KİŞİSELLEŞTİRİLMİŞ OC SEÇİMİ

KOK 1960 1970 1980 1990 2000 İlk oral kontraseptif: 150 g mestranol  9.35 mg noretinodrel 1960 Yan etki  Risk  Prodrug mestranol Etinil Estradiol (50 g) 1970 EE (50 g) 35 g 30 g 20 g Yeni, düşük dozda ama daha güçlü progestinler - Estran’lar (1. kuşak) yerine Gonan’lar (2.kuşak) (noretisteron levonorgestrel) 1980 1990 3. kuşak (Gonan’lar) 2000 4. kuşak (Dienogest, Drospirenon) Wilkie J,. Combined oral contraceptives in the new millennium. What pharmacists know. Canadian Pharmacists Association 2007 Home Study Program. 2

Kontraseptif Seçeneklerin Gelişimi Anovlar Avrupa’daki ilk OK Diane 35 İlk anti- androjenik OK Microgynon İlk düşük doz Mirena İlk rahimiçi sistem 1961 1972 1973 1979 1985 1987 1990 1995 2001 2006 2009 İlk DRSP içeren OK Sınıfının ilk E2 içeren OK’sı Microlut Avrupa’daki ilk progesteron Triquilar İlk 3 fazlı OK Ginera İlk GSD içeren OK DNG/EE2 İlk DNG içeren OK İlk 24+4 DRSP İçeren OK Etinilestradiol dozunu azaltmak Kontrasepsiyonla birlikte ek faydaları olan progestinler Uygulama rejimindeki değişiklikler Doğala özdeş östrojen kullanımı

Östrojen ve Progestinler Östrojenler - Etinil östradiol (EÖ) (17. Karbona etinil eklenmesi degradasyonunu yavaşlatmıştır) - Mestranol (EÖ+metil grubu) - Estradiol Valerat Progestinler - Estran (19-nor progestinler) testosterona benzer yapı - Pregnan(17-asetoksi bileşikleri) Progesterona benzer

Östrojen ve Progestinler Estran grubu: OK’lerde kullanılmakta Levonorgestrel, norethindrone reseptörlere direkt bağlanır Norgestimate, Gestodene, Desogestrel bioaktivasyona gereksinim vardır. Diğer 19- norprogestinlerden daha selektifler Pregnan grubunda: Medroksiprogesteron asetat majör enjektabl progestin

Fertilite önleyici etki mekanizmaları Ö ve P tek tek ovulasyonu inhibe ederler Kombine edildiğinde farmakolojik sinerjizm= daha düşük dozlar Metod başarısızlığı % 0.1-0.3 Sadece P ile % 20-40 ovulatuar siklüsler Servikal mukusa etki Endometriuma etki Tubal motiliteye etki Metod başarısızlığı % 0.5

Progestinlerin antiöstrojenik etkileri Nukleustaki Östrojen reseptörleri azalır 17 hidroksisteroid dehidrogenazı aktive ederek doğal 17 beta estradiolün metabolizasyonunu indükler Progesteron reseptörlerini azaltır

Kombine OK’lardaki Östrojenin etkileri Endometrial stabilite Kırılma kanamaları azalır Progesteronun etkisini artırmadaki rolü P reseptörlerini artırır

Doz azaltımında amaç İstenmeyen etkilerin azaltılması İstenen etkilerin devamının minimum dozda sağlanması Azaltılması istenenler MI riski İnme (SVO) Venöz tromboemboliler (VTE) Yan etkiler Başağrısı Bulantı Göğüslerde dolgunluk Kilo artışı

Korunmak istenenler Kontraseptif etkinlik Siklüs kontrolü Non kontraseptif yararlar Anemi PID Over ve endometrium ca Dismenore Ektopik gebelik Fonksiyonel over kistleri Benign meme hast. Kolorektal kanser? Uterin Leiomyom? (Oxford Family Planning)

