Dienogest

Source: Wikipedia, the free encyclopedia.
Dienogest
Clinical data
Trade namesAlone: Dinagest, Visanne, Zalkya
With EVTooltip estradiol valerate: Natazia, Qlaira
With EETooltip ethinylestradiol: Valette
Other namesDNG; Dienogestril; Cyanomethyldienolone; BAY 86-5258; Endometrion; M-18575; MJR-35; SH-660; SH-T00660AA; STS-557; ZK-37659; δ9-17α-Cyanomethyl-19-nortestosterone; 17α-Cyanomethylestra-4,9(10)-dien-17β-ol-3-one; 17β-Hydroxy-3-oxo-19-nor-17α-pregna-4,9-diene-21-nitrile
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • AU: B3
Progestin; Steroidal antiandrogen
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
conjugation)[3][5]
Metabolites• 9α,10β-Dihydro-DNG[1]
• 3,5α-Tetrahydro-DNG[1]
(Both said to be inactive)[2][3]
Elimination half-life7.5–10.7 hours[2]
ExcretionUrine[4]
Identifiers
  • 2-[(8S,13S,14S,17R)-17-hydroxy-13-methyl-3-oxo-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl]acetonitrile
JSmol)
Density1.2 g/cm3
Melting point210 to 218 °C (410 to 424 °F) (experimental)
Boiling point549 °C (1,020 °F)
  • C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@]2(CC#N)O
  • InChI=1S/C20H25NO2/c1-19-8-6-16-15-5-3-14(22)12-13(15)2-4-17(16)18(19)7-9-20(19,23)10-11-21/h12,17-18,23H,2-10H2,1H3/t17-,18+,19+,20-/m1/s1 ☒N[pubchem]
  • Key:AZFLJNIPTRTECV-FUMNGEBKSA-N ☒N[pubchem]
  (verify)

Dienogest, sold under the brand name Visanne among others, is a

heavy periods.[8][11][12] Dienogest is available both alone and in combination with estrogens.[13][11] It is taken by mouth.[1]

hormonal activity.[1][2][7][15][16]

Dienogest was discovered in 1979 and was introduced for medical use in 1995.[17][18][19] Additional formulations of dienogest were approved between 2007 and 2010.[10][20] It is sometimes referred to as a "fourth-generation" progestin.[21][22] Dienogest is marketed widely throughout the world.[13] It is available as a generic medication.[23]

Medical uses

Birth control

Dienogest is used primarily in

birth control pills in combination with ethinylestradiol under the brand name Valette.[24][7][25] It is also available in a quadriphasic birth control pill combined with estradiol valerate, marketed as Natazia in the United States and Qlaira in some European countries and Russia.[26][27][28]

Endometriosis

Dienogest is approved as a standalone medication under the brand names Visanne and Dinagest in various places such as Europe, Australia, Japan, Singapore, and Malaysia for the treatment of endometriosis.[29][10][30] It has been found to be equally effective as gonadotropin-releasing hormone agonists (GnRH agonists), such as leuprorelin, in the treatment of endometriosis.[29]

Heavy periods

Birth control pills containing dienogest and estradiol valerate are approved in the

menorrhagia (heavy menstrual bleeding).[12]

Menopausal symptoms

Dienogest is used in combination with estradiol valerate in the treatment of

symptoms in certain countries such as Germany and the Netherlands.[8][11]

Available forms

See also: Estradiol valerate/dienogest

Dienogest is available both alone and in combination with estrogens.[13][11] The following formulations are available:[13][11]

