Seminar Evidence Based Obstetric & Gynecology POGI Cabang Surabaya 17 Juli 2016 - Pullman Hotel Surabaya

1. :
YASMIN/ YAZ® : Pil Kecil, resiko kecil
dengan manfaat yang tak kecil
SURABAYA 17- 07-2016
BUDI SANTOSO

2. 21/7
ED
21/7
triphasic
Qlaira
POP
levonelle
Evra NuvaRing
ulipristal
Depo-Provera
Nexplanon
IUS Cu IUDs
Essure
Filshie clip
non-latex
condoms
Pasante
Unique
Mates Skyn
Avanti Ultima
Latex
condom Femidon
Silicone
diaphragm
FemCap
Persona
NFP
Spermicide

3. Ideal Contraception
 100% Safe
 100% Effective
 Independent of Sexual Intercourse
 Reversible
 Simple to use
 Cheap
 Easy to obtain
 Acceptable to all beliefs
*** Has non contraceptive benefit
How to choose the right contraception for
women

4. Reasons for discontinuation
12%
7%
5%
5%
4%
4%
9%23%
14%
17%
Bleeding irregularities
Nausea
Weight gain
Mood changes
Breast tenderness
Headache
Clinician recommended
No further need
Method related
Unspecified
Most common reason for discontinuation: Bleeding irregularities
Reasons for Discontinuations

5. PENTINGNYA CONSELING

6. Discovered 1960
Introduced in 1961
Very popular very quickly
Changed society and
womens lives
Still most popular method
in most countries

7. Florida Atlantic University Libraries
May 9, 1960 - US FDA approved first ‘COC’
Florida Atlantic
University
Libraries
Father of “The Pill”

8. – Incorporation of the estradiol
(E2) derivative
ethinylestradiol (EE)
– Reduction of EE dose from
greater than 50 mcg/day to
less than 20 mcg/day1
– Introduction of selective
progestogens2
– Recently, development of OCs
using E2, estradiol valerate
(E2V) and estetrol (E4)
Development of Modern OCs
1Barbosa et al. Contraception 2006;73:30–3; 2Sitruk-Ware. Hum Reprod Update 2006;12:169–78.
50 years of
clinical
development
of COCs

9. “Oral contraception is safer than
most people think it is, and low-dose
preparations are extremely safe”
Leon Speroff and Philip Darney
In: A Clinical Guide for Contraception (4th Ed) 2005; 90.

10. 3 Cara Kerja Utama
Pil Kontrasepsi Kombinasi
1. Mencegah Implantasi
2. Mengentalkan Mukus Servik
3. Menekan Terjadinya Ovulasi

11. Klasifikasi Progestin
Progesteron Progesteron alami
Retroprogesteron Didrogesteron
Turunan progesteron Medrogeston
Turunan 17a-hidroksiprogesteron (pregnanes) C21 Medroksi progesteron asetat; megestrol asetat;
Klormadinon asetat; Siproteron asetat
Turunan 17a-hidroksinorprogesteron (norpregnanes) Gestonoron kaproat; Nomegestrol asetat
Turunan 19-Norprogesteron (norpregnanes) C20 Demegestone; Promegeston; Nesteron; Trimegeston
Turunan 19-Nortestosteron (estranes) C18 Noretisteron=Noretindron; Noretisteron asetat;
Linestrenol; Etinodiol asetat; Noretinodrel
Turunan 19-Nortestosteron (gonanes) C17 Norgestrel: Levonorgestrel; Desogestrel;
Etenogestrel; Gestoden; Norgestimet; Dienogest
Turunan Spironolakton Drospirenon
Schindler AE et al. 2003. Maturitas; 46S1:S7-16

12. Profil farmakologis Progestin
Progestogenic / Androgenic Antiandrogenic Antimineralo- Glucocorticoid
activity activity activity corticoid activity activity
Progesterone + - (+) + -
Drospirenone + - + + -
Cyproterone acetate + - + - (+)
Desogestrel + (+) - - -
(active metabolite 3-ketodesogestrel)
Dienogest + - + - -
Gestodene + (+) - (+) -
Levonorgestrel + (+) - - -
Norgestimate + (+) - - -
(main metabolite levonorgestrel)
(+), negligible at therapeutic dosages; -, no effect; +, distinct effect;