Sentetik progestinlerin sınıflandırması Progestagenler C-21 progestojenler C-19 nortestosteron Spirolakton Pregnanlar Estranlar Gonanlar Drospirenone MPA Megestrol asetat Siproteron asetat Klormadinon asetat Trimegeston Noretindron Noret. asetat Etinodiol diasetat Linestrenol Noretinodrel Norgestrel Levonorgestrel Norgestimat Desogestrel Gestoden Dienogest C27 Kolesterin C21-Steroid hormonu (Progesteron) C19 Testosteron C18 Östrojen Drospirenon 17-spirolaktondan türetilen yeni bir progestin kategorisinin ilkidir. Tüm hormonal kontraseptifler östrojen bileşenine sahip olan ya da olmayan progestin içerir. Şu an mevcut olan OK preparatlarında, progestin "haptan hapa" değişirken, östrojen bileşeni neredeyse her zaman etinilestradioldür. Progestinler, türetildikleri ana moleküle bağlı olarak farklı farmakolojik özelliklere sahiptir. Genellikle türetilme durumlarına göre üç gruba ayrılırlar: 17-spirolakton, 17-hidroksiprogesteron (veya C-21 progestin ) ve C-19 nortestosteron. Drospirenon OK preparatlarında kullanılan, bir cinsiyet steroidinden türetilmeyip 17a-spirolaktondan türetilen ilk sentetik progestindir ve kimyasal olarak diüretik ve antihipertensif bir ilaç olan spironolaktona benzerlik gösterir. Diğer progestinlerin aksine, antimineralokortikoid (aldosteron antagonistik) ve antiandrojenik özelliklere sahiptir ve farmakolojik bakımdan endojen progesterona benzer. Drospirenon, steroid hormonların temel dört halkalı yapısal özelliğine sahiptir, ancak aynı zamanda iki metilen grubuna sahiptir; biri C-6 ve C-7'ye ve diğeri de C-15 ve C-16'ya bağlıdır. Ayrıca, bir karbolakton grubu C-17'ye bağlıdır. 17-hidroksiprogesteron olarak adlandırılan bir diğer progestin grubu da progesterondan türetilir. Bu grup, siproteron asetat (Diane-35) ve medroksiprogesteron asetat (Depo-Provera) gibi az sayıda progestini içine alır. Testosterondan türetilen progestinler androjen reseptörünü bağlar ve çok değişken androjenlik derecelerine sahiptir. Bu progestinler arasında noretindron (Ortho 1/35), levonorgestrel (Alesse, Triphasil, Triquilar ve Mirena), norgestimat (Tri-Cyclen) ve desogestrel (Marvelon, Linessa) yer alır. Norelgestromin transdermal kontraseptif yamada (Evra) bulunan progestindir. Etonogestrel vajinal kontraseptif halkada (NuvaRing) bulunan progestindir. MPA = medroksiprogesteron asetat 11

PROGESTİNLERİN FARMAKOLOJİK AKTİVİTELERİ Farmakolojik Aktivite Progesteron& Progestinler Farmakolojik Aktivite Progestojenik Androjenik Anti androjenik Antimineralo kortikoid Glukokortikoid Progesteron + - (+) Drospirenon Gestoden Norgestimate Levonogestrel Desogestrel Siproteron asetat Dienogest Nomegestrol Nestorone Trimegestone Krattenmacher R. Contraception 2006;62:29-38 -: etki yok, (+): zayıf etki, +: etkili

Progestinlerin etki düzeyleri farklıdır. CPA: Siproteron asetat; DSG: Desogestrel: LNG: Levonorgestrel; MPA: Medroksiprogesteron asetat; NES: Nesteron; NET: Noretisteron; NOMAc: Nomegestrol asetat; TMG: Trimegeston Simon JA. : The Journal of Family Practice 2007;Suppl:3-5.

Estrojen Dozu 30/20

2013

Kontraseptif etkinlik

Düzensiz Kanama 3. siklus

Düzensiz Kanama 6. siklus

Düşük Doz Östrojen İçeriğinin Avantajları Oral kontraseptiflerin östrojen dozlarının düşürülmesi VTE Kardiyovasküler komplikasyonlar Meme hassasiyeti, bulantı, şişkinlik hissinde azalma sağlamıştır. Dezavantajı Ara kanamalar VTE riski 50 mcg 30-40 mcg 1.6 1.2 0.8 0.4 Etinil östradiol dozu 20 mcg

Estrojen Tipi E2V/EE

Neden Östradiol Valerat? EE yan etkilerden sorumlu1,2 Karaciğer metabolizması üzerine etki Venöz thromboemboli riskinde artış (VTE) Lipid seviyeleri ve kan basıncı üzerine etki Karaciğer üzerine olan etkilerin etinil grup3 ile ilgili olduğu düşünülüyor 1. Kuhl. Ideal dose of ethinylestradiol. In: Elstein, ed. Extragenital effects of oral contraceptives. New York: Parthenon Publishing Group; 1997;27–38; 2. Hoffmann et al. Drugs Today. 1999;35(Suppl C):105–113; 3. Hoffman et al. Exp Toxicol Pathol. 1998;50:459–464.

