Identification

Summary

Ganirelix is a GnRH antagonist used in assisted reproduction in women undergoing controlled ovarian hyperstimulation to control ovulation by inhibiting the premature LH surges.

Brand Names
Fyremadel, Orgalutran
Generic Name
Ganirelix
DrugBank Accession Number
DB06785
Background

Ganirelix is a synthetic decapeptide and a competitive gonadotropin-releasing hormone (GnRH) antagonist. Derived from endogenous GnRH, ganirelix has amino acid substitutions. Ganirelix is indicated for controlled ovarian hyperstimulation in assisted reproduction techniques.5 The first case of pregnancy achieved after the use of ganirelix in an assisted reproduction program was reported in 1998.2 Ganirelix was first approved by the FDA on July 29, 1999.7

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 1570.35
Monoisotopic: 1568.8423035
Chemical Formula
C80H113ClN18O13
Synonyms
  • Ganirelix
External IDs
  • Org 37462
  • RS 26306
  • SML0241

Pharmacology

Indication

Ganirelix is indicated for the inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation for assisted reproduction techniques (ART).4,5

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Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Ganirelix modulates the hypothalamic-pituitary-gonadal axis by causing a rapid, profound, reversible suppression of endogenous gonadotropins. During controlled ovarian stimulation, it suppresses luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion from the pituitary gland.4 Unlike GnRH agonists that causes an initial increase in gonadotropin levels, ganirelix does not cause this effect before premature LH surge inhibition.1 Ganirelix is also not associated with hypo‐estrogenic side effects, flare‐up, and a long down‐regulation period induced by GnRH agonists.3

In patients undergoing controlled ovarian stimulation, the median duration of ganirelix treatment was five days.4 In one study, multiple-dose administration of 0.25 mg ganirelix decreased serum LH, FSH and estradiol (E2) concentrations from baseline by 74, 32, and 25% after the last dose, respectively.1 Serum hormone levels returned to pre-treatment levels within two days after the last injection.4,5

Mechanism of action

Gonadotropin-releasing hormone (GnRH) is a hypothalamus-derived releasing hormone responsible for the synthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary.2 At midcycle, a large increase in GnRH release results in an LH surge, which leads to several physiologic actions such as ovulation, resumption of meiosis in the oocyte, and luteinization. Luteinization results in a rise in serum progesterone with an accompanying decrease in estradiol levels.5

Controlled ovarian hyperstimulation (COH) is performed in conjunction with other interventions like in vitro fertilization (IVF) during assisted reproductive technology (ART).3 COH is beneficial as it allows the scheduling of IVF treatments.2 During this intervention, inhibiting premature surges of LH is important because premature elevated LH levels can hinder effective multiple follicular maturation 3 and can lead to an undesirable increase in progesterone levels.1 Ganirelix aims to suppress premature LH surges by competitively blocking the GnRH receptors on the pituitary gonadotroph and subsequent transduction pathways. Ganirelix-induced suppression of gonadotropin secretion is rapid and reversible. The suppression of pituitary LH secretion by ganirelix is more pronounced than that of FSH. An initial release of endogenous gonadotropins has not been detected with ganirelix, which is consistent with an antagonist effect.5

TargetActionsOrganism
AGonadotropin-releasing hormone receptor
antagonist
Humans
Absorption

Ganirelix is rapidly absorbed following subcutaneous administration with a mean absolute bioavailability of approximately 91%.5 It has a Tmax ranging from one to two hours.4,5 Ganirelix reaches steady-state serum concentrations after three days of administration.5

Volume of distribution

The mean (SD) volume of distribution of ganirelix in healthy females following subcutaneous administration of a single 250-mcg dose is 43.7 (11.4) L.5

Protein binding

In vitro protein binding to human plasma is 81.9%.5

Metabolism

The metabolites are small peptide fragments formed by enzymatic hydrolysis of ganirelix at restricted sites.4 The 1–4 peptide and 1–6 peptide of ganirelix are the primary metabolites observed in the feces.5

Route of elimination

Following single-dose intravenous administration of radiolabeled ganirelix to healthy female volunteers, Ganirelix is the major compound present in the plasma (50–70% of total radioactivity in the plasma) up to 4 hours and urine (17.1–18.4% of administered dose) up to 24 hours. Ganirelix is not found in the feces. On average, 97.2% of the total radiolabeled ganirelix dose is recovered in the feces and urine (75.1% and 22.1%, respectively) over 288 h following intravenous single dose administration of 1 mg [14C]-ganirelix. Urinary excretion is virtually complete in 24 h, whereas fecal excretion starts to plateau 192 h after dosing.5

Half-life

The elimination half-life (t½) following subcutaneous administration of a single 250-mcg dose is approximately 13 hours.4,5

Clearance

Clearance following subcutaneous administration of a single 250-mcg dose is approximately 2.4 L/h.4