13. Drospirenon

14. Sifat Drospirenon
•drsp berbeda dengan progestin lain
– Derivat dari 17 α-spironolactone1,2
– Bersifat Progestogenic, antimineralocorticoid dan
antiandrogenic 1–4
– Tidak ada aktivtas estrogenic, androgenic atau
glucocorticoid1,3,4
– Profil farmakologi mirip dengen progesteron endogen1,3
drsp = drospirenone; 1Krattenmacher R. Contraception 2000;62:29–38;
2Oelkers W, et al. J Clin Endocrinol Metab 1991;73:837–42;
3Muhn P, et al. Contraception 1995;51:99–110;
4Fuhrmann U, et al. Contraception 1996;54:243–51

15. Perbandingan drsp dengan progestin
lain
drsp = drospirenone; MPA = Medroxyprogesterone acetate
Krattenmacher R. Contraception. 2000;62:29–38;
Schindler AE, et al. Maturitas. 2003;46(Suppl 1):S7–16
Progestogenic
activity
Androgenic
activity
Antiandrogenic
activity
Antimineralo-
corticoid activity
Glucocorticoid
activity
Progesterone + - (+) + -
drsp + - + + -
Cyproterone
acetate
+ - + - (+)
Desogestrel + (+) - - -
Dienogest + - + - -
Gestodene + (+) - (+) -
Levonorgestrel + (+) - - -
Norgestimate + (+) - - -
MPA + (+) - - +
Norethisterone + + - - -
+ relevant activity; (+) activity not clinically relevant; – no activity
Positive
effect on
acne and skin
Fewer water
retention-related
symptoms

16. Renin-angiotensin-aldosterone system
Na+/ water retention
K+ elimination
Renin substrate
(angiotensinogen)
- Increased plasma volume
- Increased blood pressure in susceptibles
- Water retention-related symptoms
(edema, bloating, weight gain)
- Increased plasma volume
- Increased blood pressure in susceptibles
- Water retention-related symptoms
(edema, bloating, weight gain)
- Increased plasma volume
- Increased blood pressure in susceptibles
- Water retention-related symptoms
(edema, bloating, weight gain)
ACE
Angiotensin I
Angiotensin II
Aldosterone
Renin
Halbreich V, Monacell E. Prim Psychiatry 2004;11(12):33–40
Drosperinone
Estrogen+
Volume plasma meningkat
Tekanan darah meningkat
Gejala terkait retensi cairan (edema,
kembung, kenaikan berat badan)

17. Aktivitas antimineralokorticoid dari drsp
drsp = drospirenone;
1Krattenmacher R. Contraception 2000;62:29–38;
2Oelkers W, et al. J Clin Endocrinol Metab. 1991;73:837–42;
3Muhn P, et al. Contraception 1995;51:99–110;
4YAZ® prescribing information
drsp
drsp
drsp
Aldosterone receptor
drsp•drsp memiliki aktivitas
antimineralocortikoid 1–4
– drsp berikatan dengan reseptor
aldosterone dan menghambat kerja
hormon aldosterone di ginjal1–3
• Menghasilkan peningkatan
ekskresi sodium dan air serta
retensi beberapa potasium
• Dapat mencegah kembung terkait
estrogen, nyeri payudara, dan
kenaikan berat badan akibat
retensi cairan yang dipicu
estrogen.

18. Aktivitas antiandrogenik dari drsp
1Muhn P, et al. Contraception 1995;51:99–110;
2Thorneycroft IH, et al. Cutis 2004;74:123–30;
3van Vloten WA, et al. Cutis 2002;69(suppl 4): 2–15
drsp drsp
drsp
drsp
Androgene receptor
drsp
drsp = drospirenone; SHBG = sex hormone-binding
globulin
 drsp memiliki sifat anti
androgenik yang
signifikan, dan tidak ada
sifat potensial
androgenik 1
 drsp secara kompetitif
menghambat ikatan
androgen pada reseptor
androgen2
– Menurunkan derajat
keparahan akne dan
seborea.3,4

