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

1. Dienogest
For Treatment of Endometriosis

2. Declaration
• No conflict of interest at all with this product
or the manufacturing company

3. Why this talk?
• To update our knowledge
• A real breakthrough in management of
endometriosis
• To share

4. Treatment of Endometriosis
• Treatment could be surgical or medical
• Combined
• There is no permanent cure !!!

5. Q1: What is the problem
• Endometriosis has high rate of recurrence up
to 60% within 5 years of surgery

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. Q2: How to prevent recurrence?
• GnRH agonist
• Progestin
• others

8. GnRHa
• Effective
• Severe hypoestrogenic state
• Limited to 6 month
• Bone loss

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. Dienogest (Visanne)
• is a synthetic oral progestogen with unique
pharmacological properties
• highly selective for the progesterone receptor

11. Unique
• strong progestational effects
• moderate antigonadotrophic effects
•noandrogenic, glucocorticoid or
mineralocorticoid activity.

12. Administration
• 2mg once-daily
• Can start at any day of menstrual cycle
• Must be continued regardless of vag. Bleeding

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. 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. License
• An EU marketing authorisation application for
the use of dienogest to treat endometriosis
was granted by The Netherlands in December
2009.

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.

18. 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)

19. 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

20. 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)

21. Results
• The 52-week extension study results showed a
progressive reduction in the frequency of and
improvements in endometriosis-associated
pelvic pain scores.

22. 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%).

23. 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

24. 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)

26. 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.

27. 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).

28. 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)

29. 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.

30. 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

31. 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.

32. 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)

33. 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.

34. 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.

35. 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]

36. 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]

37. 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]

38. 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

39. Conclusion
• DNG represents a promising new medication
for safe and effective long-term
management of pain of endometriosis.