Qlairista - E2V/DNG Östradiol valerat (E2V) ve dienogest (DNG) içeren bir dinamik doz rejimi Östrojen ve progesteron arasında bir denge var Nahum et al. Obstet Gynecol. 2008;111(Suppl 4):15S (abstract plus poster presentation); Ahrendt et al. Contraception. 2009; DOI 10.1016/j.contraception.2009.03.018.

E2V, E2'ye hidrolize olur Östradiol valerat Gİ kanal Östradiol Karaciğer E2 E2 E3 Östriol E3 E1S E1 Östron E1 E1S Östron sülfat V CO2 ve H2O Düsterberg & Nishino. Maturitas 1982;4:315–24.

farmakokinetik / farmakodinamik benzer E2V, E2'ye hidrolize olur Östradiol valerat Gİ kanal E2V ve E2 farmakokinetik / farmakodinamik benzer Östradiol V E2 V E2 E2 E2 V E2 E2 V Karaciğer E2 E2 E3 Östriol E3 E1S E1 Östron E1 E1S Östron sülfat V CO2 ve H2O Düsterberg & Nishino. Maturitas 1982;4:315–24.

EE'ye kıyasla E2V'nin Biyolojik Etkileri FSH baskılama E2V 2 mg = yaklaşık 20 mcg EE1–3 Endometrial stimülasyon E2V 2 mg = yaklaşık 20 mcg EE3 Vajinal yüzey hücre olgunlaşması Hepatik protein sentezi E2V 2 mg, 20 mcg EE'den azdır1,4-6 FSH: Folikül uyarıcı hormon. 1Mashchak et al. Am J Obstet Gynecol 1982;144:511–8; 2Endrikat et al. Contraception 2008;78:218–25; 3Dosyada yer alan veriler; klinik çalışma raporu B709, 2000; 4Lindberg et al. Thromb Haemost 1989;61:65–9; 5Wiegratz et al. Contraception 2004;70:97–106; 6Helgason. Acta Obstet Gynecol Scand 1982;107(Suppl.):1–29.

Oral Kontraseptifler Tedavide kullanımı

RUHSATLI ENDİKASYONLAR Gebeliğin önlenmesinde onaylanmıştır* Kontrasepsiyonda isteyen kadınlarda emosyonel ve fiziksel semptomların PMDD tedavisinde onaylıdır** Orta derecede akne tedavisinde onaylıdır***

RUHSATSIZ ENDİKASYONLAR PCOS Hiperandrojenemi (Hirsutizm vb.) Endometriozis Dismenore Anormal uterin kanama (Qlairista®) Menstruel Siklüs düzensizlikleri

Endometriyum, Over ve Kolorektal Kanserlerde azalma İleri yaşta KMD nin artması Düzenli Menstrüel siklus sağlama İhtiyaç anında amenore sağlamak için siklus kontrolü Premenstrüel migrenlerde azalma Akne tedavisi Leiomyom kanamalarının tedavisi Dismenore tedavisi Hirsutizm tedavisi Menoraji tedavisi Endometriozise bağlı pelvik ağrı tedavisi Premenstrüel sendrom tedavisi ACOG Bülten no 110, Obstet Gynecol, 2010

