Dienogest for pain induced endometriosis

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Vissane is a new drug for treatment of endometriosis : how effective it is ??: this talk may help in illustrating this

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Dienogest for pain induced endometriosis

  1. 1. Dienogest For Treatment of Endometriosis
  2. 2. Declaration • No conflict of interest at all with this product or the manufacturing company
  3. 3. Why this talk? • To update our knowledge • A real breakthrough in management of endometriosis • To share
  4. 4. Treatment of Endometriosis • Treatment could be surgical or medical • Combined • There is no permanent cure !!!
  5. 5. Q1: What is the problem • Endometriosis has high rate of recurrence up to 60% within 5 years of surgery
  6. 6. Ideal Goal • As stated by the ASRM, “Endometriosis should be viewed as a chronic disease that requires a life-long management plan with the goal of maximizing the use of medical treatment and avoiding repeated surgical procedures.” Fertil & Steril, 2008
  7. 7. Q2: How to prevent recurrence? • GnRH agonist • Progestin • others
  8. 8. GnRHa • Effective • Severe hypoestrogenic state • Limited to 6 month • Bone loss
  9. 9. Progestins • effective in endometriosis only at high doses • This may increase the likelihood of adverse effects, such as weight gain and androgenic effects • may elevate the risk of CVS adverse events
  10. 10. Dienogest (Visanne) • is a synthetic oral progestogen with unique pharmacological properties • highly selective for the progesterone receptor
  11. 11. Unique • strong progestational effects • moderate antigonadotrophic effects •noandrogenic, glucocorticoid or mineralocorticoid activity.
  12. 12. Administration • 2mg once-daily • Can start at any day of menstrual cycle • Must be continued regardless of vag. Bleeding
  13. 13. 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.
  14. 14. For How Long? • Based on Its relatively short half-life of 10 hours means that there is no risk of accumulation after repeated dosing. • Suggested for long term treatment
  15. 15. License • An EU marketing authorisation application for the use of dienogest to treat endometriosis was granted by The Netherlands in December 2009.
  16. 16. Where is the evidence? • There are a number of studies comparing dienogest treatment with buserelin (double- dummy), and triptorelin (open-label), and one longer-term study. • Some of these studies have been carried out in Japanese, not European, women. • None of these were sponsored by Bayer.
  17. 17. Pivotal study • The safety and efficacy of dienogest 2mg daily for 12 weeks was assessed in 198 women with endometriosis and pain above 30mm on a visual analogue scale (VAS), in a randomised, placebo-controlled study. (Strowitzki et al, 2010)
  18. 18. Results • Reductions on the VAS in endometriosis- associated pelvic pain (the primary endpoint) were 27.4mm with dienogest and 15.1mm with placebo, (mean difference in core of 12.3mm; 95% CI 6.4 to 18.1, p<0.0001). • 168 women have continued with a further 52 weeks of dienogest treatment
  19. 19. Long term study • open-label extension study of dienogest for up to 52 additional weeks, providing an overall treatment period of up to 65 weeks. (~ 5 yrs)
  20. 20. Results • The 52-week extension study results showed a progressive reduction in the frequency of and improvements in endometriosis-associated pelvic pain scores.
  21. 21. Surrogate outcomes • During the long-term study, laboratory parameters, vital signs, and body weight remained stable or underwent minimal changes. • Adverse effects considered potentially treatment-related developed in 16.1% of women, including breast discomfort (4.2%), nausea (3.0%), and irritability (2.4%).
  22. 22. SE • The most commonly reported treatment- related adverse event was metrorrhagia (71.9%), followed by headaches (18.5%) and constipation (10.4%). None of the treatment- related adverse events was rated as serious
