Identification

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Name
Etonogestrel
Accession Number
DB00294  (APRD00766)
Type
Small Molecule
Groups
Approved, Investigational
Description

Etonogestrel molecule is a 3-ketodesogestrel or 19-nortestosterone which is a synthetic biologically active metabolite of progestin desogestrel.2 The first product including etonogestrel was developed by the Merck subsidiary Organon and FDA approved in 2001.6

Structure
Thumb
Synonyms
  • 3-Ketodesogestrel
  • 3-Oxodesogestrel
  • Etonogestrel
  • étonogestrel
  • Etonogestrelum
External IDs
ORG 3236 / ORG-3236
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ImplanonImplant68 mg/1SubcutaneousOrganon2011-09-06Not applicableUs
NexplanonImplant68 mg/1SubcutaneousOrganon USA Inc.2013-09-27Not applicableUs
NexplanonImplant68 mg/1SubcutaneousOrganon Pharmaceuticals USA2011-05-092011-05-09Us
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
NuvaRingEtonogestrel (0.12 mg/1d) + Ethinylestradiol (0.015 mg/1d)Insert, extended releaseVaginalOrganon USA Inc.2001-10-03Not applicableUs
NuvaringEtonogestrel (0.12 mg/1d) + Ethinylestradiol (0.015 mg/1d)Insert, extended releaseVaginalA-S Medication Solutions2001-10-03Not applicableUs
NuvaRingEtonogestrel (0.12 mg/1d) + Ethinylestradiol (0.015 mg/1d)Insert, extended releaseVaginalCentral Texas Community Health Centers2001-10-03Not applicableUs
NuvaRingEtonogestrel (11.7 mg/1) + Ethinylestradiol (2.7 mg/1)Insert, extended releaseVaginalPhysicians Total Care, Inc.2011-11-04Not applicableUs
NuvaringEtonogestrel (11.4 mg) + Ethinylestradiol (2.6 mg)RingVaginalMerck Ltd.2004-12-02Not applicableCanada
Categories
UNII
304GTH6RNH
CAS number
54048-10-1
Weight
Average: 324.4565
Monoisotopic: 324.20893014
Chemical Formula
C22H28O2
InChI Key
GCKFUYQCUCGESZ-BPIQYHPVSA-N
InChI
InChI=1S/C22H28O2/c1-4-21-13-14(3)20-17-9-7-16(23)12-15(17)6-8-18(20)19(21)10-11-22(21,24)5-2/h2,12,17-20,24H,3-4,6-11,13H2,1H3/t17-,18-,19-,20+,21-,22-/m0/s1
IUPAC Name
(1S,2R,10S,11S,14R,15S)-15-ethyl-14-ethynyl-14-hydroxy-17-methylidenetetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadec-6-en-5-one
SMILES
[H][C@@]12CC[C@@](O)(C#C)[C@@]1(CC)CC(=C)[C@]1([H])[C@@]3([H])CCC(=O)C=C3CC[C@@]21[H]

Pharmacology

Indication

Etonogestrel is administered in subdermal implants as long-acting reversible contraception. It is known to be effective in postpartum insertion including breastfeeding women.1

Etonogestrel is part of the long-acting contraceptive implants that prevent pregnancy. The implant's effect can remain for 5 years.8

Associated Therapies
Pharmacodynamics

Etonogestrel attains its therapeutic effect inhibiting fertility by impairing the release of the luteinizing hormone which is one of the most important reproductive hormones for ovulation. As well, etonogestrel is known to increase the viscosity of the cervical mucus hindering the passage of the spermatozoa and altering the lining in the uterus to prevent the implantation of the fertilized eggs in the endometrium.7

In clinical trials, etonogestrel was implanted and reported to avoid 100% of pregnancies over a three year period. When the implant was removed, normal periods were reinstalled within 90 days in 91% of the individuals. Fertility was established quickly with 20 reported pregnancies within 3 months of implant removal.7

The implants of etonogestrel release 40 mcg of etonogestrel daily and they usually provide a continuous contraception effect for 3 years. When the implant is administered, the failure rate is reported to be 0.1%. Some non-contraceptive effects are improved dysmenorrhea.4 All data of etonogestrel comes from patients between 80-130% of the body mass.