En sık uygulanan kombinasyonlar 2 mg dienogest (n = 114; 37 En sık uygulanan kombinasyonlar 2 mg dienogest (n = 114; 37.5%) ve  3 mg drospirenone (n = 69; 22.7%). OBJECTIVES: To investigate prescribing preferences and personal experience of female gynaecologists with extended-cycle use of combined oral contraceptives (COCs) in Germany and Austria. METHODS: A questionnaire on prescribing patterns and personal experience with extended COC regimens was delivered to female gynaecologists practising in Germany and Austria. RESULTS: Of 2,500 delivered questionnaires, 1,113 were returned. After exclusion of 22 invalid questionnaires, the remaining 1,091 (43.6% of delivered questionnaires) remained eligible for analysis and were considered as the full analysis set (100%). Nearly all gynaecologists (97%) reported prescription of extended-cycle regimens to their patients, independent of their personal experience as users. The main medical reasons for prescription were cycle-related headache (93.8%), dysmenorrhoea (88.2%), cycle-related complaints (74.5%), and hypermenorrhoea (70.9%). In total, 863 gynaecologists had personally used COCs, 321 (37.2%) in extended-cycle regimen. The most commonly employed combinations were 30 μg ethinylestradiol (EE) + 2 mg dienogest (n = 114; 37.5%) and 30 μg EE + 3 mg drospirenone (n = 69; 22.7%). CONCLUSIONS: Although considered off-label use, extended-cycle use of COCs is widely prescribed and personally used by German and Austrian female gynaecologists. The lack of personal experience with extended-cycle use does not impair the prescribing habit of gynaecologists with regard to extended-cycle regimens

Adolesan kızlarda dismenore tedavisinde oral kontraseptif kullanımı: Randomize çalışma. OBJECTIVE: To assess whether a low-dose oral contraceptive (OC) is more effective than placebo treatment for dysmenorrhea pain in adolescents. METHODS: This was a randomized, double-blind, placebo-controlled clinical trial of 76 healthy adolescents aged 19 years or younger reporting moderate or severe dysmenorrhea. Subjects were randomly allocated to receive either an OC (ethinyl estradiol [E2] 20 microg and levonorgestrel 100 microg) or a matching placebo for 3 months. Participants used their usual pain medications as needed during the trial. The main outcome measure was score on the Moos Menstrual Distress Questionnaire (pain subscale) for the third menstrual cycle on treatment. Secondary outcomes included pain intensity (rated 0 to 10), days of any pain, days of severe pain, hours of pain on worst day, and use of pain medications. RESULTS: The mean Moos Menstrual Distress Questionnaire pain score was lower (less pain) in the OC group than the placebo group (3.1, standard deviation 3.2 compared with 5.8, standard deviation 4.5, P = .004, 95% confidence interval for the difference between means 0.88-4.53). By cycle 3, OC users rated their worst pain as less (mean pain rating 3.7 compared with 5.4, P = .02) and used fewer pain medications than placebo users (mean pain pills used 1.3 compared with 3.7, P = .05). By cycle 3, OC users reported fewer days of any pain, fewer days of severe pain, and fewer hours of pain on the worst pain day than placebo users; however, these differences did not reach statistical significance. CONCLUSIONS: Among adolescents, a low-dose oral contraceptive relieved dysmenorrhea-associated pain more effectively than placebo. MMDQ: Moos Mentruel Distress Questionnaire KOK: 20µg EE+100 µg LNG Davis AR, 2005

