1 Contraception orale avec extension ou continue : l’aménorrhée serait-elle la règle ? XII ème JLGO Liège, septembre 2009 David Serfaty, Paris

2  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 :

3  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 :

4 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 ?

5 Part - I - Shortening the pill free interval

6 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). Shortening the pill free interval (1)

7 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… Shortening the pill free interval (2)

8 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   …

9 « … 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

10 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

11 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.   Design ► ► Phase 2, double blind, randomized, single-center, parallel-group, regimen validation study. ► ► One ovulatory pretreatment cycle followed by three treatment cycles. ► ► n = 80 SERFATY David, CHRTISTIN MAITRE Sophie, OCHSENBEIN Edith, THOMAS Jean-Louis. FIGO 2009, Cape Town

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13 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

14 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)*… » Contraceptive Technology Update. August, 2008 * And probably for the treatment of withdrawal symptoms, primary dysmenorrhoea, and sexual dysfunctions…

15 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 :

16 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 : Yaz ® has been approved in 74 countries in contraception ; in PMDD in 30 countries, and in acne in 34 countries.

17 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

18 Part - II - Extended or continuous cycle versus cyclic use of COCs

19 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 :

20 Conditions for which reduced menstrual frequency or amenorrhea may have therapeutic benefit   Menorrhagia associated with : ► ► Uterine bleeding disorders (leiomyoma / adenomyosis) ► ► Inherited bleeding disorders : - - Von Willebrand’s disease - - Hemophilia - - Factor XI deficiency ► ► Acquired bleeding disorders - - 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 :

21 « … 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 : Den Tonkelaar et al. Contraception, 1999 ; 59 : Ferrero S et al. Contraception, 2006 ; 73 : Thomas SL et al. Lancet, 2000 ; 355 : Edelman A et al. Contraception, 2007 ; 75 : Snow R et al. Contraception, 2007 ; 76 : 23-29

22   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

23 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

24 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

25 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

26 Long-term safety of an extended regimen oral contraceptive (Seasonale ® ) : A 2-year multicenter open label trial « … 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 … » D. Portman et al. Contraception 2005 ; 72 :

27 Extending the 21/7 pill regimen : The pros and cons AdvantagesDisadvantages  ↑ Convenience  ↑ Compliance  Minimization of cyclic symptoms  Increased non contraceptive benefits  Seasonale ® = ↑ 23 % of annual total doses of estrogen and progestin  Theoretical concerns : long-term avderse effects ? ► Cardiovascular risk ? ► Cancer risk ? ►...

28 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

29 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 = )   USER FAILURE : PEARL INDEX* = 0.34 (95 % CI = ) D.F.Archer Contraception, 2006 ; 74 (6) :

30 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) : Contraceptive Technology Update, July 2007

31 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 … » * Contraceptive Technology Update July, 2007 * Sulak et al., 2006 (Prospective analysis comparing a 21/7 day regimen vs a 168-day extended regimen of an OC drospirenone/EE formulation)

32 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

33 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 :

34 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 :

35 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 long- term health effects of continuous administration. Randomized controlled trials are not useful for studying potential long-term sequelae, so case-control studies or post- marketing surveillance will be required… » Edelman A. et al. The Cochrane Library 2009, Issue 3.

36 Part - III - To bleed or not to bleed ?

37 Choosing when to menstruate... You decide ! Finally, for women, choosing when to menstruate on their own may be the role of extended/continuous contraception

38 « … 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

39 To have one’s period... if I want… when I want. To have one’s period... if I want… when I want. 1970’s 2010’s ?

40 Women : The second liberation ? To have one’s period... if I want… when I want.

41 «… Il faut être prudent mais non pas timide …» Voltaire ( ) Pensées détachées de M. l’Abbée de Saint-Louis «… We must be prudent but not timid …»