DIENOGEST BY DR SHASHWAT JANI

DIENOGEST BY DR SHASHWAT JANI

1. Dienogest Dr. Shashwat Jani . M. S. ( Obs – Gyn ) Diploma in Advance Laparoscopy. Consultant Assistant Professor , Smt. N.H.L. Municipal Medical College. Sheth V. S. General Hospital , Ahmedabad. Mobile : [phone]. E-mail : [email protected]

2. Progestins : Overview Used for  40 years in Rx of endometriosis Synthetic hormones with progesterone-like activity Show excellent activity through suppression of the HPO axis, cause anovulation , reduced estrogen levels and decidualization & atrophy of both ectopic and eutopic endometriotic lesions ( ESHRE Capri Workshop Group 2001, Schweppe 2001 ) Also inhibit angiogenesis, maintain the endometriotic implants, restricts proliferation . Anti-inflammatory activity, reduces associated pain Excellent Rx to prevent recurrence and increase the duration of symptom free period, post surgery 27-Jun-17 Dr Shashwat Jani. 99099 44160. 2

3. Progestins: Advantages over other Rx options Exhibit excellent efficacy in the treatment of endometriosis Highly safe in comparison to GnRH agonists, Danazol etc. Lesser risk of androgenic and metabolic S/Es No significant loss of BMD ; can be given to all age groups Extensive clinical data support Progestins: Recommendations Progestins may be an appropriate alternative for longer-term management of endometriosis due to their safety, tolerability and cost ESHRE Capri Workshop Group 2001, Vercellini et al 2003 Progestin may be considered as a ‘ first line therapy’ SOCG Clinical Practice Guidelines, July 2010 27-Jun-17 Dr Shashwat Jani. 99099 44160. 3

4. DIENOGEST A new Hybrid, Designer progestin for the treatment of endometriosis!

5. Dienogest – Global Status - Available in combination with ethinyl estradiol Indicated for contraception Natazia / Qlaira Available as Dienogest 25 mg Indicated for treatment in Endometriosis Visanne UNITED STATES OF AMERICA EUROPE Dienogest was synthesized in 1979 in Jena, Germany and first brand was Valette (contraceptive) in 1995 27-Jun-17 5

6. Dienogest – Status in India Dienogest is the first oral drug approved and indicated for the treatment of Endometriosis It was launched in 2014 More than 1,00,000 patients treated with Dienogest INDIA 27-Jun-17 6

7. Dienogest It’s a synthetic oral progestogen with unique pharmacological properties H ighly selective for the progesterone receptor 27-Jun-17 Dr Shashwat Jani. 99099 44160. 7

8. Pharmacological effects Excellent anti-proliferative and anti-inflammatory effects in the treatment of endometriotic lesions. It also shows: Considerable anti-androgenic properties No glucocorticoid and no anti-mineralocorticoid activity No anti-estrogenic activity No effect on metabolic and cardiovascular systems High efficacy and safety on long term use Less adverse effect profile 27-Jun-17 Dr Shashwat Jani. 99099 44160. 8

9. 27-Jun-17 Dr Shashwat Jani. 99099 44160. Dienogest: Pharmacokinetics 9

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12. Dose It appears that at a dose of 2 mg dienogest per day, ovulation is inhibited but ovarian hormone production is not completely suppressed . Thus, compared to other endometriosis treatments, estrogen-deficiency related side effects are expected to be of low intensity with 2 mg dienogest . 27-Jun-17 Dr Shashwat Jani. 99099 44160. 12

13. Dienogest - MOA Suppresses the HPO axis , reduces GnRH secretion, hypoestrogenic effect It binds to the progesterone receptor with high specificity but with relatively low affinity, at 10% that of progesterone. Shows pronounced progestogenic effect attributed to the high circulating levels of the unbound molecule. Thus, it produces a progesterone – rich environment, enhancing the stability of the endometrium. 27-Jun-17 Dr Shashwat Jani. 99099 44160. 13

14. Dienogest: Effect on PGE2 Macrophages and Endometrial cells Dienogest inhibits PGE 2 production & Aromatase Yamanaka et al, Fertil Steril, 2012; 97(2): 477 - 82 Prostaglandin E2 levels are increased in endometriosis . Lowers Estrogen levels Inhibits vascular proliferation Inhibits angiogenesis Promotes Apootosis Inhibition of PGE2 and Aromatase contributes to the therapeutic effects of Dienogest in Endometriosis 27-Jun-17 14

