Dienogest

Identification

Summary

Dienogest is an oral progestin used for the treatment of endometriosis as monotherapy or contraception in combination with ethinylestradiol.

Brand Names
Natazia, Visanne
Generic Name
Dienogest
DrugBank Accession Number
DB09123
Background

Dienogest is an orally-active semisynthetic progestogen which also possesses the properties of 17α-hydroxyprogesterone. It is a derivative of 19-nortestosterone and has antiandrogenic properties. It is primarily used as a contraceptive in combination with ethinylestradiol, or in other combination form pills approved in United States and Europe however it is not available in the US by itself. In Europe, Australia, Malaysia, Singapore and Japan, dienogest single therapy is an approved treatment for endometriosis to alleviate painful symptoms of endometriosis and reduce endometriotic lesions 1. Dienogest is commonly marketed as Visanne, Natazia and Qlaira.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 311.425
Monoisotopic: 311.188529049
Chemical Formula
C20H25NO2
Synonyms
  • 17-alpha-Cyanomethyl-17-beta-hydroxy-estra-4,9(10)-dien-3-one
  • 17alpha-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile
  • Dienogest
  • Dienogestril
  • Dienogestum
  • Endometrion
External IDs
  • BAY 86-5258
  • M 18575
  • MJR-35
  • STS 557
  • ZK 37659

Pharmacology

Indication

Indicated for use as the treatment of endometriosis alone and as a contraceptive in combination with ethinylestradiol.

Pharmacology
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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Dienogest exhibits a very potent progestagenic effect in the endometrium, and causes endometrial atrophy after prolonged use 2 . It also mediates an antiandrogenic effect that is equivalent to approximately one third that of cyproterone acetate 4. A dose of 2 mg inhibits the growth of ovarian follicles at 10 mm and maintains the concentration of progesterone at a low level, but has a weak inhibitory effect on FSH and LH. 1mg/kg of dienogest also directly inhibits ovulation 2. In clinical trials composing of patients with endometriosis, dienogest therapy effectively reduced painful symptoms and endometriotic lesions associated with the disorder 1. Dienogest displays no antiestrogenic activity as it activate neither estrogen receptor (ER) α nor ERβ [A16570], and causes hypoestrogenic effects instead as it is shown to decrease the relative expressions of ERβ and ERα 3. It has no glucocorticoid or mineralocorticoid effects. In combined oral contraceptive pills (COCP) with ethinyloestradiol, dienogest conjuction therapy effectively reduces the symptoms of acne and hirsutism, as well as improving excessively heavy or prolonged menstrual bleeding 2.

Mechanism of action

Dienogest acts as an agonist at the progesterone receptor (PR) with weak affinity that is comparable to that of progesterone but has a very potent progestagenic effect in the endometrium, causing endometrial atrophy after prolonged use 2. It promotes antiproliferative, immunologic and antiangiogenic effects on endometrial tissue. Dienogest reduces the level of endogenous production of oestradiol and thereby suppressing the trophic effects of oestradiol on both the eutopic and ectopic endometrium 5. Continous administration of dienogest results in hyperprogestogenic and moderately hypoestrogenic endocrine environment, which causes initial decidualization of endometrial tissue 4. It is an antagonist at androgen receptors, improve androgenic symptoms such as acne and hirsutism [A16570].

TargetActionsOrganism
AProgesterone receptor
agonist
Humans
AAndrogen receptor
antagonist
Humans
Absorption

Dienogest is rapidly absorbed following oral administration, with 91% bioavailability. The peak plasma concentration of 47 ng/mL is reached at about 1.5 hours after single ingestion of 2 mg 4. The stable concentrations of the drug are reached after two days of initial treatment 2.

Volume of distribution

The apparent volume of distribution (Vd/F) of dienogest is 40 L 4.

Protein binding

Dienogest is 90% nonospecifically bound to albumin. It displays no binding to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG) 4.

Metabolism

Dienogest undergoes complete metabolism that is mainly mediated by CYP3A4. The metabolites are pharmacologically inactive and rapidly eliminated from the plasma.

Route of elimination

The ratio of renal elimination to fecal elimination of dienogest is 3:1, where dienogest is predominantly excreted in the form of inactive metabolites. Most of orally administered drug is excreted in the urine within the first 24 hours of ingestion 4.

Half-life

Elimination half-life of dienogest is around 9-10 hours. The half-life of urinary metabolites excretion is 14 hours 4.

Clearance

The metabolic clearance rate from serum (Cl/F) is 64 mL/min 4.