  • Dienogest 1 mg oral tablets (Dinagest) and 2 mg oral tablets (Valette) (not available in U.S.) – indicated for endometriosis
  • Dienogest 2 mg and estradiol valerate 3 mg oral tablets (Natazia) (U.S.) – indicated for contraception and menorrhagia[12][31]
    • 2 dark yellow tablets each containing 3 mg estradiol valerate
    • 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest
    • 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest
    • 2 dark red tablets each containing 1 mg estradiol valerate
    • 2 white tablets (inert)
  • Dienogest 2 to 3 mg and estradiol valerate 1 to 3 mg oral tablets (Qlaira) (not available in U.S.) – indicated for contraception[32]
    • Each dark yellow active tablet contains 3 mg estradiol valerate
    • Each medium red active tablet contains 2 mg estradiol valerate and 2 mg dienogest
    • Each light yellow active tablet contains 2 mg estradiol valerate and 3 mg dienogest
    • Each dark red active tablet contains 1 mg estradiol valerate
  • Dienogest 2 mg and ethinylestradiol 30 µg oral tablets (Valette) – indicated for contraception
  • Dienogest 2 mg and estradiol valerate 1 or 2 mg oral tablets (various) – indicated for menopausal hormone therapy

The availability of these formulations differs by country (see Availability).[13]

Contraindications

hormone-dependent cancers such as breast cancer, and undiagnosed vaginal bleeding.[10][33]

Side effects

hemostatic parameters.[34]

Birth control pills containing

venous thromboembolism.[35] However, they are associated with a significantly lower risk of venous thromboembolism than birth control pills containing ethinylestradiol and a progestin.[35]

Overdose

In safety studies, dienogest has been assessed in women with endometriosis at high doses of as much as 20 mg/day for up to 24 weeks and produced no clinically relevant effects on

liver enzymes, the coagulatory system, or thyroid metabolism.[11]

Interactions

Dienogest is

area-under-curve concentrations of dienogest by 50% and 80%, respectively.[10]

Pharmacology

Pharmacodynamics

Dienogest has

safety and tolerability compared to various other progestins.[1][2]

Relative affinities (%) of dienogest and metabolites
Compound PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid binding globulin
Dienogest 5 10 0 1 0 0 0
9α,10β-Dihydrodienogest 26 13 ? ? ? ? ?
3α,5α-Tetrahydrodienogest 19 16 ? ? ? ? ?
Notes: Values are percentages (%). Reference
CBGTooltip Corticosteroid-binding globulin. Sources: [1]

Progestogenic activity

Dienogest is an

affinity for the PR in vitro in human uterine tissue, about 10% that of progesterone.[2][7][3] Despite its low affinity for the PR however, dienogest has high progestogenic activity in vivo.[2] In addition, although its metabolites, such as 9α,10β-dihydrodienogest and 3α,5α-tetrahydrodienogest, have greater affinity for the PR than does dienogest itself, the medication is not considered to be a prodrug.[2][1][7][3]

Relative potencies of progestogens[36]
Progestogen TFD
(mg/cycle)		 OID
(mg/day)		 TFD/OID
ratio
Chlormadinone acetate 25 1.7 1.5
Cyproterone acetate 20 1.0 2.0
Dienogest 6 1.0 0.6
Norethisterone 120 0.4 30
Norethisterone acetate 50 0.5 10
Norgestimate 7 0.2 3.5
Levonorgestrel 5 0.06 8.3
Desogestrel 2 0.06 3.3
Gestodene 3 0.04 7.5
Drospirenone 50 2.0 2.5
Nomegestrol acetate 100 5.0 2.0

Dienogest has been described as "special" progestogen, possessing low or moderate

19-nortestosterone progestins like levonorgestrel.[36]

Unlike other progestogens, except in the case of its strong effects in the uterus, dienogest has been described as lacking

vascular systems.[2]

Dienogest showed some possible antiprogestogenic activity in one animal bioassay when administered before but not at the same time as progesterone.[7]

The minimum effective dose of oral dienogest required to inhibit

gonadotropin-releasing hormone analogues (GnRH analogues), which suppress estradiol levels to lower concentrations and readily induce menopausal-like symptoms.[2]

Dienogest appears to have similar effects in the breasts as norethisterone acetate, and may likewise increase the risk of breast cancer when combined with an estrogen in postmenopausal women, although this has yet to be confirmed in clinical studies.[2]

Antigonadotropic effects

Testosterone levels with 2, 5, or 10 mg/day dienogest, 10 mg/day oral cyproterone acetate, or placebo in healthy young men.[37]