  23. 23. Comparison with leuprorelin • Dienogest 2mg/day (n=124) was compared with leuprorelin 3.75mg/4 weeks (n=128) in a randomised 24- week study. • Improvements in VAS scores of endometriosis-associated pelvic pain were similar in both groups (reductions of 47.5mm with dienogest and 46.0 with leuprorelin)
  24. 24. Comparison with intranasal buserelin • In Japan, a Phase III, randomized, double- blind, multicenter, controlled trial was conducted to compare the efficacy and safety of DNG with intranasal buserelin acetate in patients with endometriosis.
  25. 25. VAS at 24 ws • In both groups the change was large enough to be clinically relevant. For the objective symptoms, the change was from 3.8±2.1 to 1.9±1.9 in the dienogest group and from 3.7±2.0 to 1.5±1.3 in the buserelin group (difference of mean change -0.35, 9% CI -0.75 to 0.05).
  26. 26. Moreover • The study demonstrated that DNG causes less bone mineral density loss, resulting in the use on a commercial basis for endometriosis patients in Japan from 2008. (Momoeda et al, 2009)
  27. 27. Comparison with triptorelin • Dienogest 2mg/day (n=59) was compared with triptorelin 3.75mg/4 weeks (n=61) in an open-label 16-week study. Patients had undergone an operative laparoscopy and drug treatment was used as consolidation therapy.
  28. 28. Results • No reappearance of endometrial tissue was achieved in 25% of patients in each group. • 86.2% of patients treated with dienogest and 80% of patients treated with triptorelin were satisfied with treatment. • Fifteen patients in the dienogest group and 12 in the triptorelin group had spontaneous pregnancies in the 12 months following the end of treatment, p=0.71
  29. 29. Potential benefits over existing technologies • Dienogest appears to be safe and effective when taken for up to 2 years. Current treatments are limited to shorter treatment intervals. • Dienogest is an oral therapy • Treatment of endometriosis with dienogest is not inferior to that with GnRH agonists.
  30. 30. Contraindications (CVS & liver) • DVT • Arterial and cardiovascular disease, past or present (e.g. myocardial infarction, cerebrovascular accident, ischemic heart disease) • Presence or history of severe hepatic disease as long as liver function values have not returned to normal • Presence or history of liver tumours (benign or malignant)
  31. 31. Limitations • Uterine bleeding may be aggravated with the use of Visanne® . • Longer-term treatment (up to a year) is required before a positive effect on the number and duration of days/ episodes of bleeding or spotting (a reduction) can be seen.
  32. 32. Ovulation inhibition • doses ≥1 mg dienogest per day inhibited ovulation. However, follicular maturation processes evident by a rise in serum estradiol levels were not completely suppressed even with the highest dose of 2 mg dienogest.
  33. 33. Share : Meta-analysis Absolute reduction in VAS Mean Difference (IV, Fixed, 95% CI) -1.60 [-9.17, 5.97] Proportion of women experienced improvement in VAS Odds Ratio (M-H, Fixed, 95% CI) 1.26 [0.27, 5.80]
  34. 34. SE Alopecia Odds Ratio (M-H, Fixed, 95% CI) 0.60 [0.17, 2.09] Migraine Odds Ratio (M-H, Fixed, 95% CI) 0.52 [0.13, 2.13] Sleep disorder Odds Ratio (M-H, Fixed, 95% CI) 0.20 [0.04, 0.93] Vaginal dryness Odds Ratio (M-H, Fixed, 95% CI) 0.22 [0.05, 1.06] Hot flushes Odds Ratio (M-H, Fixed, 95% CI) 0.40 [0.25, 0.65] Abnormal genital Bleeding Odds Ratio (M-H, Fixed, 95% CI) 8.41 [3.60, 19.63]
  35. 35. Others Decreased Libido Odds Ratio (M-H, Fixed, 95% CI) 0.65 [0.21, 2.05] Depression Odds Ratio (M-H, Fixed, 95% CI) 0.56 [0.20, 1.56] weight gain Odds Ratio (M-H, Fixed, 95% CI) 1.76 [0.56, 5.53] Headache Odds Ratio (M-H, Fixed, 95% CI) 0.62 [0.40, 0.95]
  36. 36. More to Share: RCTs • Dienogest in endometriosis associated Infertility: Visanne for 3 month Then clomid vs clomid alone • Dienogest associated menstrual irregularities: Visanne with Cycloprogenova for the first 3 month vs Visanne alone
  37. 37. Conclusion • DNG represents a promising new medication for safe and effective long-term management of pain of endometriosis.

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