Oral contraceptives for pain relief from dysmenorrhea: a review Two NSAID trials (N=10–337). Ethinylestradiol/chlormadinone acetate was the only formulation that provided a more pronounced relief of suggest a beneficial effect for dysmenorrheic pain relief and were conducted mainly in larger populations (N=41–6169) than those in the RCTs and six nonrandomized observational or prospective studies assessing the effect of hormonal contraceptives on dysmenorrhea strongly Two RCTs that report the effects of hormonal contraceptives widespread between the hormonal contraceptive studies. dysmenorrheic pain compared with a parallel alternative or previously used hormonal contraceptive. Methodological inconsistencies were two trials, a small (N=76), single-center trial that enrolled have been published since 2004 [80,81]. One of these (specifically COCs) on pain caused by dysmenorrhea adolescent females aged 19 years or younger with moderate dysmenorrheic pain [80]. Significantly lower pain scores ethinylestradiol (EE)/0.1 mg levonorgestrel (LNG) on or severe dysmenorrhea, measured the effect of 0.02 mg Furthermore, analgesic use was reduced in both group (p=.004 using the Moos Menstrual Distress Questionnaire). were recorded in the OC group compared with the placebo groups during the study, but the reduction was significantly reduction in pain frequency and severity, although these Cycle 3, the EE/LNG group also reported a comparative more pronounced in the OC group (p=.05). By Medication reviewed here was a larger (N=998), multicenter trial The other RCT investigating a hormonal contraceptive secondary outcomes did not reach statistical significance. conducted in Germany and the Netherlands that compared control, quality of life and acne in an adult female population either 0.15 mg desogestrel (DSG) or 0.1 mg LNG on cycle the effect of two low-dose COCs containing 0.02 mg EE and diary cards completed by the trial subjects. The baseline assessed at baseline and Medication Cycles 1, 3 and 6 using (18–45 years). In addition, changes in dysmenorrhea were occurrence of dysmenorrhea was 56.7% and 54.7% in drop in dysmenorrhea occurrence to 40% and 38%, respectively, and treatment with COCs resulted in an equal women assigned to the EE/DSG and EE/LNG groups, are provided is not stated). Also, the severity of dysmenorrhea although the specific treatment cycle from which these data respectively (presumably recorded at Treatment Cycle 6, decreased comparably in both treatment groups at Cycle resulting from medication was not analyzed statistically. did not employ any numerical scales and the decrease in pain 6 compared with baseline. The methods of pain assessment the effect of hormonal contraceptives on dysmenorrhea: four either a lack of a control group or nonrandomization) studied Six studies not conforming to an RCT model (due to using COCs [84–87], one using a noncombined formulation under investigation improved the symptoms of dysmenorrhea, although three of these do not support their [83]. All six studies found the hormonal contraceptives [82] and one delivering a combined formulation transdermally either a complete resolution or an improvement of Despite a lack of statistical support, Ahrendt et al. [82] found dysmenorrhea findings with statistical analyses [82,83,87]. dysmenorrhea symptoms in 93% of subjects receiving oral EE/norelgestromin transdermal patch (actual subject numbers dysmenorrhea symptoms was reported following use of an DSG without EE by the study end; a 39% decrease in rare dysmenorrhea and 1939 subjects reporting frequent dysmenorrhea at admission (N=6169; 4230 subjects reporting not provided) [83]; and in a subgroup of women who had hormonal contraceptive to a COC containing 0.03 mg EE/2 resolution in 61.1% following a switch from their former dysmenorrhea), Schramm and Heckes [87] report complete dysmenorrhea on admission, with 95% reporting an greatest benefit was documented in those with frequent mg CMA (actual subject numbers not provided). The improvement or complete resolution of symptoms. A observational study carried out in 170 healthy females (aged EE/CMA intake has also been described in a prospective comparatively greater reduction in dysmenorrhea following mg drospirenone (DRSP). A progressive and significant benefits of 0.03 mg EE combined with either 2 mg CMA or 3 between 14 and 19 years) that assessed the noncontraceptive reduction in mild and moderate dysmenorrhea was found compared with baseline, but the benefits subsequently advantages were achieved for both groups after three cycles only in the EE/CMA group (pb.01) [86]. Noncontraceptive assessed the effects of a collection of COCs (containing EE In a small (N=41), multicenter study, Kido et al. [84] increased only in the EE/CMA group. combined with LNG, norethisterone or norgestrel in various placebo pill was administered). In the OC group, the degree comparison to a group not receiving an OC (although no formulations) on uterine contractility and menstrual pain in In a prospective Japanese quality-of-life (QoL) study, 217 severe menstrual pain occurred. of experienced pain was statistically lower (p=.012) and no women were divided into groups based on their reasons for QoL, and the assessment tool employed was the WHOQOLBREF [85]. The aim was to evaluate the impact of COCs on taking OC, including wanting an improvement of dysmenorrhea months after, taking OC. The dysmenorrhea group showed a domains, and was completed by subjects before, and 3 questionnaire, which consists of 26 questions and five significant improvement in all domains of the WHOQOLBrief (p=.019). physical health domain, which covers pain and discomfort questionnaire following intake of OC, including the documented in these hormonal contraceptive studies were contraceptives that tend to be mild and tolerable. The AEs There are many common AEs associated with hormonal commensurate with those expected with this type of Additionally, from the studies comparing two or morehormonal contraceptive treatments that provided safety data, in treatment groups than in nontreatment groups [80,84]. medication, and, hence, AEs were reported more frequently compared with EE/DRSP (9 vs. 16 [86]) and after four with EE/LNG (10 vs. 16 [81]), with EE/CMA intake fewer AEs were reported with EE/DSG intake compared (2434 subjective complaints vs. 7452 [87]). cycles of EE/CMA intake than with a previous choice of OC Hans-Peter Zahradnik, 2010

ACOG Noncontraceptive Uses of Hormonal Contraceptives ( Jan 2010) Which hormonal contraceptives are beneficial for treatment of dysmenorrhea? *combined OC have been shown to reduce uterine PG production and relieve dysmenorrhea up to 70-80% of patients.