Dienogest has been found to suppress testosterone levels in men by 43% at 2 mg/day, 70% at 5 mg/day, and 81% at 10 mg/day.[37][38] The suppression of testosterone levels with 10 mg/day dienogest was comparable to that with 10 mg/day cyproterone acetate.[38][37] In general, progestogens are able to suppress testosterone levels in men by a maximum of about 70 to 80% at sufficiently high doses.[39][40][41][42][43]

Antiandrogenic activity

Dienogest is one of the only 19-nortestosterone derivative progestins that does not have

plasma protein or increase the free fractions of these hormones.[2]

Other activities

Dienogest does not inhibit or induce CYP3A4, unlike many other related progestins.[7][1] Because of this, it may have a lower propensity for drug interactions.[2]

Dienogest weakly stimulates the

progesterone receptor membrane component-1 (PGRMC1).[45] Certain other progestins are also active in this assay, whereas progesterone acts neutrally.[45] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.[46]

Pharmacokinetics

Dienogest is rapidly

corticosteroid-binding globulin.[2][7][3] The lack of affinity of dienogest for SHBG is in contrast to most other 19-nortestosterone progestins.[2] The volume of distribution of dienogest is relatively low at 40 L.[7]

Dienogest is

conjugates and as free steroid.[4]

Chemistry

See also: List of progestogens and List of steroidal antiandrogens

Dienogest, also known as δ9-17α-cyanomethyl-19-nortestosterone or as 17α-cyanomethylestra-4,9-dien-17β-ol-3-one, is a

anabolic–androgenic steroid (AAS) dienolone, as well as the C17α cyanomethyl analogue of the AAS methyldienolone (17α-methyldienolone) and ethyldienolone (17α-ethyldienolone).[47]

In terms of

metabolic stability and potency of dienogest.[54][55]

History

Dienogest was synthesized in 1979 in Jena, Germany under the leadership of Kurt Ponsold, was initially referred to as STS-557.[17][18] It was found that its potency was 10 times that of levonorgestrel.[56] The first product on the market to contain dienogest was a combined birth control pill (with ethinylestradiol), Valette, introduced in 1995 and made by Jenapharm.[19] In 2007, dienogest was introduced as Dinagest in Japan for the treatment of endometriosis, and it was subsequently marketed for this indication as Visanne in Europe and Australia in December 2009 and April 2010, respectively.[10] Qlaira was introduced in Europe in 2009 and Natazia was introduced in the United States in 2010.[20]

Society and culture

Generic names

Dienogest is the

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name, while diénogest is its DCFTooltip Dénomination Commune Française.[47][13] It is also known by its synonyms dienogestril and cyanomethyldienolone as well as by its numerous former developmental code names including BAY 86-5258, M-18575, MJR-35, SH-660, SH-T00660AA, STS-557, and ZK-37659.[47][13]

Brand names

Dienogest is marketed in combination with

menopausal hormone therapy under a variety of brand names including Climodien, Climodiène, Estradiol Valeraat / Dienogest, Klimodien, lafamme, Lafleur, Mevaren, Valerix, and Velbienne.[13] Dienogest is marketed as a standalone medication for the treatment of endometriosis primarily under the brand name Visanne, but is also available under the brand names Alondra, Dinagest, Disven, Visabelle, and Visannette in various countries.[13]

Availability

See also: List of progestogens available in the United States
Known availability of dienogest in countries throughout the world (as of August 2018). Alone is dienogest as a standalone medication. EV is estradiol valerate and EE is ethinylestradiol.

