new oral contraceptive pills has to be evaluated

1. Update on Contraception:
21/7 vs 24/4
Hesham Al-Inany, M.D, PhD

2. Change
1960 2017

3. Change
Combined oral contraceptive (COC):
 Usually ethinylestradiol combined with a progestogen (1/2/3/4 generation)
1st generation 2nd generation 3rd generation 4th generation
norethisterone
(e.g. Loestrin®)
levonorgestrel
(e.g. Microgynon®)
desogestrel
(Mercilon®, Marvelon®)
Yasmin®
etynodiol diacetate
(only in progestogen-
only pill)
gestodene
(e.g. Gynera®,
Femodene®)
Yaz
norgestimate (Cilest®)

4. So Why this talk?
New concept in OCP intake

5.  The progestogen Drospirenone (DRSP) resembles
natural progesterone more than any other synthetic
progestogen contained in currently marketed pills:
 antimineralocorticoid effect = counteracts water
retention
 no androgenic effect = beautiful skin
What is special ?

6. yasmin
Regular Cycles
91%
Well Tolerated
94%

7. However
often allow follicular development
23 - 37% of cycles have follicles >13 mm
with 30 µg EE*
Up to 60% of cycles have follicles >13 mm
with 20 µg EE*

8. Traditionally
Traditional forms of OCP contain 21 days
of hormone-containing pills and 7 days of
placebo during the hormone-free interval
(HFI).
Menses usually starts within 48hrs
Start OCP again on CD5
21/7

9. However
The increase in FSH during the pill-free
interval is responsible for follicular growth
and estradiol production

10. NEW concept
24/4

11. contains EE 20 µg/drospirenone 3 mg
New : Yaz
Three additional days of
antimineralocorticoid and
antiandrogenic activity per
28-day cycle

12. Mean
follicle
size
(mm)
12
10
8
6
4
2
0
2
4
6
8
10
12
Mean
follicle
size
(mm)
Pre-treatment cycle1
Concept has to be tested
1Klipping C, et al. Contraception 2008; 78: 16–25; 2Bayer HealthCare
Pharmaceuticals, data on file (protocol number 308382)
12
10
8
6
4
2
0
2
4
6
8
10
12
YAZ® Yasminelle®

13. YAZ® effectively inhibits follicular
development
Cycle 21
Correct dosing regimen
Mean
follicle
size
(mm)
12
10
8
6
4
2
0
2
4
6
8
10
12
12
10
8
6
4
2
0
2
4
6
8
10
12
Mean
follicle
size
(mm)
1Klipping C, et al. Contraception 2008; 78: 16–25; 2Bayer HealthCare
Pharmaceuticals, data on file (protocol number 308382)
YAZ® Yasminelle®

14. YAZ® effectively inhibits follicular
development
Mean
follicle
size
(mm)
12
10
8
6
4
2
0
2
4
6
8
10
12
12
10
8
6
4
2
0
2
4
6
8
10
12
Mean
follicle
size
(mm)
Cycle 31
3 intentionally missed pills at beginning of cycle
1Klipping C, et al. Contraception 2008; 78: 16–25; 2Bayer HealthCare
Pharmaceuticals, data on file (protocol number 308382)
YAZ® Yasminelle®

15. So 24/4 concept
Shortening the hormone-free interval to 3
or 4 days results in greater inhibition
follicular development and suppression of
ovarian steroid synthesis

16. EE-Dprs
24/4 regimen provides 3 extra days of anti-
mineralocorticoid and antiandrogenic
activity per 28-day cycle relative to
conventional 21+7 day OCs Blode H, et al. 2000

17. S.E
The shortened HFI interval with the 24/4
regimen could minimize hormone-
withdrawal symptoms that may occur with
conventional regimens
 i.e. headaches, cramps, breast
tenderness and bloating/swelling

18. Results
Sulak et al. 2000
Symptoms
Hormone treatment
(21 days)
%
Hormone-Free
Interval (7 days)
% P-value
Pelvic pain 21 70 <0.001
Headaches 53 70 <0.001
Breast tenderness 19 58 <0.001
Bloating/swelling 16 38 <0.001
Use of pain medications 43 69 <0.001

19. Extended-contraceptive regimen delays
menses and reduces bleeding, a profile
that may be preferred by women who
seek flexibility with their contraceptive
method Bustillos-Alamilla 2010