Evaluation of a low-dose oral contraceptive pill for primary dysmenorrhea: a placebo-controlled, double-blind, randomized trial (N: 115) Objective: To evaluate the efficacy and safety of low-dose oral contraceptives (IKH-01; 0.035 mg ethinyl estradiol and 1 mg norethisterone) for patients with primary dysmenorrhea. Design: Placebo-controlled, double-blind, randomized trial. Setting: Clinical trial sites in Japan. Patient(s): One hundred fifteen patients with primary dysmenorrhea. Intervention(s): Patients randomly assigned to receive IKH-01 or placebo for four cycles. Main Outcome Measure(s): Total dysmenorrhea score, verbal rating scale defining pain according to limited ability to work and need for analgesics, and visual analog scale (VAS). Result(s): Reduction in total dysmenorrhea score and VAS before and after treatment was significantly higher in the IKH-01 group than in the placebo group. Total dysmenorrhea score and VAS in the IKH-01 group significantly decreased from cycles 2 to 5. Overall incidence of adverse events was significantly higher in the IKH-01 group. Incidence decreased over time in the IKH-01 group; it was invariable in the placebo group. No serious adverse events occurred. Conclusion(s): IKH-01 could be used as a single agent or in combination with analgesics for treatment of primary dysmenorrhea. Tasuku Harada, 2011

2011 Objectives The aim of this Phase III, multicentre, open-label, randomised study was to compare the effi cacy and safety of ethinylestradiol (EE)/drospirenone (DRSP) in a new fl exible extended regimen that allowed the management of intracyclic (breakthrough) bleeding (MIB) with that of EE/DRSP in a conventional 28-day regimen in women with moderate-to-severe primary dysmenorrhoea. Methods Women (aged 18–40 years) with moderate-to-severe primary dysmenorrhoearelated pain received a fl exible extended regimen with MIB (fl exibleMIB; minimum 24, maximum 120 days of continuous tablet intake for a fl exible number of cycles to reach a treatment duration of at least 140 days with 4-day breaks between cycles) or a conventional 28-day regimen (24 active and four placebo tablets for fi ve cycles) of EE/DRSP. The primary outcome was the number of days with dysmenorrhoeic pain over 140 days. Secondary outcomes included other dysmenorrhoea-related pain outcomes, bleeding profi le, satisfaction and safety. Results Overall, 223 patients received study medication. There were signifi cantly fewer days with dysmenorrhoeic pain with the fl exibleMIB regimen than the conventional regimen (difference −4.2 days, 95% CI −6.5 to −2.0; p=0.0003), as well as considerably fewer days with at least moderate dysmenorrhoeic pain (difference −2.5 days, 95% CI −3.7 to −1.3), dysmenorrhoeic pain that interfered with daily activities (difference −2.2 days, 95% CI −4.2 to −0.1) and pelvic pain (difference −3.4 days, 95% CI −5.9 to −0.9). Adverse events were similar with both regimens. Conclusions Compared with the conventional regimen, the fl exible extended regimen of EE/DRSP with MIB was associated with

O.K. PRİMER DİSMENORE Farklı O.K. preparatları arasında (<35 mcg & >35 mcg estrojen) fark yok. 3. jenerasyon progestinler (desogestrel and gestodene) > 1. ve 2. jenerasyon progestinler (norgestrel, levonorgestrel, norethisterone, norethindrone). Gözlemsel ve diğer randomize çalışmalar; 20 mcg E içeren O.K’ların da etkin (+).