15. Progesterone resistance in Endometriosis The endometrial dysfunction is due to diminished response to Progesterone. It is seen that the Estrogen receptors’ levels increase and the Progesterone receptors’ levels decrease. This leads to hyper-proliferative changes and anti-apoptotic process. Dienogest improves the Progesterone resistance in endometrial tissue. It significantly improved the expression of Progesterone receptors, thus exhibiting clinical improvements in endometriosis. Hayashi et al. Journal of Ovarian Research 2012, 5:31 27-Jun-17 Dr Shashwat Jani. 99099 44160. 15

16. Main drawbacks of other drugs Combined Oral Contraceptives: Many women do not respond adequately, due to Progesterone resistance Thromboembolism GnRH agonists: Androgenic effects, Hypoestrogenic S/Es Use restricted to 6 months, in absence of add on HT Effects on BMD Danazol : Androgenic effects, Use restricted to 6 months, due to side effects Other Progestins: Androgenic effects, Breakthrough bleeding, thromboembolism Effects on metabolic systems and CVS Short term pain relief 27-Jun-17 16

17. DIENOGEST Let us have a look at the CLINICAL DATA … 27-Jun-17 Dr Shashwat Jani. 99099 44160. 17

18. Dienogest vs. GnRH agonists Comparative Recent trials Author Drug and Dose N Duration (Wks) Results A/Es Strowitzki T et al (2010) Leuprorelin 3.75 mg/4 wk 128 24 = improved VAS scores Non Inferiority for DNG Higher QoL – DNG Mean BMD – 4% LA, + 0.25% DNG No change in body weight Headache Hypoestrogenic S/Es – LA = Bleeding episodes Harada T et al (2009) Buserelin 300 mcg tds 134 24 = change in subjective symptom scores Non inferiority for DNG = % reduction in chocolate cysts BMD : -2.6% BA, -1.0% DNG Headache Hypoestrogenic S/Es – BA Spotting – DNG Cosson M et al (2002) Triptorelin 3.75 mg/4 wks 61 16 = Endometrial tissue scores = No reappearance of endometrial tissue in 25% in each group Higher patient satisfaction – DNG (86.2 %vs. 80%) 15 pts DNG vs. 12 pts T : spontaneous pregnancies Spotting – DNG (61.6 vs 25.4%) Hot flushes (61.2 vs. 9.6%) 27-Jun-17 18

19. Dienogest vs. GnRH agonists Safety Jeng CJ et al, Expert Opin . Pharmacother , 2014; 15(6): 767-773 27-Jun-17 Dr Shashwat Jani. 99099 44160. 19

20. Dienogest vs Buserelin Effect on size of chocolate cysts Harada T et al, Jpn Pharmacol Ther, 2008 Harada T et al, Fertility ans Sterility, 2009 27-Jun-17 Dr Shashwat Jani. 99099 44160. 20

21. One important drawback with GnRH agonists is the recommended duration of Rx… Not more than 6 months Can Dienogest be continued for a longer time ? 21

22. Dienogest : Long term use Long-term use of  dienogest  for the treatment of endometriosis J Obstet Gynaecol Res. 2009 Dec;35(6):1069-76. Momoeda M1, Harada T,  Terakawa N,  Aso T,  Fukunaga M,  Hagino H,  Taketani Y. Objective :  To investigate the safety and efficacy of 52 weeks of  dienogest  treatment in patients with endometriosis. 135 patients with endometriosis received 2 mg of  dienogest  orally each day for 52 weeks Adverse drug reactions and bone density were evaluated every 4 weeks Global improvement was assessed based on the changes in severity categories of five subjective symptoms during non-menstruation 22

23. Dienogest : Long term use Efficacy Momoeda M, et al. J Obstet Gynecol Res 2009. 23

24. Dienogest : Long term use Efficacy Momoeda M, et al. J Obstet Gynecol Res 2009. 24

25. Dienogest and Fertility considerations Most of the medical options cause anovulation and amenorrhea in patients What is the experience with Dienogest? 25

26. Dienogest : Long term use Resumption of menses Resumption of menses after the EOT was confirmed in all 132 cases The number of days from the EOT to the first day of menstruation was 29.9 ± 11.8 days Menstruation was confirmed within 2 months after the EOT in 97.0% (128/132 cases) of the patients. It can be concluded from this study that Dienogest shows very minimal effect on BMD, whereas the efficacy is cumulative. It can be used for long term (~ 52 weeks) Momoeda M, et al. J Obstet Gynecol Res 2009. Long term safety and efficacy seen. 26