Adverse Effects
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Toxicity

LD50 in rats was 40 mg/kg following subcutaneous administration.6

There have been no reports of overdosage with ganirelix in humans.5 Clinical studies with subcutaneous administration of ganirelix at single doses up to 12 mg did not show systemic adverse reactions. In acute toxicity studies in rats and monkeys, non-specific toxic symptoms such as hypotension and bradycardia were only observed after intravenous administration of ganirelix over 1 and 3 mg/kg, respectively. As there is no known antidote for ganirelix, the drug should be discontinued in case of an overdose.4

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.
Not Available
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Ganirelix acetate56U7906FQW129311-55-3OVBICQMTCPFEBS-SATRDZAXSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Ganirelix AcetateInjection, solution250 ug/0.5mLSubcutaneousOrganon USA Inc.1999-07-29Not applicableUS flag
Ganirelix AcetateInjection, solution250 ug/0.5mLSubcutaneousOrganon LLC2021-06-01Not applicableUS flag
Ganirelix Gedeon RichterInjection, solution0.25 mg/0.5mLSubcutaneousChemical Works Of Gedeon Richter Plc. (Gedeon Richter Plc.)2022-07-25Not applicableEU flag
Ganirelix Gedeon RichterInjection, solution0.25 mg/0.5mLSubcutaneousChemical Works Of Gedeon Richter Plc. (Gedeon Richter Plc.)2022-07-25Not applicableEU flag
OrgalutranInjection, solution0.25 mg/0.5mLSubcutaneousN.V. Organon2016-09-08Not applicableEU flag
OrgalutranSolution250 mcg / 0.5 mLSubcutaneousOrganon Canada Inc.2002-08-23Not applicableCanada flag
OrgalutranInjection, solution0.25 mg/0.5mLSubcutaneousN.V. Organon2016-09-08Not applicableEU flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FyremadelInjection, solution250 ug/0.5mLSubcutaneousFerring Pharmaceuticals Inc.2021-12-14Not applicableUS flag
Ganirelix AcetateInjection, solution250 ug/0.5mLSubcutaneousMeitheal Pharmaceuticals Inc.2022-06-06Not applicableUS flag
Ganirelix AcetateInjection, solution250 ug/0.5mLSubcutaneousFerring Pharmaceuticals Inc.2019-01-01Not applicableUS flag
Ganirelix AcetateInjection250 ug/0.5mLSubcutaneousAmphastar Pharmaceuticals, Inc.2022-06-20Not applicableUS flag
Ganirelix AcetateInjection, solution250 ug/0.5mLSubcutaneousSun Pharmaceutical Industries, Inc.2019-11-072020-01-18US flag

Categories

ATC Codes
H01CC01 — Ganirelix
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
Kingdom
Organic compounds
Super Class
Organic Polymers
Class
Polypeptides
Sub Class
Not Available
Direct Parent
Polypeptides
Alternative Parents
Peptides / Tyrosine and derivatives / Phenylalanine and derivatives / Leucine and derivatives / N-acyl-alpha amino acids and derivatives / Proline and derivatives / Serine and derivatives / Alpha amino acid amides / Alanine and derivatives / Naphthalenes
show 23 more
Substituents
1-hydroxy-2-unsubstituted benzenoid / Acetamide / Alanine or derivatives / Alcohol / Alpha peptide / Alpha-amino acid amide / Alpha-amino acid or derivatives / Amphetamine or derivatives / Aromatic heteropolycyclic compound / Aryl chloride
show 46 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
IX503L9WN0
CAS number
124904-93-4
InChI Key
GJNXBNATEDXMAK-PFLSVRRQSA-N
InChI
InChI=1S/C80H113ClN18O13/c1-9-84-79(85-10-2)88-38-17-15-24-60(70(104)94-62(41-49(5)6)71(105)93-61(25-16-18-39-89-80(86-11-3)87-12-4)78(112)99-40-20-26-68(99)77(111)90-50(7)69(82)103)92-73(107)64(44-53-30-35-59(102)36-31-53)97-76(110)67(48-100)98-75(109)66(46-55-21-19-37-83-47-55)96-74(108)65(43-52-28-33-58(81)34-29-52)95-72(106)63(91-51(8)101)45-54-27-32-56-22-13-14-23-57(56)42-54/h13-14,19,21-23,27-37,42,47,49-50,60-68,100,102H,9-12,15-18,20,24-26,38-41,43-46,48H2,1-8H3,(H2,82,103)(H,90,111)(H,91,101)(H,92,107)(H,93,105)(H,94,104)(H,95,106)(H,96,108)(H,97,110)(H,98,109)(H2,84,85,88)(H2,86,87,89)/t50-,60-,61+,62+,63-,64+,65-,66-,67+,68+/m1/s1
IUPAC Name
(2R)-6-{[bis(ethylamino)methylidene]amino}-N-[(1S)-1-{[(2S)-6-{[bis(ethylamino)methylidene]amino}-1-[(2S)-2-{[(1R)-1-carbamoylethyl]carbamoyl}pyrrolidin-1-yl]-1-oxohexan-2-yl]carbamoyl}-3-methylbutyl]-2-[(2S)-2-[(2S)-2-[(2R)-2-[(2R)-3-(4-chlorophenyl)-2-[(2R)-2-acetamido-3-(naphthalen-2-yl)propanamido]propanamido]-3-(pyridin-3-yl)propanamido]-3-hydroxypropanamido]-3-(4-hydroxyphenyl)propanamido]hexanamide
SMILES
CCNC(NCC)=NCCCC[C@@H](NC(=O)[C@H](CC1=CC=C(O)C=C1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC1=CC=CN=C1)NC(=O)[C@@H](CC1=CC=C(Cl)C=C1)NC(=O)[C@@H](CC1=CC2=CC=CC=C2C=C1)NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=O