Mechanism of action

Etonogestrel binds with high affinity to the progesterone and estrogen receptors in the target organs.7 From the target organs, they include the female reproductive tract, mammary gland, hypothalamus, and pituitary. Once bound, this drug changes the synthesis of different proteins which in order decreases the level of gonadotropin-releasing hormone and the luteinizing hormone.9

TargetActionsOrganism
AProgesterone receptor
agonist
Humans
AEstrogen receptor alpha
agonist
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

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Absorption

Vaginal administration of etonogestrel is known to be significantly absorbed through the vaginal epithelium but it does not increase the levels of etonogestrel in the urine. On the other hand, oral administration is absorbed in the GI tract and it goes through the first-pass metabolism.2

When etonogestrel is administered subdermally it is absorbed rapidly into the bloodstream and it presents a bioavailability of 82%.5 It is reported that the implant releases around 60 mcg per day in the first 3 months and then decreases steady reaching a concentration of 30 mcg at the end of year 2.3

Volume of distribution

The apparent volume of distribution of etonogestrel is of around 201 L.3

Protein binding

Etonogestrel is highly bound to plasma proteins being mainly albumin followed by sex-hormone binding globulin.7 The protein bound form of the etonogestrel represents around 96-99% of the administered dose.5

Metabolism

Etonogestrel is highly metabolized in the liver by the action of the cytochrome isoenzyme 3A4 mainly by the presence of hydroxylation, sulfate conjugation and glucuronide conjugation reactions.7

Route of elimination

The elimination of etonogestrel and its metabolites is mainly done renally.7

Half life

The elimination half-life of etonogestrel is reported to be of 25 hours which indicates a reversible contraceptive effect.7

Clearance

The clearance rate of etonogestrel is reported to be of 7.5 L/h.3

Toxicity

The reported LD50 of oral etonogestrel in the rat is reported to be higher than 2000 mg/kg.MSDS Overdosage can only happen when more than one implant is inserted. In cases of overdose, removal of the implant is recommended.Label

There aren't reports relating etonogestrel with carcinogenesis, mutagenesis or impaired fertility.Label

Affected organisms
  • Humans and other mammals
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
(R)-warfarinEtonogestrel may decrease the anticoagulant activities of (R)-warfarin.
(S)-WarfarinEtonogestrel may decrease the anticoagulant activities of (S)-Warfarin.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Etonogestrel.
4-hydroxycoumarinThe therapeutic efficacy of 4-hydroxycoumarin can be decreased when used in combination with Etonogestrel.
7-NitroindazoleThe metabolism of Etonogestrel can be increased when combined with 7-Nitroindazole.
AbacavirEtonogestrel may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbciximabEtonogestrel may decrease the anticoagulant activities of Abciximab.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Etonogestrel.
AceclofenacAceclofenac may decrease the excretion rate of Etonogestrel which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Etonogestrel which could result in a higher serum level.
Additional Data Available
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    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
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Food Interactions
  • Avoid alcohol.
  • Avoid excessive quantities of coffee or tea (Caffeine).
  • Increase dietary intake of magnesium, folate, vitamin B6, B12, and/or consider taking a multivitamin.
  • Take at the same time everyday.
  • Take with food.

