
= 24 x NETA 1 mg + EE 20 g + 4 iron-containing
placebo pills
Mircette®
= 21 x DSG 150 g + EE 20 g + 2 placebo pills +
5 pills containing 10 g EE
…
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« … Subjects receiving low-dose estrogen for 7 days
during the hormone-free interval demonstrated more
pronounced ovarian suppression compared to placebo
as evidenced by attenuation of increases in serum
inhibine B, FSH and estradiol levels … »
KZ. Reape et al.
Contraception 2008 ; 77 : 34-39
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Some pills with short hormone-free
interval (2)
▲
Qlaira®
= 26 active pills




2 days E2V 3 mg
5 days E2V 2 mg + DNG 2 mg
17 days E2V 2 mg + DNG 3 mg
2 days E2V 1 mg
+ 2 days placebo
▲
Nomac / E2
= 24 active pills

E2 1 mg + nomegestrol acetate 2,5 mg
+ 4 days placebo
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Comparison of two regimens of new monophasic
oral contraceptive combining 17 -estradiol and
nomegestrol acetate


Objective
►
To compare the effects on ovarian activity of a new monophasic
combined oral contraceptive containing 17 -estradiol 1,5 mg and
nomegestrol acetate 2,5 mg given in two regimens : 21 out of 28
days and 24 out of 28 days, for 3 consecutive cycles.
►
Phase 2, double blind, randomized, single-center, parallel-group,
regimen validation study.
One ovulatory pretreatment cycle followed by three treatment
cycles.
n = 80
Design
►
►
SERFATY David, CHRTISTIN MAITRE Sophie, OCHSENBEIN Edith,
THOMAS Jean-Louis. FIGO 2009, Cape Town
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Nomac/E2 24/4 versus 21/7

Conclusion :
Both regimens suppressed ovarian activity
but the 24-day regimen was associated with
stronger follicular suppression and a
shorter duration of withdrawal and
breakthrough bleeding/spotting events than
the 21-days regimen
D. SERFATY et al., FIGO 2009
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COCs with short free interval :
▲Potential therapeutical indications (1)
Qlaira® and dysfunctional uterine bleeding
« … Bayer is eyeing use of the E2
valerate/dienogest formulation (26/2) for the
treatment of the prolonged, frequent, and
excessive bleeding noted in dysfunctional
uterine bleeding (DUB)*… »
* And probably for the treatment of withdrawal symptoms, primary dysmenorrhoea, and sexual
dysfunctions…
Contraceptive Technology Update. August, 2008
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COCs with short free interval :
▲Potential therapeutical indications (2)
Yaz® and acne

Efficacy and safety of 3 mg drospirenone/20mcg
ethinylestradiol oral contraceptive administered
in 24/4 regimen in the treatment of acne vulgaris :
a randomized, double-blind, placebo-controlled trial
►
►
Yaz® : n = 266 ; placebo : n = 268 for 6 cycles of 28 days
Conclusion :
« …The 3 mg DRSP/20mcg EE, 24/4 regimen COC was
significantly more effective than placebo in treating moderate
acne vulgaris… »
William Koltum et al. Contraception, 2008 ; 77 : 249-256
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COCs with short free interval :
▲Potential therapeutical indications (3)
Yaz® and PMDD

Treatment of premenstrual dysphoric disorder with a new
drospirenone-containing oral contraceptive formulation
►
►
►
►
Multicenter, double-blind, placebo-controlled crossover study
3 mg DRSP/20mcg EE, 24/4 regimen COC or placebo
n = 64 ; treatment for 3 cycles, then washout
1 treatment-free cycle, then alternate treatment
Conclusion :
« … Drospirenone/EE, given in a 24/4 regimen, was superior to
placebo for improving symptoms associated with PMDD… »
Teri B. Pearlstein et al. Contraception, 2005 ; 72 : 414-421
Yaz® has been approved in 74 countries in contraception ; in PMDD in 30 countries,
and in acne in 34 countries.
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Mais…


Jasminelle® (21/28) = 273 comprimés par an et 91 comprimés placebo
Yaz® (24/28) = 312 comprimés actifs par an et 52 comprimés placebo
Yaz® = Jasminelle® + 14,2 % de DRSP et d’EE/an
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Part - II Extended or continuous cycle
versus
cyclic use of COCs
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In oral contraceptive pills users :
is monthly menstruation necessary ?
« … The dogma that women using
contraception must regularly menstruate
is changing and reversible amenorrhea
is becoming more acceptable to
women… »
Leslie Miller et al. Obstet Gynecol 2005 ; 106 : 473-482
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Conditions for which reduced menstrual frequency
or amenorrhea may have therapeutic benefit