References

Synthesis Reference

"Patent Link":http://www.google.ca/patents/US5767082

General References
  1. Gillies PS, Faulds D, Balfour JA, Perry CM: Ganirelix. Drugs. 2000 Jan;59(1):107-11; discussion 112-3. doi: 10.2165/00003495-200059010-00007. [Article]
  2. Out HJ, Mannaerts BM: The gonadotrophin-releasing hormone antagonist ganirelix--history and introductory data. Hum Fertil (Camb). 2002 Feb;5(1):G5-10; discussion G10-2, G41-8. doi: 10.1080/1464727992000199771. [Article]
  3. Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ: Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2016 Apr 29;4:CD001750. doi: 10.1002/14651858.CD001750.pub4. [Article]
  4. EMA Approved Drug Products: Ganirelix Gedeon Richter (Ganirelix) Subcutaneous Injection [Link]
  5. DailyMed Label: Ganirelix Acetate Subcutaneous Injection [Link]
  6. Organon: Ganirelix MSDS [Link]
  7. FDA Drug Approval Package: Antagon (Ganirelix Acetate) [Link]
KEGG Drug
D08010
PubChem Compound
16130957
PubChem Substance
310264884
ChemSpider
17287671
BindingDB
50102454
RxNav
35825
ChEBI
135910
ChEMBL
CHEMBL1251
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Ganirelix

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedOtherInfertility1
4CompletedTreatmentControlled Ovarian Stimulation1
4CompletedTreatmentEgg Donation1
4CompletedTreatmentFertility / Optimal Stimulation Protocol / Reproductive Endocrinology1
4CompletedTreatmentInfertile Women Undergoing Assisted Reproductive Technology (ART)1
4CompletedTreatmentInfertility2
4CompletedTreatmentInfertility / IVF Treatment1
4CompletedTreatmentInfertility / Premature Ovarian Failure (POF)1
4RecruitingTreatmentInfertility / IVF2
4RecruitingTreatmentIVF1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous0.25 MG/0.5ML
InjectionSubcutaneous250 ug/0.5mL
Injection, solutionSubcutaneous250 ug/0.5mL
Injection, solutionParenteral
SolutionSubcutaneous250 mcg / 0.5 mL
Injection, solution
InjectionSubcutaneous0.25 mg/0.5ml
SolutionSubcutaneous0.25 mg
SolutionSubcutaneous0.5 mg/1ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5767082No1998-06-162015-06-16US flag
US6653286No2003-11-252018-06-16US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)100https://www.organon.com/docs/product/safety-data-sheets/Ganirelix%20Formulation_HH_NZ_6N.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.00531 mg/mLALOGPS
logP3.42ALOGPS
logP1.62Chemaxon
logS-5.5ALOGPS
pKa (Strongest Acidic)9.5Chemaxon
pKa (Strongest Basic)12.14Chemaxon
Physiological Charge2Chemaxon
Hydrogen Acceptor Count20Chemaxon
Hydrogen Donor Count16Chemaxon
Polar Surface Area451.49 Å2Chemaxon
Rotatable Bond Count44Chemaxon
Refractivity423.46 m3·mol-1Chemaxon
Polarizability170.37 Å3Chemaxon
Number of Rings6Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
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

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Peptide binding
Specific Function
Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone...
Gene Name
GNRHR
Uniprot ID
P30968
Uniprot Name
Gonadotropin-releasing hormone receptor
Molecular Weight
37730.355 Da
References
  1. Oberye J, Mannaerts B, Huisman J, Timmer C: Local tolerance, pharmacokinetics, and dynamics of ganirelix (Orgalutran) administration by Medi-Jector compared to conventional needle injections. Hum Reprod. 2000 Feb;15(2):245-9. [Article]
  2. DailyMed Label: Ganirelix Acetate Subcutaneous Injection [Link]
  3. EMA Approved Drug Products: Ganirelix Gedeon Richter (Ganirelix) Subcutaneous Injection [Link]

Drug created at September 14, 2010 16:21 / Updated at October 06, 2022 03:22