Hirsutizm KOK’lar hiperandrojenik kadınlarda hirsutizm’i %60-100 azaltır. Antiandrojenik progestin içeren KOK’lar tercih edilmeli. (drospirenone, trimegestone) 6. ayın sonuna kadar anlamlı bir fark izlenmeyebilir. Kıl follikülünün ömrü 6 aydır. Martin KA, Chang RJ, Ehrmann DA, Ibanez L, Lobo RA, Rosenfield RL, Shapiro J, Montori VM, Swiglo BA. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(4):1105.

O.K. ve PMS/PMDD Drospirenon, antimineralokortikoid etki FDA 2006’ da drospirenon + 20 µg EE içeren OK. PMDD tedavisinde onay (+) 5 çalışma, 1920 kadın (toplam) Drospirenon & diğer O.K Drospirenone 3 mg+ EE 30 µg & LNG 150 µg/ Desogestrel 150 µg+ EE 30 µg Drospirenon grubunda semptomlarda daha fazla iyileşme (+) (6 ayın sonunda) 2 yıl sonunda semp. ve yan etkiler açısından gruplar benzer Lopez LM1,  Cochrane Database Syst Rev. 2012

2. siklustan itibaren menseslerde %88 azalma sağlar. Şiddetli Menstruel kanamada FDA onayı olan ilk OKS, Estradiol valerat + Dienogest 2. siklustan itibaren menseslerde %88 azalma sağlar. Median menstrüel kan kaybı azalması (ml) 421 menoraji şikayeti olan kadının katıldığı, çift kör, randomize kontrollü çalışmanın değerlendirilmesi. Fraser IS, et al. Eur J Contracept Reprod Health Care. 2011;16(4):258-69. Jensen JT, Parke S, Mellinger U, Machlitt A, Fraser IS. Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: a randomized controlled trial. Obstet Gynecol. 2011 Apr. 117(4):777-87.

Qlairista® HMB İki Randomize, çift-kör, paralel grup, plasebo kontrollü çalışma Her grup 7 adet 28 günlük siklus süresince takip ediliyor Kuzey Amerika, 47 merkez (N=190)2 Avrupa/Avusturalya, 34 merkez (N=231)3 Her çalışmada randomizasyon (2:1) aşırı kanaması olan, uzamış kanaması olan, sık kanaması olan kadınlar 1EE/LNG: Miranova® (21/7 EE 20 mcg/LNG 100 mcg). 1Ahrendt et al. Contraception 2009;80:436-44. 2Jensen et al. Fertil Steril 2009;92(3, Suppl.):S32; 3Fraser et al. Int J Gynaecol Obstet 2009;107(Suppl. 2):S183.

Aşırı menstrüel kanaması olan kadınların menstrüel kan kaybını azaltmada Qlairista® etkili bulunmuş1 Menstrüel kan kaybında ortalama değişim): Qlairista® çalışmalarının birlikte analizi P<0.0001 -400 -350 -300 -250 -200 -150 -100 -50 Qlairista® Plasebo –414 mL –109 mL Median change in MBL (mL) -450 MBL change (mL) from 90-day run-in period to 90-day efficacy period in women without organic pathology who desire oral contraception Qlairista®: Dienogest/estradiol valerate (26/2 multiphasic) 1. Fraser et al. Eur J Contracept Reprod Health Care 2011;16:258–69

Sonuç Analizi – Tüm Çalışmaların analizi (ITT Group*) Qlarista® Plasebo P-değeri Menstrüel kan kaybında ortalama azalma 414 mL 109 mL <0.0001 Menstrüel kan kaybında ortanca azalma 343 mL 62 mL Kanamalı gün sayısında ortalama azalma 5.2 gün 2.6 gün <0.0038 Kanamalı gün sayısında ortanca azalma 4 gün 2 gün Ped kullanımında ortalama azalma 40.6 18.5 Ped kullanımında ortanca azalma 40.0 12.0 90-day efficacy period. * Intention-to-treat population excluding missing data patients. ITT: Intention-to-treat; MBL: Menstrual blood loss.