References

Synthesis Reference
US20130123523
General References
  1. Gariepy AM, Duffy JY, Xu X: Cost-Effectiveness of Immediate Compared With Delayed Postpartum Etonogestrel Implant Insertion. Obstet Gynecol. 2015 Jul;126(1):47-55. doi: 10.1097/AOG.0000000000000907. [PubMed:26241255]
  2. Roumen FJ: Review of the combined contraceptive vaginal ring, NuvaRing. Ther Clin Risk Manag. 2008 Apr;4(2):441-51. [PubMed:18728840]
  3. Wenzl R, van Beek A, Schnabel P, Huber J: Pharmacokinetics of etonogestrel released from the contraceptive implant Implanon. Contraception. 1998 Nov;58(5):283-8. [PubMed:9883383]
  4. Feisullin K. and Westhoff C. (2010). Principles of gender-specific medicine (2nd ed.). Academic press.
  5. Zaragoza Dorwald F. (2012). Lead optimization for medicinal chemists. Wiley-VCH.
  6. FDA approvals [Link]
  7. PMC [Link]
  8. NIH [Link]
  9. NIH [Link]
External Links
Human Metabolome Database
HMDB0014439
PubChem Compound
6917715
PubChem Substance
46505321
ChemSpider
5292944
BindingDB
50423516
ChEBI
50777
ChEMBL
CHEMBL1531
Therapeutic Targets Database
DAP000855
PharmGKB
PA164771231
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Etonogestrel
ATC Codes
G03AC08 — Etonogestrel
FDA label
Download (1010 KB)
MSDS
Download (197 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1WithdrawnPreventionContraception1
2CompletedPreventionContraception2
2CompletedTreatmentContraception1
2CompletedTreatmentMenstrual Cramps1
2RecruitingTreatmentContraception / Human Immunodeficiency Virus (HIV)1
2RecruitingTreatmentContraception / Human Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS)1
2TerminatedTreatmentBenign Prostatic Hyperplasia (BPH)1
3Active Not RecruitingPreventionFamily Planning / Postpartum Contraception1
3CompletedPreventionBleeding Acceptability / Contraceptive Usage / Pregnancy Prevention in Adolescents / Proportion of Participants Using Implanon at 3, 6, and 12 Months After Insertion1
3CompletedPreventionContraception4
3CompletedTreatmentContraception: Optional Applicator for Insertion of Vaginal Ring1
3TerminatedPreventionContraception1
3TerminatedTreatmentModerate to Severe Primary Dysmenorrhea1
4Active Not RecruitingPreventionBacterial Vaginosis (BV)1
4Active Not RecruitingTreatmentSickle Cell Disorders1
4CompletedBasic ScienceContraception1
4CompletedPreventionBacterial Vaginosis (BV) / Human Immunodeficiency Virus (HIV)1
4CompletedPreventionContinuation Rate of Contraceptive Implant1
4CompletedPreventionContraception3
4CompletedPreventionEarly Pregnancy Termination / Medical Abortion / Postabortion Contraception1
4CompletedTreatmentBreastfeeding / Post Partum1
4CompletedTreatmentComplications; Contraceptive / Female Lactation1
4CompletedTreatmentContraception2
4CompletedTreatmentContraception / Human Immunodeficiency Virus (HIV)1
4CompletedTreatmentEndometriosis1
4Not Yet RecruitingPreventionEmergency Contraception / Healthy, Reproductive Age Women1
4RecruitingTreatmentContraception1
4RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
4TerminatedNot AvailableInfertilities1
4Unknown StatusDiagnosticBleeding1
4Unknown StatusPreventionAdolescence / Contraception / Postpartum1
4Unknown StatusTreatmentBacterial Vaginosis (BV)1
4Unknown StatusTreatmentMenstrual Problem1
Not AvailableActive Not RecruitingNot AvailableContraception / Human Immunodeficiency Virus (HIV) / Immune Cells (Mucosal and Systemic)1
Not AvailableCompletedNot AvailableAbortion; Induced / Medical Abortion, Complete or Unspecified, Without Complication1
Not AvailableCompletedNot AvailableContraception1
Not AvailableCompletedNot AvailableContraceptive Behavior / Opiate Addiction / Pregnancy / Sexual Behavior1
Not AvailableCompletedNot AvailableContraceptive Usage / Vaginal Epithelial Disruption1
Not AvailableCompletedNot AvailableFemale Sexual Function1
Not AvailableCompletedNot AvailableHormonal Contraception1
Not AvailableCompletedNot AvailablePharmacokinetics1
Not AvailableCompletedNot AvailablePregnancy1
Not AvailableCompletedBasic ScienceWeight1
Not AvailableCompletedHealth Services ResearchOvarian Follicle1
Not AvailableCompletedSupportive CareContraception / Postpartum Period1
Not AvailableCompletedTreatmentContraception1
Not AvailableCompletedTreatmentHealthy Volunteers1
Not AvailableCompletedTreatmentHypermenorrhea1
Not AvailableRecruitingNot AvailableHormonal Contraception1
Not AvailableRecruitingPreventionContraception1
Not AvailableTerminatedPreventionAdolescents Seeking Contraception / Contraception Desired1
Not AvailableTerminatedTreatmentIn-Vitro Fertilization / Infertilities1

