dienogest by dr shashwat jani

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 : 99099 44160.

E-mail : [email protected]

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

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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


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DIENOGEST

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

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 6/26/2017 5

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

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Dienogest

• It’s a synthetic oral progestogen with unique pharmacological properties

• Highly selective for the progesterone receptor


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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


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Dienogest: Pharmacokinetics

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Dose

• It appears that at a dose of 2 mg dienogestper 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.


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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.


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Dienogest: Effect on PGE2

PGE2

Increases Aromatase

Increases Estrogen

Increases Fibroblast

Growth factor – 9 (FGF-9)

Cell proliferation

Affects Leukocyte levels &

VEGF levels

Promotes Angiogenesis & Vasculogenesis

Inhibits apoptosis

Cell proliferation

Macrophages and Endometrial cells

Dienogest inhibits PGE2

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

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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


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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 6/26/2017 16

DIENOGEST

Let us have a look at the CLINICAL DATA …


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Dienogest vs. GnRH agonistsComparative Recent trials

Author Drug and Dose

N Duration (Wks)

Results A/Es

Strowitzki T et al (2010)

Leuprorelin3.75 mg/4 wk

128 24 = improved VAS scores Non Inferiority for DNG Higher QoL – DNG Mean BMD – 4% LA, + 0.25% DNGNo change in body weight

HeadacheHypoestrogenic S/Es – LA = Bleeding episodes

Harada T et al (2009)

Buserelin 300 mcg tds

134 24 = change in subjective symptomscores Non inferiority for DNG = % reduction in chocolate cysts BMD : -2.6% BA, -1.0% DNG

HeadacheHypoestrogenic S/Es – BA Spotting – DNG

Cosson M et al (2002)

Triptorelin3.75 mg/4 wks

61 16 = Endometrial tissue scores = No reappearance of endometrial tissue in 25% in each groupHigher 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%)

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Dienogest vs. GnRH agonists Safety

Jeng CJ et al, Expert Opin. Pharmacother, 2014; 15(6): 767-773


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Dienogest vs BuserelinEffect on size of chocolate cysts

Harada T et al, Jpn Pharmacol Ther, 2008

Harada T et al, Fertility ans Sterility, 2009


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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

?

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Dienogest : Long term use

Long-term use of dienogest for the treatment of endometriosisJ 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

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Dienogest : Long term use Efficacy

Momoeda M, et al. J Obstet Gynecol Res 2009. 23

Dienogest : Long term use Efficacy


Dienogest and Fertility considerations

Most of the medical options cause anovulation and amenorrhea in patients

What is the experience with Dienogest? 25

Dienogest : Long term useResumption 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)


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

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)

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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 1st choice progestin for treatment in endometriosis

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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

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DienogestPost-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).

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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

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Dienogest and Adenomyosis

Group Cases (n) Age

(median)

Rx

Duration

(m)

Chocolat

e 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 adenomyosisrelated pelvic pain in 17 patients

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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

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

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)

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• 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.

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26-Jun-17 38Dr Shashwat Jani.

9909944160.

dienogest by dr shashwat jani

Health & Medicine