Aşırı Menstrüel Kanama Sonuç Aşırı Menstrüel Kanama Qlairista® aşırı menstrüel kanamayı ilk aydan itibaren azaltır.1 Qlairista® menstrüel kan kaybını 88% azaltır.1 Ağır olgular dahil Qlairista® 3 kadının 2 sinde menstrüel siklusu normale döndürür.1 Qlairista® AMK tedavisinde endikasyon almış tek OK dır.*2 Qlairista® etkisi, kullanım devam ettikçe sürer1,3 1. Fraser IS, et al. Eur J Contracept Reprod Health Care. 2011;16:258-69. 2. Qlairista Summary of Product Characteristics; 3. Jensen JT, et al. Obstet Gynecol 2011;117:777-87.

Hangi kadına hangi OK Kontrasepsiyon Tedavi Yazz Yasmin Şiddetli menstrüel kanama: Qlairista Akne: Yazz / Yasmin PMS: Yazz İlk seçenek: Düşük doz OK kullanımı Adet kanaması fazla veya azaltmak istiyorsa Adet kanaması normal ise Qlairista (Doğala özdeş) Yazz Ara kanama ve lekelenme durumunda Ara kanama ve amenore konusunda bilgilendirme 3-4 ay içinde düzene girer Düzenli kullanılmış mı? Yasmin

KOK seçiminde, ürünlerin sağladığı ek yararlar önemlidir. Hasta özelliği KOK özelliği Uygun KOK İlk kez OK kullanımı Düşük doz etinil östradiol Qlairista, Yazz Aşırı adet kanaması * Dienogest Qlairista OK konusunda endişe; hormon fobisi Doğala özdeş östrojen Akne ve hirsutizm Antiandrojenik etki Yazz, Qlairista, Yasmin Tedavi uyumu gerekliliği (ör. adolesanlar) 28 gün sürekli kullanım Premenstrüel sendrom - disforik bozukluk Drospirenon ve 28 gün sürekli kullanım Yazz Adet kanamasının düşük dozlu preparatlarla 3 aydan uzun süreyle kontrol altına alınamaması 30 mcg etinil östrojen Yasmin *Yedi günden uzun süren veya günde 3’ten fazla pet kullanımına (80 ml’den fazla kan kaybına) neden olan adet kanaması veya hastanın yaşam kalitesini fiziksel, duygusal, sosyal ve maddi olarak etkileyen; tek başına veya diğer semptomlarla birlikte görülen aşırı kan kaybı Demir D ve ark. İtil İM. (Ed). Oral Kontrasepsiyon Kılavuzu. 2012. World Health Organization. Medical eligibility criteria for contraceptive use. 4th ed. Geneva:WHO; 2009. www.who.int/reproductivehealth/publications/family_planning/9789241563888/en/, 5.4.2012. Bonnema RA, et al. Contraception Choices in Women with Underlying Medical Conditions. Am Fam Physician. 2010;82(6):621-628. Estrogen and Progestin (Oral Contraceptives). http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601050.html, 24.02.2014.

KOK kararı verirken devamlılığı arttırmak için dikkat edilmesi gerekenler Yan etki yönetimi Düşük doz kullanımı Doğala özdeş östrojen kullanımı 28 gün sürekli kullanılan preparatların önerilmesi Ara kanama ve amenore etkilerinin yönetimi Ek faydaların anlatılması Danışmanlık

21 3 mg drospirenon 30 mcg etinilestradiol Dünya çapında en fazla kullanılan Antiandrojenik etkili drospirenon içeren İlk oral kontraseptif Endikasyonları: Kontrasepsiyon Hormonlarla ilişkili su tutulması belirtileri Akne ve sebore 3 mg drospirenon 21 30 mcg etinilestradiol

24+4 3 mg drospirenon 20 mcg etinilestradiol Drospirenon içeren, Yenilikçi 24+4 rejimli, Düşük dozlu doğum kontrol hapı Endikasyonları: Kontrasepsiyon Hormonlarla ilişkili su tutulması belirtileri Akne Premenstrüel sendrom 3 mg drospirenon 24+4 20 mcg etinilestradiol

Türkiye’de doğal östrojen içeren ilk ve tek oral kontraseptif Dienogest / Etinil Estradiol Türkiye’de doğal östrojen içeren ilk ve tek oral kontraseptif Aşırı adet kanamasında endike olan tek oral kontraseptif Dinamik doz rejimi ile iyi siklüs kontrolü Adet kan kaybında %88 azalma Yüksek kullanıcı memnuniyeti Endikasyonları: Kontrasepsiyon Aşırı adet kanaması

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