Menorrhagia
associated with :
►
►
Uterine bleeding disorders (leiomyoma / adenomyosis)
Inherited bleeding disorders :
-
►
Acquired bleeding disorders
-





Von Willebrand’s disease
Hemophilia
Factor XI deficiency
Chronic anticoagulation
Thrombocytopenia
Dysmenorrhea (primary or acquired)
Endometriosis / chronic pelvic pain
Premenstrual syndrome
Anemia
Polycystic ovarian syndrome (PCOS) (EM. Coutinho, 2007)
A.M. Kaunitz,
Contraception 2000 : 62 : 11 : 277-284
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« … Consideration should be given to the changing attitude of
modern women regarding the benefits of suppressing
menstruation. Studies show that given the alternative of bleeding
regularly, bleeding only occasionally or not at all, most women
would opt for bleeding less or not at all [1]. For those who suffer
from catamenial diseases the reason for the preference is obvious,
but it appears that even women with no menstrual-related
symptoms would prefer not to bleed … » [1, 2, 3, 4, 5]
EM Couthintho
Contraception, 2007; 76 : 263-266
1.
2.
3.
4.
5.
Den Tonkelaar et al. Contraception, 1999 ; 59 : 357-62
Ferrero S et al. Contraception, 2006 ; 73 : 537-41
Thomas SL et al. Lancet, 2000 ; 355 : 922-4
Edelman A et al. Contraception, 2007 ; 75 : 450-3
Snow R et al. Contraception, 2007 ; 76 : 23-29
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
Numerous studies have shown that extended cycle COCs
use are safe and effective

« … Women taking the extended-cycle usually experience
reduced total bleeding periods and dysmenorrhea. They may
also experience amenorrhea. This amenorrhea may be
beneficial and suited to the lifestyle of many women … »
(Nelson, 2007)

Conversely they may experience more unscheduled
spotting (BTS) and bleeding (BTB) in the initial cycles but
those problems decrease with longer use
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Options for extended use of COCs
include the following :

Brief manipulation of cycle for convenience

Bi-cycling (2 x 21 = 42 active pills followed by 7 placebo pills)

Tricycling (3 x 21 = 63 active pills followed by 7 placebo pills)

Taking Seasonale® (or Quasense®) (4 x 21 = 84 active pills followed by
7 placebo pills) ( = four periods a year)

No-cycling = taking active pills continuously for many months or years
without placebo phase or pill-free interval. For instance :
►
►
Lybrel® = 365 pills a year
Yaz Flex ® = 4 x 24 = 96 active pills (not followed by placebo pills)
Adapted from Hatcher, 2004
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COCs with extended cycle available
in United-States

Seasonale®
= 84 active pills containing 150 mcg LNG
and 30 mcg EE + 7 placebo pills

Quasense®
= generic of Seasonale®

Seasonique®
= Seasonale® + 7 pills containing 10 mcg EE
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Seasonale® : Summary
« … Seasonale® is
the first FDA-approved extended-cycle oral contraceptive
for the prevention or pregnancy.
Breakthrough bleeding is more common in the initial extended-cycle
compared to 21/7-day OC regimens, but bleeding tends to decrease with time.
The side effect profile of Seasonale® is comparable with 21/7-day regimen…
The discontinuation rate of Seasonale® may be slightly higher than that of
21/7-day regimens, but this may be overcome with proper counseling.
Overall satisfaction with this form of contraception appears high … »
R.S. Legro et al.
Contraceptive Technology Reports, Novembre 2003
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Long-term safety of an extended regimen oral
contraceptive (Seasonale®) :
A 2-year multicenter open label trial
D. Portman et al.
Contraception 2005 ; 72 : 229-245
« … Following completion of the initial trial (1-year
study), 189 patients received Seasonale® for up to an
additional 2 years (eight extended cycles)…
This study confirms the findings from 1-year study
and demonstrates that Seasonale® is safe, effective and
well tolerated … »
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Extending the 21/7 pill regimen :
The pros and cons
Advantages




↑ Convenience
↑ Compliance
Minimization of cyclic symptoms
Increased non contraceptive
benefits
Disadvantages


Seasonale® = ↑ 23 % of annual
total doses of estrogen and
progestin
Theoretical concerns : long-term
avderse effects ?
► Cardiovascular risk ?
► Cancer risk ?
► ...
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Continuous use of COCs