Adverse Effects
Adverseeffects
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Toxicity

Oral LD50 in mouse is 4 mg/kg MSDS. In a long-term carcinogenicity study involving rats and mice, exposure of 10 times the dose of maximum recommended clinical dose of dienogest resulted in increased incidences of pituitary adenomas, fibroepithelial mammary tumours, stromal polyps of the uterus and malignant lymphoma 5. These tumors are thought to arise from marked species differences in the optimal oestrogen:progestogen ratio for reproductive function. In rat liver foci assay, dienogest did not induce tumor promotion activity 5. Dienogest does not display genotoxic potential.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Dienogest which could result in a higher serum level.
AbametapirThe serum concentration of Dienogest can be increased when it is combined with Abametapir.
AbciximabThe risk or severity of adverse effects can be increased when Dienogest is combined with Abciximab.
AbirateroneThe metabolism of Dienogest can be decreased when combined with Abiraterone.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Dienogest.
AceclofenacAceclofenac may decrease the excretion rate of Dienogest which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Dienogest which could result in a higher serum level.
AcenocoumarolThe risk or severity of adverse effects can be increased when Dienogest is combined with Acenocoumarol.
AcetaminophenThe metabolism of Dienogest can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Dienogest can be increased when combined with Acetazolamide.
Interactions
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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of dienogest, which may increase its serum concentration.
  • Avoid St. John's Wort. This herb induces the CYP3A metabolism of dienogest and may reduce its serum concentration.
  • Take at the same time every day.

Products

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Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Aspen-dienogestTablet2 mgOralAspen Pharmacare Canada Inc.2020-04-14Not applicableCanada flag
VisanneTablet2 mgOralBayer2011-10-25Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Jamp DienogestTablet2 mgOralJamp Pharma Corporation2020-12-10Not applicableCanada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ABLDIEVAL®Dienogest (2 mg) + Estradiol valerate (2 mg)Tablet, coatedOralGrünenthal Colombiana S.A.2014-08-112021-10-01Colombia flag
ACOTOL EXDienogest (2 mg) + Ethinylestradiol (0.03 mg)Tablet, coatedOralLABORATORIO FRANCO COLOMBIANO - LAFRANCOL S.A.S.2012-04-16Not applicableColombia flag
BELLAFACE®Dienogest (2 mg) + Ethinylestradiol (0.03 mg)Tablet, film coatedOralLABORATORIO FRANCO COLOMBIANO - LAFRANCOL S.A.S.2009-01-15Not applicableColombia flag
BELLAFACE® SUAVEDienogest (2 mg) + Ethinylestradiol (20 mcg)Tablet, coatedOralLABORATORIO FRANCO COLOMBIANO - LAFRANCOL S.A.S.2014-06-13Not applicableColombia flag
BELLANEW®Dienogest (2 mg) + Estradiol hemihydrate (1.5 mg)Tablet, coatedOralLABORATORIO FRANCO COLOMBIANO - LAFRANCOL S.A.S.2019-03-11Not applicableColombia flag
DADU®Dienogest (2 mg) + Dienogest (3 mg) + Estradiol valerate (3 mg) + Estradiol valerate (2 mg) + Estradiol valerate (2 mg) + Estradiol valerate (1 mg)Tablet, coatedOralLABORATORIO FRANCO COLOMBIANO - LAFRANCOL S.A.S.2019-01-102019-06-21Colombia flag
DADU®Dienogest (2 mg) + Dienogest (3 mg) + Estradiol valerate (3 mg) + Estradiol valerate (2 mg) + Estradiol valerate (2 mg) + Estradiol valerate (1 mg)Tablet, coatedOralLABORATORIO FRANCO COLOMBIANO - LAFRANCOL S.A.S.2019-01-102019-06-21Colombia flag
DIENILLE 2 MG/0.03 MG FILM KAPLI TABLET ,126 TABLETDienogest (2 mg) + Ethinylestradiol (0.03 mg)Tablet, coatedOralEXELTIS İLAÇ SAN. VE TİC. A.Ş.2020-08-14Not applicableTurkey flag
DIENILLE 2 MG/0.03 MG FILM KAPLI TABLET ,21 TABLETDienogest (2 mg) + Ethinylestradiol (0.03 mg)Tablet, coatedOralEXELTIS İLAÇ SAN. VE TİC. A.Ş.2020-08-14Not applicableTurkey flag
DIENILLE 2 MG/0.03 MG FILM KAPLI TABLET ,63 TABLETDienogest (2 mg) + Ethinylestradiol (0.03 mg)Tablet, coatedOralEXELTIS İLAÇ SAN. VE TİC. A.Ş.2020-08-14Not applicableTurkey flag

Categories

ATC Codes
G03AB08 — Dienogest and estradiolG03DB08 — DienogestG03FA15 — Dienogest and estrogenG03AA16 — Dienogest and ethinylestradiol
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as oxosteroids. These are steroid derivatives carrying a C=O group attached to steroid skeleton.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Oxosteroids
Direct Parent
Oxosteroids
Alternative Parents
3-oxosteroids / 17-hydroxysteroids / Cyclohexenones / Tertiary alcohols / Cyclic alcohols and derivatives / Nitriles / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
17-hydroxysteroid / 3-oxosteroid / Alcohol / Aliphatic homopolycyclic compound / Carbonitrile / Carbonyl group / Cyclic alcohol / Cyclic ketone / Cyclohexenone / Hydrocarbon derivative
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
aliphatic nitrile, 3-oxo Delta(4)-steroid, 17beta-hydroxy steroid, steroid hormone (CHEBI:70708)
Affected organisms
Not Available