19. Comparative Clinical Evidence
Drospirenone vs Desogestrel

20. • It is a well-known fact that DSG/EE 30μg
(Novelon) has over 99% contraceptive
efficacy (Pearl Index: 0.05)1
• Data from several studies indicate a Pearl
Index of <0.5 for DRSP/EE 30μg pills is
comparable to any other oral contraceptive
pill.2,3,4
Contraceptive Efficacy

21. 31%
4%
14%
51%
No bleeding Spotting Breakthrough Bleeding (BTB) BTB with spotting
33%
4%
17%
46%
DRSP/EE 30 μg DSG/EE 30 μg
Fig. 3. Cycle control in women taking DRSP/EE 30μg and DSG/EE 30μg pills
INCIDENCE OF INTERMENSTRUAL BLEEDING (SPOTTING AND BREAKTHROUGH BLEEDING)
WAS SIMILAR IN BOTH THE GROUPS
Multicenter, randomised study between DRSP/EE 30μg (n = 311) and DSG/EE 30μg (n = 314)
Foidart JM et al. Eur J Contracept Reprod Health Care 2000;5:124-134.
Keam SJ et al. Treat Endocrinol 2003;2:49-70.
Cycle Control

22. • DRSP pills have been proposed to be of special benefit to those
women who are sensitive to estrogen and therefore susceptible to
fluid-related weight gain.1
• Theoritically, the anti-mineralocorticoid properties of DRSP may
help to counteract this effect, thus decreasing the likelihood for
weight gain.
However it is important to note that
One of the factors responsible for possible water
retention is the EE dose in contraceptive pills. 3
1.Huber J et al. Eur J Contracept Reprod Health Care 2000;5:25-34.
2.Krattenmacher R. Contraception 2000;62:29-38.
3.Oelkers W. Mol Cell Endocrinol 2004;217:255-61.
Effect on Body Weight

23. Open-label, multicenter study
Mean changes in baseline body weight among 326 women using a DRSP/EE 30μg pill for 13 cycles
After an initial statistically significant (p=0.03) weight loss of 0.6 kg by cycle 6,
there was an increase in weight over the remaining 7 cycles,
resulting in a statistically significant (p=0.03) weight gain of 0.7 kg by cycle 13.
Parsey KS et al. Contraception 2000;61:105-111.
Effect on Body Weight with DRSP/EE pill

24. Effect on body weight
DSG/EE 30μg vs DRSP/EE 30μg
Results of a multicenter, open-label, randomised trial with
DRSP/EE 30μg (n=310) and DSG/EE 30μg (n =317):
• Body weight was maintained (+/- 2kg) in most young women
who received DRSP/EE pills for upto 26 cycles.
• Majority of women in both groups did not experience any
change in body weight.
• Weight fluctuations over the treatment period were minor in
most women and the proportions were found to be almost
similar in both groups.
Foidart JM et al. Eur J Contracept Reprod Health Care 2000;5:124-134.
Keam SJ et al. Treat Endocrinol 2003;2:49-70.

25. The mean blood pressure
recordings in young, healthy
women taking either DRSP/EE
or DSG/EE pills remained
within normal limits in clinical
trials
Foidart JM et al. Eur J Contracept Reprod Health Care 2000;5:124-134.
Keam SJ et al. Treat Endocrinol 2003;2:49-70.
EFFECTS ON BLOOD PRESSURE

26. Both contraceptive pills (DRSP / 20EE and DSG / 20EE):
• Are effective, safe and well-tolerated
• Had high user-satisfaction and good cycle control
• Had negligible effect on body weight
Gruber DM et al. Treat Endocrinol 2006;5:115-121.