Lybrel® from Wyeth Pharmaceuticals represents
the first combination contraceptive pill designed
to be taken 365 days a year, without a placebo
phase or pill-free interval. Lybrel® has been
approved by the Food and Drug Administration in
May 2007
► The pill comes in a 28-day pill pack with
combination tablets that contain 90 mcg
levonorgestrel and 20 mcg ethinyl estradiol
Contraceptive Technology Update
July 2007
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Evaluation of a continuous regimen of
levonogestrel 90 g / ethinyl estradiol 20 g (Lybrel®)
Phase 3 Study (1)





n = 2134 (18-49 years)
Open-label study
LNG 90 g / EE 20 g x 12 months
METHOD FAILURE : PEARL INDEX* = 1.26
(95 % CI = 0.71-2.8)
USER FAILURE : PEARL INDEX* = 0.34
(95 % CI = 0.09-0.86)
D.F.Archer
Contraception, 2006 ; 74 (6) : 439-445
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Evaluation of a continuous regimen of
levonogestrel 90 g / ethinyl estradiol 20 g (Lybrel®)
Phase 3 Study (2)

Amenorrhea = 58.7 % (Pill Pack 13)

Overall, the number of bleeding and spotting days
per pill pack declined progressively

Adverse events and discontinuations were
comparable to those reported for cyclic OC
regimen except for higher rates in those related to
uterine bleeding
D.F. Archer, Contraception, 2006 ; 74 (6) : 439-445
Contraceptive Technology Update, July 2007
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Continuous regimen pills :
How to manage BTB / BTS ?
« … One
approach that may be effective in dealing with
unscheduled bleeding with a continuous regimen pill
is to stop use of pills for two to three days to intensify
the withdrawal bleed...
Instituting a three-day hormone-free interval was
significantly more effective in resolving unscheduled
bleeding / spotting than continuing active pills … » *
* Sulak et al., 2006 (Prospective analysis comparing a 21/7 day regimen vs a 168-day extended regimen of
an OC drospirenone/EE formulation)
Contraceptive Technology Update
July, 2007
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Endometrial histology following 1 year
of continuous daily regimen of
levonorgestrel 90 g / ethinyl estradiol 20 g (LYBREL®)
« … The results of a 1-year continuous regimen
of LNG 90 g / EE 20 g were shown to have a
good endometrial safety profile* »
* No hyperplasia or malignancy
Johnson J.V et al.
Contraception, 2007 ; 75 (1) : 23-26
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Continuous or extended cycle versus cyclic
use of COCs ? (1)
« … One size does not fit all.
For patients on a 21/7 regimen with no hormone
withdrawal symptoms who are not bothered and in
fact are reassured by monthly withdrawal bleeding,
alterations in the standard regimen are not
necessary and are not recommended … »
P.J. Sulak et al. Contraception 2004 ; 70 : 281-287
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Continuous or extended cycle versus cyclic
use of COCs ? (2)
« … However, for patients who are experiencing significant
symptomatology induced by a monthly 7-day HFI, alterations
can be implemented successfully. Rather than mandating
patients to conform to a set regimen, our approach allows
flexibility in active and hormone-free days to conform to
individual patient needs and desires by incorporating simple
guidelines … »
P.J. Sulak et al. Contraception 2004 ; 70 : 281-287
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Continuous or extended cycle versus cyclic
use of COCs ? (3)
« … Continuous dosing of COCs is a reasonable approach
for women without contraindications to COCs.
Implications for research
More attention needs to be directed towards participant
satisfaction, menstruation-associted symptoms, and longterm health effects of continuous administration.
Randomized controlled trials are not useful for studying
potential long-term sequelae, so case-control studies or postmarketing surveillance will be required… »
Edelman A. et al. The Cochrane Library 2009, Issue 3.
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Part - III To bleed or not to bleed ?
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Choosing when to menstruate... You decide !
Finally, for women, choosing when to
menstruate on their own may be the role of
extended/continuous contraception
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« … To bleed or not to bleed
that is the question … »*
Physicians must help their patients taking COCs how to
manipulate these COCs if and when they want
to bleed or not to bleed
* Coutinho, 2007
Counseling is the key
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To have one’s period...
if I want…
when I want.
1970’s
2010’s ?
To have one’s
period...
if I want…
when I want.
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Women : The second liberation ?
To have one’s period...
if I want…
when I want.
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«… Il faut être prudent mais
non pas timide …»
Voltaire (1694-1778)
Pensées détachées
de M. l’Abbée de Saint-Louis
«… We must be prudent
but not timid …»
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