Pharmacoeconomics

Manufacturers
  • Organon usa inc
Packagers
  • Diversified Healthcare Services Inc.
  • NV Organon
  • Organon Pharmaceuticals
Dosage forms
FormRouteStrength
ImplantSubcutaneous68 mg/1
Insert, extended releaseVaginal
RingVaginal
Prices
Unit descriptionCostUnit
Implanon 68 mg implant714.34USD each
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5150718No1992-09-292009-09-29Us
US5989581No1999-11-232018-04-08Us
US8722037No2014-05-132027-09-28Us
US8888745No2014-11-182026-08-28Us
US9757552No2017-09-122030-07-28Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)196-200ºC'MSDS'
boiling point (°C)473.1ºC at 760 mmHg'MSDS'
water solubilityInsoluble'MSDS'
logP3.32Zaragoza F. Lead optimization for medicinal chemists. 2012. Wiley
pKa10.4Toral M. et al. J. Chil. Chem. 2013
Predicted Properties
PropertyValueSource
Water Solubility0.00737 mg/mLALOGPS
logP3.19ALOGPS
logP3.6ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)17.99ChemAxon
pKa (Strongest Basic)-1.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.3 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity96.35 m3·mol-1ChemAxon
Polarizability37.77 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9437
Caco-2 permeable+0.8167
P-glycoprotein substrateSubstrate0.6699
P-glycoprotein inhibitor IInhibitor0.6143
P-glycoprotein inhibitor IINon-inhibitor0.8387
Renal organic cation transporterNon-inhibitor0.7587
CYP450 2C9 substrateNon-substrate0.8195
CYP450 2D6 substrateNon-substrate0.9147
CYP450 3A4 substrateSubstrate0.7187
CYP450 1A2 substrateNon-inhibitor0.8898
CYP450 2C9 inhibitorNon-inhibitor0.8939
CYP450 2D6 inhibitorNon-inhibitor0.9224
CYP450 2C19 inhibitorInhibitor0.8755
CYP450 3A4 inhibitorNon-inhibitor0.7496
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5624
Ames testNon AMES toxic0.9091
CarcinogenicityNon-carcinogens0.9281
BiodegradationNot ready biodegradable0.9864
Rat acute toxicity2.1164 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8206
hERG inhibition (predictor II)Non-inhibitor0.7741
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as estrogens and derivatives. These are steroids with a structure containing a 3-hydroxylated estrane.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Estrane steroids
Direct Parent
Estrogens and derivatives
Alternative Parents
3-oxo delta-4-steroids / 17-hydroxysteroids / Delta-4-steroids / Cyclohexenones / Ynones / Tertiary alcohols / Cyclic alcohols and derivatives / Acetylides / Organic oxides / Hydrocarbon derivatives
Substituents
Estrogen-skeleton / 3-oxo-delta-4-steroid / 3-oxosteroid / 17-hydroxysteroid / Oxosteroid / Hydroxysteroid / Delta-4-steroid / Cyclohexenone / Ynone / Cyclic alcohol
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
terminal acetylenic compound, 3-oxo steroid, 3-oxo Delta(4)-steroid, 17beta-hydroxy steroid (CHEBI:50777)

Targets

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. Macpherson AM, Archer DF, Leslie S, Charnock-Jones DS, Makkink WK, Smith SK: The effect of etonogestrel on VEGF, oestrogen and progesterone receptor immunoreactivity and endothelial cell number in human endometrium. Hum Reprod. 1999 Dec;14(12):3080-7. [PubMed:10601100]
  2. Charnock-Jones DS, Macpherson AM, Archer DF, Leslie S, Makkink WK, Sharkey AM, Smith SK: The effect of progestins on vascular endothelial growth factor, oestrogen receptor and progesterone receptor immunoreactivity and endothelial cell density in human endometrium. Hum Reprod. 2000 Aug;15 Suppl 3:85-95. [PubMed:11041225]
  3. Sitruk-Ware R: Pharmacological profile of progestins. Maturitas. 2004 Apr 15;47(4):277-83. [PubMed:15063480]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissu...
Gene Name
ESR1
Uniprot ID
P03372
Uniprot Name
Estrogen receptor
Molecular Weight
66215.45 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
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. PMC [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Carrier
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Zaragoza Dorwald F. (2012). Lead optimization for medicinal chemists. Wiley-VCH.
  2. PMC [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Carrier
General Function
Androgen binding
Specific Function
Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone...
Gene Name
SHBG
Uniprot ID
P04278
Uniprot Name
Sex hormone-binding globulin
Molecular Weight
43778.755 Da
References
  1. Zaragoza Dorwald F. (2012). Lead optimization for medicinal chemists. Wiley-VCH.
  2. PMC [Link]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2019 00:22