27. Gynecological Endocrinology
Metabolic changes in overweight and obese
women above 35 years using Ethinylestradiol/
drosperinone combined contraceptive pills: a
3- year case-control study
Mohamed Rezk, Tarek Sayyed, Hamid Ellakwa,
Ahmed Zahran & Awni Gamal
Published online: 05 May 2016.
M. Rezk et al. 2016
Conclusion
Ethinylestradiol/drospirenone combined contraceptive pills do not
alter blood pressure or affect the body weight with favorable
effects on blood lipids in overweight and obese women above the

28. Yaz
Page 28 • BHC 4:3 Template 2003 • June 2011

29. The first low-dose OC with drsp in a unique 24/4-day
regimen
 YAZ® contains EE 20 µg/drsp 3 mg
 The 24/4-day regimen provides three additional days of
EE/drsp with antimineralocorticoid and antiandrogenic
activity
30 hour half-life of drsp extends its
unique activity into the shortened
hormone-free interval (HFI)1,2
Three additional days of
unique antimineralocorticoid
and antiandrogenic activity
OC = Oral contraceptive; EE = ethinylestradiol; drsp = drospirenone
1Radhika D, et al. Gynaecology Forum 2008;13:3–8;
2Blode H, et al. Eur J Contracept Reprod Health Care 2000;5:256–64

30. YAZ® – Angka Pendarahan Intermenstruasi
Sama dengan regimen 21/7
AngkaKejadian(%)
30
25
20
15
10
5
0
Data on file
0 1 2 3 4 5 6 7 8 9 10 11 12
YAZ®
YASMIN®

31. To overview non-contraceptive benefits
ENDOMETRIOSIS
PCOS
AUB
HMB
DISMENORE/
PMS/PMDD
HMB
AUBAUB
PCOS
PMS/PMDD

32. PMS & PMDD
Regimen 24/4 menjaga tingkat fluktuasi hormonal
Another benefits of YAS

33. Definisi PMS
• American College of Obstetrics and Gynecologists (ACOG) menyatakan
bahwa untuk mendiagnosis PMS, wanita setidaknya harus mengalami
salah satu gejala somatik dan afektif1:
• Gejala terjadi tiap siklus pada tiga siklus awal (konfirmasi retrospektif)
dan dialami paling tidak pada dua siklus sebagai konfirmasi prospektif
• Gejala terjadi 5 hari sebelum menstruasi dan berhenti dalam 4 hari saat
menstruasi
• Terjadinya disfungsi sosial ataupun ekonomi (yang dapat diidentifikasi)
Afektif Somatik
 Depresi  Nyeri pada payudara
 Marah meledak-ledak  Kembung
 Gelisah  Sakit kepala
 Bingung  Bengkak pada anggota gerak
 Mudah marah
 Menarik diri dari lingkungan sosial
1. ACOG (American College of Obstetricians and Gynecologists) 2000

34. Definisi PMDD
 Depresi mood nyata*  Sulit berkonsentrasi
 Gelisah/merasa tertekan*  Letargi/lelah
 Labil afektif*  Perubahan nafsu makan/mudah lapar
 Marah/mudah marah*  Gangguan tidur
 Menurun minat pada aktifitas normal*  Perasaan berlebihan
 Gejala fisik (seperti nyeri pada payudara,
bengkak)
1. DSM-IV 2000. *Gejala inti.
• Diagnostic and Statistical Manual of Mental Diseases, 4th ed. (DSM IV)
menyatakan bahwa untuk mendiagnosis PMDD, setidaknya 5 dari gejala
berikut harus terjadi saat premenstruasi (salah satu harus menjadi gejala
inti*)1:
• Gejala dialami pada kebanyakan siklus menstruasi selama setahun
terakhir (konfirmasi retrospektif) dan sedikitnya selama 2 siklus sebagai
konfirmasi prospektif
• Gejala terjadi 5 hari sebelum menstruasi dan berhenti dalam 4 hari saat
menstruasi
• Gangguan aktivitas pekerjaan/sosial/ hubungan dengan sesama (dapat
diidentifikasi)

35. Perbaikan Gejala dengan YAZ®
*p<0.005; change from baseline assessed in subscales from Daily Record of Severity of Problems (DRSP)
Yonkers et al. 2005
• Proporsi pasien dengan YAZ® mencatat adanya penurunan pada gejala DRSP
lebih besar daripada plasebo
YAZ® pada PMDD: desain studi paralel
Proporsiwanita(%)
Gejala fisik Gejala tingkah lakuGejala mood
Plasebo
Perubahan dari baseline dinilai dalam subskala DRSP