20. What about the safety?

21. Effectiveness of YAZ® in a real-life
setting: INAS-OC study outline (1)
Design1
• Prospective, controlled, active surveillance, noninterventional cohort
study in the USA and 6 European countries
• Participants recruited via an international network of gynecologists
• Follow-up via direct contacts with study participants
Cohorts1
• EE/drospirenone in a 24/4 regimen, e.g. YAZ®, EE/drospirenone in a
21/7 regimen, e.g. Yasmin®, OCs containing progestins other than
drospirenone
EE = ethinylestradiol; INAS-OC = International Active Surveillance Study on Oral
Contraception; OC = oral contraceptive
1Dinger J, et al. BMC Med Res Methodol 2009; 9: 77

22. Effectiveness of YAZ® in a real-life
setting: INAS-OC study outline (2)
Sample Size1
• >85,000 OC users (52,218 US; 33,042 Europe)
• >220,000 WY of exposure
Study Period1
• 2005 to 2012
INAS-OC = International Active Surveillance Study on Oral Contraception;
OC = oral contraceptive; WY = women-years
1Dinger J, et al. BMC Med Res Methodol 2009; 9: 77

23. Effectiveness of YAZ® in a real-life
setting: INAS-OC study objectives
Study objectives1
• To compare cardiovascular safety of EE/drospirenone in a
24/4 regimen, e.g. YAZ®, to established OCs during standard clinical
practice (e.g., DVT, PE, AMI, stroke)
• To investigate incidence of rare SAEs associated with use of
EE/drospirenone in a 24/4 regimen, e.g. YAZ®, and established OCs
• To investigate contraceptive failure rates associated with use of
EE/drospirenone in a 24/4 regimen, e.g. YAZ®, EE/drospirenone in a
21/7 regimen, e.g. Yasmin®, and OCs containing progestins other than
drospirenone
AMI = acute myocardial infarction; DVT = deep vein thrombosis; EE = ethinylestradiol;
INAS-OC = International Active Surveillance Study on Oral Contraception; OC = oral
contraceptive; PE = pulmonary embolism; SAE = serious adverse event
1Dinger J, et al. BMC Med Res Methodol 2009; 9: 77

24. Effectiveness of YAZ® in a real-life setting:
INAS-OC contraceptive effectiveness findings (1)
Contraceptive failure was assessed in 52,218 US participants with 1,634
unintended pregnancies during 73,269 WY of OC use (interim data)1
 YAZ® cohort showed the lowest contraceptive failure rate1
Lower rate of contraceptive failure was even more pronounced in
adolescents:2
• Pearl Index for 24/4 regimens: 2.5 (95% CI 2.1–2.9)
• Pearl Index for 21/7 regimens: 5.1 (95% CI 3.7–6.8)
CI = confidence interval; EE = ethinylestradiol; OC = oral contraceptive; WY = women-years
1Dinger J, et al. Obstet Gynecol 2011; 117(1): 3340;
2Dinger J. J Fam Plann Reprod Health Care 2011; 37(2): 118
OC Pearl Index (95% CI)
Overall 2.2 (2.1–2.3)
EE 20 µg/drospirenone 3 mg in a 24/4 regimen, e.g. YAZ® 1.6 (1.4–1.9)
EE 30 µg/drospirenone 3 mg in a 21/7 regimen, e.g. Yasmin® 2.2 (1.8–2.6)
Other OCs containing progestins other than drospirenone 2.6 (2.4–2.7)

25. Effectiveness of YAZ® in a real-life setting:
INAS-OC contraceptive effectiveness findings (2)
Adjusted hazard ratio = 0.7 (95% CI 0.6–0.8) for EE 20 µg/drospirenone 3 mg
in a 24/4 regimen, e.g. YAZ®, versus EE 30 µg/drospirenone 3 mg in a 21/7
regimen, e.g. Yasmin®1
EE 20 µg/drospirenone 3 mg in a 24/4 regimen, e.g. YAZ®, had the highest
contraceptive effectiveness during routine usage1
INAS-OC, a large post-approval study under real-life conditions,
shows that YAZ® has high contraceptive effectiveness1
CI = confidence interval; EE = ethinylestradiol; OC = oral contraceptive
1Dinger J, et al. Obstet Gynecol 2011; 117(1): 3340

28. COC & VTE…
Situation Risk - VTE Incidence -VTE
Gen. population - 5/100,000
COC – LNG/NET 3 fold 15/100,000
COC – gestodene or desogestrel 5 fold 25/100,000
Pregnancy 12 fold 60/100,000

29. 24/4