Chemical Identifiers

UNII
46M3EV8HHE
CAS number
65928-58-7
InChI Key
AZFLJNIPTRTECV-FUMNGEBKSA-N
InChI
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
IUPAC Name
2-[(10S,11S,14R,15S)-14-hydroxy-15-methyl-5-oxotetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadeca-1,6-dien-14-yl]acetonitrile
SMILES
[H][C@@]12CC[C@@](O)(CC#N)[C@@]1(C)CCC1=C3CCC(=O)C=C3CC[C@@]21[H]

References

General References
  1. Schindler AE: Dienogest in long-term treatment of endometriosis. Int J Womens Health. 2011;3:175-84. doi: 10.2147/IJWH.S5633. Epub 2011 Jul 6. [Article]
  2. Binkowska M, Woron J: Progestogens in menopausal hormone therapy. Prz Menopauzalny. 2015 Jun;14(2):134-43. doi: 10.5114/pm.2015.52154. Epub 2015 Jun 22. [Article]
  3. Hayashi A, Tanabe A, Kawabe S, Hayashi M, Yuguchi H, Yamashita Y, Okuda K, Ohmichi M: Dienogest increases the progesterone receptor isoform B/A ratio in patients with ovarian endometriosis. J Ovarian Res. 2012 Nov 1;5(1):31. doi: 10.1186/1757-2215-5-31. [Article]
  4. Bayer Inc: VISANNE (2mg dienogest tablets) Product Monograph [Link]
  5. Bayer Inc: VISANNE (2mg dienogest tablets) Product Information [Link]
PubChem Compound
68861
PubChem Substance
310265039
ChemSpider
62093
RxNav
22968
ChEBI
70708
ChEMBL
CHEMBL1201864
ZINC
ZINC000004215629
Wikipedia
Dienogest
MSDS
Download (24.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedOtherContraception1
4CompletedTreatmentPrimary Dysmenorrhoea1
4RecruitingTreatmentEndometriosis1
4RecruitingTreatmentOvarian Reserve1
4TerminatedTreatmentUterine Fibroids (Leiomyomas)1
4Unknown StatusPreventionEndometriosis1
4Unknown StatusTreatmentEndometriosis of Uterus1
4Unknown StatusTreatmentInfertility1
4Unknown StatusTreatmentUterine Fibroids (Leiomyomas)1
3CompletedPreventionOral Contraceptives1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Tablet, coatedOral
TabletOral
Tablet, film coatedOral
Tablet, film coatedOral2 MG
Kit; tablet, film coatedOral
KitOral
Tablet, coatedOral2 mg
Tablet, delayed releaseOral
Tablet, sugar coatedOral
TabletOral2 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6133251No2000-10-172016-10-25US flag
US8071577No2011-12-062026-05-13US flag
US8153616No2012-04-102028-01-30US flag
US6884793No2005-04-262016-10-25US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)210-218Bayer Product Monograph
water solubilityPractically insolubleBayer Product Monograph
Predicted Properties
PropertyValueSource
Water Solubility0.0761 mg/mLALOGPS
logP3.37ALOGPS
logP2.31ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)13.78ChemAxon
pKa (Strongest Basic)-3.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area61.09 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity90.19 m3·mol-1ChemAxon
Polarizability35.4 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-03di-0019000000-8b6511db078a7ef4a6d7
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0006-0093000000-b1ea74e40f8e85986825
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0006-0390000000-58a5bd49692ab6bd5ef9
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-00dl-0950000000-d53345d5771b7bff2bae
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-00di-0910000000-6c64873dce18fb49e840
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-00di-1910000000-5dd58f138435ec0555a4
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-03di-0009000000-f354babe14ff8cd78da5
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-03di-0109000000-aa4e4dd10536f9ed7fb4
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-03di-0924000000-0a4b5e59ffb5fd090a1a
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0btl-1910000000-baa05a6be42e71aa9634
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0a4u-2900000000-d615a57fc7b003b3df8d
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-05ox-3900000000-17cbf8436dfbbec977c2

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Zinc ion binding
Specific Function
The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor ...
Gene Name
PGR
Uniprot ID
P06401
Uniprot Name
Progesterone receptor
Molecular Weight
98979.96 Da
References
  1. Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Imada K, Kato S, Mizuguchi K: Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile. Steroids. 2008 Feb;73(2):222-31. Epub 2007 Oct 22. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription ...
Gene Name
AR
Uniprot ID
P10275
Uniprot Name
Androgen receptor
Molecular Weight
98987.9 Da
References
  1. Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Imada K, Kato S, Mizuguchi K: Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile. Steroids. 2008 Feb;73(2):222-31. Epub 2007 Oct 22. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Binkowska M, Woron J: Progestogens in menopausal hormone therapy. Prz Menopauzalny. 2015 Jun;14(2):134-43. doi: 10.5114/pm.2015.52154. Epub 2015 Jun 22. [Article]
  2. Bayer Inc: VISANNE (2mg dienogest tablets) Product Monograph [Link]

Drug created on September 23, 2015 16:17 / Updated on September 18, 2021 03:33