27. Dienogest : Ovulation & Fertility Klipping C et al, 2011 evaluated 104 patients on 0.5 mg, 1 mg, 2 mg and 3 mg doses of Dienogest (DNG) Women with higher dose of DNG (2/3 mg) did NOT show ovulation Follicle size varied as per the dose, highest for lowest dose (0.5 mg – 26.3mm) Ovarian activity (Hoogland score) in each dienogest dose group (% participants) Klipping C et al, J Clin Pharmacol, 2011 27

28. Dienogest : Ovulation & Fertility An LH surge in urine was identified in 60 of 87 women (69.0% overall, 2 mg- 80.0%), occurring between days 1 and 43 after cessation of treatment. Only 2 women failed to ovulate Shows a prompt return to fertility This is an unique feature of DNG, not shared by any other medication It was well tolerated during the study. The intensity of bleeding/spotting decreased during continued treatment in all dose groups. Klipping C et al, J Clin Pharmacol, 2011 Mean endometrial thickness at each visit during the pretreatment (combined groups) and treatment period (individual dose groups) 28

29. Dienogest Vs. Norethisterone 17 women with rectovaginal endometriosis Persistent pain after Rx with NE DNG 2 mg/day for 6 months Primary end point - Patient satisfaction Secondary end point – Pain symptoms, A/Es Results: Patient satisfaction improved at 3 and 6 months DNG decreased deep dyspareunia and pelvic pain (31.3 & 18.3 mm resp , 24 week) Analgesic use reduced No A/Es reported DNG may be the 1 st choice progestin for treatment in endometriosis 29

30. Dienogest : Key clinical benefits in Endometriosis Decreases the endometriosis associated pelvic pain Reduces symptoms, signs and severity As effective as GnRH agonists More safer side effects profile Not associated with clinically relevant androgenic A/Es No changes in BMD No alterations in lipid, metabolic or hematic parameters Long term efficacy evaluated (> 1 yr) Restores fertility post cessation (1 – 43 days) Newer applications established 30

31. Dienogest Post-0pertive Medical Treatment and Recurrence The recurrence rate (pain or chocolate cysts) was compared between patients with post-operative medical treatment (DNG or OC) (n= 134) and patients without treatment (n= 234). 31

32. New Clinical applications Adenomyosis Extragenital endometriosis (bladder, colon etc ) Post-operative therapy Pretreatment for hysteroscopy Long term effect after discontinuation Low-dose therapy (2mg/day to 1mg/day) Infertility treatment Pre IVF 32

33. Dienogest and Adenomyosis Group Cases (n) Age (median) Rx Duration (m) Chocolate cyst (%) Pain Relief (%) Side effects (%) Continued 28 43 17.5 14.3 100 32.1 Shimada E. et al. presented at Kanto Society of Obstetrics and Gynecology 2011. [Pilot study] Sasa H et al, 2014 showed DNG equivalent to Danazol in adenomyosis (n=20) in efficacy, with lower side effects Hirata T et al, 2014 showed that DNG significantly reduced the adenomyosis related pelvic pain in 17 patients 33

34. Dienogest: Cyclic administration It has been seen that cyclic administration of Dienogest may relieve: The intermittent uterine bleeding, a major side effect of Dienogest Equally reduce the associated menstrual pain in patients post surgery Yanase T et al, 2014 Showed disappearance of intestinal endometriosis Marked reduction in lower abdominal pain Significant reduction in endometriotic cyst size Disappearance of endometriotic lesions (endoscopy) Tamura R et al, 2013 Week 1 Week 2 Week 3 Week 4 DNG 2 mg/day DNG 2 mg/day DNG 2 mg/day Withdrawn 34

35. Thus, to summarize Dienogest proves to be an excellent, safe and effective treatment option in Endometriosis!

36. Dienogest – Summary Dienogest is an orally active, 19-nortestosterone derivative Displays strong progestational effects Reduces signs, symptoms and severity of endometriosis Decreased endometriosis-associated pelvic pain As effective as GnRH agonists , with better side effect profile Well tolerated and safe for long term Rx (15 – 18 months ) 36

37. Not associated with clinical relevant androgenic adverse effects Does not exhibit any alterations in BMD No adverse effects on glucose metabolism , liver and cardiovascular system Efficacy and tolerability sustained with long term (>1yr) treatment Improved QOL of patients and lowers recurrence rates . 37

38. 27-Jun-17 38 Dr Shashwat Jani. 9909944160.