Dienogest is available both alone and in combination with ethinylestradiol and estradiol valerate widely throughout the world, including but not limited to Canada, Europe, Latin America, and Southeast Asia.[13][57] It is available specifically as a standalone medication in Canada, Europe, Latin America, Russia, Australia, South Africa, Georgia, Israel, Japan, South Korea, Hong Kong, and Thailand.[13][57] It is notably not available as a standalone medication in the United States or the United Kingdom.[13][57]

Research

Dienogest has been studied as a form of

pre-registration in Europe for the treatment of acne.[60] Dienogest is also being evaluated for the potential treatment of anorexia nervosa.[61]

References

  1. ^
    S2CID 24616324
    .
  2. ^
    PMID 22364708
    .
  3. ^
    PMID 26327902
    .
  4. ^
    S2CID 37627607
    .
  5. ^
    S2CID 44601264
    .
  6. ^ "TGA eBS - Product and Consumer Medicine Information Licence".
  7. ^
    S2CID 262326901
    .
  8. ^ a b c d "Dienogest - Bayer HealthCare Pharmaceuticals/Mochida Pharmaceutical - AdisInsight".
  9. ISBN 978-1-4614-6837-0
    . Dienogest is a 19-nortestosterone derivative that is approved in the European Union for the treatment of endometriosis. It is not available in the United States as a separate drug. It is only available in the oral contraceptive Natazia (Bayer Pharmaceuticals, Montville, NJ, USA) (estradiol valerate/dienogest), which is a newer four-phasic pack that contains dienogest.
  10. ^
    S2CID 249871173
    .
  11. ^ a b c d e f Bartsch V, Römer T (2015). "Gynaecological uses of dienogest alone and in combination with oestrogens" (PDF). J Med Drug Rev. 5: 1–31.
  12. ^
    S2CID 31125733
    .
  13. ^ a b c d e f g h i j k l m n "Dienogest".
  14. ^
    PMID 26648643
    .
  15. ^
    S2CID 28436828
    .
  16. PMID 29137347
    .
  17. ^
    doi:10.1002/prac.19843260606
    .
  18. ^
    S2CID 21769309
    .
  19. ^ a b "Die Jahre 1965 - 1995". Archived from the original on 2008-03-07. Retrieved 2008-01-18.
  20. ^
    PMID 21151673
    .
  21. ISBN 978-1-107-43611-4
    .
  22. ^
    ISBN 978-3-319-14385-9
    .
  23. ^ "Generic Natazia Availability".
  24. S2CID 46374974
    .
  25. PMID 16759929
    .
  26. S2CID 207297417
    .
  27. S2CID 33366375
    .
  28. PMID 22468839
    .
  29. ^
    S2CID 22168242
    .
  30. ^ "Dienogest for the treatment of endometriosis" (PDF). London New Drugs Group. Archived from the original (PDF) on 2011-10-02. Retrieved 2010-12-07.
  31. ^ "Highlights of Prescribing Information" (PDF). Natazia website. Bayer. Retrieved 16 January 2023.
  32. ^ "Qlaira Tablets". NPS Medicinewise Australia. 13 July 2020.
  33. ^ "Visanne, tablets, 2 mg Bayer BV, The Netherlands (dienogest)" (PDF). Medicines Evaluation Board. The Netherlands. 3 March 2010.
  34. PMID 11929644
    .
  35. ^
    PMID 30519125
    .
  36. ^
    S2CID 27088428
    .
  37. ^
    PMID 11994349
    .
  38. ^
    S2CID 22458746
    .
  39. ISBN 978-1-4160-6911-9
    .
  40. PMID 6237116
    .
  41. PMID 7000222
    .
  42. PMID 694436
    .
  43. S2CID 5836155
    .
  44. S2CID 23112620
    .
  45. ^
    S2CID 29808177
    .
  46. PMID 31512725
    .
  47. ^
    ISBN 978-1-4757-2085-3
    .
  48. ^
    PMID 26327902
    .
  49. ISBN 978-1-284-05748-5
    .
  50. ISBN 978-3-319-20185-6
    .
  51. PMID 10637363
    .
  52. PMID 3928974
    .
  53. PMID 3695484
    .
  54. PMID 6683343
    .
  55. S2CID 9659302
    .
  56. PMID 7357870
    .
  57. ^
    ISBN 978-0-85369-840-1
    .
  58. S2CID 21283244
    .
  59. PMID 19442786
    .
  60. ^ "Estradiol valerate/dienogest - AdisInsight".
  61. PMID 29631553
    .

Further reading

External links

  • "Dienogest". Drug Information Portal. U.S. National Library of Medicine.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Dienogest&oldid=1193459579"