36. YAZ® Memperbaiki Poin Daily Record of Severity of
Problems (DRSP) fungsional dibanding plasebo
Perubahanskor/mean’
daribaseline
*p<0,05 vs. placebo; decrease = an improvement
Pearlstein et al. 2005
*
*
*
YAZ® pada PMDD: desain studi silang (hal 4/6)
plasebo; penurunan = adanya perbaikan
Plasebo
Penurunan
produktivitas
Terganggunya
aktivitas sosial
Gangguan
relationship

37. Kesimpulan
 YAZ® adalah kontrasepsi oral dosis rendah yang
mengandung drospirenon
Drospirenon memiliki sifat anti androgenik dan anti mineralokortikoid yang
sama dengan progesteron endogen
 YAZ® terdiri dari terapi aktif 24 hari, dilanjutkan dengan 4
hari interval bebas hormon (regimen 24/4)
Interval bebas hormon selama 4 hari memungkinkan terjadinya menstruasi
tiap bulannya, seperti yang diinginkan oleh kebanyakan wanita
 Interval bebas hormon yang dipersingkat dengan YAZ®
menyebabkan:
Berkurangnya fluktuasi estradiol endogen
 Tambahan 3 hari aktifitas anti androgenik dan anti
mineralokortikoid setiap siklus 28 hari

40. Conclusions
The risk of venous thromboembolism is increased among
OC users (3–9/10,000 woman-years) compared with
nonusers who are not pregnant and not taking hormones
(1–5/10,000 woman-years), and some data have
suggested that the use of drospirenone-containing OC
pills has a higher risk (10.22/10,000) than the use of
other progestin-containing Ocs . However this risk is still
very low and is much lower than the risk of
thromboembolism during pregnancy (approximately 5–
20/10,000 woman-years) and the postpartum period
(40–65/10,000 woman-years)

41. Rekomendasi
Berdasarkan laporan mengenai peningkatan thromboembolisme vena pada pengguna
kontrasepsi oral yang mengandung drospirenone, American College of Obstetricians and
Gynecologists Committee on Gynecologic Practice merekomendasikan hal-hal sebagai
berikut:
 Keputusan mengenai pilihan kontrasepsi oral harus diserahkan pada klinisi dan pasien,
dengan memperhatikan faktor-faktor berikut ini:
 Resiko peningkatan thromboembolisme vena minimal yang mungkin terjadi pada
pengguna baru kontrasepsi oral yang mengandung drospirenone dibandingkan
dengan pengguna kontrasepsi oral yang dikombinasi (10.22/ 10,000 wanita-tahun
dibandingkan dengan 3-9/10,000 wanita-tahun)
 Preferensi pasien
 Alternatif yang tersedia
 Wanita hendaknya memiliki berbagai macam pilihan kontrasepsi, termasuk kontrasepsi
oral yang mengandung drospirenone
 Jika pasien sedang menggunakan kontrasepsi oral yang mengandung drospirenone dan
mentoleransi rejimen, maka tidak perlu menghentikan kontrasepsi oral tersebut
 Ketika memberi resep kontrasepsi oral, klinisi hendaknya mempertimbangkan faktor
resiko pada wanita untuk thromboembolisme vena (Kotak 1) dan merujuk pada US
Medical Eligibility Criteria untuk Penggunaan Kontrasepsi (16, 17)
 Materi pendidikan pasien, termasuk pelabelan produk, hendaknya menempatkan
informasi mengenai resiko thromboembolisme vena dalam konteks dengan
memberikan informasi tentang keseluruhan resiko thromboembolisme vena dan resiko
thromboembolisme vena selama kehamilan dan periode pasca persalinan

42. High-Risk Factors for Venous Thromboembolism in Users of
Combined Oral Contraceptives*
• Smoking and age 35 years or older
• Less than 21 days postpartum or 21–42 days postpartum with
other risk factors
• Major surgery with prolonged immobilization
• History of deep vein thrombosis or pulmonary embolism
• Hereditary thrombophilia (including antiphospholipid
syndrome)
• Inflammatory bowel disease with active or extensive disease,
surgery, immobilization, corticosteroid use, vitamin
deficiencies, or fluid depletion
• Systemic lupus erythematosus with positive (or unknown)
antiphospholipid antibodies